bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebral Blood Flow in the Internal Carotid Artery Throughout the Menstrual Cycle in Young, Healthy Women
Authors: Favre Michelle E. , Serrador Jorge M. 
Published: April 2020

BackgroundPrevious reports suggest female sex hormones may affect cerebral blood flow and cerebral flow velocity in women. The purpose of this study was to examine whether changes in cerebral blood flow occur throughout the menstrual cycle phases that are associated with fluctuations in sex hormones in young, healthy women.MethodsA subset of eight female participants (mean age 25 yrs) from our previously published study (Favre & Serrador, 2019) underwent one minute of supine steady‐state cerebral blood flow measurements in the internal carotid artery. Women were studied at three different time points across the menstrual cycle: the early‐follicular (EF) phase associated with low levels of estrogen and progesterone, the late‐follicular (LF) phase associated with high levels of estrogen and low levels of progesterone, and the mid‐luteal (ML) phase associated with high levels of both estrogen and progesterone. Cerebral blood flow in the internal carotid artery was measured using duplex ultrasonography. Beat‐by‐beat blood pressure, end‐tidal CO2, ECG, and middle cerebral flow velocity (MCAv) using transcranial Doppler ultrasonography were also obtained.ResultsThere were no statistically significant changes (P=0.269) in internal carotid blood flow across the menstrual cycle phases (EF=203.9±42.2, LF=227.0±53.7, ML=203.2±47.8 ml/min). When examined as a percent of flow from the early follicular phase, there were also no significant changes (P=0.207) across the menstrual cycle (EF=100.0±0.0, LF=111.6±14.5, ML=100.8±17.0 %). Additionally, there were no significant changes (P=0.488) in MCAv (EF=84.7±19.9, LF=89.5±21.2, ML=87.9±24.1 cm/s). End‐tidal CO2 significantly decreased (P=0.025) during the mid‐luteal phase compared to the late follicular phase (EF=38.0±3.0, LF=39.3±2.8, ML=37.0±3.1 mmHg). There were no significant changes (P=0.174) in internal carotid velocity (EF=41.5±7.0, LF=44.8±7.7, ML=40.1±9.2 cm/s) or internal carotid diameter (P=0.327) across the menstrual cycle phases (EF=0.45±0.02, LF=0.46±0.03, ML=0.46±0.01 cm).ConclusionAlthough we did not observe statistically significant changes in internal carotid blood flow across the menstrual cycle phases, we recognize that women demonstrated a 11% increase in flow during the late follicular phase, corresponding to a large effect size (Partial Eta Squared= 0.201). Because of our small sample size, we cannot rule out the possibility that the fluctuations in female sex hormones affect cerebral blood flow. Additionally, it is possible that the decreased end‐tidal CO2 in the mid‐luteal phase hid an underlying increase in cerebral blood flow. However, a larger sample of women is needed to conclude whether cerebral blood flow is affected throughout the menstrual cycle phases.Support or Funding InformationThis work was supported by the Pharmacology, Physiology and Neuroscience Department at Rutgers Biomedical and Health Sciences.
Overcoming multidrug resistance in cancer cells: Biochemical evaluation of new lead drug candidates
Authors: de Oliveira Maisa C. , Okwuone Dakota D.D. , Jensen Madeline K. , Wise John G. , Vogel Pia D. 
