bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzymatically Modified Low-Density Lipoprotein Promotes Foam Cell Formation in Smooth Muscle Cells via Macropinocytosis and Enhances Receptor-Mediated Uptake of Oxidized Low-Density Lipoprotein
Authors: Chellan Bijoy , Reardon Catherine A. , Getz Godfrey S. , Hofmann Bowman Marion A. 
Published: April 2016

Objective—
Enzyme-modified nonoxidized low-density lipoprotein (ELDL) is present in human atherosclerotic lesions. Our objective is to understand the mechanisms of ELDL uptake and its effects on vascular smooth muscle cells (SMC).

Approach and Results—

Transformation of murine aortic SMCs into foam cells in response to ELDL was analyzed. ELDL, but not acetylated or oxidized LDL, was potent in inducing SMC foam cell formation. Inhibitors of macropinocytosis (LY294002, wortmannin, amiloride) attenuated ELDL uptake. In contrast, inhibitors of receptor-mediated endocytosis (dynasore, sucrose) and inhibitor of caveolae-/lipid raft–mediated endocytosis (filipin) had no effect on ELDL uptake in SMC, suggesting that macropinocytosis is the main mechanism of ELDL uptake by SMC. Receptor for advanced glycation end products (RAGE) is not obligatory for ELDL-induced SMC foam cell formation, but primes SMC for the uptake of oxidized LDL in a RAGE-dependent manner. ELDL increased intracellular reactive oxygen species, cytosolic calcium, and expression of lectin-like oxidized LDL receptor-1 in wild-type SMC but not in RAGE
−/−
SMC. The macropinocytotic uptake of ELDL is regulated predominantly by intracellular calcium because ELDL uptake was completely inhibited by pretreatment with the calcium channel inhibitor lacidipine in wild-type and RAGE
−/−
SMC. This is in contrast to pretreatment with PI3 kinase inhibitors which completely prevented ELDL uptake in RAGE
−/−
SMC, but only partially in wild-type SMC.

Conclusions—
ELDL is highly potent in inducing foam cells in murine SMC. ELDL endocytosis is mediated by calcium-dependent macropinocytosis. Priming SMC with ELDL enhances the uptake of oxidized LDL.
Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report
Authors: Thedrez Aurélie , Sjouke Barbara , Passard Maxime , Prampart-Fauvet Simon , Guédon Alexis , Croyal Mikael , Dallinga-Thie Geesje , Peter Jorge , Blom Dirk , Ciccarese Milco , Cefalù Angelo B. , Pisciotta Livia , Santos Raul D. , Averna Maurizio , Raal Frederick , Pintus Paolo , Cossu Maria , Hovingh Kees , Lambert Gilles 
Published: April 2016

Objective—
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)?

Approach and Results—
Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells.

Conclusions—
PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.
High-Density Lipoprotein Proteomic Composition, and not Efflux Capacity, Reflects Differential Modulation of Reverse Cholesterol Transport by Saturated and Monounsaturated Fat Diets
Authors: O’Reilly Marcella , Dillon Eugene , Guo Weili , Finucane Orla , McMorrow Aoibheann , Murphy Aoife , Lyons Claire , Jones Daniel , Ryan Miriam , Gibney Michael , Gibney Eileen , Brennan Lorraine , de la Llera Moya Margarita , Reilly Muredach P. , Roche Helen M. , McGillicuddy Fiona C. 
Published: April 2016

Background—
Acute inflammation impairs reverse cholesterol transport (RCT) and reduces high-density lipoprotein (HDL) function in vivo. This study hypothesized that obesity-induced inflammation impedes RCT and alters HDL composition, and investigated if dietary replacement of saturated (SFA) for monounsaturated (MUFA) fatty acids modulates RCT.

