bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure
Authors: Caplin Ben , Wang Zhen , Slaviero Anna , Tomlinson James , Dowsett Laura , Delahaye Mathew , Salama Alan ,   The International Consortium for Blood Pressure Genome-Wide Association Studies, Wheeler David C. , Leiper James 
Published: September 2012

Objective—
Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure.

Methods and Results—

In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (
P
=0.0052).

Conclusion—
Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure.
Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein
Authors: Bojic Lazar A. , Sawyez Cynthia G. , Telford Dawn E. , Edwards Jane Y. , Hegele Robert A. , Huff Murray W. 
Published: September 2012

Objective—
Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin-resistant patients at risk for atherosclerosis. VLDL readily induces macrophage lipid accumulation and inflammatory responses, for which targeted therapeutic strategies remain elusive. We examined the ability of VLDL to induce macrophage foam cells and the inflammatory response and sought to define the cell signaling cascades involved. We further examined the potential of peroxisome proliferator-activated receptor (PPAR) δ activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression.

Methods and Results—

THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPARδ activation. PPARδ agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced β-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1β, macrophage inflammatory protein 1α, and intercellular adhesion molecule-1. VLDL treatment significantly increased the phosphorylation of both extracellular signal-related kinase 1 and 2 and p38. VLDL reduced AKT phosphorylation as well as its downstream effector forkhead box protein O1, concomitant with increased nuclear forkhead box protein O1. Cells treated with PPARδ agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogen-activated protein kinase (MAPK)
erk
and AKT/forkhead box protein O1 signaling.

Conclusion—
The combined PPARδ-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis.
Rivaroxaban Delivery and Reversal at a Venous Flow Rate
Authors: Haynes Laura M. , Orfeo Thomas , Mann Kenneth G. 
Published: September 2012

Objective—

Rivaroxaban is an oral anticoagulant that directly targets both free factor Xa and factor Xa in complex with its protein cofactor, factor Va, in the prothrombinase complex. It is approved in the United States for the prophylaxis of deep vein thrombosis and stroke in patients with atrial fibrillation; however, it also carries a black box warning regarding the risk of thrombosis after discontinuation of treatment. The purpose of this study was to determine the degree to which rivaroxaban, over a range of physiologically relevant free plasma concentrations, inhibits preassembled prothrombinase at a typical venous shear rate (100 s
−1
) and to determine the dynamics of rivaroxaban washout.

Methods and Results—
Prothrombinase was assembled on phospholipid-coated glass capillaries. Its activity was characterized with respect to the activation of prothrombin (mean plasma concentration, 1.4 μmol/L) in the absence and presence of rivaroxaban (2, 5, and 10 nmol/L). The degree of inactivation of preassembled prothrombinase is sensitive to the solution-phase rivaroxaban concentration; however, prothrombinase unmasking upon removal of rivaroxaban is concentration independent.

Conclusion—
The model system presented suggests that when rivaroxaban plasma concentrations decrease after cessation of therapy, there will be an unmasking of thrombus-associated prothrombinase that may be related to the reported rebound phenomena.
p62 Binding to Protein Kinase C ζ Regulates Tumor Necrosis Factor α–Induced Apoptotic Pathway in Endothelial Cells
Authors: Kim Geun-Young , Nigro Patrizia , Fujiwara Keigi , Abe Jun-ichi , Berk Bradford C. 
Published: September 2012

Objective—
Protein kinase C (PKC) ζ is a key pathological mediator of endothelial cell apoptosis. p62 is a scaffold protein that regulates several cell signaling pathways by binding to target proteins. Because PKCζ and p62 contain Phox/Bem1p (PB1) modules that mediate protein–protein interactions, we hypothesized that an interaction between p62 and PKCζ is required for tumor necrosis factor α–induced PKCζ signaling in endothelial cells.

Methods and Results—
In human umbilical vein endothelial cell, tumor necrosis factor α (10 ng/mL) enhanced the interaction between p62 and PKCζ. Transfection with p62 small interfering RNA reduced the activation of both PKCζ and its downstream targets JNK and caspase 3, suggesting that p62 is necessary for PKCζ signaling. Overexpression of only the PB1 domain of p62 inhibited p62–PKCζ interaction, showing that binding of these 2 proteins is mediated by their PB1 domains. Furthermore, overexpression of the p62 PB1 domain suppressed tumor necrosis factor α–induced PKCζ activation and subsequent activation of JNK and caspase 3. Finally, transfection of either p62 small interfering RNA or the PB1 domain of p62 inhibited human umbilical vein endothelial cell apoptosis.