Published: April 2020

P‐glycoprotein (P‐gp) overexpression is often correlated with multidrug‐resistance (MDR) of cancer cells due to its role in the transport of chemotherapeutic drugs out of the cells in an ATP‐dependent process. To search for P‐gp inhibitors as co‐therapeutics to combat MDR, we previously used high‐throughput in silico ligand docking studies to identify drug‐like compounds. To assess functionality of the hit compounds we measured their effects on P‐gp ATPase hydrolysis activity. Some of the compounds inhibited ATP hydrolysis of purified P‐gp and successfully reversed the MDR in prostate and ovarian cancer cell lines. We subsequently used computational approaches and structure‐based design to produce variants of one of the hit compounds with predicted higher affinity to P‐gp. The efficacy of these variants in reversing MDR in cell culture as well as the biochemical evaluation of inhibition was assessed. High expression of human P‐gp in the yeast Pichia pastoris in a biologically active form was previously reported and the purified P‐gp was used on our recent assays. Currently, reconstitution of P‐gp into nanodiscs allowed for human P‐gp to be solubilized in its active form with ATPase activity enhanced by 2–3 fold as well as increased stability. Here we report the evaluation of the potential of our previously discovered drug‐like compounds to serve as inhibitors of human P‐gp ATP hydrolysis activity.Support or Funding InformationThis work was supported by NIH NIGMS [R15GM094771‐02] to PDV and JGW, SMU University Research Council, SMU Hamilton Undergraduate Research Scholars and Undergraduate Research Assistantship Programs, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and private gifts from Ms. Suzy Ruff of Dallas, Texas, and Ms. Myra Williams, Ph.D. of Naples Florida. The authors would like to thank Dr. Ina L. Urbatsch, Texas Tech University Health Science Center, for providing the P. pastoris cells expressing the human wild‐type MDR1 used in this work.
Resolvin E1 is a pro‐repair mediator that promotes intestinal epithelial wound healing
Authors: Quiros Miguel , Feier Darius , Birkl Dorothee , Agarwal Rachit , Zhou Dennis W. , Parkos Charles A. , Garcia Andres J. , Nusrat Asma 
Published: April 2020

Resolution of inflammation and epithelial repair are active processes mediated by bioactive lipids known as specialized pro‐resolving mediators (SPMs). Resolvin E1 (RvE1), a SPM derived from omega‐3 fatty acid, has been reported to mediate anti‐inflammatory response in different tissues. Nevertheless, the role of RvE1 in mediating intestinal epithelial wound healing is not well understood.We identified increased RvE1 in healing colonic wounds. RvE1 treatments enhanced intestinal epithelial wound repair in‐vitro. Analysis of the signaling pathways revealed activation of pathways such as CREB, mTOR and Src‐FAK in response to RvE1 exposure. Additionally, RvE1 increased activation of the small GTPase Rac1, leading to increased intracellular reactive oxygen species (ROS) production, cell‐matrix adhesion and cellular protrusions at the leading edge of migrating cells. To harness this mechanism of repair, we performed intramucosal injection of synthetic nanoparticles containing RvE1 in injured murine colon. RvE1 nanoparticles increased wound closure compared to naked RvE1 and empty nanoparticles. In summary, the above findings provide important insight on mechanisms of intestinal mucosal wound repair driven by RvE1 and determine its potential as a therapeutic agent aimed at facilitating mucosal wound closure and epithelial barrier recovery in the intestineSupport or Funding InformationThis work was supported by a Crohn’s and Colitis Foundation Career Development Award (544599, to MQ) and NIH grants (HL127236 to AJG; DK055679, DK089763, DK059888, to AN; and DK61739, DK72564, DK79392, to CAP).
