bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the Interactions between Intrinsically Disordered Transactivation Domains and the KIX Domain
Authors: Xiong Junwen , Huang Yongqi 
Published: June 2021

Intrinsically disordered proteins (IDPs) are widely involved in cellular processes related to signal transduction and molecular recognition. Many IDPs interact with their biological targets via short recognition segments and different IDPs or different segments of an IDP are able to interact with a common target. The kinase‐inducible domain interacting (KIX) domain of the transcriptional coactivator CBP protein contains two distinct binding sites and is able to bind to numerous disordered transactivation domains (TAD) carrying the “ΦXXΦΦ” motif, where “Φ” is a hydrophobic residue, and “X” is an arbitrary residue. In this study we investigated the binding kinetics of various disordered TADs to the KIX domain via computer simulation and stopped‐flow technique. We found that the binding rates were heavily affected by salt concentration, indicating the involvement of long‐range electrostatic interactions during association. The basal rate constants derived from experiments under high salt conditions were similar for different KIX binding peptides. However, both experimental determined and theoretical predicted values indicated that the binding rates for peptides with the MLL site were greater than those for peptides with the c‐Myb site under low salt conditions. Electrostatic potential analysis showed that the MLL site was more positively charged than the c‐Myb site. Therefore, favorable electrostatic interactions between the MLL site and the negatively charged residues within the KIX binding peptides may steer the conformational search process and enhance the association. Site‐directed mutagenesis removing the positively charged residues on KIX domain significantly reduced the association rate constant with minor effect on the dissociation rate constant. Our results suggest that electrostatic interactions may be widely involved in interactions between disordered TAD and the KIX domain to achieve rapid signaling.Support or Funding InformationThis work was supported by National Natural Science Foundation of China (Grant number: 21603121) and Hubei University of Technology.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hypertension alters Gut Microbial Metabolites
Authors: Cheema M. Umar , Pluznick Jennifer 
Published: June 2021

Hypertension is a global public health challenge. Although multiple host signaling pathways have been discovered to play a role in hypertension, recent studies have revealed an important role of the commensal gut microbiota in contributing to blood pressure regulation. The gut microbiota can affect the host through the production of metabolites which activate signaling pathways in the host; these metabolites include those thought to largely promote host health, such as short chain fatty acids, as well as metabolites which are known to be uremic toxins (p‐cresol sulphate, indoxyl sulphate). In this study, we hypothesized that hypertension would alter gut microbial metabolite production. Furthermore, we hypothesized that an unbiased screen for changes in gut microbial metabolites would allow us to identify novel microbial metabolites. To pursue these hypotheses, six week old C57BL/6 conventional (conv, n=6) and germ‐free (GF, n=6) mice were infused with angiotensin‐II (AngII) for 4 weeks (400ng.kg−1.min−1; Alzet 1004); in parallel control groups, conv (n=6) and GF (n=6) mice received saline via minipumps. The inclusion of the GF group allows us to distinguish changes in host metabolites from changes in microbial metabolites. Following minipump implantation, animals were housed singly to prevent cross‐contamination of microbiota. At the end of fourth week, feces and blood was collected from mice. Both plasma and feces samples were processed and analyzed by using Liquid Chromatography‐Tandem Mass Spectroscopy (LC‐MS/MS) for metabolite detection (Metabalon). In feces, 33 of the top 35 metabolites which were significantly upregulated after angiotensin‐II treatment in conventional mice (saline‐conv vs. AngII‐conv) either were not detected or did not change in germ‐free mice (saline‐GF vs. AngII‐GF), indicating that they are of microbial origin. The most significant among them are choline phosphate (phospholipid metabolite, p ≤0.0029), taurohyodeoxycholic acid (bile acid metabolite, p ≤0.0203), taurolithocholate (bile acid metabolite, p ≤0.0093), and taurodeoxy cholate (bile acid metabolite, p ≤0.0166). In plasma, there were 11 metabolites which were significantly upregulated in AngII‐conv vs. saline‐conv; none of these 11 metabolites were upregulated by AngII in GF mice (saline‐GF vs. AngII‐GF). These metabolites include 4‐ethylphenylsulphate (benzoate metabolism, p ≤0.0001), p‐cresol sulfate (benzoate metabolism, known uremic toxin, p ≤0.0026), p‐cresol glucuronide (Tyrosine metabolism, p ≤0.0001), and taurodeoxycholate (Bile acid metabolite, p ≤0.0273). In summary, these data indicate that the great majority of metabolites which are upregulated in hypertension are gut microbial in origin, further strengthening the argument that the gut microbiome plays an important role in influencing host physiology in hypertension.Support or Funding InformationAmerican Heart Association (AHA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mitochondrial‐targeted H2S Donor (AP39) Ameliorates Doxorubicin‐Induced Cardiomyopathy
Authors: Veeranki Sudhakar 
Published: June 2021

