bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kaposi's sarcoma‐associated herpesvirus reduces cellular myeloid differentiation primary response gene‐88 (MyD88) expression via modulation of its RNA
Authors: Zhang Luwen 
Published: June 2021

Kaposi's sarcoma (KS)‐associated herpesvirus (KSHV) is a human gamma herpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Interleukin 1(IL1) is a major mediator for inflammation and plays an important role in both innate and adaptive immunity. Myeloid differentiation primary response gene 88 (MyD88) is an essential adaptor molecule for IL1 as well as most Toll‐like receptors signaling. In this report, we identified a novel mechanism by which KSHV interferes with host inflammation and immunity. KSHV RTA specifically reduces the steady state protein levels of MyD88, and physiological levels of MyD88 are down regulated during KSHV lytic replication when RTA is expressed. The N‐terminal region of RTA is required for the reduction of MyD88. Additional studies demonstrated that RTA targets MyD88 expression at the RNA level, inhibits RNA synthesis of MyD88, and may bind MyD88 RNA. Finally, RTA inhibits interleukin 1(IL1)‐mediated activation of NF‐kappaB (NF‐kB). Because IL1 is abundant in KS microenvironment and inhibits KSHV replication, this work may expand our understanding on how KSHV evades host inflammation and immunity for its survival in vivo.Support or Funding InformationThis work was supported in part by grants from the National Institute of Health (CA138213, RR15635), Department of Defense (W81XWH‐12‐1‐0225), and National Multiple Sclerosis Foundation (PP3446)(LZ).
Safety of combined bambuterol and theophylline as a potential treatment of high altitude‐induced fatigue in humans
Authors: Schroeder Thies , Khiabani Hasse Z , Noveck Robert J , Bell Christopher , Hamilton Karyn , Irwin David C , Strand Trond‐Eirik 
Published: June 2021

Theophylline is moderately effective against high altitude‐induced malaise, but may be more valuable if combined with other compounds. We hypothesized that theophylline can be combined with a β2 adrenergic receptor (β2AR) agonist in humans to treat high altitude‐induced fatigue. We demonstrate that the β2AR agonist bambuterol alone (high dose = 0.05 mg/kg i.p.) significantly improves exercise performance in rats at simulated high altitude. Combined with theophylline (15 mg/kg), low‐dose bambuterol (0.01 mg/kg) was ergogenic in the same model, whereas theophylline or low‐dose bambuterol alone was not. In a phase‐1 human safety trial, neither single‐dose oral theophylline and bambuterol (Theo‐Dur 400 mg and Bambec 20 mg) nor their combination produced any SAEs. Bambuterol alone decreased plasma potassium (from 3.78 mM to a base average of 3.37 mM), which was not aggravated further by the addition of theophylline (3.83 mM to 3.33 mM). Most frequent AEs were K+<3.5mM and tremor. There was a small influence of each drug on the metabolism of the co‐administrate, decreasing Tmax of the bambuterol metabolite terbutaline and delaying t1/2 of theophylline. We conclude that the combination of theophylline and bambuterol is promising and feasible in humans and should undergo testing for safety and efficacy at high altitude.Support or Funding InformationThis work was supported by grants from the Norwegian Armed Forces Medical Service, Institute of Aviation Medicine, the US Defense Advanced Research Projects Agency (DARPA), prime Award Number N66001‐10‐C‐2134, and by the US Office of Naval Research, prime award number N0014‐14‐0699
The Fibronectin III‐1 Domain Activates a PI3‐Kinase/Akt Signaling Pathway Leading to αvβ5 Integrin Activation and TRAIL Resistance in Human Lung Cancer Cells
Authors: Cho Christina , McKeown‐Longo Paula 
Published: June 2021