Low Birth Weight Pigs Exhibit Altered Cerebral Hemodynamics and Vasomotor Control
Authors: El Karsh Zeyad , Morton Jude , Jarque Maria T. , Patton Breanna , Rodrigues Lucas , Illing Kate , Chicoine Al , Sands Jade , Wellette-Hunsucker Austin , Ferguson David , Columbus Daniel A. , Weber Lynn , Olver T. Dylan 
Published: April 2020

Low birth weight (LBW) offspring have a higher prevalence of long‐term cognitive impairments, possibly the result of altered blood flow control in the brain. Using a pig model, we tested the hypothesis that LBW progeny exhibit abnormal cerebral hemodynamics and vasomotor control during early developmental stages of growth. At birth, littermate pigs were identified as normal (NBW=1.7±0.1 kg) or low birth weight (LBW=1.2±0.2 kg). Measurements were obtained at 28 d (weaning) and 56 d of age (n=8/group, 4M/4F per group) : i) 28‐d old NBW (28‐NBW; body mass=10.0±0.4 kg); ii) 28‐d old LBW (28‐LBW; body mass=8.0±0.4 kg); iii) 56‐d old NBW (56‐NBW; body mass=23.0±1.0 kg); and iv) 56‐d old LBW (56‐LBW; body mass=17.0±0.8 kg). Cerebral blood flow velocity was measured using Transcranial Doppler ultrasound. Thereafter, pigs were euthanatized, their brains were harvested, weighed and their pial arteries were dissected for pressure myography experiments. Briefly, pial artery vasomotor control was studied in response to a Ca2+‐activated potassium (BK) channel α‐subunit agonist NS1619 (elicits vasodilation; 1e‐10‐1e‐4 M) and sympathetic co‐transmitter neuropeptide Y (NPY; potent vasoconstrictor; 1e‐10‐1e‐4 M). Brain mass and body mass were significantly lower in LBW vs. NBW pigs (p<0.01). Mean cerebral blood flow velocities were similar between LBW and NBW pigs (p≥0.20). Peak systolic velocities were greater (main effect of BW, p<0.01) and reductions in end diastolic velocities approached significance in LBW vs. NBW pigs (main effect of BW, p=0.08). Accordingly, the resistive index was greater in LBW vs. NBW pigs (main effect of BW, p<0.01). The maximum vasodilator response to NS1619 was not significantly different between LBW and NBW pigs (p=0.12). However, the overall magnitude of dilation (area under the curve) was lower in LBW vs. NBW pigs (main effect of BW, p<0.05). The maximum vasoconstrictor response to NPY was greater in LBW vs. NBW groups (main effect of BW, p<0.05). Similarly, the overall magnitude of constriction was greater in LBW vs. NBW pigs (main effect of BW, p<0.01). With respect to cerebral hemodynamics and vasomotor control, no main effects of age were observed (p≥0.50). Results from this study show that LBW pigs display alterations in cerebral hemodynamics as well as cerebral vasomotor control that persist for at least 56 days. Impaired BK channel function and enhanced vasoreactivity to sympathetic co‐transmitter NPY may underlie altered cerebrovascular hemodynamics in LBW pigs.Support or Funding InformationSHRF Establishment grant (#4522) and NSERC
Transient Reductions in Serotonin Transporter Expression and Function Elicited by Blast‐Induced Traumatic Brain Injury
Authors: Benton Avery A. , Collins Sean M. , Robson Matthew J. 
Published: April 2020

Traumatic brain injury (TBI) is a leading cause of disability among civilians and the hallmark injury associated with modern military conflicts around the globe. TBI is associated with enduring psychiatric comorbidities such as post‐traumatic stress disorder (PTSD), major depressive disorder (MDD), anxiety and social dysfunction. The molecular mechanisms by which TBI results in the generation of neuropsychiatric disorders are currently not well understood, however these disorders have classically been linked to serotonin (5‐HT) signaling. The single largest determinant of the cessation of 5‐HT signaling is the serotonin transporter (SERT), a Na+/Cl−‐dependent transporter that is the target of clinically utilized serotonin reuptake inhibitors (SRI’s) and is highly expressed on 5‐HT neurons located within the raphe nucleus of the mammalian CNS. We hypothesized that TBI results in alterations in the regional expression and/or function of SERT within the CNS. To test this hypothesis, we utilized a combination of a model for blast‐induced TBI, scaled in intensity and duration for murine subjects in combination with adult, wildtype C57Bl/6J mice. Subjects received a single, blast‐induced TBI or sham treatment followed by sample collection at 3, 10 and 30 days post‐injury (dpi). Righting reflex time (RRT) was recorded for all subjects immediately following injury. TBI was found to significantly increase RRT as compared to sham treatment, indicative of a loss of consciousness in rodent subjects. Western blot analysis or [3H] 5‐HT synaptosomal uptake assays were utilized to determine SERT protein expression levels and SERT‐mediated 5‐HT uptake post‐injury, respectively. Reductions in SERT protein expression were found in the dorsal raphe nucleus (DRN) 3 dpi. Concomitant reductions in SERT‐mediated midbrain synaptosomal [3H] 5‐HT uptake were found 3 dpi. These effects were found to be time dependent as SERT protein expression normalized by 10 dpi. Further, no post‐injury differences in SERT expression or [3H] 5‐HT uptake in the prefrontal cortex (PFC), a region of dense 5‐HT innervation were found. Data contained here are the first to show that blast‐induced TBI results in transient and regional alterations in SERT expression/function. A more thorough understanding of the temporal regulation of SERT function following neurotrauma may allow for better utilization of currently available pharmacotherapies for the treatment of TBI‐elicited neuropsychiatric disorders.Support or Funding InformationStudies were supported by the PhRMA Foundation, the University of Cincinnati ASPET SURF Program and the University of Cincinnati.
