bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduction of cAMP and cGMP inhibitory effects in human platelets by MRP4-mediated transport
Authors: Borgognone Alessandra , Pulcinelli Fabio 
Published: September 2012

SummaryCyclic nucleotide-dependent inhibition of platelets represents the most important physiological way to limit thrombus formation. cAMP and cGMP increase in platelets as a consequence of prostacyclin and nitric oxide production by endothelial cells and act through PKA and PKG, respectively. The cytosolic concentration of cyclic nucleotides in platelets is regulated by AC- and GC-dependent synthesis and PDE-dependent degradation. In some cells cyclic nucleotides are eliminated also through MRP4/5/8-dependent efflux. As only MRP4 is expressed in platelets, at high levels in dense granules, we determined its role in the elimination of cyclic nucleotides from platelet cytosol. We studied the effects of MRP4 inhibition on cAMP/cGMP effects in platelets. Cyclic nucleotide inhibitory effects triggered by cAMP and cGMP-elevating agents on platelet aggregation are strongly enhanced by MRP4 inhibition and so is cyclic nucleotide-dependent phosphorylation of the common substrate VASP. MRP4 inhibition decreases cAMP concentration in platelet granules and both cAMP and cGMP compete with an established substrate of MRP4 (fluo-cAMP) for entrance in granules. Here we provide the first evidence of the transport of cyclic nucleotides mediated by MRP4 as part of their physiological mechanism of elimination in human platelets, which might represent a novel target to increase cyclic nucleotide-dependent inhibition.
Estimation of the warfarin dose with a pharmacogenetic refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation
Authors: Yang Jie , Gao Lei , Zhang Yan , Wang Hongjuan , Lu Caiyi , Zhao Yusheng , Xu Qiang , Xu Bin , Zhang Yuxiao , Yin Tong 
Published: September 2012

SummaryPharmacogenetic (PG) dosing algorithms have been confirmed to predict warfarin therapeutic dose more accurately;however, most of them are based on standard intensity of warfarin anticoagulation, and their utility outside this range is limited. This study was designed to develop and validate a PG refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation. Consented Chinese-Han patients (n=310) under stable warfarin treatment were randomly divided into a derivation (n=207) and a validation cohort (n=103), with 83% and 80% of the patients under low-intensity anticoagulation, respectively. In the derivation cohort, a PG algorithm was constructed on the basis of genotypes (CYP2C9*3 and VKORC1–1639A/G) and clinical data. After integrating additional covariates of international normalised ratio (INR) values (INR on day 4 of therapy and target INR) and genotype of CYP4F2 (rs2108622), a PG refinement algorithm was established and explained 54% of warfarin dose variability. In the validation cohort, warfarin dose prediction was more accurate (p <0.01) with the PG refinement algorithm than with the PG algorithm and the fixed dose approach (3 mg/day). In the entire cohort, the PG refinement algorithm could accurately identify larger proportions of patients with lower dose requirement (≤2 mg/day) and higher dose requirement (≥4 mg/day) than did the PG algorithm. In conclusion, PG refinement algorithm integrating early INR response and three genotypes CYP2C9*3, VKORC1–1639A/G, CYP4F2 rs2108622) improves the accuracy of warfarin dose prediction in Chinese patients mainly under low-intensity anticoagulation.
Thrombus and antiplatelet therapy in type 2 diabetes mellitus
Authors: Viswanathan Girish , Marshall Sally , Schechter Clyde , Balasubramaniam Karthik , Badimon José , Zaman Azfar 
Published: September 2012

