bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of MOR‐1A, an intron‐retention splice variant of the mu opioid receptor (OPRM1) gene, by miR‐107
Authors: Lu Zhigang , Xu Jin , Xu Mingming , Pasternak Gavril W , Pan Ying‐Xian 
Published: June 2021

The mu opioid receptor (OPRM1) gene undergoes extensive alternative splicing, generating an array of splice variants. Of these variants, MOR‐1A was quite abundant and conserved from rodent to humans. Loss of splicing from exon 3a to its downstream exons leads to the intron retention, producing MOR‐1A. Several miRNAs have been indicated to regulate expression of the original mu opioid receptor, MOR‐1. However, there has been a lack of studies on miRNA regulation of the OPRM1 splice variants. In the present study, we report identification of complete 3′UTR for both mouse and human MOR‐1A, and regulation of MOR‐1A expression by miR‐107 through a target site within the 3′UTRs. Using a 3′RACE approach, we first identified a polyadenylation site for both mouse and human MOR‐1A, which was further confirmed by Northern blot analyses. We then identified a conserved miR‐107 targeting site in the 3′UTR of both mMOR‐1A and hMOR‐1through several computer models including miRBase, Targetscan and RNAhybrid. The functional relevance of the miR‐107 targeting sites was verified by using luciferase‐based reporter system combined with miR‐107 inhibitor in HEK293 cells, as well as Be(2)C cells that endogenously express hMOR‐1A. Our results also indicated that miR‐107 regulated expression of mMOR‐1A or hMOR‐1A mainly at translation level.Supported by DA13997/DA029244 (YXP) and DA02615/DA07242 (GWP) from NIDA.
Quantitative Prediction of Impact of Left Ventricular Assist Device (LVAD) on Hemodynamics
Authors: Kakino Takamori , Saku Keita , Sakamoto Takafumi , Sakamoto Kazuo , Akashi Takuya , Tobushi Tomoyuki , Murayama Yoshinori , Fujino Takeo , Onitsuka Ken , Ikeda Masataka , Oga Yasuhiro , Nishizaki Akiko , Kuwabara Yukimitsu , Ide Tomomi , Sunagawa Kenji 
Published: June 2021

BackgroundAlthough LVAD has been saving many lives in patients with end stage heart failure, the quantitative prediction of LVAD on hemodynamics remains to be established.Theoretical analysisWe developed a framework of circulatory equilibrium where the cardiac output (CO) curve and venous return surface (VRS) were expressed as the function of right (PRA) and left atrial pressure (PLA). The CO curve is algebraically derived using the concept of ventricular arterial (VA) elastance coupling. Incorporating LVAD into the VA coupling indicates that LVAD support (COVAD) increases left ventricular (LV) afterload and decreases native CO (COLV). The total CO (COtotal) becomes COtotal=COLV+COVADEFe where EFe approximates ejection fraction. In contrast, LVAD does not change the VRS or right ventricular CO curve. Equilibrating the COtotal curve and VRS yields CO, PRA and PLA.Methods/ResultsIn 6 anesthetized, vagotomized dogs, we isolated the carotid sinuses to abolish baroreflex. We ligated coronary arteries to create LV failure and inserted LVAD. We changed COVAD stepwise from 0 to 100 ml/kg/min and predicted COtotal, PLA and PRA in each LVAD support. As shown, predicted COtotal, PLA and PRA quantitatively matched well with those measured.ConclusionThe proposed framework predicts the impact of LVAD on hemodynamics and thus contributes to the optimal management of patents on LVAD.
AMENDMENT AND VENTRICULAR HYPERTROPHY IN CALCIUM HOMEOSTASIS AS A MECHANISM OF CARDIAC DYSFUNCTION IN THE EVOLUTION OF HYPERTENSION AND AGING
Authors: Pereira Elenize Jamas , Leopoldo Ana Paula Lima , Matsubara Beatriz Bojikian , Matsubara Luiz Shiguero 
Published: June 2021

