bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autonomic dysfunction in veterans with Gulf War illness (1068.19)
Authors: Reyes Levy , Falvo Michael , Blatt Melissa , Ghobreal Bemin , Acosta Amanda , Serrador Jorge 
Published: June 2021

Gulf War Illness (GWI) is a complex, idiopathic condition affecting Veterans deployed during the first Gulf War. Common symptoms reported in Veterans with GWI include but are not limited to chronic fatigue, diffuse muscle pain, gastrointestinal disorders, as well as autonomic dysfunction. While the cause of GWI is not known, there is evidence that autonomic dysfunction may be an important element underlying GWI and the associated disability. In this study Veterans with and without GWI (as defined by Kansas screening) underwent autonomic function testing, including transcranial Doppler in the middle (MCA) and anterior cerebral artery (ACA) as well as blood pressure during multiple tests (orthostatic challenge, hyper/ hypocapnia, cold pressor). Our results show that the autoregulation index (ARI) for both MCA (Control 3.5 ± 0.58 vs GWI 2.1 ± 0.48) and ACA (Control 3.7 ± 0.67 vs GWI 2.6 ± 0.50) are both lower in GWI Veterans vs. Non‐GWI vets; suggesting autonomic impairment in GWI individuals. Blood pressure nadirs did not change between groups (Control 9.9 ± 0.30s vs GWI 10.1 ± 0.32s); however, there was a difference when comparing nadirs from MCA mean blood velocity (7.6 ± 0.61s vs 8.9 ± 0.51s) between groups, further illustrating autonomic dysfunction in GWI Veterans. Our findings suggest a level of autonomic impairment in Veterans with GWI, and further studies should be performed to determine if interventions can ameliorate autonomic impairment in this group of individuals.Grant Funding Source: Department of Veterans Affairs and Office of Public Health
Mitochondrial modulation of calcium pulsars in native endothelial cells (1075.3)
Authors: Béziau Delphine , Charbel Chimène , Toussaint Fanny , Blanchette Alexandre , Mayer Gaétan , Ledoux Jonathan 
Published: June 2021

Calcium homeostasis is the crux of endothelial function and the regulation of vascular tone. Endothelial Ca2+ is thus highly dynamic and finely tuned. Amongst Ca2+ dynamics, Ca2+ pulsars are spontaneous Ca2+ release by IP3 receptors within myoendothelial projections (MEP). However, regulatory mechanisms of endothelial Ca2+ pulsars remain to be determined. Mitochondria play a major role in intracellular Ca2+ regulation in several cell types and may represent a modulator of endothelial Ca2+ dynamics like Ca2+ pulsars. We then hypothesized that mitochondria are active regulators of Ca2+ pulsars. Given the specific localization of Ca2+ pulsars, we first established the mitochondrial distribution in native mouse endothelium by confocal and electron microscopy. Mitochondria appeared heterogeneously distributed in endothelial cells but were found to be three times more concentrated near MEP. The functional interaction between mitochondria and Ca2+ pulsars was then investigated with real‐time confocal microscopy. Interestingly, mitochondrial uncouplers FCCP and CCCP significantly decreased Ca2+ pulsars frequency. Our data suggest that mitochondria are clustered near MEP to modulate Ca2+ pulsars and might therefore be an important regulator of endothelial function.Grant Funding Source: Supported by FRQS, HSFC, CFI, SQHA and CIHR.
Nerve‐evoked contraction of isolated resistance arteries is modulated by protease‐activated receptors (1079.16)
Authors: Wei Ran , Zwozdesky Myron , Chen Michael , Plane Frances , Kerr Paul 
Published: June 2021

