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Find video protocols related to scientific articles indexed in Pubmed.
Reducing the breast cancer menace: the role of the male partner in ghana.
Asian Pac. J. Cancer Prev.
PUBLISHED: 10-24-2014
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Breast cancer continues to be the most common type of cancer afflicting many women worldwide. Presently, educational campaigns and research target only women as if men have no role in the management of this disease. The study examined the willingness of male partners to assist in early female breast cancer detection as well as their awareness and knowledge levels.
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The biology of A20-like molecules.
Adv. Exp. Med. Biol.
PUBLISHED: 10-11-2014
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A20 is a ubiquitin-editing molecule. It belongs to a novel family of deubiquitinating cysteine proteases, called the ovarian tumor (OTU) family, which can cleave monoubiquitin from modified proteins. In addition, A20 contains seven Cys2-Cys2 zinc fingers, one of which is believed to regulate E3 ubiquitin ligase activity. Here we review the biology of human genes that encode OTU domains or contain A20-type zinc fingers. The human genome contains 15 members of the OTU family including the deubiquitinating enzymes Cezanne, VCIP135 and Otubain 1. Genomic analysis also identified 10 genes that contain A20-type zinc fingers including Rabex5, Znf216 and AWP1. In Rabex5 the A20-zinc finger regulates E3 ligase activity whereas A20-type zinc fingers of Znf216 and AWP1 function as ubiquitin-binding motifs. A20 and its relatives regulate highly divergent physiological activities including NF-kappaB activity (A20, Cezanne, Znf216, Rabex5), endocytosis (Rabex5, AWP1), skeletal muscle atrophy (Znf216), Golgi membrane fusion (VCIP135) and T-cell anergy (Otubain 1). Further studies are required to characterize the biology of other A20-related molecules whose function remains largely undefined.
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Biomechanical factors in atherosclerosis: mechanisms and clinical implications†
Eur. Heart J.
PUBLISHED: 09-17-2014
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Blood vessels are exposed to multiple mechanical forces that are exerted on the vessel wall (radial, circumferential and longitudinal forces) or on the endothelial surface (shear stress). The stresses and strains experienced by arteries influence the initiation of atherosclerotic lesions, which develop at regions of arteries that are exposed to complex blood flow. In addition, plaque progression and eventually plaque rupture is influenced by a complex interaction between biological and mechanical factors-mechanical forces regulate the cellular and molecular composition of plaques and, conversely, the composition of plaques determines their ability to withstand mechanical load. A deeper understanding of these interactions is essential for designing new therapeutic strategies to prevent lesion development and promote plaque stabilization. Moreover, integrating clinical imaging techniques with finite element modelling techniques allows for detailed examination of local morphological and biomechanical characteristics of atherosclerotic lesions that may be of help in prediction of future events. In this ESC Position Paper on biomechanical factors in atherosclerosis, we summarize the current 'state of the art' on the interface between mechanical forces and atherosclerotic plaque biology and identify potential clinical applications and key questions for future research.
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Preparation, anti-trypanosomal activity and localisation of a series of dipeptide-based vinyl sulfones.
Org. Biomol. Chem.
PUBLISHED: 08-20-2014
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An improved, Weinreb amide-based, synthesis of anti-trypanosomal lysine-containing vinyl sulfones is described incorporating, as a feature, diversity at the ?-lysine amino group. Members of this family demonstrated moderate to good efficacy as anti-trypanosomal agents and a fluorescent dansyl (19) derivative was used to investigate subcellular localisation of the compound class.
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Piezo1 integration of vascular architecture with physiological force.
Nature
PUBLISHED: 08-10-2014
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The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca(2+)-permeable non-selective cationic channels for detection of noxious mechanical impact. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology. Global or endothelial-specific disruption of mouse Piezo1 profoundly disturbed the developing vasculature and was embryonic lethal within days of the heart beating. Haploinsufficiency was not lethal but endothelial abnormality was detected in mature vessels. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear-stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells. Downstream of this calcium influx there was protease activation and spatial reorganization of endothelial cells to the polarity of the applied force. The data suggest that Piezo1 channels function as pivotal integrators in vascular biology.
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Mechanoresponsive networks controlling vascular inflammation.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 06-19-2014
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Atherosclerosis is a chronic inflammatory disease of arteries that develops preferentially at branches and bends that are exposed to disturbed blood flow. Vascular function is modified by flow, in part, via the generation of mechanical forces that alter multiple physiological processes in endothelial cells. Shear stress has profound effects on vascular inflammation; high uniform shear stress prevents leukocyte recruitment to the vascular wall by reducing endothelial expression of adhesion molecules and other inflammatory proteins, whereas low oscillatory shear stress has the opposite effects. Here, we review the molecular mechanisms that underpin the effects of shear stress on endothelial inflammatory responses. They include shear stress regulation of inflammatory mitogen-activated protein kinase and nuclear factor-?B signaling. High shear suppresses these pathways through the induction of several negative regulators of inflammation, whereas low shear promotes inflammatory signaling. Furthermore, we summarize recent studies indicating that inflammatory signaling is highly sensitive to pulse wave frequencies, magnitude, and direction of flow. Finally, the importance of systems biology approaches (including omics studies and functional screening) to identify novel mechanosensitive pathways is discussed.
