bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of Smad4 SUMOylation impairs spatial learning and memory in rats
Authors: Lee Hsiao‐Yuan , Hsu Wei‐Lun , Ma Yun‐Li 
Published: November 2023

We have previously found that the protein inhibitor of activated STAT1 (pias1) gene is differentially expressed between fast learners and slow learners from the water maze learning task with fast learners showing a higher expression level of pias1 in hippocampal neurons. Spatial training also increases PIAS1 expression in rat CA1 area. Further, overexpression of PIAS1 in CA1 neurons enhances whereas knockdown of PIAS1 impairs spatial learning and memory performance in rats. Because PIAS1 is a transcriptional regulator that possesses small ubiquitin‐like modifier (SUMO) E3 ligase activity, in this study, we aimed to examine the mechanism underlying PIAS1‐mediated learning and memory facilitation. Smad4 is a downstream target of transforming growth factor‐beta signaling. Smad4 has been well studied in the immune system, but its role in the brain has been rarely examined. In this study we examined whether Smad4 could be SUMO‐modified by PIAS1 in the brain and whether Smad4 SUMOylation plays a role in spatial learning and memory formation. Our results showed that Smad4 could be SUMO‐modified by PIAS1 at Lys‐113 and Lys‐159 both in cell lines and in rat hippocampus in vivo. Further, water maze training increased the level of Smad4 SUMOylation in CA1 neurons compared with the swim controls. Smad4 SUMOylation is also induced by neuronal activation. On the other hand, transduction of the lenti‐Smad4WT vector did not apparently affect spatial learning and memory, but transduction of the lenti‐Smad4 sumo‐mutant vector (Smad4K113RK159R) significantly impaired spatial learning and memory performance. In future studies, we will identify the downstream genes that are regulated by Smad4 SUMOylation and are involved in spatial learning and memory formation.Support or Funding InformationThis work was supported by Grant No. MOST104‐2320‐B‐001‐002‐MY3 from Taiwan.
Cognitive impairment in adolescents 10–14 years old with Type 2 Diabetes Mellitus risk factors and daily stress
Authors: Flores‐Resendiz Constantino , Benitez‐Arciniega Alejandra D. , Martínez‐Carrillo Beatriz E. , Fernando Shane , Soto‐Piña Alexandra E. 
Published: November 2023

Daily Stress (DS) is a low intensity stress that can alter cognitive processes, it modifies the Hypothalamus‐Pituitary‐Adrenal (HPA) axis and may promote the development of Type 2 Diabetes Mellitus (T2DM) risks factors. T2DM cardiovascular changes can lead to prefrontal cortex alterations and cognitive impairment. We hypothesized that DS in adolescents with T2DM risks factors impairs cognition. Our aim was to assess the effects of DS and T2DM risks factors on attention and working memory in teenagers 10–14 years old. We evaluated Body Mass Index, blood pressure, fasting blood glucose, family history of T2DM or hypertension. Neuropsi was used to assess attention and memory. Participants were classified in two groups; High Risk (HR), (n=31) and Low Risk (LR) (n=32). The HR group exhibited significantly poorer scores on attention and memory (p< 0.05) relative to the LR group and a higher, but not significant DS percentage. The proportion of DS in general was higher in girls than in boys (p<0.05), but there were no significant differences between boys and girls relative to memory or attention. Plasma cortisol was lower in girls with DS and cognitive deficits (8.8 ± 1.0 μg/dL, p<0.05) than girls without DS and cognitive deficits. Plasma epinephrine (EPI) in girls was significantly lower (56.8 ± 9.1 pg/mL) than boys with DS (114.9 ± 17.2 pg/mL, p<0.001) and no stress (114.9 ± 17.2 pg/mL, p<0.5). These results suggest that the HPA axis and sympathoadrenal system respond differently to stress related T2DM risk factors and cognitive deficits.Support or Funding InformationBridge grant UAEMEX‐UNTHSCCONACYT
Activation of the Chemo‐ and Cardiopulmonary Reflexes Blunt Baroreflex Sensitivity through Independent Mechanisms
Authors: Petersen‐Jones Humphrey G , Holbein Walter W , Johnson Blair D , Convertino Victor A , Curry Timothy B , Joyner Michael J 
Published: November 2023