SummaryType 2 diabetes mellitus (T2DM) is associated with higher rates of thrombotic complications in patients with coronary artery disease (CAD) despite optimal medical therapy. Thrombus area was measured in T2DM and non-diabetic patients receiving aspirin and clopidogrel 7–10 days after troponin positive Non ST-elevation acute coronary syndrome (NSTE-ACS). Secondly, we assessed response to clopidogrel in naive patients with T2DM and stable CAD in a randomised controlled trial. Thrombus area was measured by Badimon chamber and platelet reactivity by VerifyNow®. In T2DM patients presenting with NSTE-ACS, thrombus area was greater compared to non-diabetic patients (mean ± SD, 20,512 ± 12,567 [n=40] vs. 14,769 ± 8,531 [n=40] μm2/mm, p=0.02) Clopidogrel decreased thrombus area among stable CAD patients with T2DM (mean ± SD, Clopidogrel [n=45]: 13,978 ± 5,502 to 11,192 ± 3,764 μm2/mm vs. placebo [n=45]: 13,959 ± 7,038 to 14,201 ± 6,780 μm2/mm, p<0.001, delta values: clopidogrel vs. placebo, mean ± SD, 2,786 ± 4,561 vs. –249 ± 2,478, p<0.0005). Only 44% of patients with CAD and T2DM responded to clopidogrel as per VerifyNow® (cut-off PRUz value of ≥240). Importantly, no correlation was observed between thrombus area and VerifyNow® values (rho 0.08, p=0.49). Thrombus area values were similar among hypo-responders and good responders to clopidogrel (mean thrombus area ± SD: 12,186 ± 4,294 vs. 10,438 ± 3,401; p=0.17). Type 2 diabetes mellitus is associated with an increased blood thrombogenicity among NSTE-ACS patients on currently recommended medical therapy. Thrombus area was significantly reduced in all stable CAD patients independently of their response to clopidogrel therapy.
Contribution of the NH2-terminal EGF-domain of factor IXa to the specificity of intrinsic tenase
Authors: Qureshi Shabir , Yang Likui , Rezaie Alireza 
Published: September 2012

SummaryFactor IXa (FIXa) is a vitamin K-dependent coagulation serine protease which binds to factor VIIIa (FVIIIa) on negatively charged phospholipid vesicles (PCPS) to catalyse the activation of factor X (FX) to factor Xa (FXa) in the intrinsic pathway. Fluorescence resonance energy transfer (FRET) studies have indicated that the Gla-domain-dependent interaction of FIXa and FX with PCPS in the presence of FVIIIa positions the active-site of the protease at an appropriate height above the membrane surface to optimise the catalytic reaction. In this study, we investigated the contribution of the NH2-terminal EGF-domain (EGF1) of FIXa to the recognition specificity of intrinsic tenase by constructing an EGF1 deletion mutant of FIXa (FIXa-desEGF1) and characterising the properties of the mutant in kinetic, direct binding and FRET assays. The results of direct binding and kinetic studies demonstrated that the binding affinity of the mutant for interaction with FVIIIa on PCPS has been impaired greater than 10-fold and the catalytic efficiency of the mutant protease FVIIIa-PCPS complex in the activation of FX has been decreased 100-fold. By contrast, the mutant protease exhibited a normal activity toward FX in the absence of the protein cofactor. FRET measurements revealed that the distance of the active-site of the mutant FIXa relative to PCPS vesicles has been decreased 10 Åfrom 75 ±2 Åfor FIXa to 65 ±2 Åfor FIXa-desEGF1 independent of FVIIIa. These results suggest that the NH2-terminal EGF-domain of FIXa provides a binding-site for FVIIIa and plays an essential spacer function in the intrinsic tenase complex.
Elevation of Plasma High-Density Lipoproteins Inhibits Development of Experimental Abdominal Aortic Aneurysms
Authors: Torsney Evelyn , Pirianov Grisha , Charolidi Nicoletta , Shoreim Azza , Gaze David , Petrova Slaveia , Laing Ken , Meisinger Trevor , Xiong Wanfen , Baxter B. Timothy , Cockerill Gillian W. 
Published: September 2012

Objective—
Patients with abdominal aortic aneurysms have lower concentrations of high-density lipoproteins (HDLs), leading us to investigate whether increasing plasma HDLs could influence aneurysm formation.

Methods and Results—

Using the angiotensin II−induced hypercholesterolemic and the CaCl
2
-induced normocholesterolemic mouse model of AAA, we investigated the hypothesis that elevation of HDLs inhibits AAA. HDLs elevated before or at the time of AAA induction reduced AAA formation in both models but had no effect on early ruptures. Analysis of protein lysates from specific aortic segments demonstrated site-specific effects of HDLs on early signal transduction and cellular attrition. We found that HDLs reduced extracellular signal related kinases 1/2 activation in the suprarenal segment, while having no effect on p38 mitogen-associated protein kinase activation in any aortic segment and inhibiting c-Jun N-terminal kinase activation in all aortic segments. In addition, HDL elevation inhibited angiotensin II−induced apoptosis while inducing autophagy in the suprarenal segment of the aorta. Using Illumina gene array profiling we investigated the ability of HDL to modulate basal suprarenal aortic gene expression.