The sympathetic nervous system is a key regulator of arterial diameter and thus blood flow and pressure. Protease‐activated receptors (PARs) are a novel class of G‐protein coupled receptors activated by proteolytic cleavage of the extracellular domain to reveal a tethered ligand. Four sub‐types of PARs have been identified, of which PAR‐1 and PAR‐2 are expressed in the vasculature. Activation of either PAR‐1 or PAR‐2 can evoke endothelium‐dependent relaxation but whether these receptors can modulate nerve‐mediated vascular responses has not been examined. We have investigated whether activators of PAR‐2 can modulate sympathetic nerve‐evoked increases in tone in rat isolated mesenteric resistance arteries.In endothelium‐denuded segments of mesenteric artery, stimulation of peri‐arterial nerves (0.5 to 20 Hz) elicited frequency‐dependent increases in tone which were abolished by either prazosin, an α1‐adrenoceptor antagonist, or tetrodotoxin, an inhibitor of neuronal sodium channels, but were unaffected by depletion of sensory nerves with capsacin. Activation of PAR‐2 by either trypsin, the tethered ligand mimetic peptide fLIGRL or AC 264613, a synthetic PAR‐2 ligand, significantly attenuated nerve‐mediated responses. Increases in tone to bath applied noradrenaline were also attenuated by trypsin and fLIGRL but to a significantly lesser extent than the nerve‐evoked responses. The effects of trypsin on nerve‐evoked increases in tone were prevented by the trypsin inhibitor aprotinin. Thrombin, an activator of PAR‐1 also attenuated nerve‐evoked increases in tone although the effect was significantly less than that seen with PAR‐2 activation.These data indicate that PARs directly modulate nerve‐mediated vasoconstriction of resistance arteries providing a novel mechanism for regulation of sympathetic vascular tone.Supported by HSFC.
Sympathetic escape in a theoretical model of microvascular flow regulation (1079.18)
Authors: Roy Tuhin , Secomb Timothy 
Published: June 2021

A mathematical simulation of flow regulation is used to investigate the hypothesis that vasoconstriction due to sympathetic nerve activity (SNA) in smaller arterioles is inhibited by functional vasodilation at higher values of oxygen demand, termed functional sympatholysis. A network with 13 vessel compartments in series is used, each compartment representing different size ranges of arterioles and venules. The model includes 5 actively regulating arteriolar segments with diameters influenced by shear stress, wall tension, metabolic regulation, and SNA. Metabolic signals are assumed to be propagated upstream along vessel walls via a conducted response. We show that for appropriately chosen parameter values, the vasoconstriction due to SNA in feed arterioles overcomes metabolic vasodilation at higher oxygen demand, resulting in persistent vasoconstriction throughout the period of SNA. In smaller arterioles under similar conditions, however, the initial vasoconstriction with SNA is followed by partial relaxation, consistent with the experimentally observed phenomenon of sympathetic escape. This implies that metabolic responses can account for observed characteristics of functional sympatholysis, including the different responses of large and small arterioles.Grant Funding Source: Supported by NIH grant HL070657.
Impact of age and body position on the contribution of nitric oxide to femoral artery shear rate: implications for atherosclerosis (1079.21)
Authors: Trinity Joel , Groot H. , Layec Gwenael , Rossman Matthew , Ives Stephen , Richardson Russell 
Published: June 2021

Age‐related alterations in shear rate in humans have only been examined in the atherosclerotic‐resistant conduit vessels of the arm. This study sought to examine the contribution of nitric oxide (NO) to age‐related alterations in shear rate and the impact of common body positions (supine and seated) in the atherosclerotic‐prone conduit artery of the leg. Inhibition of NO synthase (NOS) was accomplished by intra‐arterial infusion of L‐NMMA and common femoral artery diameter and blood velocity were measured by Doppler ultrasound in 8 young (24±1 yr) and 8 old (75±3 yr) healthy men. Old subjects exhibited reduced mean shear rate in the supine (18.2±2.5 sec‐1) and seated positions (17.2±2.5 sec‐1) compared with young subjects (supine: 41.5±5.9 sec‐1, seated: 32.2±4.0 sec‐1). This reduced mean shear in the old was driven by attenuated antegrade shear as there were no differences in retrograde shear. NOS inhibition reduced antegrade shear in the young such that age‐related differences were abolished. In contrast, NOS‐induced reductions in retrograde shear rate were similar between groups. The seated position reduced mean shear rate in the young to that normally observed in old. Overall, this study reveals that age‐related reductions in mean shear rate, assessed in the atherosclerotic‐prone vasculature of the leg, are largely explained by reductions in antegrade shear rate as a result of reduced NO bioavailability.Grant Funding Source: Support by VA Advanced Fellowship in Geriatrics, VA Merit Award, and NIH PPG
Targeting inflammatory serine proteases for cardiac repair after Ischemia Reperfusion injury (1080.10)
Authors: Hooshdaran Bahman , Kolpakov Mikhail , Rafiq Khadija , Guo Xinji , Kiani Mohammad , Sabri Abdelkarim 
Published: June 2021

