bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variability in the strength of AT1R Ca2+ signaling
Authors: Scott Lena , Bernhem Kristoffer , Brismar Hjalmar , Aperia Anita 
Published: June 2021

The renin angiotensin system is a principal physiological regulatory system for blood pressure and the Angiotensin type 1 receptor (AT1R) is an important target for treatment of hypertension.Using AT1R expressing HEK293a cells we study the Ca2+ response to repeated doses of physiological, 1 nM [Ang II] and pharmacological, 100 nM [Ang II] at 0, 7 and 37 min. AT1R activation results in Ca2+ release from intracellular stores. AT1R signaling has typically been studied at pharmacological 100 nM [Ang II]. At 100 nM [Ang II] a significant desensitization was seen in response to the 2nd dose with partial recovery observed at the 3rd dose. Mean Δ [Ca2+]i was 150, 30 and 70 nM respectively. At 1 nM [Ang II] no desensitization was observed between the first two doses, both at 15 nM, and the response to the 3rd dose, 40 nM, is significantly increased. As recent studies suggest a crosstalk between AT1R and Voltage Gated Calcium Channels, we also studied the effect of blocking Ca2+ channels with Nifedipine, therapeutically used in hypertension treatments, on AT1R response. No change to basal [Ca2+] was seen in presence of Nifedipine, whilst an increase was found in Ca2+ response from repeated doses of 1 nM [Ang II], 130, 110 and 80 nM. The same trend was seen in Podocyte enriched primary cultures.In summary this study shows novel aspects to the AT1R signaling modulation with implications for the treatment of hypertension.
Inhibition fibroblast growth factor receptor (FGFR) attenuates anti‐aging gene klotho deficiency induced hypertension
Authors: Schuman Mariano , Sun Zhongjie 
Published: June 2021

Klotho is a newly‐discovered anti‐aging gene. Klotho (KL) gene delivery prevented progression of spontaneous hypertension and attenuated kidney damage. The purpose of this study is to determine if KL deficiency affects blood pressure and investigate the underlying mechanism. Two groups of wild‐type (WT) and 2 groups of KL heterozygous (+/−) mice were used. Blood pressure was elevated significantly in KL(+/−) mice vs the WT mice (mean BP 126 vs 103 mmHg), suggesting that KL gene deficiency causes hypertension. Plasma level of FGF23 was increased significantly in the KL(+/−) mice. We then inhibited FGF23 by a FGF receptor inhibitor (PD173074). One group of each strain received PD at 1 mg/kg/day (IP) for one week followed by 10 mg/kg for another week, while the other group received vehicle and served as a control. Following the 2‐week treatment, the mice were euthanized and blood, kidney, heart were collected. Distal convoluted tubules (DCT) were isolated from 1 kidney of each animal. PD significantly attenuated hypertension and cardiac hypertrophy. Interestingly, the level of urine norepinephrine was increased in KL(+/−) mice (KL(+/−) 490 ng/ml vs WT 350 ng/ml). PD abolished the KL deficiency‐induced increase in urine norepinephrine. PD also decreased expression of mineralcorticoid receptor (MR) in the DCTs.ConclusionsKlotho deficiency causes hypertension and cardiac hypertrophy probably via upregulation of FGF23.
Detecting Structural Similarity between BK Binding Domains on Iberiotoxin and ASIC1 at Different pH
Authors: Snitsarev Vladislav , Abdulsalam Safanah S , Petroff Elena 
Published: June 2021