Fibronectin is a mechanically sensitive protein which is organized in the extracellular matrix as a network of interacting fibrils. The lung tumor stroma is enriched for fibronectin which is thought to contribute to metastasis and drug resistance. Fibronectin is an elastic, multi‐modular protein made up of individually folded domains, some of which can stretch in response to increased mechanical tension. Very little is known about the relationship of fibronectin's unfolded domains to lung cancer resistance to chemotherapy. In the present study, we evaluated the impact of unfolding the first Type III domain of fibronectin (FnIII‐1c) on TRAIL resistance. FnIII‐1c inhibited TRAIL‐induced activation of caspase 8 and subsequent apoptosis in H460 lung cancer cells. FnIII‐1c treatment was associated with the activation of the PI3K/Akt pathway and the αvβ5 integrin receptor for vitronectin, both of which were required for TRAIL resistance. Immunohistochemical staining of sections from non‐small cell lung cancers showed that vitronectin was localized around blood vessels and in the tumor‐stroma interface. These findings suggest that unfolding of Type III domains within the fibronectin matrix may promote TRAIL resistance through the activation of a PI3K/Akt/αvβ5 signaling axis and point to a novel mechanism by which changes in secondary structure of fibronectin contribute to cancer cell resistance to apoptosis.Support or Funding InformationThis study was supported by NIH CA058626 and by DoD LC090169 to PM‐L
Chronic Hypoxia uncouples Ca2+ and eNOS in bradykinin‐induced relaxation of Ovine pulmonary arteries
Authors: Blum‐Johnston Carla M , Romero Monica M , Wee Chelsea , Blood Quintin , Wilson Rachael H , Blood Arlin B. , Francis Michael , Taylor Mark S , Longo Lawrence D , Wilson Sean M 
Published: June 2021

Bradykinin‐induced activation of the pulmonary endothelium triggers a rise in intracellular Ca2+, which activates a nitric oxide (NO)‐dependent signaling pathway. This pathway leads to vasodilation, thereby regulating pulmonary blood flow and 02 uptake. This vasodilation process includes stimulation of endothelial nitric oxide synthase (eNOS) and downstream activation of large‐conductance K+ (Maxi K+) channels. Chronic hypoxia (CH) is known to increase pulmonary pressures and restrict arterial relaxation, and can contribute to the development of pulmonary hypertension. We thus examined the effects of CH on bradykinin‐induced Ca2+ signals, bradykinin‐induced vasorelaxation, and the roles of eNOS and Maxi K+ channels in this relaxation. Wire‐myography and confocal microscopy studies were performed on pulmonary arteries (PA) from nonpregnant ewes that lived in a normoxic state at low altitude or a hypoxic state at high altitude (3,801 m) for >100 days. eNOS was inhibited with 100 μM NG‐nitro‐L‐arginine methyl ester (LNAME), and Maxi K+ channels were blocked with 1mM tetraethylammonium (TEA). The data show CH augmented endothelial Ca2+ signals, but restricted bradykinin relaxation. Further, CH caused bradykinin‐induced contraction. LNAME sensitivity was restricted, which suggests eNOS dysfunction is central to the uncoupling of Ca2+ signals and bradykinin relaxation. CH also abolished TEA‐sensitivity in bradykinin relaxation, suggesting there is loss of Maxi K+ function following CH. Overall, these results suggest that CH causes uncoupling of endothelial Ca2+ signaling and eNOS function and mediates major changes in the mechanisms of membrane hyperpolarization. It follows that CH‐induced Ca2+‐eNOS uncoupling and Maxi K+ channel dysfunction are important mechanisms to examine as future therapeutic avenues for pulmonary hypertension.Support or Funding InformationSupport from NIH, NSF and Loma Linda University School of Medicine
The Effect of Aging and Rapid Saline Infusion on Compensatory Reserve during Whole‐Body Passive Heat Stress
Authors: Gagnon Daniel , Romero Steven A , Ngo Hai , Poh Paula YS , Convertino Victor A , Crandall Craig G 
Published: June 2021