Methods and Results—

Macrophage-to-feces RCT, HDL efflux capacity, and HDL proteomic profiling was determined in C57BL/6j mice following 24 weeks on SFA- or MUFA-enriched high-fat diets (HFDs) or low-fat diet. The impact of dietary SFA consumption and insulin resistance on HDL efflux function was also assessed in humans. Both HFDs increased plasma
3
H-cholesterol counts during RCT in vivo and ATP-binding cassette, subfamily A, member 1–independent efflux to plasma ex vivo, effects that were attributable to elevated HDL cholesterol. By contrast, ATP-binding cassette, subfamily A, member 1–dependent efflux was reduced after both HFDs, an effect that was also observed with insulin resistance and high SFA consumption in humans. SFA-HFD impaired liver-to-feces RCT, increased hepatic inflammation, and reduced ABC subfamily G member 5/8 and ABC subfamily B member 11 transporter expression in comparison with low-fat diet, whereas liver-to-feces RCT was preserved after MUFA-HFD. HDL particles were enriched with acute-phase proteins (serum amyloid A, haptoglobin, and hemopexin) and depleted of paraoxonase-1 after SFA-HFD in comparison with MUFA-HFD.

Conclusions—
Ex vivo efflux assays validated increased macrophage-to-plasma RCT in vivo after both HFDs but failed to capture differential modulation of hepatic cholesterol trafficking. By contrast, proteomics revealed the association of hepatic-derived inflammatory proteins on HDL after SFA-HFD in comparison with MUFA-HFD, which reflected differential hepatic cholesterol trafficking between groups. Acute-phase protein levels on HDL may serve as novel biomarkers of impaired liver-to-feces RCT in vivo.
Association of Get With The Guidelines-Stroke Program Participation and Clinical Outcomes for Medicare Beneficiaries With Ischemic Stroke
Authors: Song Sarah , Fonarow Gregg C. , Olson DaiWai M. , Liang Li , Schulte Phillip J. , Hernandez Adrian F. , Peterson Eric D. , Reeves Mathew J. , Smith Eric E. , Schwamm Lee H. , Saver Jeffrey L. 
Published: April 2016

Background and Purpose—
Get With The Guidelines (GWTG)-Stroke is a national, hospital-based quality improvement program developed by the American Heart Association. Although studies have suggested improved processes of care in GWTG-Stroke–participating hospitals, it is not known whether this improved care translates into improved clinical outcomes compared with nonparticipating hospitals.

Methods—
From all acute care US hospitals caring for Medicare beneficiaries with acute stroke between April 2003 and December 2008, we matched hospitals that joined the GWTG-Stroke program with similar hospitals that did not. Using a difference-in-differences design, we analyzed whether hospital participation in GWTG-Stroke was associated with a greater improvement in clinical outcomes compared with the underlying secular change.

Results—
The matching algorithm identified 366 GWTG-Stroke–adopting hospitals that cared for 88 584 acute ischemic stroke admissions and 366 non–GWTG-Stroke hospitals that cared for 85 401 acute ischemic stroke admissions. Compared with the Pre period (18–6 months before program implementation), in the Early period (0–6 months after program implementation), GWTG-Stroke hospitals had accelerated increases in discharge to home and reduced mortality at 30 days and 1 year. In the Sustained period (6–18 months after program implementation), the accelerated reduction in mortality at 1 year was sustained, with a trend toward sustained accelerated increase in discharge home.

Conclusions—
Hospital adoption of the GWTG-Stroke program was associated with improved functional outcomes at discharge and reduced postdischarge mortality.
The Associative Memory Deficit in Aging Is Related to Reduced Selectivity of Brain Activity during Encoding
Authors: Saverino Cristina , Fatima Zainab , Sarraf Saman , Oder Anita , Strother Stephen C. , Grady Cheryl L. 
Published: April 2016

