bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cocaine‐Induced Lipidomic Alterations in Human Blood for the Study of Addictive Behaviors
Authors: Pati S. , Sahin S. , Wagner J.J. , Furnari M. , Phillips K.A. , Epstein D.H. , Preston K.L. , Cummings B S 
Published: June 2021

While a majority of cocaine research focuses on identification of therapies targeting dependence, few detection strategies exist to aid in clinical determination of susceptibility or likelihood of relapse. To enhance our understanding of the full spectrum of cocaine‐induced effects, we used a lipidomics approach to investigate the ability of cocaine to remodel the blood lipidome. Lipids were extracted from 190 human blood samples (123 drug users, 67 non‐users) and analyzed using electrospray ionization‐mass spectrometry. The resulting data were assessed using multivariate analysis, which indicated differences in the lipid profiles of drug users compared to non‐users. Identification of m/z features suggested alterations in glycerolipids, fatty acids, phosphatidylcholines, and phosphatidic acids. A subset of repeat abusers were asked to rate the positive and negative effects following their first cocaine exposure in comparison to their most recent use. These scores were used to assess the extent of enhanced rewarding and/or adverse effects of the drug, referred to as “sensitization”. Relative levels of several m/z features found to be significantly altered between the lipid profiles of sensitized and nonsensitized cocaine users correlated with positive and/or negative sensitization scores. These findings indicate a potential effect of cocaine on the blood, which could be exploited for the identification of lipid species correlating to the occurrence of cocaine‐induced responses and addictive behaviors in humans.*This work was sponsored in part by the National Institute on Drug Abuse (NIDA), Intramural Research Program, National Institutes of Health (NIH).
Biventricular Differences in β‐adrenergic Receptor Signaling Following Burn Injury
Authors: Guillory Ashley , El Ayadi Amina , Mifflin Randy , Herndon David , Finnerty Celeste 
Published: June 2021

Burn injury has been shown to have detrimental effects on the myocardium primarily due to over‐activation of β‐adrenergic receptors (β‐AR). Autopsy reports from our institution reveal that patients often suffer from right ventricle (RV) failure. Since burn injury affects β‐AR signaling in the left ventricle (LV), we proposed that β‐AR signaling may also be altered in the RV.We used a rat model of 60% total body surface area burn. Ventricles were isolated at 7 days post‐burn. We examined the expression of β‐ARs and downstream proteins via Western blotting. cAMP production and PKA activity were measured in membrane and cytosolic fractions, respectively, using enzyme immunoassay kits.β1‐AR expression was significantly increased in the RV following burn injury compared to non‐burned RV but remained normal in the LV (p=0.0002). Similarly, Gαs expression was increased in the RV post‐burn but not in the LV (p=0.04). There were no differences in β2‐AR expression among the groups. Gαi expression was significantly higher in the LV post‐burn compared to non‐burned LV, burned RV and non‐burned RV (p<0.0001). Similarly, cAMP production and PKA activity were significantly lower in the LV post‐burn compared to non‐burned LV, burned RV and non‐burned RV (p=0.0063, 0.0042, respectively).These data indicate that burn injury affects the β‐AR signaling pathway in the RV independently of the LV. Additionally, non‐canonical β‐AR signaling may be involved as cAMP production and PKA activity were unchanged.This study was supported by grants from the National Institutes of Health (P50‐GM60338, KL2RR029875, UL1RR029876) and Shriners Hospital for Children (80100, 84291, 80500, 84202, 71001).
TUG Mediates GLUT4 Translocation by AMP‐Activated Protein Kinase in the Heart
Authors: Ma Yina , Wang Jinli , Wang Yanqing , Bogan Jonathan , Li Ji 
Published: June 2021