Conclusion—
Our results suggest a novel function of p62 that regulates the activity of PKCζ by binding to PKCζ, thereby activating the PKCζ-JNK-caspase 3 apoptotic pathway in endothelial cells.
Multimarker Risk Assessment Including Osteoprotegerin and CXCL16 in Acute Coronary Syndromes
Authors: Jansson Anna M. , Hartford Marianne , Omland Torbjørn , Karlsson Thomas , Lindmarker Per , Herlitz Johan , Ueland Thor , Aukrust Pål , Caidahl Kenneth 
Published: September 2012

Objective—
CXCL16 and osteoprotegerin (OPG) both predict mortality in acute coronary syndromes. We hypothesized that a combination of CXCL16 and OPG concentrations would add prognostic information to the Global Registry of Acute Coronary Events (GRACE) score in patients hospitalized for acute coronary syndromes.

Methods and Results—

We assessed the associations between circulating OPG and soluble CXCL16 levels, obtained within 24 hours of admission (day 1) and after 3 months, and mortality, heart failure and reinfarction in 1322 patients admitted with acute coronary syndromes. After adjustment for the GRACE score, medication, diabetes mellitus and sex, the combination of high values (fourth quartile) for OPG and CXCL16 at baseline was associated with increased short-term (3 months) cardiovascular mortality (hazard ratio, 3.28; 95% CI, 1.84–5.82;
P
<0.0001). The combined high values were also significantly associated with the long-term (median 91 months) prognosis after adjustment, with hazard ratios 2.18 for cardiovascular mortality (95% CI, 1.62–2.92;
P
<0.0001), and 2.22 for heart failure (95% CI, 1.67–2.96;
P
<0.0001). These long-term associations remained significant after further adjustment for left ventricular ejection fraction, C-reactive protein, and pro B-type natriuretic peptide. For 635 patients with blood samples within 24 hours and at 3 months, the combination of high CXCL16 and OPG values (fourth quartile) in the early or stable phase was of a similar order associated with mortality and morbidity beyond 3 months.

Conclusion—
Circulating CXCL16 and OPG are independent predictors of long-term mortality and heart failure development in acute coronary syndromes patients, even after extensive adjustments. Their combination gives more information than either marker alone.
Myeloid Deletion of Nuclear Factor Erythroid 2−Related Factor 2 Increases Atherosclerosis and Liver Injury
Authors: Collins Alan R. , Gupte Anisha A. , Ji Ruirui , Ramirez Maricela R. , Minze Laurie J. , Liu Joey Z. , Arredondo Magda , Ren Yuelan , Deng Tuo , Wang Jun , Lyon Christopher J. , Hsueh Willa A. 
Published: September 2012

Objective—
To determine the impact of hematopoietic deletion of nuclear factor− (erythroid-derived 2) like 2 factor (Nrf2) on the development of atherosclerosis and liver injury in an obese, hypercholesterolemic mouse model.

Methods and Results—

Two-month-old male low-density lipoprotein receptor–deficient mice were lethally irradiated and transplanted with either wild type or Nrf2-deficient (Nrf2
−/−
) bone marrow cells. At 3 months of age, mice were placed on an obesogenic high-fat diet (HFD), high-cholesterol diet for 7 months. Despite no differences in body weight, body fat percentage, liver fat, plasma glucose, lipids, or insulin, the HFD-fed Nrf2
−/−
bone marrow recipients had increased proinflammatory vascular gene expression, a significant increase in atherosclerosis area (18% versus 28%;
P
=0.018) and lesion complexity, and a marked increase in liver fibrosis. The acceleration of vascular and liver injury may arise from enhanced macrophage migration, inflammation, and oxidative stress resulting from myeloid Nrf2 deficiency.

Conclusion—
Myeloid-derived Nrf2 activity attenuates atherosclerosis development and liver inflammation and fibrosis associated with obesity. Prevention of oxidative stress in macrophage and other myeloid lineage cells may be an important therapeutic target to reduce inflammation-driven complications of obesity.
Opposing Actions of Heat Shock Protein 90 and 70 Regulate Nicotinamide Adenine Dinucleotide Phosphate Oxidase Stability and Reactive Oxygen Species Production
Authors: Chen Feng , Yu Yanfang , Qian Jin , Wang Yusi , Cheng Bo , Dimitropoulou Christiana , Patel Vijay , Chadli Ahmed , Rudic R. Dan , Stepp David W. , Catravas John D. , Fulton David J.R. 
Published: September 2012

Objective—
Excessive reactive oxygen species contribute to vascular dysfunction. We have previously shown that heat shock protein (Hsp90) inhibitors potently suppress Nox 1 to 3 and 5, and the goals of this study were to identify how molecular chaperones regulate Nox function.