Abstract
Human aging is characterized by reductions in the ability to remember associations between items, despite intact memory for single items. Older adults also show less selectivity in task-related brain activity, such that patterns of activation become less distinct across multiple experimental tasks. This reduced selectivity or dedifferentiation has been found for episodic memory, which is often reduced in older adults, but not for semantic memory, which is maintained with age. We used fMRI to investigate whether there is a specific reduction in selectivity of brain activity during associative encoding in older adults, but not during item encoding, and whether this reduction predicts associative memory performance. Healthy young and older adults were scanned while performing an incidental encoding task for pictures of objects and houses under item or associative instructions. An old/new recognition test was administered outside the scanner. We used agnostic canonical variates analysis and split-half resampling to detect whole-brain patterns of activation that predicted item versus associative encoding for stimuli that were later correctly recognized. Older adults had poorer memory for associations than did younger adults, whereas item memory was comparable across groups. Associative encoding trials, but not item encoding trials, were predicted less successfully in older compared with young adults, indicating less distinct patterns of associative-related activity in the older group. Importantly, higher probability of predicting associative encoding trials was related to better associative memory after accounting for age and performance on a battery of neuropsychological tests. These results provide evidence that neural distinctiveness at encoding supports associative memory and that a specific reduction of selectivity in neural recruitment underlies age differences in associative memory.
The Dopaminergic Midbrain Mediates an Effect of Average Reward on Pavlovian Vigor
Authors: Rigoli Francesco , Chew Benjamin , Dayan Peter , Dolan Raymond J. 
Published: April 2016

AbstractDopamine plays a key role in motivation. Phasic dopamine response reflects a reinforcement prediction error (RPE), whereas tonic dopamine activity is postulated to represent an average reward that mediates motivational vigor. However, it has been hard to find evidence concerning the neural encoding of average reward that is uncorrupted by influences of RPEs. We circumvented this difficulty in a novel visual search task where we measured participants' button pressing vigor in a context where information (underlying an RPE) about future average reward was provided well before the average reward itself. Despite no instrumental consequence, participants' pressing force increased for greater current average reward, consistent with a form of Pavlovian effect on motivational vigor. We recorded participants' brain activity during task performance with fMRI. Greater average reward was associated with enhanced activity in dopaminergic midbrain to a degree that correlated with the relationship between average reward and pressing vigor. Interestingly, an opposite pattern was observed in subgenual cingulate cortex, a region implicated in negative mood and motivational inhibition. These findings highlight a crucial role for dopaminergic midbrain in representing aspects of average reward and motivational vigor.
Assessing the Skill and Value of Seasonal Thermal Stress Forecasts for Coral Bleaching Risk in the Western Pacific
Authors: Griesser A. G. , Spillman C. M. 
Published: April 2016

AbstractOver the last 30 years, coral reefs around the world have been under considerable stress because of increasing anthropogenic pressures, overfishing, pollution, and climate change. A primary stress factor is anomalously warm water events, which can cause mass coral bleaching and widespread reef damage. Forecasts of sea surface temperature (SST) and the associated risk of coral bleaching can assist managers, researchers, and other stakeholders in monitoring and managing coral reef resources. At the Australian Bureau of Meteorology, monthly forecasts of SST and thermal stress metrics have been developed that are based on a dynamical seasonal prediction system known as the Predictive Ocean Atmosphere Model for Australia (POAMA). To support the effective use of these forecasts in risk-based decision-making frameworks in the western and central tropical Pacific Ocean, the skill of these forecast tools in this region was assessed using several categorical forecast skill scores. It was found that the model provides SST forecasts with statistically significant skill up to 8 months in advance (correlation coefficient > 0.4; p = 0.05) across the region. The highest skill (r > 0.9) was achieved over the central equatorial Pacific Ocean, likely as a result of this region’s strong relationship with the El Niño–Southern Oscillation (ENSO). Potential forecast value was assessed using a simplified cost–loss ratio decision model, which indicated that POAMA’s seasonal hot-spot thermal stress forecasts can provide valuable information to reef management and policy makers in the western Pacific region.
Sea Spray Generation at a Rocky Shoreline
Authors: Andreas Edgar L 
Published: April 2016