Conclusion—
Increasing plasma HDLs inhibit experimental AAA formation, independent of hypercholesterolemia via reduced extracellular signal related kinases 1/2 activation and alteration of the balance of cellular attrition. HDLs modulate genes involved in matrix remodelling, cell migration, and proliferation.
Myeloid-Specific IκB Kinase β Deficiency Decreases Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice
Authors: Park Se-Hyung , Sui Yipeng , Gizard Florence , Xu Jinxian , Rios-Pilier Jennifer , Helsley Robert N. , Han Seong-Su , Zhou Changcheng 
Published: September 2012

Objective—
Inflammatory responses are the driving force of atherosclerosis development. IκB kinase β (IKKβ), a central coordinator in inflammation through regulation of nuclear factor-κB, has been implicated in the pathogenesis of atherosclerosis. Macrophages play an essential role in the initiation and progression of atherosclerosis, yet the role of macrophage IKKβ in atherosclerosis remains elusive and controversial. This study aims to investigate the impact of IKKβ expression on macrophage functions and to assess the effect of myeloid-specific IKKβ deletion on atherosclerosis development.

Methods and Results—

To explore the issue of macrophage IKKβ involvement of atherogenesis, we generated myeloid-specific IKKβ-deficient low-density lipoprotein receptor–deficient mice (IKKβ
ΔMye
LDLR
−/−
). Deficiency of IKKβ in myeloid cells did not affect plasma lipid levels but significantly decreased diet-induced atherosclerotic lesion areas in the aortic root, brachiocephalic artery, and aortic arch of low-density lipoprotein receptor–deficient mice. Ablation of myeloid IKKβ attenuated macrophage inflammatory responses and decreased atherosclerotic lesional inflammation. Furthermore, deficiency of IKKβ decreased adhesion, migration, and lipid uptake in macrophages.

Conclusion—
The present study demonstrates a pivotal role for myeloid IKKβ expression in atherosclerosis by modulating macrophage functions involved in atherogenesis. These results suggest that inhibiting nuclear factor-κB activation in macrophages may represent a feasible approach to combat atherosclerosis.
Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo
Authors: Pircher Joachim , Fochler Franziska , Czermak Thomas , Mannell Hanna , Kraemer Bjoern F. , Wörnle Markus , Sparatore Anna , Del Soldato Piero , Pohl Ulrich , Krötz Florian 
Published: September 2012

Objective—

Hydrogen sulfide (H
2
S)–releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H
2
S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets.

Methods and Results—
In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acid–induced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day). ACS14 led to a significantly longer arterial occlusion time after light-dye–induced endothelial injury as well as decreased thrombus formation after ferric chloride-induced injury in the carotid artery. Bleeding time was not prolonged compared with animals treated with equimolar doses of aspirin. In vitro, in human whole blood, ACS14 (25–500 µmol/L) inhibited arachidonic acid–induced platelet aggregation, but compared with aspirin additionally reduced thrombin receptor–activating peptide–, ADP-, and collagen-dependent aggregation. In washed human platelets, ACS14 (500 µmol/L) attenuated αIIbβ3 integrin activation and fibrinogen binding and increased intracellular cAMP levels and cAMP-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation.

Conclusion—

The H
2
S-releasing aspirin derivative ACS14 exerts strong antiaggregatory effects by impairing the activation of the fibrinogen receptor by mechanisms involving increased intracellular cyclic nucleotides. These additional antithrombotic properties result in a more efficient inhibition of thrombus formation in vivo as achieved with aspirin alone.
tDCS Modulation of Visually Induced Analgesia
Authors: Mancini Flavia , Bolognini Nadia , Haggard Patrick , Vallar Giuseppe 
Published: September 2012