Impaired Endothelial Caveolin‐1‐TRPV4 Channel Signaling Contributes to Endothelial Dysfunction in Pulmonary Hypertension
Authors: Daneva Zdravka , Marziano Corina , Ottolini Matteo , Cope Eric , Chen Yen-Li , Sonkusare Swapnil 
Published: April 2020

Impaired endothelium‐dependent vasodilation is a key contributor to elevated pulmonary arterial pressure (PAP) in pulmonary hypertension (PH). While the mechanisms of pathogenesis of PH remain elusive, recent studies show that spatially localized Ca2+ influx via endothelial transient receptor potential vanilloid 4 (TRPV4EC) channels promotes vasodilation in resistance‐sized pulmonary arteries (PAs) by activating endothelial nitric oxide synthase (eNOS) and releasing nitric oxide (NO). Caveolin‐1 (Cav‐1EC) is an essential structural protein within the pulmonary endothelium, where it has been found to associate with TRPV4EC channels in cultured endothelial cells. We hypothesized that Cav‐1EC regulates TRPV4EC channel activity and PAP, and that impaired Cav‐1EC‐TRPV4EC signaling contributes to elevated PAP in PH. To test these hypotheses, we used right ventricular systolic pressure (RVSP) and PAP measurements in normoxic or chronic hypoxic Cav‐1EC−/− and TRPV4EC−/− mice, and pressure myography and high‐speed Ca2+ imaging studies in PAs from these mice. TRPV4EC channel activity and TRPV4EC‐mediated vasodilation were significantly impaired in PAs from Cav‐1EC−/− mice, suggesting that Cav‐1EC enhances TRPV4EC channel activity in PAs. Purinergic signaling plays an important role in pulmonary circulation, and we recently identified adenosine triphosphate (ATP) as a novel physiological activator of TRPV4EC channels in PAs. ATP activation of TRPV4EC channels was abolished by protein kinase C (PKC) inhibition, and was absent in the arteries from Cav‐1EC−/− mice, supporting a Cav‐1EC‐PKC‐TRPV4EC signaling that enables ATP activation of TRPV4‐EC channels. Resting RVSP and PAP were elevated in Cav‐1EC−/− and TRPV4EC−/− mice supporting the concept that Cav‐1EC‐TRPV4EC signaling lowers resting PAP. Moreover, exposure to chronic hypoxia (CH, 3 weeks) resulted in higher increases in RVSPs in Cav‐1EC−/− and TRPV4EC−/− mice when compared to the respective wild‐type control mice, suggesting that Cav‐1EC‐TRPV4EC channel signaling is protective against CH‐induced PH. We further used two well‐established models of PH— CH and sugen 5416 injection + CH. TRPV4EC channel activity, and ATP‐ and PKC‐activation of TRPV4EC channels were impaired in PAs from both the models of PH, suggesting that Cav‐1EC‐PKC‐TRPV4EC signaling may be impaired in PH. Taken together, these results suggest that Cav‐1EC‐PKC‐TRPV4EC signaling lowers resting PAP, and is impaired in PH. Deciphering the mechanisms that impair the Cav‐1EC‐PKC‐TRPV4EC signaling in PH may lead to novel therapeutic strategies to restore endothelium‐dependent vasodilation in PH.Support or Funding InformationHL121484‐01, HL‐138496
Quantifying over expression of FoxP2 in the brain of budgerigars using immunohistochemistry
Authors: McGee Ryan Michelle 
Published: April 2020