The compensatory reserve is defined as the physiological capacity to compensate for reductions in central blood volume. It is measured by a machine learning algorithm, called CRI, which analyzes continuous changes in the features of a photoplethysmographic signal obtained by finger pulse oximetry. The purpose of this study was 2‐fold. First, we examined the effect of healthy aging on compensatory reserve during normothermic and heat stress conditions. Second, we examined the effect of rapid saline infusion during heat stress on compensatory reserve. Eleven young (6 males/5 females; mean ± SD: age, 25 ± 4 years; height, 165 ± 6 cm; weight, 63 ± 9 kg) and ten aged (4 males/6 females; age, 69 ± 4 years; height, 165 ± 9 cm; weight, 68 ± 9 kg) adults were exposed to central hypovolemia via 15 and 30 mmHg of lower‐body negative pressure (LBNP) under normothermic and heat stress (increase in core temperature of 1.5°C) conditions. Approximately 10 min after the heat stress LBNP challenge, warm saline was rapidly infused (15 ml/kg in ~6 min) while subjects remained hyperthermic. Absolute CRI values (Table) range between 0 and 1, where 0 represents little to no reserve for cardiovascular compensation and 1 represents maximal physiological reserve to compensate for central hypovolemia. Under normothermic conditions, an age × LBNP level interaction was observed (P<0.01). Relative to baseline, CRI was reduced during 15 mmHg LBNP in young (P<0.01) but not aged (P=0.21) adults. During 30 mmHg LBNP, CRI was reduced in both groups (P≤0.01). During whole‐body passive heat stress, CRI was lower relative to normothermic baseline in both groups (P<0.01). During subsequent LBNP, CRI was further reduced in young adults during 15 and 30 mmHg (P<0.01). In aged adults, CRI was further reduced at 30 mmHg during heating (P=0.06), but not at 15mmHg (P=0.27). Relative to heat stress, rapid saline infusion did not affect CRI in young (P=0.47) or aged (P=0.99) adults. These results demonstrate that CRI responses at low levels of central hypovolemia (i.e. 15 mmHg ≈ 250 ml) differ between young and aged adults under normothermic and heat stress conditions. Furthermore, CRI is unaffected by rapid saline infusion performed under heat stress conditions in both young and aged adults.Support or Funding InformationFunded by the Department of Defense (W81XWH‐12‐1‐0152).

CRI responses in young and aged adults.

Normothermic baseline
LBNP15
LBNP30
Heat stress
LBNP15
LBNP30
Infusion

Young
0.88±0.06
0.77±0.11*
0.53±0.17*
0.43±0.27*
0.31±0.20†
0.18±0.13†
0.40±0.18

Aged
0.84±0.20
0.79±0.21
0.67±0.24*
0.45±0.20*
0.40±0.20
0.35±0.23†
0.41±0.15

Values are mean ± SD.
different from baseline at P≤0.05;
different from heat stress at P≤0.06.
Epinephrine Does Not Influence Baroreflex Sensitivity During Lower Body Negative Pressure to Physiological Tolerance
Authors: Scruggs Zachariah M. , Petersen‐Jones Humphrey G. , Convertino Victor A. , Joyner Michael J. , Curry Timothy B. , Baker Sarah E. 
Published: June 2021

