bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role for RUNX2/HDAC6 Axis in Pulmonary Arterial Hypertension
Authors: Ruffenach Grégoire , Chabot Sophie , Potus Francois , Tanguay Virginie , Vaillancourt Mylène , Tremblay Ève , Breuils‐Bonnet Sandra , Provencher Steeve , Bonnet Sébastien 
Published: June 2021

IntroductionPulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation, migration, calcification and suppressed apoptosis. Numerous biological pathways have been implicated in this phenotype, including HIF‐1α. Recent studies have shown that miR‐204 downregulation upregulates the expression of RUNX2. RUNX2 is implicated in many features seen in PAH‐PASMC in part through the activation of HIF‐1α by a HDAC6‐depepdent mechanism. Thus we hypothesis that miR‐204‐dependent upregulation of RUNX2/HDAC6 axis promotes HIF‐1α and development of PAH.ResultsUsing human lungs, distal PAs and isolated PASMC from both control and PAH patients, we demonstrated a significant upregulation of RUNX2 and HDAC6 in PAH. Gain and loss of functions experiments in PASMC showed that downregulation of miR‐204 in controls PASMC increase RUNX2 expression, while increases miR‐204 in PAH‐PASMC decrease it. In controls PASMC, RUNX2 upregulation increases calcification,migration, proliferation, resistance to apoptosis through an HDAC6 and HIF‐1α dependent mechanism, as both tubastatin A (HDAC6 inhibitor) and siHIF‐1α blocks RUNX2 effects. Similarly in PAH‐PASMC siRUNX2 has the opposite effects. Finally, in sugen/hypoxia rat model of PAH, nebulization of siRUNX2 decreased mean PA pressure, pulmonary vascular resistance and increased compliance and cardiac output.ConclusionTaken together, our study uncovers a new miR‐204 dependent up regulation of RUNX2/HDAC6 axis contributing to calcification and to normoxic activation of HIF‐1α leading to proliferation, migration and resistance to apoptosis in PAH‐PASMC.
Lung ACE is Not Involved in The Progression of Pulmonary Arterial Hypertension
Authors: Joshi Sachindra , Gupte Sachin 
Published: June 2021

RationaleAlthough ACE–Ang II–AT1R axis has been well documented in promoting vasoconstriction, proliferation, and fibrosis‐the hallmarks of pulmonary arterial hypertension (PAH), the role of lung ACE in the progression of PAH is not clear. Pharmacological inhibition of ACE to effectively attenuate the progression of PAH has been ambiguous. Therefore, we sought to determine if knocking out lung ACE would prevent the progression of PAH.MethodsTo test this hypothesis we evaluated development of PAH in ACE knock‐out (ACE.3) and wild type C57BL mice using Sugen 5416‐Hypoxia PAH model. Wild type and ACE knock‐out mice were exposed to 3 weeks of normoxia or chronic hypoxia and simultaneously administered the sugen 5416 at 0, 1, and 3 weeks. Pulmonary artery acceleration time (PAAT) was measured by transthoracic echocardiography on week 0 and week 3. Right ventricular hypertrophy was assessed by taking the RV/LV+S weight. Cardiac function was assessed by left heart catheterization using Millar 1.4 F catheter. Pulmonary arteriopathy was assessed from hematoxylin and eosin stained formalin fixed paraffin embedded lung sections.ResultsSignificant decrease in PAAT in sugen hypoxia wild type and ACE knock‐out compared to vehicle or sugen normoxia control was similar. The degree of right ventricular hypertrophy in sugen hypoxia ACE knock‐out and wild type was not different. Decreased cardiac output between sugen hypoxia wild type and the ACE knock‐out was similar. The arteriopathy in sugen hypoxia wild type and ACE knock‐out were also similar, which included medial thickening, occlusive lesions and plexiform‐like lesions.ConclusionIt appears that lung ACE may not be involved in the progression of the PAH.
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Regulation of Sodium/bicarbonate Co‐transporter 1, NBCe1, in Murine Hippocampal and Cortical Astrocytes
Authors: Schroedl Magdalena , Roussa Eleni 
Published: June 2021