INTRODUCTIONThe arterial hypertrophy, and aging are factors that promote ventricular dysfunction and consequently heart failure.OBJECTIVEEvaluate cardiac function in the presence of hypertension and aging and their interaction with hypertrophy and mRNA expression of regulatory proteins of Calcium homeostasis.MATERIAL AND METHODSWe studied 60 spontaneously hypertensive rats (SHR) and 50 non‐hypertensive rats (WKY) were divided into groups of 30, 45, 60 and 90 weeks of age. Four animals from each group were used only for the analysis of RNA by RT‐PCR.Ventricular function (RPVs and RPVd) was studied in isolated heart Langendorff technique. A curved sectional myocyte (Area cel) and collagen volume fraction (CVF) was measured in slides stained with HE and Sirius red Picro respectively.The variables were analyzed by 2‐way ANOVA considering factors strain (SHR, WKY) and age. The association between age and the variables was analyzed by Spearman correlation test The significance level was p <005.RESULTSThere was a statistically significant difference between SHR and WKY in the studied variables except for Log PVdiast, phospholamban and RyanodineSignificant correlations were observed between age and SBP (SHR r = 0.53, p <0.012, FVC (r WKY = 0.55, p = 0.001).Area Cel (SHR r = 0.70, p = 0.001, r WKY = 0.543, p = 0.001), second Serca (WKY r = 0.73, p = 0.008 and phospholamban (WKY r = 0.60 p = 0, 04).CONCLUSIONIn aging there is increased cell area, independent of hypertension and decreased systolic function and decreased phospholamban and SERCA2a mRNA in animals, not hypertensive.The mechanical stress secondary to HA alters calcium homeostasis by promoting instead hypertrophy of ventricular contractile function.
Effects of GLP‐1 receptor agonist on Ca2+ handling in coronary smooth muscle cells from metabolic syndrome Ossabaw swine with coronary artery disease
Authors: Lee McKenney Mikaela , Suh Daniel , Martin John , Alloosh Mouhamad , Schultz Kyle , Sturek Michael 
Published: June 2021

Chronic effects of glucagon‐like peptide (GLP‐1) receptor agonists were studied in Ossabaw swine with metabolic syndrome (MetS). MetS was induced by hypercaloric atherogenic diet for 6 months. Subcutaneous injections were given twice daily for 6 months after induction of MetS. Consistent with clinical effects, food consumption and weight gain were attenuated. MetS increases coronary artery disease (CAD) and coronary smooth muscle (CSM) Ca2+ dysfunction. CSM cells were isolated enzymatically from the coronary arteries and Ca2+ was digitally imaged with fluorescent fura‐2. In normal physiological salt solution we released sarcoplasmic reticulum (SR) stores with caffeine. Treated cells showed a larger Ca2+ transient, ΔF360/380=0.26±0.02, compared to placebo cells, ΔF360/380=0.16±0.01 (p<0.001). In lean CSM, acute exposure to exenatide markedly increased activity of the sarcoplasmic‐endoplasmic reticulum Ca2+ ATPase (SERCA). This activity was confirmed by cyclopizaonic acid block. The increased SERCA activity may explain increased SR Ca2+ store in chronic MetS CSM. Acute exposure of placebo MetS CSM to exenatide has shown no effect on SERCA activity (n=43). Evidence for myocardial resistance to GLP‐1 in MetS is consistent with the lack of acute response. Our interpretation is that chronic exposure attenuates the decline in CSM Ca2+ handling associated with more severe CAD and dedifferentiation of CSM.(Support: NIH HL062552, TL1 TR000162, Amylin Pharmaceuticals Inc.)
Investigation of Bisphenol A administration on skeletal muscle force generation in mice
Authors: Benson Marisa C , Liang Chen , Receno Candace N , DeRuisseau Keith C 
Published: June 2021

Bisphenol A (BPA) is a chemical used in the manufacturing of numerous products including plastics and food‐contact materials and is classified as an endocrine disruptor because it can mimic actions of estrogen in the body. The purpose of this study was to examine BPA effects on muscle force generation since estrogen may influence muscle contractile properties. Eight‐week old male CD‐1 mice were housed in polypropylene cages and provided a soybean oil‐free diet (AIN‐93G) (control; C) for two weeks. Thereafter, animals were randomly assigned to C (n=5), C+BPA (BPA; 50 mg BPA/kg diet; n=4), or C+ethinyl estradiol (EE; 0.1 ppb; n=5) diets for one month. Soleus muscles were harvested for measurement of twitch and tetanic force generation (N/cm2) in vitro. Peak twitch tension of EE (3.5±0.1) was greater (p<0.05) than BPA (2.6±0.1) and C (2.8±0.2). Peak tetanic tension of EE (24.8±1.2) was greater (p<0.05) than BPA (19.2±0.7) but was similar (p>;0.05) to C (22.31±0.3). Soleus force generation between BPA and C was similar (p>;0.05). Post‐experiment animal body mass and soleus muscle mass did not differ between groups (p>;0.05). Preliminary findings revealed augmented force generation of the soleus following administration of EE, but not BPA. Therefore, BPA administration does not appear to influence twitch or maximal force generation of mouse soleus muscle.Supported by the Hill Collaboration on Environmental Medicine (KCD)
Extraocular muscles produce more non‐mitochondrial reactive oxygen species
Authors: Sims Lorrie , Garcia‐Cazarin Mary , Andrade Francisco 
Published: June 2021