Methods and Results—
In vitro, protein expression of Nox 1 to 2, 5 was decreased by Hsp90 inhibitors in multiple cell types (human pulmonary artery endothelial cells, neutrophils, macrophages, and human saphenous vein). In mice treated with Hsp90 inhibitors, Nox1 expression was reduced in lung along with reduced reactive oxygen species from leukocytes. Elevated reactive oxygen species production in obese (db/db) aorta was suppressed by Hsp90 inhibition. Hsp90 inhibitors did not alter Nox5 micro RNA levels, and proteasome inhibition prevented Nox2 and 5 protein degradation and increased ubiquitin incorporation. Inhibition of Hsp90 upregulated the expression of Hsp70 and Hsp70-bound Nox2, 5 and promoted degradation. Silencing Hsp70 prevented Hsp90 inhibitor–mediated degradation of Nox5. The Hsp70-regulated ubiquitin ligase, carboxyl terminus of Hsp70-interacting protein (CHIP), also bound Nox5 and promoted increased Nox5 ubiquitination and degradation. The chaperone binding and ubiquitination domains of CHIP were required, and the silencing of CHIP blunted Hsp90 inhibitor–mediated degradation of Nox2 and 5.

Conclusion—
We conclude that Hsp90 binds to and regulates Nox protein stability. These actions are opposed by Hsp70 and CHIP, which promote the ubiquitination and degradation of Nox proteins and reduce reactive oxygen species production.
Long-term Memories Bias Sensitivity and Target Selection in Complex Scenes
Authors: Patai Eva Zita , Doallo Sonia , Nobre Anna Christina 
Published: September 2012

Abstract
In everyday situations, we often rely on our memories to find what we are looking for in our cluttered environment. Recently, we developed a new experimental paradigm to investigate how long-term memory (LTM) can guide attention and showed how the pre-exposure to a complex scene in which a target location had been learned facilitated the detection of the transient appearance of the target at the remembered location [Summerfield, J. J., Rao, A., Garside, N., & Nobre, A. C. Biasing perception by spatial long-term memory. The Journal of Neuroscience, 31, 14952–14960, 2011; Summerfield, J. J., Lepsien, J., Gitelman, D. R., Mesulam, M. M., & Nobre, A. C. Orienting attention based on long-term memory experience. Neuron, 49, 905–916, 2006]. This study extends these findings by investigating whether and how LTM can enhance perceptual sensitivity to identify targets occurring within their complex scene context. Behavioral measures showed superior perceptual sensitivity (d′) for targets located in remembered spatial contexts. We used the N2pc ERP to test whether LTM modulated the process of selecting the target from its scene context. Surprisingly, in contrast to effects of visual spatial cues or implicit contextual cueing, LTM for target locations significantly attenuated the N2pc potential. We propose that the mechanism by which these explicitly available LTMs facilitate perceptual identification of targets may differ from mechanisms triggered by other types of top–down sources of information.
Disentangling Spatial Perception and Spatial Memory in the Hippocampus: A Univariate and Multivariate Pattern Analysis fMRI Study
Authors: Lee Andy C. H. , Brodersen Kay H. , Rudebeck Sarah R. 
Published: September 2012

AbstractAlthough the role of the hippocampus in spatial cognition is well accepted, it is unclear whether its involvement is restricted to the mnemonic domain or also extends to perception. We used fMRI to scan neurologically healthy participants during a scene oddity judgment task that placed no explicit demand on long-term memory. Crucially, a surprise recognition test was administered after scanning so that each trial could be categorized not only according to oddity accuracy but also according to subsequent memory. Univariate analyses showed significant hippocampal activity in association with correct oddity judgment, whereas greater parahippocampal place area (PPA) activity was observed during incorrect oddity trials, both irrespective of subsequent recognition performance. Consistent with this, multivariate pattern analyses revealed that a linear support vector machine was able to distinguish correct from incorrect oddity trials on the basis of activity in voxels within the hippocampus or PPA. Although no significant regions of activity were identified by univariate analyses in association with memory performance, a classifier was able to predict subsequent memory using voxels in either the hippocampus or PPA. Our findings are consistent with the idea that the hippocampus is important for processes beyond long-term declarative memory and that this structure may also play a role in complex spatial perception.
Less Is Not More: Neural Responses to Missing and Superfluous Accents in Context
Authors: Dimitrova Diana V. , Stowe Laurie A. , Redeker Gisela , Hoeks John C. J. 
Published: September 2012

