bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐Contrast Ultrasound Perfusion Imaging of Human Brown Adipose Tissue
Authors: George Mark K. , Weeks Abbie E. , Byram Brett C. , Walker Greg , Damon Bruce M. , Coolbaugh Crystal L. 
Published: April 2020

Brown adipose tissue (BAT) is a highly vascularized tissue that uptakes and oxidizes fatty acids from the circulation in response to a cold stimulus, resulting in thermogenesis. Tissue perfusion has been proposed as an approach to understand BAT metabolism, but current imaging techniques require invasive contrast or ionizing radiation. Power Doppler ultrasound imaging enables sensitive, high temporal resolution measures of the movement of blood as it perfuses a tissue without the need for contrast injections. The purpose of this study was to explore the utility of non‐contrast ultrasound perfusion imaging of human BAT during personalized cooling. Five healthy subjects [4 men; age: 31.8 ± 5.6 yrs.; body mass index: 22.5 ± 3.3 kg/m2; total body fat % (dual‐energy x‐ray absorptiometry scan): 22.9 ±7.0 %] underwent an individualized, perception‐based cooling protocol to stimulate BAT. Infrared thermography, a surrogate measure of BAT activity, and power Doppler ultrasound images were acquired over the right and left supraclavicular space, respectively, every five minutes in thermoneutrality (TN; duration: 15 min) and during cold exposure (CE) to the participant’s shiver threshold (duration: 58.3 ± 10.8 min; cooling dose: 319.7 ± 140.4 °C*min). Ultrasound images were post‐processed with a block‐wise, independent component analysis filter to analyze signal changes related to perfusion. BAT regions of interest were defined, and TN and CE conditions were compared as the mean ± standard deviation of the difference in the 95th percentile skin temperatures (infrared thermography) and the mean power Doppler signal (ultrasound). Supraclavicular skin temperature increased by 0.56 ± −0.21 °C (95% bootstrap confidence interval (CI): −0.57 to 1.72 °C), indicating a potential thermogenic response of BAT to individualized cooling (TN: 33.8 ± 1.1 °C vs. CE: 34.3 ± 0.9 °C). Similarly, the mean power Doppler signal increased by 11.6 ± 3.8 dB (95% CI: 3.2 to 19.4 dB) following cold exposure (TN: 46.8 ± 5.3 dB vs. CE: 58.3 ± 9.1 dB). These preliminary data demonstrate the feasibility of non‐contrast ultrasound perfusion imaging to detect the microvascular response of BAT to a cold stimulus in healthy adults. Power Doppler ultrasound imaging could prove useful when combined with existing noninvasive modalities (e.g. magnetic resonance imaging) to assess both the perfusion and metabolic substrate uptake response of BAT to potential obesity‐targeted therapies.Support or Funding InformationNIDDK/NIH R01‐DK‐105371, NCATS/NIH UL1‐TR000445
LIPOXINS SELECTIVELY CHANGE M2‐LIKE PHENOTYPE OF TUMORASSOCIATED MACROPHAGES BY CHANGING THEIR UNIQUE METABOLIC PROFILE AND IMPAIRING TUMOR PROGRESSION
Authors: Barja-Fidalgo Christina , de Brito Nat á lia Mesquita , da Costa Hayandra Cunha , Moretti Julia Duncan , Simões Rafael Loureiro 
Published: April 2020

In tumor microenvironments, most tumor‐associated macrophages (TAM) exhibit a characteristic M2 phenotype that favors tumor development, with deficient production of NO and ROS, key features of pro‐inflammatory M1 cytotoxic macrophages. Evidences have shown a positive correlation between high TAM density and poor prognosis. The balance between the different tumor derived mediators may modulate the outcome of the Mϕ response and consequent tumor development. Lipoxins (LX) are specialized pro‐resolving lipid mediators, able to shift inflammatory monocytes and macrophages towards M2‐like profile, but their effects on TAMs remained non‐elucidated. We have shown that, in vitro, LX selectively induce a switch of TAM M2‐like phenotype towards an M1‐like profile, increasing ROS and NO production, and enabling these cells to promote tumor cell apoptosis. LX did not affected the M2 profile of IL‐4‐stimulated macrophages. In