Previous studies have shown that acid sensing ion channels (ASICs) inhibit calcium‐ and voltage‐activated potassium channels (BK) at physiological pH, and the inhibition is removed at acidic pH (Petroff et al. PNAS 2008; Petroff et al. BBRC 2012). The overlay capabilities of ChemBio3D Ultra 2010 (CambridgeSoft, Cambridge, MA) were used to detect structural similarities between putative BK‐binding domain in ASIC (R191G193K194) and known iberiotoxin (IbTx) domain critical for BK‐binding (R25G26K27).We compared the structure of (R191G193K194) domain of ASIC1 at low pH (PDP ID: 2QTS) to the structure of IbTx (R25G26K27) domain obtained from Swiss‐Model Repository. We also overlaid the structure of (R191G193K194) domain of ASIC1 at pH of 7.5 (PDB ID: 3S3W) against IbTx binding domain (R25G26K27). Our results show that at pH 7.5, ASIC1's putative BK‐binding domain (R191G193K194) is structurally more similar to the IbTx BK‐binding domain (R25G26K27) than at low pH.These in silico findings support the previous experimental studies and indicate that the structure of ASIC1 at neutral pH could favor interaction with BK, while at low pH, the conformational changes in ASIC1 make it less likely. This work is supported by the NIH NS070260 grant to EP.
Overlaid R191G193K194 domain of ASIC1 at neutral pH against IbTx's BK‐binding domain (R25G26K27). The distance between the central carbon atoms of each of the residues is shown.

Residues
Distance (Å)

ASIC1 ‐ IbTx

R191 ‐ R25
1.0

G193 ‐ G26
0.9

K194 ‐ K27
0.4

Overlaid R191G193K194 domain of ASIC at low pH against IbTx's BK‐binding domain (R25G26K27). The distance between the central carbon atoms of each of the residues is shown.

Residues
Distance (Å)

ASIC1 ‐ IbTx

R191 ‐ R25
2.5

G193 ‐ G26
2.5

K194 ‐ K27
2.0
Role of BKCa channels and PKC in mesenteric artery contractility of diabetic rats
Authors: Suárez Paola Algara , Pérez Cristóbal Joel González , Espinosa‐Tanguma Ricardo 
Published: June 2021

The aim of this study was to analyze the effect of diabetes mellitus (DM), acting through protein kinase C (PKC), on vascular tone associated to BKCa channel activity in rat mesenteric artery.MethodsDM was induced in male Wistar rats by intravenous injection of streptozotocin (STZ, 60mg/kg) and mesenteric artery rings were isolated for isometric force studies. The effects of PKC inhibitor Bisindolymaleimide I (Bis 1) and BKCa channel activator NS 1619 on phenylephrine induced contractions were evaluated and expressed as % force.ResultsNS1619 decreased maximal force in control but not in STZ rats (97.4 ± 16 % vehicle v.s. 81.6 ± 25% NS1619, p=0.011, n=7 for ctrl; 84 ± 13% v.s. 71.8 ± 36%, p=0.54, n = 6 for STZ). Bis1 decreased phenylephrine contraction in both control and STZ rats (61.8 ± 33%, p= 0.003, n =8 ctrl; 34 ± 12%, p=0.0001, n=6 for STZ); although inhibition was more prominent in STZ than in ctrl rats (p= 0.005). Relaxation due to nifedipine was higher for STZ (42±15% for ctrl v.s. 19.5 ±17 for STZ, p=0.031, n=6).ConclusionsDM leads to elevated PKC and VOCC activity, probably through BKCa channel inhibition which is not reversible by NS1619.Supported by: C12‐FAI‐03–60.60, UASLP
Inflammation and sexual dimorphism in development of insulin resistance: a dual animal model comparison
Authors: Wintrob Zachary A.P. , Oppong Emmanuel K. , Tse Yu C. , Welt Jeffery M. , Boateng Hans R. , Drumea Ioana , Martorana Michael , Irlam John , LeVea Charles M. , Faitar Silviu L. , Ceacareanu Alice C. 
Published: June 2021