Although doxorubicin cardiomyopathy is a lethal disease, currently there are no effective treatments available. Doxorubicin is a potent inducer of mitochondrial reactive oxygen species (ROS), thus leading to mitochondrial damage and dysfunction. Hydrogen sulfide, a gaseous signaling molecule, is actively produced in mitochondria and impacts its function especially during stress states. Here, we tested if mitochondrial‐targeted H2S donors can ameliorate the myocardial mitochondrial dysfunction induced by the oncological drug. We used three‐months‐old C57 mice (n=8) to induce doxorubicin cardiomyopathy and treated them with different doses of AP39 compound (an H2S donor). We have characterized the histological, gravimetric and molecular changes after the treatments in the myocardium. The results suggested that the mitochondrial‐targeted H2S donor has the potential for ameliorating myocardial mitochondrial dysfunction and doxorubicin cardiomyopathy.Support or Funding InformationAmerican Heart Association‐17SDG33670578 to Dr. Veeranki and HL074185.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of Beta‐1 Adrenergic Receptor Genotype on Cardiovascular Response to Exercise in Healthy Subjects
Authors: Kelley Eli F , Snyder Eric M , Johnson Bruce D 
Published: June 2021

Background: Research suggests the beta‐1 adrenergic receptor (ADRB1) has been shown to play a functional role in cardiomyocyte function and accounts for up to 80% of the cardiac tissue adrenergic receptors with ADRB1 stimulation increasing cardiac rate, contractility, and work. Multiple polymorphisms of the ADRB1 have been identified such as the Gly49 polymorphism that includes at least one glycine (Gly) for serine (Ser) at amino acid 49 resulting in either homozygous for Gly (Gly49Gly) or heterozygous for Gly (Gly49Ser) polymorphisms. The Gly49 polymorphism has been shown to have decreased receptor density, decreased cAMP accumulation, and a dampening influence on the cardiostimulant effect during norepinephrine infusion. Heart failure patients with this polymorphism (Gly49) have also been shown to have improved cardiac function and decreased mortality risk, but if there is an effect in healthy subjects is less clear. This suggests the Gly49 polymorphism may have cardioprotective effects similar to that of a beta‐blocker.PurposeThe purpose of this study was to determine the effects of the Gly/Ser polymorphism at position 49 of the ADRB1on the cardiovascular response to exercise in healthy subjects.MethodsWe performed genotyping of the ADRB1 (amino acid 49) and high‐intensity, steady‐state exercise on 71 healthy subjects (Ser49Ser = 52, Gly49Ser = 19).ResultsThere were no differences between genotype groups in age, height, weight, BMI, or watts achieved (age = 28.9 ± 5.6yrs., 30.6 ± 6.4yrs., height = 173.6 ± 9.9cm, 174 ± 7.5cm, weight = 74.4 ± 13.3kg, 71.9 ± 13.5kg, BMI = 24.6 ± 3.5, 23.6 ± 3.3, and watts = 223.8 ± 76.8, 205 ± 49.4, for Ser49Ser and Gly49Ser respectively). Additionally, there were no differences for genotype groups for cardiac output (CO), systolic blood pressure (BPsys), or diastolic blood pressure (BPdias) at rest, peak exercise, or in change from rest to peak exercise. The genotype groups differed significantly in heart rate (HRmax) at peak exercise and cardiac index at rest (CI) (HRmax = 184.2 ± 9.5bpm, 190.7 ± 10.6bpm, CI = 0.063 ± 0.014, 0.071 ± 0.013, for Ser49Ser and Gly49Ser respectively). There was a trend towards significance (p = 0.058) for the change in stroke volume from rest to peak exercise (ΔSV) (0.016 ± 0.018L, 0.0076 ± 0.012L, for Ser49Ser and Gly49Ser respectively).Conclusion: These data suggest genetic variations of the ADRB1 may influence cardiovascular responses to exercise in healthy subjects.Support or Funding InformationNIH grants: HL108962‐06This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hookah Smoking Causes an Acute Adverse Effect on Arterial Stiffness and Wave Reflections in Young Adults
Authors: Rezk‐Hanna Mary , Doering Lynn , Robbins Wendie , Sarna Linda , Elashoff Robert M , Victor Ronald G 
Published: June 2021