vivo, the treatment of tumor‐bearing mice with LX, diminished the population of LY6Chi monocytes (TAM precursors) in spleen, blood and bone marrow, decreasing macrophage infiltration into the tumor, reducing the M2 markers expression on TAMs, and impairing tumor progression, increasing mice survival. The differential activation of macrophages is supported by profound intracellular metabolic changes, being well accepted that the pro‐inflammatory M1/M(LPS+IFN‐γ) phenotype rely on aerobic glycolysis, while anti‐inflammatory M2/M(IL‐4) macrophages depend on oxidative metabolism. However, little is known about TAM metabolism. We investigated the metabolic profile and requirements of TAMs, analyzing the lipoxin effects on their metabolic pathways. We show for the first time that despite TAMs present high expression of M2 markers, similarly to the M1, but distinct from M2 cells, have high glycolytic activity, with high lactate secretion, mTOR/Akt activity and increased GLUT‐1 expression. Inhibition of glycolysis, but not the oxidative phosphorylation or PPP, decreased M2 markers expression in TAMs. The inhibition of PPP impairs lipoxin to shift the M2‐profile and restore cytotoxic properties in TAMs. In conclusion, TAMs although phenotyped as M2, are metabolically distinct from these cells, being rather similar to M1, depending on the glycolytic metabolism to support their profile and functions, that lipoxin effects rely on PPP activation.Support or Funding Informationby: FAPERJ # E‐26/202.782/2017; CAPES: Finantial code # 001; CAPES/PROEX # 0574/2018; CNPq # 302413/2017‐0; 118566/2017‐2, Brazil.
Norepinephrine‐Alpha 2 Adrenergic Receptor Axis is Critical to Long‐Term Sequelae of Ischemic Acute Kidney Injury
Authors: Jang Hee-Seong , Noh Mi Ra , Ha LiGyeom , Kim Jinu , Padanilam Babu J. 
Published: April 2020

ObjectiveUpregulated levels of kidney norepinephrine (NE) have been recognized as a risk factor of development and progression of chronic kidney disease. Our reports showed renal denervation can prevent renal fibrosis and inflammation in renal fibrogenesis models through inhibition of NE‐alpha 2 adrenergic receptors (α2‐ARs) axis. However, the molecular mechanism by which NE‐α2‐ARs axis elicits long‐term sequelae of acute kidney injury (AKI) remains to be elucidated.MethodsBased on our published data, we hypothesized that NE‐α2‐ARs axis mediates its effect through macrophages recruited into ischemic kidneys. In this study, we investigated whether in vivo and in vitro NE‐α2‐AR axis regulates macrophage recruitment, activation and differentiation during the development of chronic kidney disease after ischemia/reperfusion injury (IRI).ResultsRenal bilateral IRI resulted in severe kidney fibrosis in medullary region over 2 weeks with enhanced tissue NE level, persistent tubular injury and massive macrophage infiltration. Inhibition of α2A‐ and/or α2C‐AR subtypes by pharmacological or genetic intervention prevented macrophage accumulation with downregulation of M1 and M2 macrophage markers, reduced levels of macrophage‐released pro‐inflammatory and/or fibrogenic cytokines, resulting in suppression of persistent renal tubular injury and fibrosis progression. In in vitro study using Raw264.7 cells, pharmacological inhibition of α2‐AR blocked macrophage migration to proximal tubule cells exposed to NE. In addition, we demonstrated that NE results in upregulation of both M1 and M2 macrophages.ConclusionsCollectively, NE‐α2‐ARs axis induces long‐term sequelae of ischemic AKI through macrophage recruitment and subsequent activation. Our data suggest that targeting NE‐α2‐ARs axis can be a potential therapeutic strategy to prevent long‐term sequelae of ischemic AKI.Support or Funding InformationThis work was supported by NIH grants DK‐116987, DK‐120533 and American Heart Association (AHA) Grant in Aid 15GRNT25080031 (BJP), AHA postdoctoral fellowship Grant 15POST25130003 (HSJ), and grants (NRF‐2016R1C1B2012080 and NRF‐2019R1F1A1041410) from the National Research Foundation of Korea (JK).