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Aortic stiffness is an indicator of cognitive dysfunction before and after aortic valve replacement for aortic stenosis.
Interact Cardiovasc Thorac Surg
PUBLISHED: 06-15-2014
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Post-cardiac surgical cognitive dysfunction occurs more commonly following valvular procedures. Cognitive function has been related to vascular health status; however, the relation between pre-existent arterial stiffness and perioperative cognitive dysfunction is yet to be defined. The objective of this study was to assess whether aortic stiffness is related to cognitive dysfunction in surgical aortic stenosis (AS) pre- and postoperatively.
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X-ray diffraction tomography employing an annular beam.
Opt Express
PUBLISHED: 06-13-2014
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We demonstrate depth-resolved materials characterization by scanning a sample through an annular beam of X-rays. We measure Bragg X-ray diffraction from a sample with a planar detector positioned centrally in a circular dark field defined by the annular beam. The diffraction maxima are optically encoded with the position of crystalline phases along this beam. Depth-resolved material phase images are recovered via tomosynthesis. We demonstrate our technique using a heterogeneous three-dimensional object comprising three different phases; cyclotetramethylene - tetranitramine, copper and nickel, distributed in a low density medium. Our technique has wide applicability in analytical imaging and is scalable with respect to both scan size and X-ray energy.
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Validation study of a ray-tracing simulator for focal construct geometry.
Appl Radiat Isot
PUBLISHED: 06-10-2014
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We present the results of a computer modelling package designed to simulate X-ray diffraction imaging employing focal construct geometry. The paths of coherently diffracted X-rays are modelled by ray-tracing. The results of the study show good agreement between simulated and measured data obtained in the laboratory. The validation of the modelling package permits the rapid optimisation and prototyping of focal construct technology, which has wide applicability in security X-ray imaging.
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Hysteretic adsorption of CO? onto a Cu?(pzdc)?(bpy) porous coordination polymer and concomitant framework distortion.
Dalton Trans
PUBLISHED: 06-06-2014
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The present study focuses on the long-range structural changes that occur in the porous coordination polymer Cu2(pzdc)2(bpy) (pzdc = pyrazine-2,3-dicarboxylate, bpy = 4,4'-bipyridine), also known as CPL-2, upon adsorption of CO2 at 25 °C and up to 7 atm. The structural data were gathered using in situ diffraction studies. CPL-2 exhibited an unexpected hysteretic adsorption-desorption process. The onset of hysteresis occurs at a pressure where full occupancy of the volume of the CPL-2 galleries is achieved while the framework retains a structure similar to what is observed under ambient conditions. Moreover, the onset occurs at a CO2 partial pressure larger than 2 atm and could be related to a combination of adsorbate-adsorbent interactions and forces exerted onto the CPL-2 framework. Pore volumes estimated from fits of the Dubinin-Astakhov isotherm model against the CO2 desorption data gathered at 25 and -78.5 °C, respectively, provided further evidence of the aforementioned CPL-2 framework changes. These findings are of relevance to the understanding of adsorption processes in metal organic frameworks or coordination polymers under conditions that are of relevance to gas capture at industrial scale.
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Structured layer of rhenium dye on SiO? and TiO? surfaces by Langmuir-Blodgett technique.
Langmuir
PUBLISHED: 05-22-2014
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We demonstrate the Langmuir-Blodgett assembly of two rhenium-bipyridine complexes containing a flexible or an aromatic bridge, and transfer of the monolayer to SiO2 and single crystal TiO2 substrates. Both of the complexes (ReEC and Re2TC) have a hydrophilic carboxylic acid group, which preferentially anchors into the water subphase, and forms stable monolayers at surface pressures up to 40 mN/m. The optimum conditions for the formation of complete monolayers of both ReEC and Re2TC were identified through characterization of the morphology by atomic force microscopy (AFM), the thickness by ellipsometry, and the surface coverage by X-ray photoelectron spectroscopy (XPS). X-ray reflectivity measurements (XRR) are consistent with the orientation of the molecules normal to the substrate, and their extension to close to their calculated maximum length. Parameters derived from XRR analysis show that there is a higher packing density for Re2TC monolayers than for ReEC monolayers, attributable to the more rigid bridge in the Re2TC molecule.