IntroductionIschemic heart disease, is mainly caused by reduced nutrient availability. Increasing nutrient uptake becomes a key approach to improve cardiomyocyte survival during the ischemia and reperfusion (I/R) period. TUG (tether containing a UBX domain, for GLUT4, 60 KDa) is a regulator of GLUT4 trafficking, which is cleaved to mobilize GLUT4 from intracellular compartments to the cell surface. The energy sensor AMP‐activated protein kinase (AMPK) is known to play an important cardioprotective role during myocardial I/R by regulating GLUT4 translocation. Antithrombin (AT) exhibits a cardioprotective function severed as AMPK activator. HypothesisTUG is one of the downstream targets of AMPK, which can be phosphorylated by hypoxia/ischemia‐induced as well as AT‐induced AMPK activation. MethodsIn vitro hypoxia chamber and in vivo I/R models were used to analyze AMPK/TUG interactions. Ex vivo isolated mouse heart perfusion Langendorff system was used to measure glucose metabolism. ResultsIn HL‐1 cardiomyocytes, TUG proteins were phosphorylated by activated AMPK during hypoxia. Moreover, TUG siRNA knockdown the TUG of HL‐1 cells caused significantly increased cell surface GLUT4 and glucose uptake. The ex vivo heart perfusion data demonstrated that AT triggered AMPK activation and significantly increase glucose uptake and GLUT4 translocation during I/R. Moreover, AT treatment increased abundance of a TUG cleavage product (42KDa) in response to I/R. All of these glucose transporter events are blunted in the AMPK kinase dead transgenic hearts. ConclusionsCardiac AMPK activation via AT during the I/R period stimulates TUG cleavage and causes the dissociation between TUG and GLUT4, followed by the enhanced glucose uptake.
Revisiting the Promethean Dream: The Role of Activation‐induced Cytidine Deaminase in the Induction to Pluripotency
Authors: Chakraborty Ritayan , Chaudhuri Jayanta 
Published: June 2021

Upon encountering antigens in the germinal centers of peripheral lymphoid organs, mature B‐lymphocytes undergo class switch recombination (CSR). CSR alters B cell expression between different immunoglobulin types. This mechanism requires activation induced cytidine deaminase (AID). However, recent speculation into AID activity has led to the conclusion that AID can function as an indirect demethylase.The aim of the experiment is the elucidation of AID's molecular mechanism during the development of induced pluripotent stem cells (iPSCs). We hypothesize that when a cocktail of 4 transcription factors Oct4, Klf4, Sox2 and cMyc are introduced into fully differentiated cells using a retroviral vector, the cell undergoes a reprogramming process that promotes its conversion to an iPSC. AID is thought to mediate this conversion. Using recombinant mice for AID mutations and chemically transfecting the retroviral cassette with Polybrene, AID expression was tested via Flow Cytometry and Western Blotting. Results with an LSRFortessa X‐20 Cell Analyzer and Zeiss Confocal lens microscope at 150x. The results indicated that upon infection with OKSM factors only AIDpositive cells began reprogramming showing certain early pluripotent factors and a down‐regulation of CSR while AID knockout cells failed to maintain the pluripotent state for an extended period of time.
Differential responses in brachial and ankle blood pressure during blood pressure reactivity tests
Authors: Pearman Miriam , Lim Ji Sok , Park Wonil , Alkatan Mohammed , Machin Daniel , Tanaka Hirofumi 
Published: June 2021

Blood pressure (BP) reactivity has been assessed by a variety of stimuli, including physical, psychological, and physiological perturbations, that can be further classified into cardiac or vascular in regard to the effector organs. In many BP reactivity studies, changes in brachial BP are taken as systemic changes and are combined with leg measurements to assess vasoactive states. Currently, it is unknown if leg BP behaves similarly to arm BP.PurposeWe compared BP changes between the brachial and post‐tibial arteries during acute BP perturbations.MethodsThirty apparently healthy subjects (57% males, 46±4 years) were studied. Both brachial and ankle systolic BP (SBP) were measured simultaneously with the oscillometric technique during resting baseline, head‐up tilt (HUT), head‐down tilt (HDT), mental stress (MS), isometric hand‐grip exercise (HG), and a cold pressor test (CPT).ResultsBrachial (bSBP) and ankle (aSBP) SBP at rest were significantly and highly correlated (r=0.81). Changes in bSBP were significantly and positively associated with changes in aSBP in response to HUT (r=0.46), HDT (r=0.53), MS (r=0.70), HG (r=0.63), and CPT (r=0.75). The magnitudes of bSBP and aSBP changes were not different n response to MS, HG, and CPT since all were within 5 mmHG. There were significant differences in the magnitude of changes in bSBP and aSBP in response to HDT (12±1 mmHg) and HUT (40±2 mmHg).ConclusionBoth brachial and ankle BP respond similarly in many vascular reactivity maneuvers. During head‐down and head‐up tilt, however, differences in their responses may be quite large, presumably due to the hydrostatic pressure gradients created during the maneuvers.Supported by Fukuda Denshi.
Loss of CD47 Attenuates Angiotensin II Mediated Hypertension
Authors: Mutchler Stephanie , Isenberg Jeffery , Straub Adam 
Published: June 2021