Effect of Acute Creatine Supplementation on Arterial Stiffness and Muscle Oxygen Saturation
Authors: Pellinger Thomas K. , Gimblet Colin J. , Vance Morgan M. , Shepherd Meghan , Ortlip Austin T. , Staudmyer Timothy B. , Lamanca John J. , Werner Timothy J. 
Published: April 2020

ObjectiveTo determine the effects of acute creatine monohydrate supplementation on arterial stiffness (AS) and skeletal muscle oxygen saturation (SmO2). There is a void in our knowledge on the impact of acute creatine monohydrate supplementation on AS in the major elastic arteries. In addition, there is a dearth of findings on the effects of creatine supplementation on SmO2 in the lower leg. Data have indicated that creatine supplementation can result in an increase in lower leg anterior compartment pressure at rest and post exercise. Although the increased pressures seen during these studies were not pathological, this and additional factors associated with creatine supplementation could possibly effect SmO2 during exercise and recovery.Methods20 male, physically active participants were randomized in a double‐blind fashion to placebo (PL) (n=10, 22.9±3.1 yrs.) or creatine (CM) (n=10, 21.3±1.8 yrs.) groups. Subjects received 0.3 g/kg/day creatine monohydrate or placebo in gelatin capsules for 7 days. Ultrasonography of the carotid artery, applanation tonometry, submaximal exercise tests (10 minute treadmill activity at 3.7 mph and 9% incline), SmO2, and lower leg pain (analog visual scale and pain test algometer) assessments were conducted at baseline and on day 7 of the study period.ResultsThere were baseline differences in central systolic blood pressure (cSBP) (mean difference, 109; 95% confidence interval (CI) 105 to 113, vs. mean difference, 130; 95% CI 114 to 146, p < 0.05) between the PLA and CM groups, respectively. Following the intervention, there were no significant differences between PL and CM in arterial stiffness indices between the groups. There was a significant group effect (P<0.03) but no significant effect of supplementation (P>0.05) on the % change in SmO2 during the exercise tests (CM: pre 66.49 ± 30.54; post 59.61 ± 23.87 vs. PL: pre 39.87 ± 16.72; post 38.51 ± 26.95 % change SmO2; M ± SD). Percent fat free mass (FFM) was significantly increased (mean, 68.5±7.5%; 95% CI 62.1% to 72.9%, to mean 69.3±7.5% 95% CI 62.9% to 73.6%, P<0.05) in the CM group only. There were no other significant changes in anthropometric measurements.ConclusionsUsing a randomly controlled, double‐blind trial with validated measurements of AS and SmO2, acute creatine supplementation does not appear to impact vascular compliance or oxygen saturation in skeletal muscle in young, healthy males.
Respiratory Muscle Activity during Maximal Efforts in ALS Patients and Healthy Controls
Authors: Sajjadi Elaheh , Ehrbar Jessica G. , Seven Yasin B. , Dickinson Patrick G. , Mitchell Gordon S. , Smith Barbara K. 