BackgroundThe baroreflex maintains blood pressure homeostasis by modulating sympathetic activity in response to changes in arterial pressure. Baroreflex sensitivity (BRS) is blunted by activation of either the chemo‐or cardiopulmonary reflex; however, little is known about the interaction of these two reflexes on BRS. We hypothesized that activation of the chemoreflex during stimulation of the cardiopulmonary reflex would attenuate the reduction in BRS.Methods10 healthy male volunteers (35±3 years, BMI: 25±1 kg/m2) underwent lower body negative pressure (LBNP) at −15mmHg for 5 minutes to stimulate the cardiopulmonary reflex, with chemoreflex activation (hypoxia; arterial oxygen saturation: 85±1%) and without (normoxia; arterial oxygen saturation: 98±0%). Heart rate (HR; ECG), blood pressure (BP; brachial arterial catheter), oxygen saturation (finger pulse oximeter), and ventilation (expired gases) were recorded continuously. BRS was calculated by arterial pressure waveform analysis (spectrum; WinCPRS) during baseline (BL) and LBNP.ResultsBaseline HR was higher during hypoxia than normoxia (62±2 vs 77±3 bpm, p<0.001) while baseline systolic BP (SBP) was not statistically differentiated between conditions (151±3 vs 149±5 mmHg, normoxia vs hypoxia, p=0.669). During normoxic LBNP, HR increased (62±2 vs 66±3 bpm, p=0.001) and SBP was unchanged (151±3 vs 151±4 mmHg, BL vs LBNP, p=0.464). During hypoxic LBNP, HR remained unchanged (77±3 vs 76±4 bpm, BL vs LBNP, p=0.693) and SBP tended to decrease (149±5 vs 139±6, BL vs LBNP, p=0.067). Baseline BRS was lower during hypoxia than normoxia (15±2 vs 9±1 ms/mmHg, p=0.012). LBNP caused a similar % reduction in BRS during normoxia and hypoxia (−14±9% vs −10±7%, p=0.772).ConclusionsContrary to our hypothesis, chemoreflex activation during LBNP does not attenuate the reduction in BRS. This suggests that the cardiopulmonary reflex and the chemoreflex blunt BRS through independent mechanisms.Support or Funding InformationFunding: W81XWH‐13‐2‐0038
Unilateral carotid body resection in patients with resistant hypertension: a safety and feasibility trial
Authors: Hart Emma C , Ratcliffe Laura E.K , Narkiewicz Krzysztof , Briant Linford J.B. , Chrostowska Marzena , Wolf Jacek , Szyndler Anna , Hering Dagmara , Burchell Amy E , Abdala Ana P , Durant Claire , Lobo Mel , Sobotka Paul A , Patel Nik , Leiter James , Engelman Zoar J.B. , Nightingale Angus K , Paton Julian F.R. 
Published: November 2023

When stimulated, carotid bodies (CBs) activate sympathetic activity causing hypertension. In hypertensive animals, CBs generate aberrant tone and their resection lowered blood pressure (McBryde et al. 2013. Nat.Communs 4, 2395). In this first prospective proof of concept study our primary outcome was safety and feasibility of unilateral (u) CB resection in drug resistant hypertensive patients; as a secondary outcome we measured blood pressure over a 12 month period. 15 participants with office blood pressure (OBP) 179±7/106±4 mmHg on 5.7±0.3 anti‐hypertensive drugs were studied at 1, 3, 6 and 12 months after removing either the right (n=11) or left (n=4) CB; the latter was confirmed histologically. Hypoxic ventilatory response, adverse events, office blood pressure (OBP), ambulatory BP, muscle sympathetic nerve activity (MSNA) and baroreflex sensitivity (BRS) were measured. The procedure was feasible as glomus cells were confirmed histologically in resected tissue from 14/15 patients. The intervention was safe as no serious adverse events or serious sleep apnoeas developed following the resection, and the hypoxic ventilatory drive was maintained. Overall, no change in either OBP or ambulatory BP was found. However, in 8/14 participants, day ambulatory BP was reduced at 3 and 6 months (−23±3, −26±4 mmHg, respectively; P<0.01) post resection and correlated temporally with reductions in MSNA (P<0.05), improved BRS (P<0.05); whole drug (anti‐hypertensive) equivalents were also reduced (P<0.01). Respiratory frequency and the ventilatory response to hypoxia were higher in responders (P<0.05) compared to the non‐responders indicative of heightened carotid body drive in these patients. In conclusion, uCB resection was feasible and safe. In a subset of patients (57%), resection lowered ambulatory BP (an effect that persisted for at least 6 months). Mechanistically, the fall in ABPM was associated with reduced MSNA and improvement in BRS. These data support the presence of aberrant carotid body drive in hypertensive patients, which can be interrupted to treat drug resistant hypertension. Cibiem funded the trial.Support or Funding InformationCibiem funded the trial.
Muscle Metaboreflex‐Induced Vasoconstriction of Ischemic Active Muscle is Exaggerated in Heart Failure
Authors: Kaur Jasdeep , Alvarez Alberto , Hanna Hanna W. , Machado Tiago M. , Senador Danielle , Krishnan Abhinav C. , Altamimi Yasir H. , O'Leary Donal S. 
Published: November 2023