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In vivo mapping of vascular inflammation using the translocator protein tracer 18F-FEDAA1106.
Mol Imaging
PUBLISHED: 05-15-2014
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Noninvasive imaging methods are required to monitor the inflammatory content of atherosclerotic plaques. FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-methoxybenzyl) acetamide) is a selective ligand for TSPO-18kDa (also known as peripheral benzodiazepine receptor), which is expressed by activated macrophages. We compared 18F-FEDAA1106 and 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG, a marker of glucose metabolism) for positron emission tomographic (PET) imaging of vascular inflammation. This was tested using a murine model in which focal inflammation was induced in the carotid artery via placement of a constrictive cuff. Immunostaining revealed CD68-positive cells (macrophages) at a disturbed flow site located downstream from the cuff. Dynamic PET imaging using 18F-FEDAA1106 or 18F-FDG was registered to anatomic data generated by computed tomographic (CT)/CT angiography. Standardized uptake values were significantly increased at cuffed compared to contralateral arteries using either 18F-FEDAA1106 (p < .01) or FDG (p < .05). However, the 18F-FEDAA1106 signal was significantly higher at the inflamed disturbed flow region compared to the noninflamed uniform flow regions, whereas differences in FDG uptake were less distinct. We conclude that 18F-FEDAA1106 can be used in vivo for detection of vascular inflammation. Moreover, the signal pattern of 18F-FEDAA1106 corresponded with vascular inflammation more specifically than FDG uptake.
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Aortic stiffness as a marker of cardiac function and myocardial strain in patients undergoing aortic valve replacement.
J Cardiothorac Surg
PUBLISHED: 04-13-2014
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Cardiac function and myocardial strain are affected by cardiac afterload, which is in part due to the stiffness of the aortic wall. In this study, we hypothesize that aortic pulse wave velocity (PWV) as a marker of aortic stiffness correlates with conventional clinical and biochemical markers of cardiac function and perioperative myocardial strain in aortic valve replacement (AVR).
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Requirement of JNK1 for endothelial cell injury in atherogenesis.
Atherosclerosis
PUBLISHED: 04-11-2014
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The c-Jun N-terminal kinase (JNK) family regulates fundamental physiological processes including apoptosis and metabolism. Although JNK2 is known to promote foam cell formation during atherosclerosis, the potential role of JNK1 is uncertain. We examined the potential influence of JNK1 and its negative regulator, MAP kinase phosphatase-1 (MKP-1), on endothelial cell (EC) injury and early lesion formation using hypercholesterolemic LDLR(-/-) mice.
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Metabolic derangement and cardiac injury early after reperfusion following intermittent cross-clamp fibrillation in patients undergoing coronary artery bypass graft surgery using conventional or miniaturized cardiopulmonary bypass.
Mol. Cell. Biochem.
PUBLISHED: 03-25-2014
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Myocardial ischemic stress and early reperfusion injury in patients undergoing coronary artery bypass grafting (CABG) operated on using intermittent cross-clamp fibrillation (ICCF) are not presently known. The role of mini-cardiopulmonary bypass (mCPB) versus conventional CPB (cCPB) during ICCF has not been investigated. These issues have been addressed as secondary objective of randomised controlled trial (ISRCTN30610605) comparing cCPB and mCPB. Twenty-six patients undergoing primary elective CABG using ICCF were randomised to either cCPB or mCPB. Paired left ventricular biopsies collected from 21 patients at the beginning and at the end of CPB were used to measure intracellular substrates (ATP and related compounds). Cardiac troponin T (cTnT) and CK-MB levels were measured in plasma collected from all patients preoperatively and after 1, 30, 60, 120, and 300 min after institution of CPB. ICCF was associated with significant ischemic stress as seen by fall in energy-rich phosphates early after reperfusion. There was also a fall in nicotinamide adenine dinucleotide (NAD(+)) indicating cardiomyocyte death which was confirmed by early release of cTnT and CK-MB during CPB. Ischemic stress and early myocardial injury were similar for cCPB and mCPB. However, the overall cardiac injury was significantly lower in the mCPB group as measured by cTnT (mean ± SEM: 96 ± 14 vs. 59 ± 8 µg/l, p = 0.02), but not with CK-MB. ICCF is associated with significant metabolic derangement and early myocardial injury. This early outcome was not affected by the CPB technique. However, the overall cardiac injury was lower for mCPB only when measured using cTnT.
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Disturbed flow promotes endothelial senescence via a p53-dependent pathway.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 03-20-2014
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Although atherosclerosis is associated with systemic risk factors such as age, high cholesterol, and obesity, plaque formation occurs predominately at branches and bends that are exposed to disturbed patterns of blood flow. The molecular mechanisms that link disturbed flow-generated mechanical forces with arterial injury are uncertain. To illuminate them, we investigated the effects of flow on endothelial cell (EC) senescence.