The product of the Slc4a4 gene, the Na+/HCO3‐ cotransporter 1 (NBCe1), is a key pH regulating plasma membrane transporter and broadly expressed in several cell types. It is well established that depolarization‐induced alkalinization of glial cells is ascribed to uptake of bicarbonate via the electrogenic NBCe1, activated by the K+‐induced membrane <a>depolarization</a>. However, in contrast to epithelial cells the molecular pathways underlying NBCe1 transcriptional regulation and trafficking in neural cells are largely unknown. In the present study we examined regulation of astrocyte NBCe1 and elucidated the underlying signalling pathways. Expression, regulation, and activity of NBCe1 was examined in acute hippocampal slices and primary cultured hippocampal and cortical astrocytes using the 4AP (4‐aminopyridine) model and following extracellular pH changes in the presence or absence of inhibitors for Src, ERK, and JNK signalling pathways.The results show upregulation of NBCe1 mRNA level, protein abundance, and surface expression in hippocampal slices after 4‐AP treatment, effects that were abolished following inhibition of JNK signalling pathway. Increased membrane expression of NBCe1 was also prevented after inhibition of Src/ERK signalling. In cultured hippocampal and cortical astrocytes, 4AP treatment and extracellular alkalosis caused activation of astrocytes and increased surface NBCe1 protein.These data demonstrate regulation of NBCe1 transcript and surface expression, via Src/ERK and JNK signalling pathways.
Microbiological Investigation of Waters of Lake Përlepnica durnig Winter Season 2013
Authors: Ismaili Muharrem , Rashiti Fahrie , Kurteshi Yll , Sahiti Naim 
Published: June 2021

AbstractPhysicochemical and bacteriological analyses were carried out on lake water, used for drinking and swimming purposes in Përlepnica nearby Gjilani city, Kosovo.The objective of this study is to assess the quality of water, of the Lake Përlepnica during winter season, 2013 year, through the microbiological analysis.None of the samples complied with bacteriological standards as Total coliform counts generally exceeded 1,600 MPN/ml, and pathogen count such as Salmonella‐Shigella counts counts were very high.Based on achieving results led us to conclude: The waters of Llake Përlepnica are high polluted by bacteria at all investigated localities(3).
Analysis of the Stapes of Krapina Neandertals
Authors: Hill Cheryl , Radovcic Jakov , Frayer David , McGechie Faye 
Published: June 2021

Auditory ossicles are found rarely in the fossil hominid record, but the available ossicles allow for some inferences about the hearing abilities of fossil hominids. Previously three Neandertal stapes in varying degrees of preservation have been described. Two complete stapes have been identified in computed tomography scans of the temporal bones of Neandertals from the Krapina site in Croatia. The purpose of this project is to complete a descriptive and quantitative analysis of the stapes from Krapina to compare them to the stapes of other extant and fossil hominids.The sample consists of three‐dimensional reconstructions of the stapes from the Krapina site (N=2). Height of the stapes, length of the crura, and the dimensions of the stapedal foot plate were acquired for each stapes reconstruction using Avizo software. These dimensions were compared to previously published values for extant and fossil hominids.The analysis indicates that the stapes from the Krapina site show asymmetry of the crura. The measured height of the stapes and the size of the stapedal footplate are smaller than recent H. sapiens. These results suggest that Krapina Neandertals may have had increased low frequency sensitivity.
Macrophage mitochondrial energy status regulates cholesterol efflux and is enhanced by anti‐miR33 in atherosclerosis
Authors: Karunakaran D , Thrush B , Geoffrion M , Ramphos E , Nguygen M , Shangari P , Harper M , Moore K , Rayner K 
Published: June 2021

Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis and miR‐33 has emerged as novel regulator of cholesterol homeostasis. Cellular energy status can significantly influence macrophage function, and bioinformatic analysis predicts that miR‐33 represses a cluster of genes controlling energy metabolism that may contribute to macrophage cholesterol efflux. We hypothesize that miR‐33 represses mitochondria metabolic pathways to reduce cholesterol efflux. Here, we show that macrophage cholesterol efflux is regulated by mitochondrial ATP production and that miR‐33 controls a network of genes that synchronize mitochondrial function. Macrophage cholesterol efflux capacity was markedly reduced by ATP synthase inhibition, confirming the importance of mitochondria in the efflux of excess cholesterol. Specifically, anti‐miR33 derepressed the novel target genes PGC‐1α, PDK4 and SLC25A25 and boosted mitochondrial respiration and ATP production, and mitochondrial respiration was key to the pro‐efflux effects of anti‐miR33. Anti‐miR33 therapy in atherosclerotic Apoe‐/‐ mice reduced aortic sinus lesion area, despite no changes in HDL‐C. Also, this therapy increased expression of mitochondrial target genes in vivo, suggesting that the regulation of mitochondrial genetic networks occur in atherosclerotic lesions.ConclusionWe showed that anti‐miR33 therapy de‐represses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, promotes macrophage cholesterol efflux and reduces atherosclerosis.
Assembly and Application of Phospholipid Nanodiscs for the Study of P‐Glycoprotein
Authors: McClean Mindy , Brewer Frances , Wise John , Vogel Pia 
Published: June 2021