CD47 plays a role in vascular reactivity by inhibiting both nitric oxide (NO) production and signaling. Because altered NO signaling is implicated in cardiovascular disease and hypertension, we explored the role of CD47 in the development of angiotensin II (AngII) mediated hypertension. In anesthetized CD47‐/‐ mice, AngII injection failed to elicit the increase in blood pressure seen in a WT mouse. Expression of the AT1R receptor was measured in homogenized vessels via Western blotting, and it was determined that levels were not significantly different between WT and knockout animals, suggesting decreased response was not due to lack of receptor availability. To further characterize this lack of response, isolated TDAs from both WT and CD47‐/‐ mice were cannulated and pressurized. Vessel diameter was assessed in response to increasing doses of AngII. Unexpectedly, we found that vessels from CD47‐/‐ mice displayed decreased sensitivity to AngII‐mediated vasoconstriction compared to WT vessels. Constriction to KCl was similar in vessels from WT and CD47‐/‐ animals, demonstrating that the contractile mechanism was still fully intact in the knockout animal. Taken together, this data suggests CD47 is important for AngII‐mediated vasoconstriction and therefore has the ability to effect systemic tone and blood pressure. We are actively investigating the molecular mechanisms governing this relationship, and plan to explore blood pressure in conscious animals via radiotelemetry units as well as whether germ line CD47 deletion and therapeutic blockade of CD47 protects against AngII‐induced organ remodeling in the heart and kidneys.Source: NIH R00 HL‐11290402, NIH R01 HL‐108954
ASK1 deficiency attenuates hyperoxia‐induced inflammation and cell apoptosis in the lung
Authors: Fukumoto Jutaro , Hosseinian Nima , Priyanshi Patel , Cho Young , R. Cox Ruan , Lakshimi Galam , Soundararajan Ramani , F. Lockey Richard , Kolliputi Narasaiah 
Published: June 2021

RationaleApoptosis signal‐regulating kinase 1 (ASK1), a member of the MAPK kinase (MAP3K) family, is activated by various stimuli including oxidative stress, ER stress, and DNA damage. Inspiration of high oxygen fraction is a palliative therapy to counteract acute lung injury (ALI). Our previous data indicates that ASK1 plays a critical role in this process. However, it is unclear whether or not deletion of ASK1 in vivo protects against HALI. We investigated whether ASK1 deletion would lead to protection against HALI.MethodsASK1 KO mice and control littermates were exposed to 100% oxygen for 48‐72 hours and euthanized to collect bronchoalveolar lavage (BAL) fluid for cell counts and cytokine measurements, and lung tissue collected for assessment of lung epithelial cell apoptosis.ResultsBAL fluid analysis revealed a significant decrease in IL‐1β level in KO mice. Differential cell count shows suppressed inflammatory cell infiltration in KO mice. Lung epithelial cell apoptosis was attenuated in ASK1 KO mice compared to WT mice as determined by TUNEL staining. Moreover, ASK1 KO mice exhibited significant increase in protein concentration in BAL fluid.ConclusionASK1 has a proinflammatory profile. Meanwhile, the permeability increase was observed in ASK1 KO mice which indicate that hyperoxia‐induced increase in permeability is independent of ASK1. Our data suggest that ASK1 can be a novel molecular target for ALI treatment.Funding source: This work was funded by the American Heart Association National Scientist Development Grant 09SDG2260957 and National Institutes of Health R01 HL105932 and the Joy McCann Culverhouse Endowment to the Division of Allergy and Immunology.
Anti‐aging Gene Klotho Deficiency Causes Arterial Calcification via Activating the Bone Morphogenetic Protein Signaling
Authors: Lin Yi , Sun Zhongjie 
Published: June 2021

BackgroundArterial calcification is an important risk factor for arterial stiffening, hypertension, stroke, and coronary heart disease. Klotho‐deficient mice display severe arterial calcification but the mechanism remains to be determined.Methods & ResultsWe found that Klotho‐deficient mice developed elastin fiber fragmentation and smooth muscle cell (SMC) apoptosis and arterial calcification. Aortas of Klotho (‐/‐) mice demonstrate higher levels of bone morphogenetic proteins (BMP2 and BMP4) and runt‐related transcription factor 2 (RUNX2, a key transcription factor for bone formation). Given that Klotho deficiency‐induced hyperphosphotemia may cause arterial calcification, Klotho deficient mice were given low phosphate diet (0.2%). Interestingly, Low phosphate diet normalized blood phosphate levels and abolished calcification in lungs and kidneys, but it did not prevent the development of aortic calcification in Klotho‐deficient mice. In cultured mouse aortic SMCs, KL‐deficient serum promoted BMP2‐induced calcification, protein expressions of Pit2 (phosphate transporter) and Runx2, and phosphorylation of Smad1/5/8 and Smad2/3. Interestingly, treatment with KL abolished the BMP2‐induced morphogenetic effects.ConclusionKlotho deficiency‐induced arterial calcification is an active process which requires activation of the BMP2 signaling pathway.
Reduction of Nitrosative Stress by Vitamin C: a New Approach for Mitigation of Doxorubicin‐induced Cardiomyopathy
Authors: Akolkar Gauri , Bagchi Ashim , Mandal Soma , Jassal Davinder , Singal Pawan 
Published: June 2021