Extraocular muscles (EOM) are constantly active, and have a high mitochondrial content. We previously showed that EOM mitochondria are different (Invest Ophthalmol Vis Sci 50:180–6, 2009). Here, we investigated this hypothesis: EOM mitochondria produce more reactive oxygen species (ROS) than mitochondria from other muscles. First, we measured ROS production in diaphragm muscle bundles and intact EOM, excised from adult male Sprague Dawley rats, and loaded with 2’,7’‐dichlorofluorescein‐diacetate (DCFH‐DA). Next, ROS generation was measured for 60 min with Amplex Red in respiring mitochondria from rat diaphragm, gastrocnemius, and EOM. Intact EOM oxidized more DCFH: 1532 ± 407 vs. 517 ± 77 arbitrary units (AU, mean ± SD), EOM and diaphragm, respectively, n=5 muscles, p=0.04. Amplex Red oxidation was not different in mitochondria from the 3 muscles during state 3 respiration (driven by glutamate/malate), inhibition of complex I with rotenone, or succinate‐driven respiration. EOM mitochondria oxidized less Amplex Red during succinate‐driven respiration combined with complex III inhibition using antimycin: 15570±2135, 13305±1020, 9502±1024 AU, diaphragm, gastrocnemius, and EOM respectively; p=0.0009, n=4 rats). These results show that intact EOM generated ROS faster than diaphragm bundles. However, EOM mitochondria did not produce more ROS than mitochondria from other muscles. Therefore, we reject our initial hypothesis, and propose that the higher rate of ROS production in EOM originates from non‐mitochondrial sources.*Research supported by APS Undergraduate Research Fellowship 2012
Energy restriction blocks bone marrow dendritic cell development
Authors: Duriancik David M. , Clinthorne Jonathan F , Gardner Elizabeth M 
Published: June 2021

Dendritic cells (DC) are antigen presenting cells and sensitive to nutritional modulation. Energy restriction (ER) is a nutritional intervention shown to extend lifespan in many experimental organisms, but recent data in non‐human primates is contradictory. Immunological outcomes of ER are mixed with several reports demonstrating ER amelioration of autoimmune disease, but ER mice are also more susceptible to some primary infections such as influenza. Due to glucocorticoid‐associated increased myelopoiesis, we hypothesized bone marrow DC development would be increased. The objective of this study was to determine the effects of ER on bone marrow DC progenitor numbers. Multicolor flow cytometry was used to characterize bone marrow DC progenitors. We observed increased myeloid progenitors and monocytes, while common DC progenitors and precursor DC were decreased in bone marrow of ER mice. Altered progenitor populations had no effect on in vitro DC development. Therefore we conclude ER bone marrow microenvironment is altered favoring myelopoiesis over lymphopoiesis, but myelopoiesis is also altered. The altered developmental pathway of DC subsets may be responsible for contradictory immunological outcomes of ER populations and provide potential targets for improving vaccination, autoimmune conditions, and infectious disease.Grant Funding Source: NIA R01AG034949 to EMG
Calcium and vitamin D supplements do not prevent loss of bone mineral density in women undergoing therapy for breast cancer
Authors: Datta Mridul , Schwartz Gary G 
Published: June 2021

Women with breast cancer (BC) are at an increased risk of osteoporosis due to accelerated bone loss caused by BC therapies. Since calcium &/or vitamin D (Ca±D) are frequently recommended for osteoporosis prevention & management to women undergoing BC therapy, we examined the effects of Ca±D supplements in preventing bone loss in these women. We reviewed guidelines for Ca±D supplementation in women with BC & conducted a systematic review of Ca±D supplementation trials in maintaining skeletal health in women with BC. We used the “before‐after” data from the comparison groups of trials that evaluated the effect of drugs such as bisphosphonates on bone mineral density (BMD) in which Ca±D were used as the comparison group. The effect of Ca±D supplements on BMD in women with BC undergoing BC therapy has not been tested against an unsupplemented control group. However, results from 15 trials of “before‐after” comparison indicate that supplements of 500 – 1500 mg calcium & 200 – 1000 IU vitamin D were inadequate to prevent loss of BMD in women with BC. Mean loss of BMD at the lumbar spine in pre‐ & postmenopausal women was −5.6% & −2.3%. Additionally, other evidence indicates that both BC therapies & calcium supplements may increase the risk of cardiovascular disease. Because cardiovascular disease is the main cause of mortality in women with BC, future trials should evaluate the safety & efficacy of Ca±D supplementation in these women.Grant Funding Source: Dr. Datta is supported by the Comprehensive Cancer Center of Wake Forest University Cancer Control Traineeship – NCI/NIH Grant# #R25CA122061
Obesity acclerates pancreatic tumor growth and increases the accummulation of myeloid derived suppressor cells
Authors: Collins Shawntawnee , Turbitt William J. , Rogers Connie J. 
Published: June 2021