The gene FoxP2 is believed to have a significant role in the vocal circuit pathway in humans and other vocal learning taxa. We wanted to understand the role that FoxP2 plays in the ability to have vocal plasticity in parrots. We hypothesized that manipulating levels of expression of the FoxP2 gene in the brain of a Budgerigar would affect the degree of vocal plasticity in the parrots. Specifically, we predicted that inserting a viral vector containing FoxP2 into the vocal learning center MMst would result in over Expression of FoxP2 and a decrease in vocal plasticity relative to birds that received a control vector containing GFP. One crucial step is to assess the efficacy of our experimental is measuring FoxP2 levels on the targeted region of the Budgerigar brain. We used immunohistochemistry to attach antibodies with fluorescence, that then bonded to cells expressing FoxP2 in the experimental birds. Our results show that manipulations were successful and that both viral vectors showed uptake in the brain cells, with increased FoxP2 expression in the MMst of treated animals relative to surrounding untreated striatal tissue. These results lend credence to behavioral measures showing that the FoxP2 manipulated birds had lower levels of call sharing than controls. Our results shed light on the neurogenetic mechanisms underlying the impressive vocal plasticity seen in parrots and have the potential to contribute to therapies for the speech deficits seen in some patients with PTSD, stroke or cochlear implants.Support or Funding InformationNational Institute of Health, Howard Hughes Medical Institute, and the Discovery Scholars program at NMSU
Contrasting Reflex Neural Modulation of Muscle Sympathetic Nerve Activity at Rest and During One‐leg Dynamic Exercise in Subjects with and without Heart Failure
Authors: Notarius Catherine F. , Keir Daniel A. , Badrov Mark B. , Millar Philip J. , Oh Paul , Floras John S. 
Published: April 2020

We previously showed that muscle sympathetic nerve activity (MSNA) is augmented at rest in patients with heart failure due to reduced ejection fraction (HFrEF), and rises further during mild and moderate dynamic 1‐leg exercise in stark contrast to the drop observed in healthy controls at similar exercise intensities. The reflex mechanisms responsible for this unique response are unknown. We hypothesized that MSNA may be reduced at rest and during exercise in HFrEF by either: 1) stimulating the sympatho‐inhibitory cardiopulmonary baroreceptors by exercising supine rather than upright; or 2) inhibiting the sympatho‐excitatory peripheral chemoreceptors by breathing 32% oxygen (O2). We studied 6 stable, non‐diabetic, medicated HFrEF men ( mean age 58 ± 3 SE [range 46 to 65] years; mean left ventricular ejection fraction 29 ± 4% [range 15–38]); of either ischemic (n=5) or non‐ischemic (n=1) etiology; plus 6 healthy, age matched, medication‐free volunteers (3 women; mean age 58 ± 3 [range 49 to 72]). We assessed peak oxygen uptake (VO2peak ) by open‐circuit spirometry. On a separate day, fibular MSNA (microneurography) was measured at rest and during upright 1‐leg cycling (2 min each unloaded and at 50% of VO2peak). The identical cycling protocol was then repeated during supine exercise (n=5 HFrEF) and again during upright cycling while breathing 32% O2 (n=4 HFrEF). Heart rate and diastolic blood pressure were similar across interventions in both groups but systolic blood pressure was significantly lower in HFrEF vs controls (main effect P=0.01). MSNA was reduced at rest only while supine in control subjects (main effect P=0.01; P=0.01 vs upright). Whereas in HFrEF, both supine posture and supplemental O2 attenuated MSNA burst frequency at rest (main effect P=0.01; P=0.02 vs upright). During exercise, MSNA burst frequency progressively decreased in healthy controls particularly during unloaded cycling (main effect of time P<0.001), and tended to be lower throughout supine cycling (P=0.06 vs upright). By