BackgroundDespite the effectiveness of Doxorubicin (Dox) as an anti‐cancer drug, the dose dependent cardiotoxic side effects are serious life threatening concerns associated with its use. In addition to the oxidative stress, there is increasing evidence of involvement of nitrosative stress in Dox‐induced cardiotoxicity. Previously, Vitamin C (Vit C) has been shown to reduce oxidative stress and improved survival of Dox‐treated cardiomyocytes. However there is no evidence on the effect of Vit C on nitrosative stress. The objective of this study was to investigate the effect of Vit C on nitrosative stress in Dox treated cardiomyocytes.Methods and ResultsCardiomyocytes isolated from adult Sprague‐Dawley rats were treated with predetermined doses of Vit C (25 µM), Dox (10 µM) or Vit C (25 µM) + Dox (10 µM) for 24 hours. Dox treatment increased levels of nitrate in cardiomyocytes as well as released in media leading to increased production of peroxynitrite. Vit C significantly reduced the levels of cellular and released nitrate, cellular peroxynitrite as well as the nitrosylation of proteins caused by Dox. Dox induced increase in Nitric oxide synthase (NOS) activity in cardiomyocytes was blunted by Vit C treatment. Western blot analysis revealed an upregulation of inducible NOS (iNOS) and phosphorylation of inhibitory site of endothelial NOS (eNOS) by Dox. In contrast Vit C downregulated iNOS and phosphorylated activating site of eNOS. Dox induced activation of apoptosis was prevented by Vit C.ConclusionThese results provide a hope and rationale for use of Vit C as an adjuvant therapy to mitigate cardiotoxic side effects of Dox by attenuating oxidative and nitrosative stress.Support: CIHR
Visualization of Dietary Patterns
Authors: Krebs‐Smith Susan , Wilson Magdalena , Reedy Jill 
Published: June 2021

Diet quality indices, such as the Healthy Eating Index 2010 (HEI‐2010), include numerous components to capture the multidimensionality of diets, but typically only the total index score indicative of overall diet quality is presented. This project examined the merit of radar graphs for depicting multidimensional dietary patterns and how those patterns vary in the US population over time and by different characteristics.National Health and Nutrition Examination Survey (NHANES) dietary intake data were used to estimate HEI‐2010 component scores for the US population, over time (from 1999/2000 to 2009/2010), by socioeconomic status (i.e. poverty income ratio), and by age and sex categories. Each component score was scaled from 0‐100% and plotted. A perfect HEI‐2010 score, representing a diet that conforms to the 2010 Dietary Guidelines for Americans, would be depicted as a line around the border of the radar plot.Points on all axes of the radar plots show the relative scores for the components, and the overall shape provides an indication of the dietary pattern, with larger shapes generally indicating higher dietary quality. The spacing between different groups' points on each axis shows the difference in quality for that component between those groups. The plots show that some components—such as whole fruit and dairy—vary greatly, while others—such as sodium and total protein foods—vary less. The components that vary greatly drive the differences in overall diet quality between groups.Radar plots are a useful tool to conceptualize dietary patterns. They allow for visualization of differences in patterns between groups, and trends in dietary patterns over time. However, as the shape of the patterns depends on the order of the components presented on the plot, it is important for the order of components to be standardized across analyses using this tool.
The consumption of a grape and blueberry polyphenol‐rich mixture is safe in dogs
Authors: Martineau Anne‐Sophie , Leray Véronique , Gaudout David , Lepoudère Anne , Ouguerram Khadija , Nguyen Patrick 
Published: June 2021