Background: Chronic inflammation predisposes tissue to adverse cardiac remodeling and contributes to heart failure (HF) progression. The mechanisms whereby inflammation affect cardiac remodeling after injury has largely focused on action of reactive oxygen species and cytokines/chemokines. However, inflammatory cells also release serine proteases and their role in myocyte loss and adverse cardiac remodeling remains largely unknown.Methods and Results: We subjected mice to myocardial ischemia for 30 minutes followed by reperfusion for 24 hours (IRI) and assessed the effect of inflammatory serine protease (ISP) inhibitor, a potent non peptide inhibitor of cathepsin G, chymase and tryptase, on myocyte apoptosis, infarct size and cardiac function. ISP inhibitor was delivered just after reperfusion either systemically (10 mg/kg, i.v.) or encapsulated in anti‐P‐selectin conjugated immunoliposomes (2 mg/kg, i.v.). Treatment with ISP inhibitor loaded immunoliposomes reduced cathepsin G and chymase activity induced after IRI compared to mice treated with empty immunoliposomes. Targeted delivery of ISP inhibitor also reduced myocyte apoptosis, limited infarct size and improved cardiac function in response to IRI. These structural and functional improvements of targeted delivery of ISP inhibitor were similar to those obtained with systemic delivery of ISP inhibitor at higher dose, but have the advantage to occur without detectable side effects of ISP inhibition on spleen, bone marrow and circulating leukocytes.Conclusions: These findings reveal the role of ISPs as key mediators of myocyte apoptosis and cardiac dysfunction post‐IRI and show that targeted inhibition of ISPs could be used as a therapy to reduce pathological cardiac remodeling and dysfunction associated with myocardial infarction.Grant Funding Source: NIH R01360998
The energy regulating upstream kinase complex LKB1/MO25/STRAD is a potential novel regulator of thin filament function (1081.3)
Authors: Behunin Samantha , Lopez‐Pier Marissa , Konhilas John 
Published: June 2021

AMP‐activated protein kinase (AMPK) is a cellular energetic regulator that is known to modify both metabolic and contractile function in the heart. Phosphorylation by an upstream kinase complex (LKB1/MO25/STRAD; LMS) is required for AMPK activation. Yet, the relationship between the LMS, AMPK activation, and myofilament function is unknown. Accordingly, we hypothesized that the upstream kinase complex can regulate myofilament function independently or in combination with AMPK. To do this, demembranated (skinned) rat cardiac trabeculae were incubated with either the LMS or with varying ratios of the LMS with AMPK and myofilament function was measured. Skinned rat trabeculae treated with the LMS alone were desensitized to Ca2+ and had lowered maximum tension. Adding increasing amounts of AMPK in combination with LMS reversed this effect increasing Ca2+‐sensitivity of tension and maximum tension. We furthered hypothesized that the mechanism underlying this relationship is mediated through direct interaction of the LMS with thin filament proteins. Western blot analysis showed an association of the LMS with myofibrils while immunofluorescence indicated that Mo25 co‐localizes with the phalloidin stained thin filament. In conclusion, the LMS has been identified as a potential novel regulator of myofilament function perhaps through a direct interaction with the thin filament.Grant Funding Source: T32HL07249
Microvascular mechanisms of age‐related cognitive decline (1082.1)
Authors: Ungvari Zoltan , Toth Peter , Tucsek Zsuzsanna , Sosnowska Danuta , Gautam Tripti , Mitschelen Matthew , Tarantini Stefano , Deak Ferenc , Koller Akos , Sonntag William , Csiszar Anna 
Published: June 2021

Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 mo) and aged (24 mo) C57/BL6 mice by chronic infusion of angiotensin II. In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values and the pressure‐induced tone of MCA was increased. In aged hypertensive mice autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice the mechanism of adaptation to hypertension involved up‐regulation of the 20‐HETE/TRPC6 pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged angiotensin II‐induced hypertensive mice include exacerbated disruption of the blood‐brain barrier and neuroinflammation (microglia activation, up‐regulation of pro‐inflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with angiotensin II‐induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation.Grant Funding Source: Supported by the American Federation for Aging Research and the Nemzeti Fejlesztési Ügynökség
Suppression of cardio‐protective molecules by diabetic marker miR‐29: a mechanism for the high rate of cardiac damage in diabetes? (1086.6)
Authors: Arnold Nicholas , Koppula Purushotham , Pulakat Lakshmi 
Published: June 2021