Severe combined immunodeficiency (SCID) and immunocompetent BALBc mice strains may constitute resourceful model‐candidates for revealing inflammation‐mediated mechanisms involved in high fat diet (HFD) induced insulin resistance (IR).This study included 32 animals in groups of 4 for all combinations of male (M), female (F), BALBc, SCID, low fat diet (LFD, 4.1% fat), and HFD (35% fat) for a total of 21 weeks. All groups switched to 10% fat, between week 12 and 15. Biweekly fasting levels of adipokines, inflammatory cytokines and growth factors were assessed. IR was verified by glucose tolerance test at week 13.By week 13 the HFD‐SCID‐F neither gained weight, nor developed IR; HFD‐BALBc‐F gained weight but did not develop IR, while all HFD‐Ms both gained weight and developed IR. Ultimately the HFD‐SCID‐F gained ~4g and had low insulin levels, while all other HFD groups gained ~10g and had 4–7 fold higher fasting insulin. Adiponectin (ADP) spiked at 3 weeks and remained elevated in HFD‐BALBc‐F. Switching food resulted in upward‐trending insulin reversing only in BALBc‐M and upward‐trending leptin decreased in all but SCID‐F. Liver pathology associated fatty liver disease with IR in HFD.Concomitant evaluation of these models suggests a combined contribution of inflammation and sexual dimorphism in developing IR. Further research may clarify whether ADP is a mediator of this mechanism.
Green tea (−)‐epigallocatechin gallate inhibits IGF‐I and IGF‐II stimulation of glucose uptake in 3T3‐L1 adipocytes
Authors: Shih Li‐Jane , Ku Hui‐Chen , Tsuei Yi‐Wei , Weng Jueng‐Tsueng , Tsai Shu‐Wei , Lin Ching‐Ling , Kuo Yow‐Chii , Kao Yung‐Hsi 
Published: June 2021

ObjectiveThis study investigated the pathways involved in EGCG modulation of IGF‐stimulated glucose uptake in 3T3‐L1 adipocytes.MethodsGlucose uptake was assayed to measure the uptake of 3H‐2‐deoxyglucose. Western blot analysis was performed to measure levels of Glucose transporters (GLUTs) and IGF signaling molecules.ResultsEGCG inhibited IGF‐I and IGF‐II stimulation of adipocyte glucose uptake in dose‐ and time‐dependent manners. Treatment with 20 μM EGCG for 2 h significantly decreased IGF‐I‐ and IGF‐II‐stimulated glucose uptake by 59% and 64%, respectively. The EGCG receptor [also known as the 67‐kDa laminin receptor (67LR)] was discovered in fat cells. Pretreatment of adipocytes with a 67LR antibody, but not normal rabbit immunoglobulin, prevented the effects of EGCG on IGF‐increased glucose uptake. Moreover, pretreatment with an AMP‐activated protein kinase (AMPK) inhibitor, such as compound C, but not with a glutathione activator, such as N‐acetyl‐L‐cysteine, blocked the anti‐IGF effect of EGCG on adipocyte glucose uptake. Further analysis for subcellular fractions indicated that EGCG decreased the IGF‐induced increases in the GLUT4 translocation from the cytosol to the plasma membrane and that EGCG had no effects on the level of GLUT1 translocation and total amounts of GLUT‐1 and GLUT‐4 proteins. In addition, EGCG suppressed the IGF‐stimulated phosphorylation of PKCζ/λ, but not Akt or ERK, proteins.ConclusionsThese results suggest that EGCG inhibits IGF‐I and IGF‐II stimulation of 3T3‐L1 adipocyte glucose uptake through downregulated GLUT‐4 translocation and IGF signaling and through 67LR‐ and AMPK‐dependent pathways.
Electrophilic nitro‐fatty acids inhibit vascular inflammation
Authors: Villacorta Luis , Chang Lin , Salvatore Sonia R. , Petrovic‐Djergovic Danica , Zhang Jifeng , Schopfer Francisco J. , Freeman Bruce A. , Chen Y. Eugene 
Published: June 2021