When oxygen delivery to active muscle is insufficient to meet metabolic demands, metabolites accumulate and stimulate skeletal muscle afferents inducing a reflex increase in blood pressure, termed the muscle metaboreflex. Muscle metaboreflex activation during submaximal dynamic exercise increases arterial pressure predominantly via an increase in cardiac output, as little peripheral vasoconstriction occurs. In heart failure, increases in cardiac output are limited and the mechanisms mediating the metaboreflex‐induced pressor response shift to mainly peripheral vasoconstriction. We recently demonstrated that muscle metaboreflex activation induces sympathetic vasoconstriction in the ischemic active muscle, which limits the ability of the metaboreflex to restore blood flow (Kaur et. al., Am J Physiol Heart Circ 2015). In the present study we tested the hypothesis that this vasoconstriction in the ischemic muscle is exaggerated in heart failure. Changes in hindlimb vascular resistance (calculated as femoral arterial pressure/hindlimb blood flow) were observed during metaboreflex activation (induced via graded reductions in hindlimb blood flow during mild exercise) in the same animals with and without α1‐adrenergic blockade (prazosin; 50 μg/kg) and before and after the induction of heart failure. Thus, each animal was observed in each state and served as its own control. During mild exercise, hindlimb skeletal muscle blood flow must be reduced below a clear threshold before the metaboreflex is engaged. In normal animals, initial flow reductions caused metabolic vasodilation. However, when blood flow was reduced below the metaboreflex threshold, vasoconstriction in the ischemic muscle occurred. In normal animals, α1‐adrenergic blockade did not markedly affect hindlimb blood flow or vascular resistance during exercise however, the metaboreflex‐induced vasoconstriction was abolished indicating that this vasoconstriction was neurogenic. After induction of heart failure, hindlimb blood flow during exercise was reduced by < 20% and hindlimb vascular resistance was substantially elevated. Metaboreflex‐induced vasoconstriction within the ischemic muscle was exaggerated after induction of heart failure. In heart failure, α1‐adrenergic blockade caused substantial hindlimb vasodilation during exercise restoring blood flow to near normal levels. Metaboreflex‐induced vasoconstriction was abolished after α1‐adrenergic blockade. We conclude that in heart failure the ability of muscle metaboreflex to restore blood flow to the ischemic muscle is impaired and this may contribute to exercise intolerance.Support or Funding InformationNIH‐HL55473
Atrial Arrhythmia and Autonomics in an Intermittent Hypoxia Rat Model of Obstructive Sleep Apnea
Authors: Jones Douglas L. , Bober Sara , Ciriello John 
Published: November 2023

IntroductionObstructive sleep apnea (OSA) is a risk factor for developing atrial fibrillation (AF), but the mechanisms underlying AF are unknown. OSA is characterized by airway obstruction and intermittent hypoxia (IH), which has been implicated in the induction of cardiovascular dysfunction. However, the role of IH in predisposing the atria to AF is not understood.HypothesisThis study tested the hypothesis that chronic repetitive IH enhances autonomic responses, and predisposes the atria to AF.Materials and MethodsAdult, male Sprague‐Dawley rats were exposed to normoxia or repeated cycles of 120 s 21% O2 alternated with 80 s 6.5–8% O2 for 8h/day for 7 days. Rats exposed to 7 days of IH or normoxia had in vivo intracardiac electrophysiology studies to evaluate electrophysiological characteristics and susceptibility to electrical inducibility of AF. Atrial effective refractory periods were determined using programmed electrical stimulation (PES) at two atrial locations. Susceptibility to electrically induced AF was determined using PES with 8 stimuli at basic drive cycle lengths of 150 or 100 ms followed by a sequentially premature single extrastimumus and burst pacing using up to 30, 1 sec burst at 50 Hz.ResultsRats following 7‐days of IH exposure were more susceptible to electrical induction of atrial arrhythmia than normoxic controls (50% vs 0%, respectively, P < 0.05). This was accompanied by an increase in inducibility in the presence of carbachol which was blocked by atropine and darifenacin. The response to isoproterenol were enhanced in the normoxic but not in the IH rats, and the effects of propranolol were less pronounced in the IH rats.ConclusionsWe have demonstrated for the first time that repeated exposure to IH in rats produced enhanced sensitivity to atrial arrhythmias. These novel findings implicating IH as a critical promoter of AF in an OSA model. Accentuation with cholinergic agonists and blockade with nonspecific and M3 specific antagonists is consistent with sensitivity to parasympathetic activation which is known to predispose the atria to AF. The diminished response to sympathetic agents suggests a potential desensitization to adrenergic activation in the IH rats. These novel findings provide an indication of the importance of IH in OSA and susceptibility to atrial arrhythmia and potential for novel therapies in OSA.Support or Funding InformationSupported in part by the Heart and Stroke Foundation of Ontario
HMB Supplementation Effects on High‐Resolution Skeletal Muscle Diffusion Tensor Imaging and Intramyocellular Fat Changes during High Intensity Military Training
Authors: Hoffman Jay R , Gepner Yiftach , Stout Jeffrey R , Hoffman Mattan W , Ben‐Dov Daniel , Funk Shany , Daimont Ido , Shelef Ilan , Rosen Philip , Avital Guy , Chen Yacov , Frankel Hagai , Ostfeld Ishay 
Published: November 2023