As many as 40% of recurring cancers often develop multidrug resistance (MDR) to chemotherapeutic treatment due to over‐expression of P‐glycoprotein (P‐gp), a member of the ABC transporter protein family. Our research has focused on finding inhibitors of P‐gp that are capable of re‐sensitizing MDR cancers to therapy. In order to investigate the mechanism of action of the discovered inhibitors, we employ electron spin resonance spectroscopy and biochemical assays. Due to the inherent instability of these mammalian membrane proteins, many of these analyses are challenging. We therefore are establishing nanodisc technology to incorporate and stabilize purified P‐gp for our drug finding and mechanistic studies. Nanodiscs are phospholipid bilayers contained within a membrane scaffold protein and mimic native membrane conditions. Initial studies indicated that a cysteine‐less mutant of the mouse MDR3 P‐gp could be incorporated into nanodiscs and showed enhanced catalytic activity and stability. We are currently establishing nanodiscs as a uniform platform from which different mutants of P‐pg can be closely studied and characterized. Nanodiscs may also enable us to utilize human MDR1 P‐gp in drug finding studies. This particular protein has been shown to be too unstable in micelle solution to be successfully used in these experiments.This work is supported by NIH NIGMS [Grant 1R15‐GM094771‐01A1] to PDV and JGW, SMU Research Council, Dean's Research Council, and CD4, and the Communities Foundation of Texas, Dallas. Undergraduate support was received from the Hamilton Family, Dallas, SMU Undergraduate Research Assistantship, and Engaged Learning Fellowship.
Biodiesel Production via Methanol Tolerant Lipase Transesterification from Proteus mirabilis in Methyl Acetate
Authors: Altier Jake , McDonnell Alaina , Carey Demetrius , Witherow Scott 
Published: June 2021

Recombinant lipase catalyzed biodiesel production is potentially more economically favorable and convenient than traditional acid/base methods. Possible advantages include less time spent, less energy required due to lower temperatures, less starting material and more efficiency if enzymes can be immobilized. A lipase from Proteus mirabilis (P. mirabilis) has been previously genetically engineered for methanol resistance and shown to be an effective catalyst for the transesterification reaction leading to the production of biodiesel in the form of fatty acid methyl esters. However, the enzyme has not previously characterized using the alternate acyl acceptor methyl acetate, which produces the fuel stabilizer triacetin as a byproduct of the reaction. These enzymes have been expressed in E. coli using a pET28 bacterial expression vector and purified using metal affinity chromatography. Subsequently, the enzymes have been kinetically characterized for transesterification activity in reactions using methyl acetate, using p‐nitrophenyl palmitate and synthetic triacylglycerides as substrates, at varying pHs and temperatures.Supported by a University of Tampa David Delo Research Professor Grant (DSW), a University of Tampa Dana Foundation Grant (DSW), and The University of Tampa Department of Chemistry, Biochemistry, and Physics (DSW, JA, AM)
MIEN1 drives breast cancer invasion by regulating cytoskeletal dynamics
Authors: Kpetemey Marilyne , Vishwanatha Jamboor 
Published: June 2021

IntroductionPreviously known as C35, C17orf37, RDX12 and MGC14832, MIEN1 is a novel gene located in the chromosomal region 17q12‐21. While absent or low in normal tissues, MIEN1 is abundantly expressed in multiple cancers including breast carcinomas. A membrane‐bound signaling adaptor, MIEN1 localizes to the leading edge of migrating cells and promotes migration and invasion by increasing filopodium formation. While MIEN1 is shown to promote motility through filopodia formation, little is known on the mechanisms by which MIEN1 influence the actin cytoskeleton. Exploring underlying mechanisms, we show that MIEN1 associates with the actin cytokeleton during motility and directly influence actin polymerization.MethodsWe performed immunofluorescence, migration and invasion assays using breast cancer cell lines, MDA‐MB 231 and MCF10CA1a to investigate the mechanisms by which MIEN1 potentiates cell motility.ResultsAblation of MIEN1 inhibited cell migration, cell adhesion and altered the phosphorylation status of motility markers. Immunofluorescence staining with FITC‐ conjugated‐phalladoin confirmed that alteration of MIEN1 expression leads to reconfiguration of the actin cytoskeleton in breast cancer cells. Furthermore we found that MIEN1 associates with cytoskeletal proteins involved in motility processes.ConclusionOur results show that MIEN1 is a critical regulator of cell migration and invasion. The importance of MIEN1 in tumor cell dissemination is well established; understanding the molecular mechanisms aiding the processes involved will enable the design of novel and effective treatments for metastatic tumors.
Testing Novel Depsipeptides for Histone Deacetylases Inhibitor Activity
Authors: Mitchell Caitlyn , Carle Sigrid , Enos Stephen , Miller Justin , Zang Xiaoyu , Vallabhaneni Deepak , Peraro Leila 
Published: June 2021