AbstractProsody, particularly accent, aids comprehension by drawing attention to important elements such as the information that answers a question. A study using ERP registration investigated how the brain deals with the interpretation of prosodic prominence. Sentences were embedded in short dialogues and contained accented elements that were congruous or incongruous with respect to a preceding question. In contrast to previous studies, no explicit prosodic judgment task was added. Robust effects of accentuation were evident in the form of an “accent positivity” (200–500 msec) for accented elements irrespective of their congruity. Our results show that incongruously accented elements, that is, superfluous accents, activate a specific set of neural systems that is inactive in case of incongruously unaccented elements, that is, missing accents. Superfluous accents triggered an early positivity around 100 msec poststimulus, followed by a right-lateralized negative effect (N400). This response suggests that redundant information is identified immediately and leads to the activation of a neural system that is associated with semantic processing (N400). No such effects were found when contextually expected accents were missing. In a later time window, both missing and superfluous accents triggered a late positivity on midline electrodes, presumably related to making sense of both kinds of mismatching stimuli. These results challenge previous findings of greater processing for missing accents and suggest that the natural processing of prosody involves a set of distinct, temporally organized neural systems.
The Importance of Accurately Measuring the Range Correlation for Range-Oversampling Processing
Authors: Torres Sebastián M. , Curtis Christopher D. 
Published: September 2012

Abstract
A fundamental assumption for the application of range-oversampling techniques is that the correlation of oversampled signals in range is accurately known. In this paper, a theoretical framework is derived to quantify the effects of inaccurate range correlation measurements on the performance of such techniques, which include digital matched filtering and those based on decorrelation (whitening) transformations. It is demonstrated that significant reflectivity biases and increased variance of estimates can occur if the range correlation is not accurately measured. Simulations and real data are used to validate the theoretical results and to illustrate the detrimental effects of mismeasurements. Results from this work underline the need for reliable calibration in the context of range-oversampling processing, and they can be used to establish appropriate accuracy requirements for the measurement of the range correlation on modern weather radars.
Nocturnal gastro-oesophageal reflux, asthma and symptoms of OSA: a longitudinal, general population study
Authors: Emilsson Össur I. , Bengtsson Anna , Franklin Karl A. , Torén Kjell , Benediktsdóttir Bryndís , Farkhooy Amir , Weyler Joost , Dom Sandra , De Backer Wilfried , Gislason Thorarinn , Janson Christer 
Published: September 2012

Nocturnal gastro-oesophageal reflux (nGOR) is associated with asthma and obstructive sleep apnoea (OSA). Our aim was to investigate whether nGOR is a risk factor for onset of asthma and onset of respiratory and OSA symptoms in a prospective population-based study.We invited 2640 subjects from Iceland, Sweden and Belgium for two evaluations over a 9-year interval. They participated in structured interviews, answered questionnaires, and underwent spirometries and methacholine challenge testing. nGOR was defined by reported symptoms.Subjects with persistent nGOR (n=123) had an independent increased risk of new asthma at follow-up (OR 2.3, 95% CI 1.1–4.9). Persistent nGOR was independently related to onset of respiratory symptoms (OR 3.0, 95% CI 1.6–5.6). The risk of developing symptoms of OSA was increased in subjects with new and persistent nGOR (OR 2.2, 95% CI 1.3–1.6, and OR 2.0, 95% CI 1.0–3.7, respectively). No significant association was found between nGOR and lung function or bronchial responsiveness.Persistent symptoms of nGOR contribute to the development of asthma and respiratory symptoms. New onset of OSA symptoms is higher among subjects with symptoms of nGOR. These findings provide evidence that nGOR may play a role in the genesis of respiratory symptoms and diseases.
Echocardiographic abnormalities in patients with COPD at their first hospital admission
Authors: Freixa Xavier , Portillo Karina , Paré Carles , Garcia-Aymerich Judith , Gomez Federico P. , Benet Marta , Roca Josep , Farrero Eva , Ferrer Jaume , Fernandez-Palomeque Carlos , Antó Josep M. , Barberà Joan Albert 
Published: September 2012

Cardiovascular disease accounts for significant morbidity and mortality in chronic obstructive pulmonary disease (COPD). Its prevalence and mechanisms of association have not been elucidated. The study aimed to assess the prevalence of echocardiographic abnormalities and potential risk factors in patients with COPD at their first exacerbation requiring hospital admission.Transthoracic echocardiography was prospectively performed in 342 patients (forced expiratory volume in 1 s 52±16% predicted) 3 months after discharge.Significant cardiac alterations were present in 64% of patients; 27% left- and 48% right-heart disorders. The most common were right ventricle enlargement (30%) and pulmonary hypertension (19%). Left ventricle enlargement was present in 6%, left ventricle systolic dysfunction in 13%, left ventricle diastolic impairment in 12% and left atrial dilatation in 29%. Echocardiographic abnormalities were unrelated to COPD severity and were more frequent in patients with self-reported cardiac disease. They were also observed in 63% of patients with no known cardiac disease or cardiovascular risk factors other than smoking.We conclude that cardiac abnormalities are highly prevalent in COPD patients at the time of their first severe exacerbation, even in the absence of established cardiac disease or cardiovascular risk factors. Considering the prognostic and therapeutic implications of cardiac comorbidity, echocardiography should be considered in the assessment of patients with clinically significant COPD.