Diabetic marker miRNA‐29 (miR‐29) is up‐regulated by pro‐inflammatory cytokines and hyperglycemia. miR‐29 induced suppression of MCL‐1, a protein essential for mitochondrial function and cell survival, occurs in pancreatic β‐cell death. We hypothesized that conditions that increase miR‐29 levels in heart would promote suppression of MCL‐1 and increase cardiomyocyte cell death. Since Rapamycin (Rap) is known to promote diabetes, we further posited that Rap treatment (750 µg/kg/day; 6 weeks) would increase miR‐29 and suppress MCL‐1 in heart tissues of Zucker Diabetic Fatty (ZDF) rat, a rodent model for the progression of Type 2 Diabetes. Rap treatment attenuated plasma insulin (INS) levels implying development of insulinopenia; however, hyperglycemia persisted. q‐PCR showed a significant increase in miR‐29a, b, and c and suppression of MCL‐1 (p<0.01) in ZDF heart. Rap treatment also resulted in significant loss of cardiomyocytes as visualized by histopathological analysis by H &amp; E and Masson's trichrome staining. Moreover, Rap treatment increased miR‐29 levels and suppressed MCL‐1 mRNA and protein levels in mouse atrial cardiomyocytes (10nM; 12hr) and in human coronary artery smooth muscle cells (20nM; 12hr). These data suggest that MCL‐1 regulation via miR‐29 family in INS‐responsive tissues is conserved across species and contributes to cardiomyocyte loss that can promote heart failure in diabetes.Grant Funding Source: NIH: 1R01HL118376‐01
Programmed ribosomal frameshifting occurs at multiple sites and by multiple paths (109.3)
Authors: Tinoco Ignacio , Yan Shannon , Kim Hee‐Kyung 
Published: June 2021

Programmed frameshifting is used by prokaryotes and eukaryotes to synthesize two or more proteins from the same messenger RNA. We have studied minus‐one frameshifting in the dnaX gene in E. coli, whose mRNA contains the usual frameshifting signals: an internal Shine Dalgarno sequence, a slippery sequence (AAAAAAG), and a stem‐loop. We used bulk mass spectrometry, single‐molecule laser tweezers, and single‐molecule FRET in our studies. We found that minus‐one frameshifting occurs at the Lys codons in the slippery sequence, but also at codons on either side. Furthermore, the minus‐one frameshift occurs by slips of the ribosome of ‐1, +2, or even ‐4 nucleotides. The translation trajectories show step‐by‐step progression as each codon is translated, but at the slippery sequence large‐scale fluctuations in position of the ribosome are seen. This agrees with the mass spectrometry results showing multiple sites and multiple paths of frameshifting.After peptide bond formation the tRNAs undergo a classic‐hybrid equilibrium before the elongation factor, EF‐G•GTP, catalyzes the translocation. Our single‐molecule FRET studies of fluorophore‐labeled ribosome and tRNA found that the presence of the stem‐loop stabilizes the ribosome in the hybrid state before translocation. The longer time spent in this state allows the ribosome to sample other states, and thus may favor sites and paths in addition to a zero‐frame move.
Spinal protein phosphatase 1 constrains respiratory plasticity after sustained hypoxia (1091.2)
Authors: Huxtable Adrianne , Peterson Timothy , Kopp Elizabeth , Mitchell Gordon 
Published: June 2021

Plasticity is an important aspect of the neural control of breathing. One well‐studied form of respiratory plasticity is phrenic long‐term facilitation (pLTF) induced by acute intermittent, but not sustained hypoxia. pLTF pattern sensitivity partially reflects differential regulation by okadaic acid‐sensitive protein phosphatases (PP) during intermittent vs. sustained hypoxia (Wilkerson et al., J Neurosci, 2008), although the relevant phosphatase has not been identified. Here, we show that pLTF is revealed after sustained hypoxia (25 min, 10.5% O2) in rats pre‐treated with bilateral intrapleural injections of small interfering RNAs (siRNAs, Accell‐modified, Thermoscientific; 30 μl/side, 3.33 μM, 3 days) targeting PP1 mRNA (40±14% baseline, n=4). siRNAs targeting PP2A (10±13%, n=3), PP5 (12±13%, n=4) and non‐targeting siRNAs (‐1±11%, n=5) had no effect. siRNAs had no effect on the response during hypoxia. Preliminary immunohistochemistry confirms a small knockdown of targeted phosphatases within the phrenic motor nucleus. PP1 appears to be the relevant okadaic acid‐sensitive phosphatase regulating pLTF.Grant Funding Source: Supported by: HL111598, HL080209, Francis Family Foundation (AGH).
Spike frequency adaptation in avian intrapulmonary chemoreceptors does not rely on Na+/H+ exchange (1092.9)
Authors: Sheridan Krystal , Hempleman Steven , Lonjaret Jean‐Guillaume , Meehan Shane , Bassett Peter 
Published: June 2021