Hookah (waterpipe) smoking is a centuries‐old, revived yet understudied epidemic of tobacco use. Despite being heavily advertised and glamorized in the media as a healthier alternative to cigarettes, the toxicology of hookah smoke suggest otherwise. Cigarette smoking unequivocally causes an acute increase in arterial stiffness, but whether hookah does the same is unknown. In 48 young healthy habitual hookah but not cigarette smokers, we measured heart rate, peripheral and central blood pressure, carotid‐femoral pulse wave velocity (measure of arterial stiffness), aortic augmentation index (measure of wave reflection), plasma nicotine, and exhaled carbon monoxide (CO) before and after 30 minutes of ad lib hookah smoking. Hookah smoking increased heart rate by +16 ± 1 beats/min and mean brachial arterial pressure by +6 ± 1 mmHg (both p < 0.05, mean ± SE). Most importantly, it increased carotid‐femoral pulse wave velocity and aortic augmentation index by +0.66 ± 0.09 m/s−1and +8.76 ± 3.99%, respectively (p <0.05, mean ± SE), denoting increased acute arterial stiffness. These vascular effects were accompanied by increases in plasma nicotine concentration (+5.8 ± 1.2 ng/ml, p<0.05) and expired CO (+25.44 ± 1.68 ppm, p< 0.05). All these parameters were unchanged during time‐control studies (n=14). Thus, in contrast to effective media marketing of hookah as a safer alternative to cigarettes, the present study shows for the first time that in young adult hookah smokers, a single hookah smoking session causes an acute increase in arterial stiffness of comparable magnitude to what has been previously reported for cigarettes. Further research is warranted to determine whether habitual hookah smoking accelerates the age‐dependent development of hypertension and its cardiovascular complications.Support or Funding InformationThis study was funded by the Tobacco‐Related Disease Research Program to Dr. Mary Rezk‐ Hanna (#23DT‐0102) and Dr. Ronald Victor (#22XT‐0017).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regional and sex differences in cerebral vasomotor reactivity to carbon dioxide
Authors: LIU JIE , Falvo Michael J. , Brewer Kelly , Favre Michelle E. , Serrador Jorge M. 
Published: June 2021