AbstractWith sea ice in the Arctic continuing to shrink, the Arctic Ocean and the surrounding marginal seas will become more like the ocean at lower latitudes. In particular, with more open water, air–sea exchange will be more intense and storms will be stronger and more frequent. The longer fetches over open water and the more energetic storms will combine to produce higher waves and more sea spray. Offshore structures—such as oil drilling, exploration, and production platforms—will face increased hazards from freezing sea spray. On the basis of sea spray observations made with a cloud-imaging probe at Mount Desert Rock (an island off the coast of Maine), the spray that artificial islands built in the Arctic might experience is quantified. Mount Desert Rock is small, low, and unvegetated and has an abrupt, rocky shoreline like these artificial islands might have. Many of the observations were at air temperatures below freezing. This paper reports the near-surface spray concentration and the rate of spray production at this rocky shoreline for spray droplets with radii from 6.25 to 143.75 μm and for wind speeds from 5 to 17 m s−1. Spray concentration increases as the cube of the wind speed, but the shape of the concentration spectrum with respect to radius does not change with wind speed. Both near-surface spray concentration and the spray-production rate are three orders of magnitude higher at this rocky shoreline than over the open ocean because of the high energy and resulting continuous white water in the surf zone.
Predictability of Dry Convective Boundary Layers: An LES Study
Authors: Mukherjee Siddhartha , Schalkwijk Jerôme , Jonker Harmen J. J. 
Published: April 2016

Abstract
The predictability horizon of convective boundary layers is investigated in this study. Large-eddy simulation (LES) and direct numerical simulation (DNS) techniques are employed to probe the evolution of perturbations in identical twin simulations of a growing dry convective boundary layer. Error growth typical of chaotic systems is observed, marked by two phases. The first comprises an exponential error growth as , with δ0 as the initial error, δ(t) as the error at time t, and Λ as the Lyapunov exponent. This phase is independent of the perturbation wavenumber, and the perturbation energy grows following a self-similar spectral shape dominated by higher wavenumbers. The nondimensional error growth rate in this phase shows a strong dependence on the Reynolds number (Re). The second phase involves saturation of the error. Here, the error growth follows Lorenz dynamics with a slower saturation of successively larger scales. An analysis of the spectral decorrelation times reveals two regimes: an Re-independent regime for scales larger than the boundary layer height and an Re-dependent regime for scales smaller than , which are found to decorrelate substantially faster for increasing Reynolds numbers.
Atmospheric Moisture Transport to the Arctic: Assessment of Reanalyses and Analysis of Transport Components
Authors: Dufour Ambroise , Zolina Olga , Gulev Sergey K. 
Published: April 2016

Abstract
The atmospheric water cycle of the Arctic is evaluated via seven global reanalyses and in radiosonde observations covering the 1979–2013 period. In the regional moisture budget, evaporation and precipitation are the least consistent terms among different datasets. Despite the assimilation of radiosoundings, the reanalyses present a tendency to overestimate the moisture transport. Aside from this overestimation, the reanalyses exhibit a remarkable agreement with the radiosondes in terms of spatial and temporal patterns. The northern North Atlantic, subpolar North Pacific, and Labrador Sea stand out as the main gateways for moisture to the Arctic in all reanalyses. Because these regions correspond to the end of the storm tracks, the link between moisture transports and extratropical cyclones is further investigated by decomposing the moisture fluxes in the mean flow and transient eddy parts. In all reanalyses, the former term tends to cancel out when averaged over a latitude circle, leaving the latter to provide the bulk of the midlatitude moisture imports (89%–94% at 70°N). Although the Arctic warms faster than the rest of the world, the impact of these changes on its water cycle remains ambiguous. In most datasets, evaporation, precipitation, and precipitable water increase in line with what is expected from a warming signal. At the same time, the moisture transports have decreased in all the reanalyses but not in the radiosonde observations, though none of these trends is statistically significant. The fluxes do not scale with the Clausius–Clapeyron relation because the increasing humidity is not correlated with the meridional wind, particularly near the surface.
BLOCKYLAND
Authors: Dhatsuwan Apinya , Precharattana Monamorn 
Published: April 2016