Grape polyphenols have beneficial health effects, but grape ingestion has been associated with acute renal failure leading most often to fatal issue in dogs. The responsible factors are unknown.Our aim was to check the safety of a supplement of polyphenol‐rich mixture (grape and blueberry extracts (specific pet Neurophenols® blend)) in dogs.Seventeen dogs were given, for 12 wks, capsules containing 4 (n=5) or 20 (n=6) or 40 (n=6) mg/kg/d of the polyphenol mixture. Five control dogs were given maltodextrin capsules. Blood and 24‐h urine were taken before the beginning of the study (W0), then after 4 wks and 12 wks of supplementation. Plasma standard analysis (creatinine (Creat), urea, minerals (Na, K, Ca, P), total protein, hepatic biomarkers (ALT, ALP)) were assayed. New biomarkers that reveal early renal damage were measured : plasma and urinary cystatin C (CysC), clusterin (Clu), neutrophil gelatinase‐associated lipocalin (NGAL). Urinary biomarkers/Creat ratios were calculated. Data were compared with limits of reference intervals or with the highest values from our control dogs and experimental dogs at W0.Whatever the week, plasma standard analysis were below high limits of reference intervals. Plasma CysC concentration was below our own high limit. Plasma Clu and NGAL concentrations were below limits of reference intervals. Urinary CysC/Creat, Clu/Creat, NGAL/Creat ratios were below our own limit.Grape extract and blueberry extract (specific pet Neurophenols® blend) consumption was not associated with any sign of renal failure and can be consumed safely in dogs.
Epigenetic Modification of Von Willebrand Factor (VWF) Leads to its Expression in Cancer Cells with Increased Metastatic Activity
Authors: Mojiri Anahita , eisenstat David , Lewis John , Stoletov Konstantin , Simmen Katia , Jahroudi Nadia 
Published: June 2021

VWF is an adhesive procoagulant protein that is exclusively expressed in endothelial cell (EC) and megakaryocytes. It is key initiator of blood clotting cascade. Increased plasma levels of VWF and alterations in coagulation system in patients with metastasis and cancer progression are reported. We hypothesised that a subpopulation of some cancer cells of non‐endothelial origin may acquire VWF expression and as a result develop enhanced metastatic potential.RT‐PCR, western blot and Immunoflourescent (IF) analyses showed significant levels of VWF expression in an osteosarcoma (Saos2) and glioma (U251, M016, M049) cell lines. Chromatin IP assays demonstrated a similar pattern of transcription factors binding as is observed for VWF gene in EC. The epigenetic modification analysis showed that histone modification of the VWF promoter in glioma (U251, M016, M049) and Saos2 is consistent with transcriptionally active VWF promoter. In vitro cell‐cell interaction analyses showed that cancer cell lines expressing VWF, exhibited increased affinity to adhere to the platelets and an EC monolayer under sheer stress. IF analyses of human glioma tumor samples, demonstrated VWF expression in some cells of non‐endothelial origin in the tumor region, highly suggestive of VWF expression in a subset of glioma cancer cells. Chick Chorioallantoic Membrane assay showed increased extravasation and metastatic lesions for cancer cells expressing VWF.A subpopulation of cancer cells of non‐endothelial origin acquires denovo expression of VWF as a result of epigenetic modification of the VWF promoter. Acquired VWF expressions by cancer cells increase their adhesive properties and may contribute to their metastatic potential.
mRNA‐binding protein IMP1 is a novel regulator of autophagy following intestinal irradiation injury
Authors: Hamilton Kathryn , Chatterji Priya , Andres Sarah , Lundsmith Emma , Whelan Kelly , Giroux Veronique , Mah Amanda , Van Landeghem Laurianne , Lund Pauline , Rustgi Anil 
Published: June 2021

BackgroundPost‐transcriptional regulation of intestinal homeostasis via mRNA‐binding proteins, including Igf2 mRNA‐binding protein 1 (IMP1), is an area of emerging interest. Imp1‐null mice exhibit severe intestinal growth defects, yet Imp1 deletion in intestinal epithelium (Imp1ΔIEC) reveals minimal phenotype. Imp1 expression is significantly increased in intestinal stem/progenitor cells post‐irradiation, and new data indicate that Imp1ΔIEC mice exhibit increased baseline autophagy. We hypothesized that Imp1 is essential for intestinal response to irradiation, possibly via modulation of autophagy.MethodsWe treated Imp1ΔIEC and control mice with 12Gy irradiation and evaluated small intestine 96 hours later. Epithelia were evaluated for changes in autophagy via western blot and FACS. Enteroids plated from crypts of Imp1ΔIEC and control mice evaluated stem cell growth.ResultsAutophagy is up‐regulated in control mice following irradiation; however, Imp1ΔIEC mice exhibit repressed autophagy. In control mice, irradiation increases the proportion of spheres (non‐differentiated) to budding enteroids (differentiated), reflecting stem cell expansion. Intriguingly, irradiated Imp1ΔIEC mice show a further increase in sphere‐like enteroids, indicating that Imp1 may function to modulate stemness/differentiation following injury.ConclusionsOur data suggest that Imp1 may regulate autophagy in response to irradiation in the intestine, representing a novel paradigm by which autophagy may influence stemness in intestinal homeostasis.