Obesity increases the risk of several solid tumors, including pancreatic cancer. One mechanism underlying the obesity‐induced increase in tumor incidence may be an obesity‐induced increase in tumor‐derived immunosuppressive factors. Thus, the goal of the current study was to evaluate the effect of diet‐induced obesity on pancreatic tumor growth, survival and the emergence of myeloid derived suppressor cells (MDSC). MDSC inhibit anti‐tumor immunity, and expand significantly as a result of numerous tumor‐derived inflammatory signals commonly elevated in obesity. C57BL/6 mice (n=8/gr) were fed either a 30% calorie restricted diet; a 10% kcal from fat diet fed ad libitum; or a 60% kcal from fat diet fed ad libitum to generate lean, control and obese mice, respectively. Mice were injected with 1 ×106 Panc02 pancreatic tumor cells after 8 weeks on each diet. Obese mice had significantly greater tumor volumes beginning at day 25 post‐tumor implantation (P<0.05), and reduced median survival as compared to lean animals (77.5 vs. 61.5 days; P<0.05). Obese mice also accumulated significantly greater number of MDSC in the spleen as compared to lean animals (87.7± 50.5 ×106 vs. 25±3.5 ×106;P<0.05). These results demonstrate that obesity accelerates pancreatic tumor growth concurrently with an increase in immunosuppressive MDSCs. Future studies will explore possible mediators of obesity‐induced MDSC accumulation.Grant Funding Source: Pennsylvania State University Internal Funding
Predicting lower extremity pain based on foot morphology and computerized gait analysis in obese children
Authors: Wong William W , Ross Jeffrey A , Abrams Stephanie H , Barlow Sarah E , Klish William J 
Published: June 2021

Promoting physical activity is a key component of all childhood obesity intervention programs. Unfortunately, physical activity puts greater strain on the musculoskeletal system. Obese children may have altered foot morphology and gait instability, which may interfere with physical activities. We assessed the foot morphology and gait among 40 obese children (11.4±1.4 y; 75% female; 17 white, 5 black, 18 Hispanic) who enrolled in a summer camp program. The assessment was done visually and using a pressure mapping MatScan System. Each child was rated for risk of lower‐extremity pain on the first 2 days of camp.ResultsPronation was diagnosed in 93% of the children. Adducted gait, pes planus and genu vaglum were each present in half of the children. Approximately 65% of children reported lower extremity pain at camp. The prediction of risk showed significant agreement (Kappa = 0.624, p<0.01) with pain. BMI z‐scores decreased less at the end of the 2‐week camp among children who reported lower‐body musculoskeletal pain (−0.101±0.352) than children who reported no pain (−0.118±0.352, p=0.12).ConclusionWe hypothesize that treating altered foot morphology and gait instability with supportive shoes, accommodative insoles, and/or prescription insoles might present an effective approach to prevent pain and overuse injuries and thereby encourage physical activity among obese children. USDA/ARS 6250–51000‐053.
Spirulina platensis inhibits lipopolysaccharide‐induced inflammation through the repression of histone deacetylases in RAW 264.7 macrophages
Authors: Pham Tho Xuan , Kim Bohkyung , Lee Jiyoung 
Published: June 2021