AimsElectrophilic nitroalkene derivatives, products of unsaturated fatty acid nitration, exert long‐term cardiovascular protection in experimental models of metabolic and cardiovascular diseases. The goal of this study is to determine whether low‐dose acute administration of nitro‐fatty acids reduces vascular inflammation in vivo.ResultsPreemptive treatment with nitro‐oleic acid (OA‐NO2), but not oleic acid (OA) inhibits lipopolysaccharide (LPS)‐induced nuclear factor‐κB (NF‐κB) activation both in vivo. An acute treatment with OA‐NO2 in vivo yielding nanomolar concentrations in plasma, is sufficient to inhibit LPS‐induced Toll‐like receptor 4 (TLR4)‐induced cell surface expression in leukocytes, NF‐κB activation and leukocyte recruitment to the vascular endothelium assessed by intravital microscopy.ConclusionsThese studies demonstrate that acute administration of nitro‐fatty acids is effective to reduce vascular inflammation in vivo. These findings reveal a direct role of nitro‐fatty acids in the disruption of the TLR4 signaling and upstream events of the NF‐κB pathway, leading to resolution of pro‐inflammatory activation of NF‐κB in the vasculature.
Non‐muscle (NM) and Smooth Muscle (SM) Myosin II Activation are Regulated by Different Mechanisms During Contractile Stimulation of Airway Smooth Muscle (ASM)
Authors: Zhang Wenwu , Wu Yidi , Gunst Susan J 
Published: June 2021

Myosin II is the major motor protein in SM, and is expressed as both SM and NM isoforms. However, the function of non‐muscle myosin II in SM is not understood. We hypothesized that NM and SM myosin II may serve different functions during ASM contraction and be regulated by different mechanisms. We detected both NM myosin IIA and IIB heavy chain isoforms in canine ASM tissues. The 20 kD myosin light chain (MLC) is expressed in both NM and SM isoforms, but these isoforms cannot be distinguished immunologically. We used 2‐D gel electrophoresis to distinguish NM and SM MLC isoforms and analyze their phosphorylation in response to acetylcholine (ACh). NM MLC represented a relatively small proportion of the total cellular MLC (20–30%). Both SM and NM MLCs were phosphorylated in similar proportions in response to ACh stimulation (about 50%). When RhoA was inactivated by expressing the inactive RhoA mutant, RhoA T19N, in muscle tissues, NM MLC phosphorylation was substantially inhibited but there was little effect on SM MLC phosphorylation. The MLC kinase inhibitor, ML‐7, suppressed ACh induced SM myosin II LC phosphorylation, but had little or no effect on NM myosin II MLC phosphorylation. We conclude that MLC kinase primarily regulates the phosphorylation of SM MLC, whereas NM MLC phosphorylation depends on RhoA activation. This suggests SM and NM myosin II play distinct roles in the regulation of SM contraction.HL29289, HL074099.
Neurotrophic growth factor response to lower body resistance training in older adults
Authors: Walsh Jeremy James , Scribbans Trisha , Bentley Robert Francis , Kellawan Jeremy Mikhail , Gurd Brendon , Tschakovsky Michael 
Published: June 2021

Multimodal cognitive interventions (resistance training + cognitive training; RT + CT) may synergistically improve cognitive function in older adults. RT stimulates the release of neurotrophic growth factors (NGF) which orchestrate structural and functional brain plasticity in the aging brain, while CT increases regional cerebral blood flow. Timing the administration of CT following a bout of RT, when NGF levels are at their highest, may maximize the blood‐borne dose of NGF delivered to active brain tissue. We refer to this as the ‘anabolic window’. Currently, when and how much NGF levels in the blood increase following a bout of RT is poorly understood. The purpose of this work was to characterize the timing and magnitude of insulin like growth factor‐1 (IGF‐1) and brain derived neurotrophic factor (BDNF) levels in venous blood for 2 hours following an acute bout of RT.Methods10 older adults (ages 60 – 77) performed 1 hour of lower‐body RT and rested for 2 hours post‐exercise. Blood was taken before and for 2 hours after RT at set time points. This procedure was repeated after 8‐weeks of regular RT.ResultsBDNF increased immediately post‐exercise then returned to resting levels before and after 8 weeks of RT. IGF‐1 levels did not change.Conclusionsthese data are the first to show an increase in BDNF immediately following RT in older adults. This may represent the anabolic window for performing CT. NSERC
Flying before diving: induction of neuroprotection against CNS‐oxygen toxicity (CNS‐OT) seizures while breathing 100% oxygen at 5 atmospheres absolute (ATA)
Authors: Pilla Raffaele , Held Heather E. , Fiorelli Tina , Landon Carol S. , Dean Jay B. 
Published: June 2021