The purpose of this study was to examine the effect of β‐hydroxy‐β‐methylbutyrate Free Acid (HMB) supplementation on muscle morphological and muscle lipid changes during highly intense military training. Thirteen soldiers from an elite combat unit were randomly assigned to either a HMB (n=6) or placebo (PL; n=7) group. Soldiers were provided with 3 g·day−1 of either HMB or PL for 23 days. During the final week of supplementation (days 18 – 23) soldiers participated in extreme physical training, which included night navigation of 6 – 8 hours across difficult terrain with approximately 35 kg of equipment on their back. During daylight hours, soldiers remained in camouflaged positions with minimal recovery. Due to a severe environmental stress (37°C and a sand storm) navigational training was performed on only the first two evenings of the week. Still, soldiers continued to be subjected to excessive physical training. During the 6 days of intense training the soldiers slept a total of 22.5 hours (3.8 ± 3.0 h per night). Prior to and following the supplementation period participants were assessed using a 3‐Tesla magnetic resonance imaging (MRI), which included diffusion tensor imaging (DTI) sequence for muscle fiber tracking analysis. Changes of intramyocellular fat percent, muscle volume, intramyocellular fat, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Data was analyzed using a two‐way mixed factorial ANOVA. To complement null hypothesis testing, magnitude based inferences were examined to provide inferences on the true effects HMB may have had on muscle morphological, intramyocellular fat and DTI variables, compared to PL, calculated from 90% confidence intervals. Following the 23‐day supplementation period a possible increase was noted for changes in muscle volume for adductor magnus for HMB (77% likelihood for an increase). Differences in muscle volume for the vastus lateralis, rectus femoris and semitendinosus between HMB and PL were unclear. A possible decrease in intramyocellular fat was noted in the rectus femoris (73% likelihood), but a likely increase in intramyocellular fat was observed in the adductor magnus (83% likelihood) in HMB compared to PL. The effect of HMB on FA in all muscles measured were unclear compared with the effect of PL. In addition, HMB ingestion resulted in a likely increase in ADC in the vastus lateralis only (86% likelihood) compared to PL. Other comparisons between HMB and PL for ADC were also unclear. In summary, short term HMB ingestion prior to intense military training appeared to provide some benefit for maintaining muscle volume but appeared to have only minimal influence on DTI responses.Support or Funding InformationMetabolic Technologies Inc.
Effect of Inhaled Nitric Oxide on Exercise Capacity and Pulmonary Gas Exchange in Adult Survivors of Preterm Birth
Authors: Haraldsdottir Kristin , Farrell Emily , Bates Melissa , Pegelow David , Palta Mari , Goss Kara , Eldridge Marlowe 
Published: November 2023