BackgroundThe baroreflex plays an integral role in blood pressure maintenance by altering heart rate and sympathetic activity in response to changes in arterial pressure. Baroreflex sensitivity (BRS) has been shown to decrease linearly during progressive exposure to central hypovolemia as induced by lower body negative pressure (LBNP), and can be used as an index of decompensation status during hemorrhage. Circulating epinephrine is significantly elevated during high stress situations such as hemorrhage; however, it is unclear whether epinephrine influences BRS during progressive exposure to central hypovolemia. Based on previous work, we hypothesized epinephrine would attenuate any reduction in spontaneous cardiac baroreflex sensitivity during LBNP.MethodsTen young (35±3 yrs), healthy (BMI 24±1 kg/m2) men and women (6M/4F) underwent LBNP protocols on 2 separate days consisting of a 10‐min pre‐infusion baseline, 15‐min infusion period (randomized to saline or epinephrine, 0.1 μg/kg/min), 10‐min post‐infusion baseline, and 5 minutes of LBNP at −15, −30, −45, −60, −70, and −80 mmHg until the onset of presyncope (range= −30 to −80 mmHg). Presyncope was defined as a rapid decrease in systolic blood pressure greater than 15 mmHg, systolic blood pressure less than 80 mmHg, bradycardia, or voluntary termination due to presyncopal symptoms. Heart rate (HR; electrocardiogram) and blood pressure (BP; radial arterial catheter) were recorded continuously. Spontaneous cardiac BRS was determined using the sequence method (WinCPRS). Data are reported from both 10‐min baselines and from 1 minute at 20, 40, 60, 80, and 100 percent of each individual's total LBNP exposure time.ResultsWe observed no significant differences in total exposure time (1475±150 vs. 1415±79s; p=0.69) or cumulative stress index (820±135 vs. 699±69 min*mmHg; p=0.37) between saline and epinephrine visits, respectively. Baroreflex sensitivity did not change during post‐infusion baselines (ΔDown‐Down =−2±1 vs. −2±2 ms/mmHg; saline vs. epinephrine, respectively; p=0.09). Baroreflex sensitivity was significantly reduced with LBNP (p<0.01 main effect of LBNP). There was no difference between the change in baroreflex sensitivity during LBNP with saline or epinephrine infusion (ΔDown‐Down =−14±4 vs. −8±4 ms/mmHg, p=0.17).ConclusionsConsistent with previous work, spontaneous cardiac baroreflex sensitivity fell during LBNP. Contrary to our hypothesis, epinephrine infusion did not attenuate the fall in spontaneous cardiac baroreflex sensitivity observed during simulated blood loss. Because epinephrine did not alter the effect of LBNP on BRS, these data suggest that BRS may accurately reflect decompensation status during traumatic hemorrhage independent of elevated circulating epinephrine.Support or Funding InformationUS Army Medical Research and Materiel Command Contract W81XWH‐13‐2‐0038
Neurovascular Complexity Index: A Potential Quantitative Measure for Assessment of Traumatic Brain Injury
Authors: Howard Jeffrey T , Janak Jud C , Bukhman Vladislav , Robertson Claudia , Frolov Iurii , Nawn Corinne D , Schiller Alicia M , Convertino Victor A 
Published: June 2021

Multimodal monitoring of brain physiology following a traumatic brain injury (TBI) shows promise as a strategy to improve management and outcomes of TBI patients. Valid and reliable measures of different aspects of brain physiology following a TBI could prove critical to accurately capturing these changes. Using a case‐control study design, we evaluated a new proprietary algorithm of cerebral blood flow variability (CBFV) called the neurovascular complexity index (NCI). Baseline NCI data from 169 healthy control participants were compared to 51 TBI patients. Unadjusted and age‐sex adjusted logistic regression models were used to assess the association between NCI and TBI. TBI patients exhibited significantly greater variability in NCI scores than healthy controls (F=131.88; p<0.0001). Compared to the continuous measure of NCI, the threshold of ± 1.96 standard deviations from the mean for the healthy control group measure (5.88<NCI>8.10) had superior ability to identify TBI patients based on the Receiver Operator Characteristic Area Under the Curve (0.84 vs. 0.61; p=0.0007), and greater sensitivity (74.5 vs. 51.0; p=0.0013). Individuals with NCI scores outside the 5.88–8.10 range had a 29‐fold increase in the odds of TBI in multivariate logistic regression models adjusted for age, sex and end tidal CO2 (OR=29.44; 95% CI 5.98–144.87; p<0.0001). Advancement in multimodal monitoring of TBI patients is important in reducing the potential risk of secondary injury. This study reports results for a new non‐invasive quantifiable assessment of TBI based on a measure of CBFV showing potential for continuous monitoring and early identification of brain‐injured patients to better inform individualized management.Support or Funding InformationUS Army MRMC Combat Casualty Care Research Program
GLP‐1 Mediates the Intrinsic Gut‐Liver Metabolic Signaling in Anti‐VLDL Overproduction and Insulin Resistance in Vagotomized Mice
Authors: Khound Rituraj , Su Qiaozhu 
Published: June 2021