In clinical and military procedures, excesses of hyperbaric oxygen (HBO) can cause CNS‐OT. We tested the hypothesis that oxidative preconditioning (PC), using a sub‐lethal dose of HBO, induces neuroprotection against seizures.99 male rats were implanted with radio‐telemetry transmitters to record diaphragmatic electromyogram, ECG, EEG, body temperature and activity. After 1 week, rats underwent PC for 1hr, every other day for 3 times over 5 days using: a‐b) air at 1ATA (control) or 2ATA; c‐d) 100%O2 at 1 or 2ATA; e) hyperbaric normoxia, f) 2ATA using 90% helium (Heliox) and g) nitrogen (Nitrox); h) normobaric hypoxia (10%O2); and i) hypobaric (0.5ATA) normoxia and j) hypobaric hypoxia (10%O2 at 0.5ATA). 24h after last PC treatment, rats were placed in a hyperbaric chamber and exposed to 5ATA O2, until CNS‐OT. Data were collected and latency to seizure (LS) determined.Results showed:1) hyperoxic PC did not provide neuroprotection against seizure; 2) inert gases PC (2ATA Nitrox/Heliox) decreased LS by 57/78%; 3) hypobaric PC significantly extended LS by 56% and 38%; and 4) hippocampi western blot suggested that hyperbaric pressure per se accelerates the CNS‐OT via downregulation of Early Growth Response‐1, involved in neuroprotection against oxidative stress.Exposing rats to intermittent flights at~16.000 feet before diving at 5ATA O2 decreases CNS‐OT risks, whereas air dives exacerbate the risk of CNS‐OT. (ONR)
A comparative study of the effect of hindlimb unloading (HLS) on male and female Sprague Dawley rats
Authors: Chowdhury Parimal , Long Ashley , Harris Gabriella , Soulsby Michael E. , Dobretsov Maxim 
Published: June 2021

The aim of this study is to test the gender‐specific effects in a hind‐limb suspended rat model of microgravity.MethodsAdult male and female rats were suspended using tail and pelvic suspension techniques for two weeks. A control non‐suspended groups of male and female rats were also used. Body weights, food and water consumption, soleus muscle weights and hind limb pressure‐pain thresholds (PPT) were measured.ResultsFor a given gender, none of measured characteristics differed between tail‐ and pelvic suspended rats. Therefore the results with different suspension techniques were pooled together for further analysis. Food and water intakes were not different between genders and between control and suspended groups. Compared to control males, control female rats had the same PPT value, but weighted less, had lower soleus muscle mass and gained weight slower. HLS nearly canceled the weight gain and resulted in the development of pressure hyperalgesia in both gender groups. However, HLS‐associated soleus muscle atrophy was detected in male rats only. Furthermore, in a sub‐group of experiments in which both PPT and plasma insulin were measured, HLS was found to decrease insulin concentrations and affect pain thresholds in male rats only.ConclusionsOverall HLS appear to influence growth, postural muscles and deep pressure sensitivity of males and it is stronger and consistent than those of female rats
Limb Movement‐Induced Central and Peripheral Hemodynamics in Heart Failure: The Role of Afferent Feedback
Authors: Ives Stephen , Amann Markus , Venturelli Massimo , Groot H. Jonathan , Witman Melissa A.H. , Morgan David E. , Wray D. Walter , Richardson Russell S. 
Published: June 2021