contrast, in HFrEF patients, there was no significant change in MSNA burst frequency during exercise while supine nor with supplemental oxygen (main effect of intervention P=0.51; time P=0.34). Thus, both at rest and during mild cycling exercise, supine posture augments the sympathoinhibitory response in control subjects. However in HFrEF patients, sympathoexcitation at rest can be reduced to a similar extent by either triggering the inhibitory cardiopulmonary baroreflex or abolishing arterial chemoreceptor activation with no further effect during exercise.Support or Funding InformationSupported by Heart and Stroke Foundation of Ontario and Canadian Institutes for Health Research
The Effects of Time Restricted Feeding and Exercise on Performance and Body Composition in Healthy Mice
Authors: Persinger Aaron , Butawan Matthew , Pryke Ashley , Rose Kyley , Faietti Martina , van der Merwe Marie , Bloomer Richard , Puppa Melissa 
Published: April 2020

Intermittent fasting refers to a period of unregulated caloric consumption paired with a period of complete, or heavily restricted, caloric consumption. One version of this involves splitting the day into a consumption period and a restricted period, known as time‐restricted feeding (TRF). TRF is shown to improve metabolic health and positively affect mitochondria, independent of weight loss. Aerobic exercise is also shown to improve these parameters; however, the combination of intermittent fasting and aerobic exercise in a healthy system has not been examined. The purpose of this study was to examine the effects of the feeding window time in relation to exercise on body weight, body fat percentage, lean mass, and run to exhaustion. Healthy, young mice were placed in one of three groups: ad libitum control group (CON), 18‐hour fasting with a 6‐hour feeding starting immediately post exercise (IM), and 18‐hour fasting with a 6 hour feeding starting 5 hours post exercise (DG). The mice ran 5 days a week, 1 hour a day, for a total of 8 weeks at the beginning of the dark cycle. A run to exhaustion (RTE) was conducted at week 0 and week 8 of the study. Mice were weighed twice weekly and underwent an MRI once a week. Data are presented as mean ± SD. A repeated measures two‐way ANOVA was used to compare groups across time. Significance was set a p< 0.05. There were no significant differences between RTE times at week 0 (p= 0.52). There was a main effect of training across all groups in RTE (p=0.04) with a 14±43% increase in RTE in the CON, 13±33% increase in IM, and 55±86% increase in DG. There was a significant increase in body fat in the DG compared to CON at week 2 (CON 7.1±4.5% DG 13.4±2.3%, p=0.002), week 3 (CON 7.2±4.8% DG 11.6±2.6, p=0.02), and week 4 (CON 7.0±4.5% DG 11.6±1.9%, p=0.006); however, there was no difference between groups at week 8. There was a significant effect of time on body weight and lean mass, demonstrating normal growth (p<0.0001). TRF did not have a significant effect (p=0.24) on body weight, however there was a significant decrease in lean mass in TRF groups at week 8 (CON 24.7±2.2g, IM 22.8±2.1g, DG 22.7±1.8g, p=0.03). Although there was a small decrease in lean mass, TRF did not lead to a change in performance as measured by RTE and timing of fasting did not impact either RTE or body composition. This suggests that performance may not be substantially impacted in individuals using TRF, regardless of the timing of the feeding window.Support or Funding InformationFunded by the University of Memphis School of Health Studies