Published: April 2020

Amyotrophic lateral sclerosis (ALS) is a type of neurodegenerative disease involving upper and lower motor neuron loss. ALS patients usually die of respiratory failure due to breathing muscle weakness from motor neuron death. It is important to better understand how breathing changes in ALS to design effective treatments to target breathing insufficiency. Breathing capacity is preserved until late stages of disease in the SOD1G93A rodent model of ALS. Possible mechanisms preserving breathing in ALS rats include: 1) spinal synaptic plasticity; 2) neuromuscular junction plasticity; and 3) transition in balance from more affected muscles (eg. diaphragm) to less affected accessory respiratory muscles. If these mechanisms also exist in humans with ALS, we predict that characteristic patterns of altered respiratory muscle activity would precede ventilatory failure, assessed via traditional pulmonary function tests. Thus, using surface EMGs (sEMG) in ALS patients, we tested the hypothesis that ALS patients exhibit differential recruitment patterns of inspiratory muscle activity during a maximal inspiratory pressure (MIP) test versus healthy age‐ and sex‐ matched controls. EMG electrodes (Bagnoli surface electrode, Delsys, Massachusetts, USA) were bilaterally placed on the diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles. Subjects (8 patients and 8 controls) were instructed to perform the MIP test. The test was repeated until 3 measurements were obtained within 10% variability. RMS EMG amplitude of MIP testing was calculated using a 100ms sliding window with MATLAB v.9.2., and relationships between MIP and EMG activity were evaluated using a linear regression. A moderate relationship (r=0.65) was seen between parasternal muscle activity and MIP in ALS patients, while the controls showed moderate correlations between neck muscle activity (sternocleidomastoid and scalene) and MIP (rSCM= 0.56 and rscalene=0.69). Moreover, MIP‐generated parasternal (r=0.76) and diaphragm (r=0.7) activity corresponded strongly with disease severity of patients, as measured by the ALS‐FRS scale. Interestingly, we did not see a clear relationship between diaphragm surface EMG activity and MIP in either patients or controls. Several factors could account for this, including the use of surface electrodes and the mass‐effort nature of the MIP test. Further analyses are underway to assess respiratory muscle activity during other inspiratory challenges and compare the amount of sEMG output distribution between controls and ALS patients. These preliminary results support the idea that ALS patients use a different pattern of muscle activity during maximal breathing effort from controls.Support or Funding InformationSupported by: UF Clinical and Translational Science Institute (supported byNIH UL1TR001427), UF “Moonshot” grant initiative, and UF McKnight Brain Institute
Impact of Nrf2‐deficiency on vasoreactivity of posterior cerebral arteries is sex‐specific.
Authors: Caldwell Jacob T. , Reid-Foley Emily , Ballehr Kelsey , Restrepo Alexis , Dewell Isabella , Wahl John , Maraj Joshua , Park Hyerim , Delp Michael , Muller-Delp Judy 
Published: April 2020

IntroductionIncreases in cellular oxidative stress lead to the activation of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and the NRf2 response element, which are responsible for maintaining cellular redox homeostasis. Activation of Nrf2 may be important in adaptations that occur in the vasculature in response to exercise training. We have previously shown that the exercise training increases Nrf2 protein in skeletal muscle; however, the role of Nrf2 in cerebral vascular adaptation remains unknown. Additionally, the role of Nrf2 in sex‐specific vascular adaptations to exercise training has not been explored in any vascular bed. We hypothesized that Nrf2 deletion would differentially impact cerebral adaptations to exercise training in male and female rats.MethodsWe exercise trained male and female wild type Sprague‐Dawley (WT) rats, and their littermates lacking the Nrf2 gene (Nrf2KO). Rats were exercise trained (EX) on a motor‐driven treadmill 5 days/wk for 10–12 weeks. A mixed moderate aerobic and high‐intensity interval training protocol was utilized. At the end of the training period, posterior cerebral arterioles were isolated and cannulated for assessment of vascular reactivity. Myogenic responsiveness (pressure 0cm H20 – 130cm H20) and the responsiveness to potassium chloride (KCl) (10–100mM), and Diethlyamine‐NONO‐ate (DEA) (1e‐9 to 1e–4M) were evaluated.ResultsMyogenic responsiveness was significantly reduced in arteries from Nrf2KO rats (p<0.01). Myogenic responsiveness was significantly greater in arteries from male Nrf2KO as compared to arteries from Nrf2KO females (p<0.01). Contractile responses to KCl (30–100 mM) responses were blunted in arteries from Nrf2KO rats, but responses were not different between males and females (p=0.13). Endothelium‐independent vasodilation to the NO donor, Dea‐NONO‐ate was reduced in arteries from Nrf2KO rats as compared to WT rats, regardless of sex.ConclusionIn conclusion, Nrf2 deficiency reduces posterior cerebral vasoreactivity; however, myogenic responsiveness is better preserved in arteries from Nrf2 males compared to females. These results may have important implications for regulation of brain blood flow and vascular adaptability to exercise training in males and females.Support or Funding InformationSupported by NIH R15AG055029
Intestinal MiR194 Regulates Hepatic Bile Acids through Intestinal FXR‐FGF15 Pathway in Alcoholic Liver Disease in Mice
Authors: Jiang Mengwei , Liu Yunhuan , Gu Zelin , Li Fengyuan , Zhang Lihua , McClain Craig , Feng Wenke 
Published: April 2020

BackgroundAlcoholic liver disease (ALD) is characterized by gut dysbiosis, higher hepatic and circulating levels of bile acids (BAs) and intestinal epithelial dysfunction. BA homeostasis is modulated by hepatic and intestinal nuclear farnesoid X receptor (FXR, Nr1h4), a ligand activated transcription factor, through regulating key genes involved in bile acid synthesis and metabolism. BA synthesis regulation by intestinal FXR is through induction of fibroblast growth factor 15 (FGF15) that inhibits hepatic Cyp7a1, the key gene in BA de novo synthesis. Previous studies showed that FXR expression is suppressed miR194 in various tissues. In this study, we investigated the regulation of FXR by miR194 in intestinal tissues in mice with ALD.MethodsC57BL6 and intestinal specific FXR knockout (FXRΔIEC) mice were subjected to the Lieber DeCarli liquid diet containing 5% alcohol for 10 days, and one bonus of alcohol (5 g/kg) was gavaged on last day 9 hours before tissue collecting. Control mice were fed isocaloric maltose dextrin. A group of mice was supplemented with Lactobacillus rhamnosus GG (LGG) at a dose of 109 CFU/day for 10 days before alcohol exposure.ResultsAlcohol feeding significantly increased hepatic fat accumulation and serum ALT and AST levels. Interestingly, the alcohol‐induced effects were associated with an increased expression of miR194 and a decreased expression of FXR and FGF15 in the intestine, and with an upregulation of hepatic Cyp7a1 and BA concentration. When the mice were supplemented with probiotic LGG, intestinal miR194 expression was suppressed, FXR‐FGF15 signaling pathway was upregulated, and hepatic BA levels were decreased. Alcohol induced hepatic steatosis and injury were markedly prevented by LGG. More importantly, the beneficial effects of LGG on hepatic BA homeostasis in ALD mice were diminished when the intestinal epithelial FXR was deleted. In vitro study showed that alcohol treatment increased miR194 and decreased FXR mRNA, and inhibition of miR194 attenuated the suppression of FXR mRNA by alcohol.ConclusionsTaken together, our results demonstrate that intestinal FXR‐FGF15 signaling plays a pivotal role in maintaining hepatic BA homeostasis in ALD mice and probiotic LGG protects against ALD through maintaining BA homeostasis regulated by intestinal miR194‐FXR‐FGF15‐mediated signaling pathways.Support or Funding InformationSupported by grants from NIH.