Studies on cerebral vasomotor reactivity (CVMR) to carbon dioxide (CO2) are often limited to middle cerebral artery (MCA), and rarely include anterior cerebral artery (ACA) and/or vertebral artery (VA); In addition, comparison of reactivity across vessels in the same individuals is rarely performed; Moreover, sex difference in CVMR has also not been carefully investigated. Therefore, it remains unknown whether there are differences in CVMR across arterial territories and/or between females and males. Twenty‐five young healthy subjects (15 females; age: 19–37 yrs, 27±5 yrs) were enrolled. The cerebral blood flow velocities (CBFVs) at the MCA, ACA and VA were simultaneously and continuously recorded with transcranial Doppler during 3‐min resting ventilation, 2‐min inspiration of 8% CO2, 21% O2, balance nitrogen, and 2‐min mild hyperventilation, in the sitting position. The CVMR of each artery is expressed as the percent change in its CBFV per mmHg change in end‐tidal CO2, as quantified by the slope of this relationship. The results are presented as Mean±SD. The experimental protocol resulted in a variation of end‐tidal CO2 from 31.8±4.7 to 46.6±5.5 (baseline, 40.4±3.5) mmHg, with a slight variation of mean blood pressure from 92±13 to 99±13 (baseline, 94±12) mmHg. The repeated‐measures ANOVA for multiple comparisons with Bonferroni correction indicated that the CVMR slope was significantly lower in the VA (1.85±0.61 %/mmHg) than in the MCA (2.30±1.04, P = 0.023) or ACA (2.33±0.92, P = 0.004). Females generally showed steeper CVMR slope than males (2.43±0.91 vs. 1.77±0.31, P = 0.019, for the 3‐artery averaged value), with no interaction found between sex and arterial territory factors. Based on these results, the CVMR appears lower in the posterior (vertebrobasilar) circulation than in the anterior circulation. Consistent with previous data we also found females had higher CVMR values in all arteries than males. The observed regional and sex CVMR differences should play an important role when assessing the cerebral blood flow response to other physiological situations (e.g. dynamic exercise; orthostatic, hypoxia, heat or cold stress), and might explain some neurological symptoms relevant to the posterior circulation ischemia and/or sex differences, which merits further investigation. Future studies are planned to examine the pressure‐ and/or flow‐induced concurrent diameter changes of the insonated artery, when using CBFV rather than volumetric cerebral blood flow to assess the CVMR.Support or Funding InformationSupported by the War Related Illness & Injury Study Center, Veterans Administration and NIH grant R21DC009900.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The effect of exercise on purinergic receptor‐mediated cerebrovascular dysfunction in Alzheimer's disease
Authors: Hong Junyoung , Lee Jonghae , Eriksen Jason , Park Yoonjung 
Published: June 2021

IntroductionCerebrovascular dysfunction is a critical initial step of Alzheimer's disease (AD). Adenosine triphosphate (ATP) regulates cerebral blood flow through purinergic receptors. The aim of this study is to investigate the protective effect of exercise training on ATP‐induced purinergic receptor‐mediated cerebrovascular dysfunction in the AD and its underlying mechanisms.MethodsWe used the control mice (CON; C57BL/6), CON with exercise training (CON‐EX), AD mice (AD; APP/PS1) and AD with EX (AD‐EX). At 7 to 9 months of age, CON‐EX and AD‐EX mice underwent 10–12 weeks of aerobic exercise training, which consisted of 1 hour of treadmill running at 15m/min at a 5% grade. To test the purinergic receptor‐dependent vasoreactivity, a posterior cerebral artery (PCA) was isolated and ATP (2‐MeS‐ATP, 1 nmol/L to 10 μmol/L)‐induced dose‐dependent vascular dilation/constriction response was determined at 10–12 months of age. Western blotting was utilized to analyze the expression of P2Y2 receptors (P2Y2R), total eNOS (t‐eNOS) and phosphorylated eNOS (p‐eNOS) in the brain.ResultsATP induced vasodilation of PCA in CON and CON+EX mice, but it induced vasoconstriction in AD mice. Notably, exercise training reverses ATP‐induced vasoconstriction in the AD to vasodilation (AD+EX) comparable to CON mice. Western blotting data demonstrated that P2Y2R and p‐eNOS expression were significantly diminished in AD mice compared to CON mice, but they were elevated in AD‐EX mice brain. There was no significant difference in t‐eNOS expression among mice groups.ConclusionOur findings suggest that ATP‐induced purinergic receptor‐dependent cerebrovascular function is impaired in the AD. However, exercise training reverses ATP‐induced purinergic receptor‐dependent vasoconstriction to vasodilation mainly through the alteration of P2Y2R and p‐eNOS expression in the AD‐EX.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Understanding Heart Rate and Blood Pressure in Older Adults During Ongoing Single‐Task and Dual‐Task Balance Testing Protocols
Authors: Dickens Cameron , Bigelow Kimberly E. , Crecelius Anne R. 
Published: June 2021