Abstract
Multisensory interactions can produce analgesic effects. In particular, viewing one's own body reduces pain levels, perhaps because of changes in connectivity between visual areas specialized for body representation, and sensory areas underlying pain perception. We tested the causal role of the extrastriate visual cortex in triggering visually induced analgesia by modulating the excitability of this region with transcranial direct current stimulation (tDCS). Anodal, cathodal, or sham tDCS (2 mA, 10 min) was administered to 24 healthy participants over the right occipital or over the centro-parietal areas thought to be involved in the sensory processing of pain. Participants were required to rate the intensity of painful electrical stimuli while viewing either their left hand or an object occluding the left hand, both before and immediately after tDCS. We found that the analgesic effect of viewing the body was enhanced selectively by anodal stimulation of the occipital cortex. The effect was specific for the polarity and the site of stimulation. The present results indicate that visually induced analgesia may depend on neural signals from the extrastriate visual cortex.
Normal Aging Delays and Compromises Early Multifocal Visual Attention during Object Tracking
Authors: Störmer Viola S. , Li Shu-Chen , Heekeren Hauke R. , Lindenberger Ulman 
Published: September 2012

Abstract
Declines in selective attention are one of the sources contributing to age-related impairments in a broad range of cognitive functions. Most previous research on mechanisms underlying older adults' selection deficits has studied the deployment of visual attention to static objects and features. Here we investigate neural correlates of age-related differences in spatial attention to multiple objects as they move. We used a multiple object tracking task, in which younger and older adults were asked to keep track of moving target objects that moved randomly in the visual field among irrelevant distractor objects. By recording the brain's electrophysiological responses during the tracking period, we were able to delineate neural processing for targets and distractors at early stages of visual processing (∼100–300 msec). Older adults showed less selective attentional modulation in the early phase of the visual P1 component (100–125 msec) than younger adults, indicating that early selection is compromised in old age. However, with a 25-msec delay relative to younger adults, older adults showed distinct processing of targets (125–150 msec), that is, a delayed yet intact attentional modulation. The magnitude of this delayed attentional modulation was related to tracking performance in older adults. The amplitude of the N1 component (175–210 msec) was smaller in older adults than in younger adults, and the target amplification effect of this component was also smaller in older relative to younger adults. Overall, these results indicate that normal aging affects the efficiency and timing of early visual processing during multiple object tracking.
Columnar Processing in Primate pFC: Evidence for Executive Control Microcircuits
Authors: Opris Ioan , Hampson Robert E. , Gerhardt Greg A. , Berger Theodore W. , Deadwyler Sam A. 
Published: September 2012

Abstract
A common denominator for many cognitive disorders of human brain is the disruption of neural activity within pFC, whose structural basis is primarily interlaminar (columnar) microcircuits or “minicolumns.” The importance of this brain region for executive decision-making has been well documented; however, because of technological constraints, the minicolumnar basis is not well understood. Here, via implementation of a unique conformal multielectrode recording array, the role of interlaminar pFC minicolumns in the executive control of task-related target selection is demonstrated in nonhuman primates performing a visuomotor DMS task. The results reveal target-specific, interlaminar correlated firing during the decision phase of the trial between multielectrode recording array-isolated minicolumnar pairs of neurons located in parallel in layers 2/3 and layer 5 of pFC. The functional significance of individual pFC minicolumns (separated by 40 μm) was shown by reduced correlated firing between cell pairs within single minicolumns on error trials with inappropriate target selection. To further demonstrate dependence on performance, a task-disrupting drug (cocaine) was administered in the middle of the session, which also reduced interlaminar firing in minicolumns that fired appropriately in the early (nondrug) portion of the session. The results provide a direct demonstration of task-specific, real-time columnar processing in pFC indicating the role of this type of microcircuit in executive control of decision-making in primate brain.
Internal Waves and Turbulence in the Antarctic Circumpolar Current
Authors: Waterman Stephanie , Naveira Garabato Alberto C. , Polzin Kurt L. 
Published: September 2012

AbstractThis study reports on observations of turbulent dissipation and internal wave-scale flow properties in a standing meander of the Antarctic Circumpolar Current (ACC) north of the Kerguelen Plateau. The authors characterize the intensity and spatial distribution of the observed turbulent dissipation and the derived turbulent mixing, and consider underpinning mechanisms in the context of the internal wave field and the processes governing the waves’ generation and evolution.The turbulent dissipation rate and the derived diapycnal diffusivity are highly variable with systematic depth dependence. The dissipation rate is generally enhanced in the upper 1000–1500 m of the water column, and both the dissipation rate and diapycnal diffusivity are enhanced in some places near the seafloor, commonly in regions of rough topography and in the vicinity of strong bottom flows associated with the ACC jets. Turbulent dissipation is high in regions where internal wave energy is high, consistent with the idea that interior dissipation is related to a breaking internal wave field. Elevated turbulence occurs in association with downward-propagating near-inertial waves within 1–2 km of the surface, as well as with upward-propagating, relatively high-frequency waves within 1–2 km of the seafloor. While an interpretation of these near-bottom waves as lee waves generated by ACC jets flowing over small-scale topographic roughness is supported by the qualitative match between the spatial patterns in predicted lee wave radiation and observed near-bottom dissipation, the observed dissipation is found to be only a small percentage of the energy flux predicted by theory. The mismatch suggests an alternative fate to local dissipation for a significant fraction of the radiated energy.
Effects of Remote Generation Sites on Model Estimates of M2 Internal Tides in the Philippine Sea*
Authors: Kerry Colette G. , Powell Brian S. , Carter Glenn S. 
Published: September 2012