Vena Caval Abnormalities Discovered During Dissection in the Anatomy Lab: Two Cadaveric Case Reports
Authors: Steiner Nicholas J. , Sgro Jonathan M. , Dowhayko Alexander P. , Raffoul Adam J. , Farias Anna 
Published: April 2020

IntroCongenital abnormalities of the inferior vena cava (IVC) are rare in the general population with the incidence of IVC duplication being between 0.2 – 3%. Persistent left superior vena cava (SVC) has an incidence of 0.3 – 0.7%. It is important to identify such variations through imaging prior to various thoracic and abdominal surgeries to minimize peri‐operative complications.MethodsTwo cadavers with vena caval abnormalities were identified in a medical school cadaveric anatomy lab. The donor’s age, sex and cause of death were identified through bequeathal services. The pathway of the aberrant structures was identified through dissection and any tributaries along their courses were isolated. Surrounding structures were examined to identify any other concurrent abnormalities.ResultsWe identified two cadavers with vena caval abnormalities. The first case was a 75‐year old female whose cause of death was a bowel obstruction with comorbid dementia. On this cadaver we identified a persistent left SVC that originated from the brachiocephalic vein on the left side that measured 19 mm in diameter. The aberrant structure drained into the right atrium via the coronary sinus, which was noticeably enlarged. The second case was a 76‐year old female whose cause of death was multiorgan failure with comorbid end stage liver failure, pulmonary edema and hypothyroidism. We identified a duplicated IVC with a diameter of 12 mm originating at the left iliac vein and draining into the left renal vein. Along the duplicated IVC were multiple branches originating from the posterior abdominal cavity.ConclusionWe present here two cases with rare vena caval abnormalities found in cadavers in our anatomy lab. The embryological origin of a duplicated IVC stems from the persistence of both left and right supracardinal veins during development. A persistent left SVC occurs when the left superior cardinal vein fails to regress inferior to the brachiocephalic vein. Although rare, recognizing these anatomical variations bears clinical relevance, especially in a surgical setting. These abnormalities are important to identify pre‐operatively to avoid unexpected peri‐operative complications.
α‐Synuclein’s Role in Platelet Exocytosis
Authors: Smith Alexis Nicole , Joshi Smita , Whiteheart Sidney W. 
Published: April 2020

Platelets use SNARE‐mediated exocytosis to maintain hemostasis and thrombosis. These processes are maintained by the exocytosis of platelet releasate from the three types of granules in platelets: dense, alpha, and lysosomal. Understanding how the process of exocytosis is regulated in secretion, we look for potential SNARE regulators and found the protein α‐synuclein. α‐Synuclein appears to be the only member of the synuclein family present in platelets and is very abundant. To address the role of α‐synuclein in platelets, we examined the hemostatic phenotype of α‐synuclein−/− mice. Using a tail‐bleeding time assay, we observed that α‐synuclein−/− mice bleed for a slightly longer time compared to the wild‐type mice, suggesting a platelet granule secretion defect. Secretion kinetic and dose‐response assays showed that platelets from α‐synuclein−/− mice have defective release from the dense granules and less so from lysosomal granules. To understand the mechanism of this defect, we asked whether α‐synuclein is acting as a VAMP‐chaperone in platelets and thus modulates secretion by controlling V‐SNARE levels. The two dominant T‐SNARES SNAP‐23 and Syntaxin‐11 are not altered in α‐synuclein−/− mice. However, the dominant V‐SNARE VAMP‐8 was reduced. Other V‐SNARES in the α‐synuclein−/− mice VAMP‐2, VAMP‐3, and VAMP‐7 were normal. Additional western blotting experiments demonstrated the presence of the α‐synuclein‐interactor Cysteine String Protein, further identifying elements of the platelet secretory machinery. These experiments demonstrate a role for α‐synuclein in platelet exocytosis and hemostasis and will further fill a gap in our knowledge on α‐synuclein’s physiological function and understanding how the process of exocytosis is regulated.Support or Funding InformationThis work was supported by a grant from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL56652) and a Veterans Affairs Merit Award to S.W.W.