RATIONALEPreterm birth affects millions of infants each year, and survival rates are on the rise. Frequently, premature birth results in alveolar simplification that may persist into adulthood. We have previously shown that pulmonary gas exchange efficiency is lower during exercise in some adults born preterm compared with control subjects. However, it is unknown whether the presence of inhaled nitric oxide (iNO), a potent broncho‐ and vasodilator, has an effect on pulmonary gas exchange and other physiological measures during exercise in preterm birth survivors. The objective of this study was to determine the effect of iNO on alveolar to arterial oxygen difference (AaO2), respiratory exchange ratio (RER), and maximum wattage during exercise in adult survivors of preterm birth.METHODSFourteen young adults born preterm (recruited from the Newborn Lung Project, birth weight <1,500 g, gestational age <36wk, age 20–23 years) and 16 term‐born, age‐matched control subjects performed incremental exercise on a cycle ergometer to volitional exhaustion while breathing normoxic air with and without iNO. Arterial and venous blood samples were taken every two minutes. Ventilation, mixed expired gases, power output, and oxygen consumption were continuously measured during rest and exercise using LabChart. Max wattage, RER, and AaO2 were calculated. Statistics were done with two‐way ANOVA to compare control and preterm with and without iNO with Tukey's for multiple comparisons.RESULTSWith respect to max power, controls attained a higher wattage than preterms in normoxia (p= 0.01). This difference was attenuated in the presence of iNO (174.3 ± 28.4 W controls without iNO v 141.4 ± 27.2 W preterms with iNO, p = 0.21). With respect to RER, there was no significant difference between controls and preterms in normoxia. In the presence of iNO, preterms had a significantly higher RER than controls without iNO throughout graded exercise (0.92 ± 0.10 v 0.89 ± 0.12, p = 0.0013). Preterms had a significantly higher AaO2 than controls during graded exercise in normoxia without iNO, which was attenuated with iNO (9.3 ±6.1 mmHg control v 11.6 ±10.8 mmHg preterm, p =0.21).CONCLUSIONSWe have previously shown that pulmonary gas exchange efficiency is lower in some adult survivors of preterm birth during exercise compared with control subjects. Here we show that iNO in preterm adults attenuates many of the metabolic and pulmonary gas exchange differences between preterm and control adults during graded exercise, including AaO2 and max power. RER in the preterm + NO group was significantly higher than the controls without NO. Overall, this suggests iNO can improve gas exchange efficiency in preterm born young adults.Support or Funding InformationNIH NHLBI, R01 HL086897 (Eldridge)Nitric oxide was supplied by Mallinckrodt Pharmaceuticals, formerly Ikaria, Inc.
The Effects of Upper vs. Lower Body Fat and Aerobic Exercise on Indices of the Metabolic Syndrome
Authors: Apolzan John William , Talbert Willie M , Earnest Conrad P , Martin Corby K , Church Timothy S 
Published: November 2023

IntroductionApple shaped (higher waist to hip ratios; WHR) people have higher levels of abdominal and visceral adiposity and therefore higher risks of having type 2 diabetes and cardiovascular disease. Pear shaped (lower WHR) people have improved lipid homeostasis and insulin sensitivity compared to apple shaped people. Physical activity has been shown to improve indices of the metabolic syndrome. The purpose of this study was to examine the differential responses of indices of the metabolic syndrome to exercise in people with different body fat depots (i.e. apple vs. pear shapes).MethodsThe original study recruited healthy sedentary persons and randomized them to an aerobic exercise or control group. Data from female completers with pre and post CT scans were used in the analyses. Female participants were grouped based on the division of the WHR at the median. Thus, the present study had 4 groups.ResultsThe study population (N=92) had an average age of 51±1 y and BMI of 31.4±0.4 kg/m2. The average WHR were: 0.88±0.04 exercise apple, 0.79±0.03 exercise pear, 089 ±0.04 control apple, and 0.79±0.04 control pear. Visceral adipose tissue decreased in both the apple and pear exercise groups (p=0.05). Apple exercisers tended to have greater reductions in blood pressure compared to the apple control group (p=0.06). Pear shaped individuals tended to have better circulating triglyceride levels (p=0.085) and VLDL levels (p=0.085) compared to apple exercise group. Body shape in aerobic exercisers tended to predict change in the following metabolic syndrome parameters: BMI (r=.25; p=0.08), hip circumference (r=.25; p=0.08), VLDL (r=.27; p=0.08), Cholesterol: HDL ratio (r=.25; p=0.06), and triglycerides (r=.27; p=0.06).ConclusionApple and pear shaped participants decreased visceral adiposity with exercise. Persons with pear shapes should increase aerobic exercise to decrease circulating triglycerides and VLDL levels, while persons with apple shapes should increase aerobic exercise to decrease blood pressure. Aerobic exercise in pear shaped women predicted positive change in metabolic health outcomes.Support or Funding InformationThis research was funded by grants from the NIH including a T35 DK093428, U54 GM104940, and a HL 75442.