The mechanoreflex has previously been reported to be sensitized in patients with heart failure (HF). Therefore, this study sought to better understand the role of afferent signaling on movement‐induced changes in central and peripheral hemodynamics.METHODSIn 10 NYHA class II HF patients we performed measurements of femoral blood flow (FBF), mean arterial pressure (MAP), femoral vascular conductance (FVC), heart rate (HR), stroke volume (SV), and cardiac output (CO) at baseline and during 3 min of passive knee extension. This was repeated after intrathecal injection of the μ‐opioid antagonist, fentanyl, to pharmacologically blunt afferent feedback.RESULTSFentanyl had no effect on baseline measures, but increased (p < 0.05, control vs. fentanyl) the movement‐induced FBF (493±155 vs. 804±198 ΔmL/min), and FVC (4.7±2 vs. 8.5±3 ΔmL/min/mmHg), while NE spillover (42 ± 8 vs. 27 ± 8 Δpg/L), and retrograde FBF (371±115 vs. 260±68 ΔmL/min) tended to be reduced (p <0.10). There was no effect of fentanyl on MAP, HR, SV, or CO in response to passive movement.CONCLUSIONAs movement‐induced central hemodynamics were unchanged while peripheral hemodynamics were augmented with fentanyl blockade, this study suggests that the heightened mechanoreflex, associated with HF, plays a selective role likely affecting peripheral sympathetic vasoconstriction and subsequently exercise tolerance. Support: NIH P01HL1091830.
Divalent cation‐dependent 3H‐L‐leucine transport in lobster intestine
Authors: Abdel‐Malak Rania , Ahearn Gregory A 
Published: June 2021

The crustacean intestine displays a diversity of transport mechanisms for the transport of dietary substances, including metal ions and amino acids. The intestine of the American lobster Homarus americanus was isolated and perfused in vitro with a physiological saline. Transmural 20 μM mucosa to serosa (MS) 3H‐L‐leucine fluxes across the intestine were a hyperbolic function of luminal Ca concentration. Ca‐dependent 3H‐L‐leucine transport exhibited low Km (high affinity) and low Jmax compared to kinetic constants when both Ca and Zn were simultaneously present, and under these conditions amino acid transport Jmax was doubled. MS flux of 3H‐L‐leucine was a hyperbolic function of L‐leucine and was stimulated by the addition of 20 μM luminal Mn. In the presence of Mn alone, 3H‐L‐leucine transport showed an increase in Jmax, but no effect on L‐leucine influx Km. With the addition of Ca, the Jmax decreased, but Ca had no effect on L‐leucine influx Km, suggesting that Ca may be acting as an allosteric inhibitor of metal‐stimulated amino acid transport. In other experiments calcium was a non‐competitive inhibitor of manganese activation of 3H‐L‐leucine transport, apparently binding to a site other than the metal binding site. Ongoing experiments are researching the nature of Ca inhibition of metal stimulated amino acid transport.Agriculture and Food Research Initiative Competitive USDA Grant no. 2010–65206‐20617.
Physician assistant anatomy education: does prior anatomy experience predict performance?
Authors: Terhune Claire E. , Melcher Betsy Q. , Taylor Andrea B. 
Published: June 2021

Anatomy education in the Duke Physician Assistant (PA) program has been historically prosection‐based and heavily clinically oriented. Based on alumni feedback, in 2009 this course was transformed into a foundational anatomy course with studentperformed dissection. As part of this modification, data were collected describing incoming students’ prior anatomy experience. These data were used to combine experienced and non‐experienced students into lab groups to optimize group learning and maximize lab resource use. At present we have three years of data for students in this new anatomy curriculum. These data also allow us to evaluate whether past experience predicts course performance and/or performance on the Physician Assistant Clinical Knowledge Rating and Assessment Tool (PACKRAT). Relationships between experience (e.g., number of semesters, dissection vs. prosection) and performance in the course and on the PACKRAT were examined using linear regression analysis and ANOVA. Contrary to our initial expectations, results indicate that prior anatomy experience is not a significant (P>;0.05) predictor of anatomy performance or PACKRAT scores. However, anatomy performance was significantly related to performance on the PACKRAT. We suggest there may multiple potential confounding factors that could be related to these outcomes, which will be incorporated into future analyses.Grant Funding Source: n/aSubmitted to PAEA 5/25/2012 (bqmelcher)