Vestibular function is known to decline as a function of aging in adults, leading to a risk for falls in otherwise healthy people. General cardiovascular function also declines with age, and can increase the risk of cardiac events. Increasingly, progressively challenging tasks are being incorporated into balance testing, some of which might increase cardiovascular stress and yet there is little research to characterize the systemic cardiovascular responses to various balance protocols in aging humans. Therefore, the purpose of this project was to understand changes in heart rate and blood pressure during ongoing balance testing protocols in aging populations. Ten subjects ages 18 to 40 and nine subjects ages 65 and above completed balance testing including under two conditions: a progressive challenge single task (removal of visual and kinesthetic cues); and a dual task (mental arithmetic and balancing a ball on a tray). Blood pressure (via arm cuff) and heart rate (via ECG) were obtained prior to and during the task and balance was assessed via posturography (force plate). As anticipated, older individuals had impaired balance, evidenced by increased sway and greater changes in center of pressure. While both age groups saw minimal changes in cardiovascular variables during the single‐task protocols, the older group experienced augmented changes from control conditions during certain dual‐task protocols compared to their younger counterparts. The older age group exhibited greater changes in systolic pressure (13 ± 3 mmHg vs. 6 ± 3 mmHg), mean arterial pressure (7 ± 2 mmHg vs. 6 ± 2 mmHg), and heart rate (3 ± 1 bpm vs. 0 ± 2 bpm) during the physical dual‐task condition (holding a tray). Overall, the young and old age groups experienced similar cardiovascular effects during ongoing balance testing, except during the physical dual‐task challenge, where the younger subjects experienced much more mild effects than the older subjects.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Preeclampsia induces the acquired salt‐sensitivity characteristics via increased vasopressin secretion in the postpartum stage
Authors: Shinohara Keisuke , Matsuura Taku , Hirooka Yoshitaka , Tsutsui Hiroyuki 
Published: June 2021

BackgroundWomen with a history of preeclampsia exhibit increased salt‐sensitivity in the postpartum stage, which might account for their increased risk of future cardiovascular disease. However, it is unclear whether the increased salt‐sensitivity is a cause or effect of preeclampsia. Various factors, such as kidney injury and renin‐angiotensin system, are associated with salt‐sensitive hypertension. Vasopressin may also play a role in the pathogenesis of both preeclampsia and salt‐sensitive hypertension.PurposeThe aim of the present study was to investigate whether the onset of preeclampsia in subjects with originally normal salt‐sensitivity induces increased salt‐sensitivity in the postpartum stage, and to elucidate the possible mechanisms.Methods and ResultsWe used the reduced uterine perfusion pressure (RUPP) rat model, which is widely used as an acquired model of preeclampsia. Pregnant Sprague‐Dawley rats at day 14 of gestation were divided into two groups: RUPP‐operated (n=7) and sham‐operated (SHAM) controls (n=8). At 3 weeks postpartum, a high‐salt diet was initiated for 1 week. The high‐salt diet‐induced changes in mean arterial pressure (MAP) and the sodium sensitive index (SSI=ΔMAP/Δurine sodium) were significantly greater in the RUPP group than in the SHAM group (ΔMAP: 19.8±2.7 vs. 9.3±1.7 mmHg, SSI: 801±140 vs. 421±95.3 mmHg/mmol, both p<0.05). Creatinine clearance was not significantly different between groups, and histological studies revealed that both groups had normal kidney structures. Plasma renin activity and plasma aldosterone levels did not differ between groups. Levels of plasma copeptin, a substitute for plasma vasopressin, were significantly increased in the RUPP group compared with the SHAM group (150±20.3 vs. 98±18.6 pg/ml, p<0.05). Double immunofluorescence staining also revealed that expression of c‐Fos, a marker of neural activity, in vasopressin‐producing neurons was significantly increased in the hypothalamic paraventricular nucleus in the RUPP group compared with the SHAM group (% of c‐Fos positive neurons in vasopressin neurons: 45.8±7.1% vs. 23.1±2.0%, p<0.05). Gavage administration of the dual V1a/V2 vasopressin receptor antagonist conivaptan (1.0 mg/kg/day) while on the high‐salt diet attenuated the increase in MAP and decreased SSI in the RUPP rats (ΔMAP: 9.5±2.1 mmHg, SSI: 437±76.9 mmHg/mmol, n=4), but not in the SHAM rats (ΔMAP: 14.5±2.8 mmHg, SSI: 574±106 mmHg/mmol, n=5).ConclusionPreeclampsia caused salt‐sensitivity of blood pressure in the postpartum stage, probably due to increased vasopressin secretion.Support or Funding InformationKanae Foundation for the Promotion of Medical ScienceThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.