Gene expression is partly controlled by posttranscriptional modifications to histones. These modifications either loosen the binding between histones and DNA, allowing for transcription, or tighten the binding, which prevents transcription. Histone acetyltransferases (HATs) are responsible for histone acetylation, while histone deacetylases (HDACs) remove acetyl groups and are involved in gene silencing. HDAC activity is often upregulated in cancer cells, leading to the repression of several genes that normally prevent tumor formation. Due to the role of HDACs in cancer development and progression, HDAC inhibitors (HDACi) are promising treatments for several cancers. Furthermore, unlike many traditional chemotherapeutics, HDACi appear to have limited effect on normal cell growth and function.Cyclic, cysteine‐containing, depsipeptides are a promising class of HDACi. These HDACi require three major characteristics: a Lewis basic group that associates with the Zn2+ ion at the heart of the active site, a cyclic region that binds to the nonpolar amino acid residues at the rim of the active site channel, and a linker of four to seven atoms that connects the nonpolar region to the Lewis basic group, presumably mimicking the structure of lysine. We tested four analogs with altered cyclic regions.An MTT assay was used to measure cytotoxicity induced by each depsipetide on the histoiocytic lymphoma cell line, U937. Depsipeptides that were cytotoxic were investigated for their ability to induce apoptosis using a CaspACETM Assay. Most effective novel depsipeptides were those with smaller, nonpolar cyclic regions.
The Gut Microbiota for Health Experts Exchange: An Online Network for Sharing Knowledge
Authors: Enck Paul , Campbell Kristina , Tap Julien , Arnoux Pierre‐Yves , Antoine Jean‐Michel 
Published: June 2021

The gut microbiota is a topic with rising importance in the scientific community where communicating the science presents huge challenges. With studies emerging from all over the world, researchers may have difficulty knowing the context of their own research in this rapidly‐evolving field.One way toward more accurate communication is to create a network of experts on gut microbiota who collaboratively curate and critique recent work in the field.Gut Microbiota for Health is an initiative with 900 existing online community members, which include scientists, clinicians, journalists, institutional representatives, and members of the public. The growing worldwide network includes 1800 Twitter followers, 1800 LinkedIn members, and 2500 newsletter subscribers with a common interest in gut microbiota.Through social media, community members engage with the content and with each other. Clinicians can also integrate the latest scientific progress on gut microbiota into their practice with the help of the Gut Microbiota for Health e‐learning materials.Gut Microbiota for Health is driven by the Gut Microbiota and Health section of the European Society for Neurogastroenterology and Motility (ESNM), with the institutional support of Danone. It was created as the digital continuum of the Gut Microbiota for Health World Summit, whose 2014 program was organized in partnership with the American Gastroenterological Association.You are more than welcome to join this scientific community on www.gutmicrobiotaforhealth.com
Green Tea Consumption Reduces Oxidative DNA Damage and Lipid Peroxidation in Smokers and Non‐Smokers
Authors: Liu Yibin , Wang Zemin , Fly Alyce , Klaunig James 
Published: June 2021