Perturbations in hepatic lipid and very low density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. In this study, our objective was to investigate the intrinsic peripheral gut‐liver vagal nerve circuit in the regulation of hepatic VLDL secretion and insulin sensitivity in sub‐diaphragmatic vagotomized mice. Specifically, by disrupting both hepatic and gastric divisions of the vagal nerve and using fast protein liquid chromatography (FPLC) to subclassify the lipoprotein particles, we discovered that vagotomy significantly decreased triglyceride (TG) contents in VLDL particles compared to that in the control mice with sham‐surgery. Vagotomy further prevented overproduction of VLDL‐TG and VLDL‐apoB induced by an acute fat load. Espousing both sham control and vagotomized mice to a long term high fat diet (HFD) for 22 weeks, we found that vagotomy protected mice from HFD induced hyperlipidemia, obesity, hepatic steatosis and insulin resistance. In an attempt to delineate the molecular mechanism for the anti‐hyperlipidemia and anti‐insulin resistant effect of vagotomy, we investigated the gut hormones and discovered that plasma glucagon‐like peptide‐1(GLP‐1) was significantly higher in the vagotomised mice compared to sham controls, which was associated with significant reduction on mRNA and protein expression of hepatic stearoyl CoA desaturase‐1 (SCD‐1), an enzyme that catalyzes the synthesis of oleyl CoA from stearolyl CoA. In vitro, pre‐treating a rat hepatoma cell line, McA‐7777 cells, with GLP‐1 inhibited SCD‐1 and Fasn mRNA expression which resulted in significant reduction on hepatic de novo lipid synthesis and VLDL secretion. Vagotomy further sensitized insulin sensitivity by upregulating expression of insulin receptors and enhanced activation of downstream signaling molecule, AKT. In conclusion, we demonstrated that increased secretion of GLP‐1 in vagotomized mice mediates the intrinsic gut‐liver metabolic signaling in preventing VLDL overproduction and insulin resistance induced by HFD. GLP‐1 inhibits SCD‐1 activity which in turn inhibits hepatic de novo lipogenesis and VLDL biogenesis. These novel findings, for the first time, provide mechanistic rationale for the application of vagotomy in clinical treatment in patients with obesity and diabetes.Support or Funding InformationHatch Funds from USDA/NIFA to Q. Su
Absorption and Excretion of Vitamin K Varies by Age and Triglycerides: A Metabolic Study in Older and Younger Adults Using Deuterium‐Labeled Collard Greens
Authors: Ellis Jessica Lea , Fu Xueyan , Al Rajabi Ala , Naumova Elena N , Grusak Michael A , Saltzman Edward , Booth Sarah L 
Published: June 2021