We observed a potent anti‐inflammatory effect of Spirulina platensis (SP), an edible blue‐green alga, in vitro and ex vivo. To gain a mechanistic insight into the anti‐inflammatory effect of SP organic extract (SPE), we examined the effect of SPE on the expression of histone deacetylases (HDAC) 1 to 11 in lipopolysaccharide (LPS)‐activated RAW 264.7 macrophages. When macrophages were treated with LPS alone (100 ng/ml), SPE alone (100 μg/ml), or SPE+LPS, mRNA and protein levels of most HDAC isoforms were significantly decreased. However, one striking difference was that HDAC1 and HDAC3 protein levels were markedly decreased by SPE but LPS had a minimal effect. The potent repression of HDAC by SPE was evidenced by a marked increase in histone 3 acetylation to a similar extent to that of 25 nM trichostatin A (TSA), a pan HDAC inhibitor. When LPSactivated macrophages were treated with TSA (25 nM), proinflammatory cytokine expression including tumor necrosis factor α and interleukin 1β was significantly decreased but the reduction was less than that of SPE (50 or 100 μg/ml). The repressive effect of SPE on HDAC is likely cell type‐specific because this effect was also observed in 3T3‐L1 preadipocytes but not in HepG2 and Caco‐2 cells. In conclusion, SPE exerts its anti‐inflammatory effect at least in part by a HDAC‐dependent mechanism via the repression of HDAC1 and HDAC3 in macrophages.Grant Funding Source: NIH R21AT005152
Fat Embolism Syndrome Following Bone Fracture May Be Exacerbated By LPS
Authors: Molteni Agostino , Torres‐Romero Luis , Black Elizabeth , Friedrich Jessie , Tanner J. Chris , Poisner Alan , Herndon Betty 
Published: June 2021

Fat embolism (FES) after major bone fracture may lead to acute respiratory distress but little clinical evidence of lung injury remains. However, a study of patients with severe fractures showed reduced pulmonary function many years post‐injury. In rats modeling FES by i.v. triolein, we saw that despite an apparent full recovery, modest fibrotic damage persisted up to 6 weeks. We tested whether at that time an additional insult could exacerbate the lung effects. The model was established with 0.2 mL triolein i.v. to 18 rats and saline to 18 controls. Six weeks later, each group received (i.p.) lipopolysaccharide (LPS) n=9 or saline n=9. At necropsy 48 hr later BALs, lungs and organs were harvested for study. Lung parenchymal, vascular and bronchial damage was scored by 3 pathologists. Saline controls receiving LPS showed pulmonary arterial medial diameters wider than those of animals given triolein before LPS (p<0.04). Adventitia of lung vessels from triolein treated rats showed a significant difference between saline vs. LPS administration (p<0.02). LPS produced a threefold increase in PMN in BAL. At 6 weeks triolein droplets remained in rat lungs localizing to the subpleural septa, smaller and more widespread when LPS was given. Thus, LPS, a “second hit”, administered after triolein FES model produces a more severe lung damage to pulmonary arteries than does LPS following saline.Funded: Gelmacher Foundation
Somatic genome alterations in triple‐negative breast cancer
Authors: Meyerson Matthew 
Published: June 2021

Breast cancer is the most common cause of cancer in women in the United States. Within breast cancer, the “triple‐negative” subtype, which is negative for estrogen receptor and progesterone receptor expression and negative for ERBB2 amplification, is the most deadly and has the fewest targeted therapies. Triple‐negative breast cancer occurs more commonly in young women and in women of African‐American descent.Identification of somatic genome alterations in cancer has led to development of many targeted therapies. To find such alterations in triple‐negative breasst cancer, we and others have performed systematic high‐throughput sequencing of genomes, exomes, and transcriptomes of these cancers. Here, I will discuss results from our studies, including AKT3 translocation in breast cancer, from The Cancer Genome Atlas, and other studies.
Problem solving in biochemistry: assessment, learning strategies, and preconceptions
Authors: Sensibaugh Cheryl A. , Osgood Marcy P. 
Published: June 2021

Discipline‐based education research has produced varied perspectives on defining and assessing scientific problem solving. The goals of this dissertation work are to describe and explain longitudinal performance gaps across a two‐year biochemistry curriculum, as well as to synthesize a more advanced pedagogical understanding of scientific problem solving from previously fragmented sources. Student performance will be measured using the Individual Problem Solving Assessment (IPSA), and achievement rates in each domain of problem solving will describe longitudinal performance. The results of a pilot study indicate that after the first year of the curriculum, domain achievement rates for students pursuing a B.S. in Biochemistry range from 9% to 64%. To explain performance gaps, potential contributors will also be investigated, using two additional measures that reflect alternate views of problem solving. The impact of our corresponding problem‐based learning strategies will also be evaluated. Multivariate multiple linear regression analyses will be used to generate quantitative models of the performance phenomena. Additionally, students’ preconceptions about problem solving are being identified. This study will ultimately elucidate connections among emerging theories of defining and assessing scientific problem solving.Research support is provided under NSF TUES Award #DUE‐1043079.