Oxidative stress is associated with the pathogenesis of human diseases. Green tea reduces oxidative stress in animal models but effects in humans are equivocal. This study was conducted to examine the effects of green tea on biomarkers of oxidative stress and antioxidants in smokers and non‐smokers, using a placebo‐controlled, double‐blind crossover design. Fifteen non‐smokers and 12 smokers consumed 32 oz daily beverage of 2.75% green tea and placebo, each for 1 week, in random order. Blood and urine samples collected pre and post treatment were analyzed for 8‐hydroxydeoxyguanosine (8‐OHdG), malondialdehyde (MDA), glutathione (GSH), α‐tocopherol and ascorbic acid by HPLC. Differences between group means were examined by 3‐way ANOVA (α=0.05). Urinary and plasma MDA of smokers were significantly higher than non‐smokers (P=0.044, P=0.016). Urinary and lymphocyte 8‐OHdG were also higher in smokers, though not significantly (P=0.206, P=0.784). Urinary MDA, urinary and lymphocyte 8‐OHdG were reduced after green tea by 65.7%, 43.2% and 42.8%, respectively (P=0.0006, P=0.037, P=0.001). No changes were seen in plasma MDA, GSH, α‐tocopherol or ascorbic acid (P=0.931, P=0.611, P=0.323, P=0.963). Two groups of subjects (high versus low basal oxidative stress) were identified based on the median of each oxidative biomarker. Urinary MDA and lymphocyte 8‐OHdG in subjects with high basal oxidative stress were significantly reduced by 53.9% and 53.4% after green tea versus placebo (P=0.026, P=0.013); and urinary and plasma MDA were lowered by 47.2% and 13.7%, though not significantly (P=0.070, P=0.183). In conclusion, green tea consumption reduced oxidative DNA damage and lipid peroxidation in smokers and non‐smokers.Supported in part by internal IU funds.
Effects of Acute Dietary Nitrate Supplementation on Aortic Blood Pressure and Wave Reflection in Young and Older Adults
Authors: Treichler David , Ueda Kenichi , Ganger Charles , Schneider Aaron , Hughes William , Casey Daren 
Published: June 2021

Inorganic nitrate supplementation reduces peripheral blood pressure (BP) in several human populations. We examined whether acute nitrate supplementation decreases central aortic pressures and indices of wave reflection in young and older adults. In 13 young (25±1 yr, 10M/3F) and 12 older (64 ± 1yr, 9M/3F) normotensive adults, noninvasive aortic pressure waveforms were synthesized from high‐fidelity radial pressure waveforms via applanation tonometry before and following (60, 90, 120, 150, and 180 min) consumption of a nitrate rich beetroot juice (BR). Aortic BP and indices of aortic wave reflection (Augmentation Index; AIx and AIx normalized for heart rate; AIx@75bpm) were calculated from the generated aortic pressure waveform. Plasma nitrite concentration increased in both groups 60‐180 min following BR (P<0.001). Peripheral (Systolic: ~5mmHg; Diastolic: ~4mmHg) and aortic BP (Systolic: ~6mmHg; Diastolic: ~4mmHg) were reduced 90‐180min post BR in older (P<0.05), but not young adults. Conversely, AIx (3±3 vs ‐5±3%) and AIx@75bpm (‐6±3 vs ‐15±3%) were reduced in young adults 180 min post BR (P<0.05 for both). Whereas, AIx (28±3 vs 28±2%, P=1.0) and AIx@75bpm (21±3 vs 20±3%, P=0.99) did not change in the older adults. Our data suggest that acute dietary nitrate supplementation reduces central aortic BP in older adults, despite not altering indices of aortic wave reflection.Supported by ACSM Foundation
The Effects of Relative Exercise Intensity vs Individual Metabolism on LV Twist and Untwisting Rate
Authors: Stöhr Eric , Samuel Jake , Yarlett Andrew , Armstrong Craig 
Published: June 2021

Left ventricular twist and untwisting rate ('LV twist mechanics') are fundamental to cardiac function during exercise. However, studies have reported large inter‐individual variability in LV twist mechanics which complicates the interpretation of patient responses. To determine the source of variability in LV twist mechanics during exercise, this study aimed to examine whether LV twist mechanics respond more consistently to the same relative exercise intensity compared with exercise performed at individual anaerobic threshold (IAT). 16 healthy non‐endurance trained males (Age: 22±4 years, O2peak: 45.5±6.9 ml/min/kg, range of IAT: 32–69% of O2peak) were enrolled. Following assessment at rest, each volunteer performed short‐duration exercise at: i) the same relative exercise intensity, 40%peak, ii) at 2% above their IAT and iii) at 40%peak during hypoxia (FiO2=12%). No differences in LV volumes were observed during exercise conditions (p>0.05). However, LV twist mechanics responded more consistently during 40%peak compared with exercise at IAT (F‐ratio 2.080). When exercise at 40%peak was performed in hypoxia, LV twist mechanics increased (P<0.05) but the variability of responses remained similar to 40%peak in normoxia. Overall, LV twist mechanics were related to myocardial work. In conclusion, LV twist mechanics respond more consistently during exercise at the same relative intensity than IAT and diagnostic exercise tests in the clinical and research setting should be standardized accordingly. Importantly, the response during hypoxia suggests that the interpretation of LV twist mechanics must take into account the prevailing myocardial work, which may further improve the diagnostic accuracy.No external funding was required for this study.