IPC are essential for avian breath‐by‐breath respiratory control and are inversely sensitive to lung PCO2. Evidence suggests IPC detect intracellular pH rather than molecular CO2, and that pHi reflects a dynamic interaction of intracellular CO2 hydration/dehydration, buffering, and transmembrane acid/base exchange. We used the Na+/H+ exchange (NHE) blocker dimethyl amiloride (DMA) to test NHE’s role in single‐unit IPC response to combined phasic and tonic CO2 step stimuli in anesthetized mallards (n=9). DMA depressed mean (tonic) IPC discharge response to CO2 step stimuli by 15%, 31%, 51%, and 58% at 1,3,8, and 13 µmol/kg, (p<0.05), but did not affect phasic discharge (spike frequency adaptation index, SFA). Depression of tonic CO2 response confirms earlier reports, and the new result that NHE has no effect on the phasic part of IPC step response demonstrates that other mechanisms must underlie SFA.Grant Funding Source: Supported by: NIH R15 HL087269‐02 and R25 GM056931‐15.
Decreased expression of activated placental heat shock protein 27 in human and ovine intrauterine growth restriction (1095.15)
Authors: Merill Daniel , Bahr Brigham , Arroyo Juan 
Published: June 2021

Intrauterine growth restriction (IUGR) has been documented to have increased placental apoptosis at term. Previous reports from our lab showed apoptosis as an early event in an ovine model of IUGR. Our objective was to determine the expression of active HSP27 in human IUGR placentas near term and to compare its expression to those found in the placenta on an ovine hyperthermia induced model of IUGR. Human placenta tissue samples were collected at term for active HSP27 determination. Pregnant sheep were placed in hyperthermic (HT) conditions to induce IUGR. Compared to controls, IUGR pregnancies showed: 1) reduced activation (1.7‐fold, p<0.009) of HSP27 in the human placenta; 2) smaller placentas (349±21g v. 169±22g; p<0.03) and fetal (2914±201g v. 1718±433g; p<0.03) weights in the ovine IUGR model; 3) Increased placental apoptosis in this model; 4) a 1.8‐fold increase (p<0.005) in active HSP27 in the ovine placenta near term; and 5) localization of active HSP27 to the trophoblast cells of the ovine placenta.We conclude that decreased active HSP27 at term is present when placental apoptosis is increased during IUGR. This could be a factor leading to the decreased placental weight observed during this disease (Supported by NIH grant 7K99HD055054‐02).Grant Funding Source: 7K99HD055054‐02
Quercetin attenuates induction of COX‐2 in rats subjected to acute unilateral ureteral obstruction (1096.8)
Authors: Carlsen Inge , Nørregaard Rikke 
Published: June 2021

In response to acute unilateral ureteral obstruction (UUO) inflammatory processes initiates. The aim of this study is to evaluate whether quercetin, a natural occurring bioflavonoid, have anti‐inflammatory and protective functions in the kidney during acute UUO.Rats were subjected to 24 hour UUO and quercetin was administrated IP at a dose of 50mg/kg/day, and functional parameters as well as immunoblotting and QPCR was performed for inflammatory markers, including COX‐2 and IL‐1β and the oxidative stress marker heme‐oxygenase‐1 (HO‐1).Kidney weight as well as plasma creatinine and urea were increased in response to 24h UUO. Quercetin administration reduces the increased plasma urea level, while kidney weight and plasma creatinine were not affected. COX‐2 and HO‐1 expression were increased in inner medulla in rats subjected to UUO, quercetin attenuates this induction. IL‐1β was induced in UUO rats, however, treatment with quercetin further increase IL‐1β mRNA level.Taken together, data demonstrated that quercetin play a role for the regulation of COX‐2 in response to acute UUO.