Background BLOCKYLAND is a city building game based on the concept of cellular automata (CA), and urban cellular automata. The game has CA-like processes that invert the role of players from passive observers in other CA applications to active thinkers. The processes challenge players to apply logical thinking and decision making from the perspective of serious games. The players’ mission is to build a city by applying the provided CA rules. Two types of CA rules are provided: 1) The logical rule, whereby players apply to build the city according to the preset conditions, and 2) The optional rule, whereby they may apply to upgrade an existing building for an extra score. Aim This article aims to present the design and development of CA-based game, BLOCKYLAND and describe its effectiveness as an instructional tool to enhance logical thinking. Results Results from the mixed-method pilot study show that BLOCKYLAND enhanced players’ logical thinking after the gameplay. Additionally, from the extensive debriefing following the game, participants stated that the game aided them with transforming their game experiences into learning experiences and relating the logical thinking practice into real-life application. Results Conclusion. As a combination of logical thinking practices and a serious game, BLOCKYLAND has several implications for educational stakeholders; both theoretical and practical.
Increased vascular sympathetic modulation in mice with Mas receptor deficiency
Authors: Rabello Casali Karina , Ravizzoni Dartora Daniela , Moura Marina , Bertagnolli Mariane , Bader Michael , Haibara Andrea , Alenina Natalia , Irigoyen Maria Claudia , Santos Robson A 
Published: April 2016

Introduction: The angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1–7)/Mas axis could modulate the heart rate (HR) and blood pressure variabilities (BPV) which are important predictors of cardiovascular risk and provide information about the autonomic modulation of the cardiovascular system. Therefore we investigated the effect of Mas deficiency on autonomic modulation in wild type and Mas-knockout (KO) mice. Methods: Blood pressure was recorded at high sample rate (4000 Hz). Stationary sequences of 200–250 beats were randomly chosen. Frequency domain analysis of HR and BPV was performed with an autoregressive algorithm on the pulse interval sequences and on respective systolic sequences. Results: The KO group presented an increase of systolic arterial pressure (SAP; 127.26±11.20 vs 135.07±6.98 mmHg), BPV (3.54±1.54 vs 5.87±2.12 mmHg2), and low-frequency component of systolic BPV (0.12±0.11 vs 0.47±0.34 mmHg2). Conclusions: The deletion of Mas receptor is associated with an increase of SAP and with an increased BPV, indicating alterations in autonomic control. Increase of sympathetic vascular modulation in absence of Mas evidences the important role of Ang-(1–7)/Mas on cardiovascular regulation. Moreover, the absence of significant changes in HR and HRV can indicate an adaptation of autonomic cardiac balance. Our results suggest that the Ang-(1–7)/Mas axis seems more important in autonomic modulation of arterial pressure than HR.
The Influence of Language Discordance Between Patient and Physician on Time-to-Thrombolysis in Acute Ischemic Stroke
Authors: Rostanski Sara K. , Stillman Joshua , Williams Olajide , Marshall Randolph S. , Yaghi Shadi , Willey Joshua Z. 
Published: April 2016

Background and purpose: Reducing door-to-imaging (DIT) time is a major focus of acute stroke quality improvement initiatives to promote rapid thrombolysis. However, recent data suggest that the imaging-to-needle (ITN) time is a greater source of treatment delay. We hypothesized that language discordance between physician and patient would contribute to prolonged ITN time, as rapidly taking a history and confirming last known well require facile communication between physician and patient. Methods: This is a retrospective analysis of all patients who received tissue plasminogen activator (tPA) in our emergency department between July 2011 and December 2014. Baseline characteristics and relevant time intervals were compared between encounters where the treating neurologist and patient spoke the same language (concordant cases) and where they did not (discordant cases). Results: A total of 279 patients received tPA during the study period. English was the primary language for 51%, Spanish for 46%, and other languages for 3%; 59% of cases were classified as language concordant and 41% as discordant. We found no differences in median DIT (24 vs 25, P = .5), ITN time (33 vs 30, P = .3), or door-to-needle time (DTN; 58 vs 55, P = .1) between concordant and discordant groups. Similarly, among patients with the fastest and slowest ITN times, there were no differences. Conclusion: In a high-volume stroke center with a large proportion of Spanish speakers, language discordance was not associated with changes in DIT, ITN time, or DTN time.