Abstract
This study investigates the impact of remotely generated internal tides on model estimates of barotropic to baroclinic tidal conversion for two generation sites bounding the Philippine Sea: the Luzon Strait and the Mariana Island Arc. A primitive equation model is used to characterize the internal tides generated by the principal semidiurnal tide (M2) over a domain encompassing the two generation sites. Energetic internal tides are generated at the Luzon Strait where nearly 17 GW of barotropic tide energy is converted to baroclinic energy, of which 44% (4.78 GW) is radiated eastward into the Philippine Sea. From the Mariana Arc, baroclinic energy propagates westward into the Philippine Sea as a result of 3.82 GW of barotropic to baroclinic energy conversion. Simulations that focus on each generation site without influence of the other are performed, and comparisons show that remotely generated internal tides have a significant effect on local conversion at the two sites. Total conversion is greater in the absence of remotely generated internal tides at both sites: 11% greater at the Luzon Strait and 65% greater at the Mariana Arc. The first three modes of the remotely generated internal tides traverse the basin and alter the amplitude and phase of bottom pressure. The arrival of the remote internal tides varies significantly with changing stratification and mesoscale circulation. The results suggest that an important source of variability in local conversion around the globe is due to remotely generated internal tides.
In Situ CO2 and O2 Measurements on a Profiling Float
Authors: Fiedler Björn , Fietzek Peer , Vieira Nuno , Silva Péricles , Bittig Henry C. , Körtzinger Arne 
Published: September 2012

Abstract
In recent years, profiling floats, which form the basis of the successful international Argo observatory, are also being considered as platforms for marine biogeochemical research. This study showcases the utility of floats as a novel tool for combined gas measurements of CO2 partial pressure (pCO2) and O2. These float prototypes were equipped with a small-sized and submersible pCO2 sensor and an optode O2 sensor for high-resolution measurements in the surface ocean layer. Four consecutive deployments were carried out during November 2010 and June 2011 near the Cape Verde Ocean Observatory (CVOO) in the eastern tropical North Atlantic. The profiling float performed upcasts every 31 h while measuring pCO2, O2, salinity, temperature, and hydrostatic pressure in the upper 200 m of the water column. To maintain accuracy, regular pCO2 sensor zeroings at depth and surface, as well as optode measurements in air, were performed for each profile. Through the application of data processing procedures (e.g., time-lag correction), accuracies of floatborne pCO2 measurements were greatly improved (10–15 μatm for the water column and 5 μatm for surface measurements). O2 measurements yielded an accuracy of 2 μmol kg−1. First results of this pilot study show the possibility of using profiling floats as a platform for detailed and unattended observations of the marine carbon and oxygen cycle dynamics.
The Multiple Altimeter Beam Experimental Lidar (MABEL): An Airborne Simulator for the ICESat-2 Mission
Authors: McGill Matthew , Markus Thorsten , Scott V. Stanley , Neumann Thomas 
Published: September 2012

Abstract
This paper presents the motivation for, and initial results from, the Multiple Altimeter Beam Experimental lidar (MABEL) instrument. The MABEL instrument provides a new capability for airborne altimetry measurements and serves as a prototype and simulator for the upcoming NASA second-generation Ice, Cloud, and Land Elevation Satellite (ICESat-2) mission. Designed to be highly flexible in measurement capability, MABEL serves as both a demonstration of measurement capability and a science tool for cryospheric and biospheric remote sensing. It is important to document the instrument specifications and essential background information to provide a suitable reference for the detailed MABEL results and science investigation publications that will be forthcoming.