Vitamin K is an essential fat‐soluble nutrient, with its most established role as a cofactor in coagulation. Emerging roles in soft tissue calcification have been proposed. However, further progress in understanding absorption and metabolism is needed, including knowledge of the factors influencing the physiologic response to vitamin K. Phylloquinone (PK) is the primary form of vitamin K in the diet and circulation. Large intra‐individual variances in circulating PK exist, and little is known about the dietary and non‐dietary factors that influence PK metabolism.The purpose of this study was to compare absorption efficiency and body retention of PK in older and younger adults following dietary vitamin K depletion and repletion.Forty‐two older (55–80 y; n=21) and younger (18–40 y; n=21) adults were maintained on sequential 28‐day vitamin K depletion (~10 ug PK/day) and vitamin K repletion (~500 ug PK/day) diets. At the end of each phase, subjects were fed deuterated collard greens (2H‐PK) and monitored over 72 hours. Liquid chromatography‐mass spectrometry (LC‐MS) was used to measure labeled and unlabeled PK in plasma and triglyceride‐rich lipoprotein (TRL) fractions, and labeled and unlabeled menadione (a PK metabolite) from 24‐hr urine collections.Absorption efficiency of 2H‐PK did not differ between PK depletion and repletion, but was significantly higher in older adults than in younger adults (p=0.02). 2H‐PK in TRL fractions was correlated with the total 2H‐PK in plasma (r=0.95, p<<0.001), corroborating previous data that PK is primarily transported in circulation associated with triglycerides. Age (p=0.015) and plasma triglycerides (p<0.001) were significant linear predictors of 2H‐PK area under the curve (AUC). Both age and plasma triglycerides retained significance in the multivariate model, and together explained 31.6% of the variance in absorbed plasma 2H‐PK during the depletion period, and 29.9% in the repletion period. Analysis of urinary 2H‐menadione showed no differences in body retention of vitamin K by age, sex, or depletion or repletion.In conclusion, age and circulating triglycerides are determinants of vitamin K absorption efficiency and together explained about 30% of the variance observed in absorbed PK. Body retention of vitamin K did not vary by age, sex, or dietary intake. There is a need to elucidate non‐traditional factors, such as genetics, that may influence absorption and metabolism of vitamin K.Support or Funding InformationStudy supported by the USDA ARS under Cooperative Agreement 58‐1950‐7‐707 and the NIH (5R01DK69341‐4).
1α,25‐dihydroxyvitamin D3 Inhibits Adipocyte Mediated Metastatic Capability of Breast Cancer Cells
Authors: Yum Chae Hyun , Wilmanski Tomasz M , Sheeley Madeline , Teegarden Dorothy 
Published: June 2021

Excess adiposity is thought to be associated with approximately 20% of all cancers, including breast cancer. However the mechanism underlying this relationship remains controversial. Adipocytes secrete a wide array of bioactive molecules which act as key mediators in several obesity‐associated diseases. Further, the active form of vitamin D, 1α,25dihydroxyvitamin D (1,25(OH)2D) regulates multiple aspects of adipocyte biology, including adipogenesis and adipocyte apoptosis, as well as modulating the release of factors associated with cancer promotion. The purpose of these studies was to investigate 1,25(OH)2D‐mediated regulation of differentiated adipocytes to determine the impact on breast cancer progression. Differentiated 3T3‐L1 adipocytes were treated with 1,25(OH)2D (10 nM) for 2 days, followed by harvesting the adipocytes and collection of adipocyte conditioned media (ACM). ACM from adipocytes treated with 1,25(OH)2D decreased cell proliferation in metastatic MDA‐MB‐231 and MCF10CA1a cells compared to vehicle treated ACM, (42% and 37% of vehicle ACM, respectively), as measured by an MTT assay. In addition, ACM from adipocytes treated with 1,25(OH)2D inhibited cell migration and wound healing in MDA‐MB‐231 cells (37% and 30% respectively relative to vehicle ACM). In order to explore the mechanism underlying these effects on breast cancer metastatic capability, the mRNA expression of IGF‐1, IL‐6 and leptin was measured in adipocytes treated with either vehicle or 1,25(OH)2D. Treatment of adipocytes with 1,25(OH)2D decreased mRNA expression of IGF‐1, IL‐6 and leptin by 23%, 85%, and 39%, respectively. Further studies aim at demonstrating the mechanism underlying the impact of 1,25(OH)2D on adipocytes to inhibit their capability of promoting breast cancer metastasis. In summary, these results suggest that 1,25(OH)2D alters adipocyte secretions to inhibit breast cancer metastasis.Support or Funding InformationThis work was supported in part by the Higher Education Challenge Grant from the National Institute of Food and Agriculture, United States Department of Agriculture (#2013‐70003‐20922).