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Localized excited charge carriers generate ultrafast inhomogeneous strain in the multiferroic BiFeO3.
Phys. Rev. Lett.
PUBLISHED: 03-03-2014
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We apply ultrafast x-ray diffraction with femtosecond temporal resolution to monitor the lattice dynamics in a thin film of multiferroic BiFeO3 after above-band-gap photoexcitation. The sound-velocity limited evolution of the observed lattice strains indicates a quasi-instantaneous photoinduced stress which decays on a nanosecond time scale. This stress exhibits an inhomogeneous spatial profile evidenced by the broadening of the Bragg peak. These new data require substantial modification of existing models of photogenerated stresses in BiFeO3: the relevant excited charge carriers must remain localized to be consistent with the data.
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Could failure of the spring ligament complex be the driving force behind the development of the adult flatfoot deformity?
J Foot Ankle Surg
PUBLISHED: 02-22-2014
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We conducted an investigation into the relative associations of magnetic resonance imaging (MRI)-defined pathologic features of the spring ligament and/or tibialis posterior tendon with radiographic evidence of a planovalgus foot position. A total of 161 patient images (MRI and plain radiographs) obtained from the foot and ankle clinic (2008 to 2011) were retrospectively reviewed. All 161 patients (64 male and 97 female; mean age 45.9 years, range 18 to 86) were included in the analysis. Lateral weightbearing radiographs were analyzed for the talo-first metatarsal angle ? 5°, calcaneal pitch ? 20°, and talocalcaneal angle ? 45°. A positive finding for ? 1 measurements identified a radiographic planovalgus position of the foot. The radiographic deformity was analyzed against the MRI evidence of either spring ligament or tibialis posterior tendon pathologic features for significance (p < .05). Evidence of a spring ligament abnormality was strongly associated with a planovalgus foot position, reaching high levels of statistical significance in all 3 categories of radiographic deformity (odds ratio 9.2, p < .0001). Abnormalities of the tibialis posterior tendon failed to demonstrate significance, unless grade I changes were excluded, and grade II and III appearances were analyzed in isolation (odds ratio 2.9, p = .04). Although absolute causal relationships were not tested, this investigation has clearly demonstrated that MRI-defined abnormalities of the spring ligament complex are possibly of at least equal importance to tibialis posterior dysfunction for the presence of a moderate to severe radiographic planovalgus foot position.
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The chemistry and biology of febrifugine and halofuginone.
Bioorg. Med. Chem.
PUBLISHED: 02-14-2014
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The trans-2,3-disubstituted piperidine, quinazolinone-containing natural product febrifugine (also known as dichroine B) and its synthetic analogue, halofuginone, possess antimalarial activity. More recently studies have also shown that halofuginone acts as an agent capable of reducing fibrosis, an indication with clinical relevance for several disease states. This review summarizes historical isolation studies and the chemistry performed which culminated in the correct structural elucidation of naturally occurring febrifugine and its isomer isofebrifugine. It also includes the range of febrifugine analogues prepared for antimalarial evaluation, including halofuginone. Finally, a section detailing current opinion in the field of halofuginone's human biology is included.
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Hemiacetal stabilization in a chymotrypsin inhibitor complex and the reactivity of the hydroxyl group of the catalytic serine residue of chymotrypsin.
Biochim. Biophys. Acta
PUBLISHED: 02-13-2014
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The aldehyde inhibitor Z-Ala-Ala-Phe-CHO has been synthesized and shown by (13)C-NMR to react with the active site serine hydroxyl group of alpha-chymotrypsin to form two diastereomeric hemiacetals. For both hemiacetals oxyanion formation occurs with a pKa value of ~7 showing that chymotrypsin reduces the oxyanion pKa values by ~5.6 pKa units and stabilizes the oxyanions of both diastereoisomers by ~32kJmol(-1). As pH has only a small effect on binding we conclude that oxyanion formation does not have a significant effect on binding the aldehyde inhibitor. By comparing the binding of Z-Ala-Ala-Phe-CHO with that of Z-Ala-Ala-Phe-H we estimate that the aldehyde group increases binding ~100 fold. At pH7.2 the effective molarity of the active site serine hydroxy group is ~6000 which is ~7× less effective than with the corresponding glyoxal inhibitor. Using (1)H-NMR we have shown that at both 4 and 25°C the histidine pKa is ~7.3 in free chymotrypsin and it is raised to ~8 when Z-Ala-Ala-Phe-CHO is bound. We conclude that oxyanion formation only has a minor role in raising the histidine pKa and that the aldehyde hydrogen must be replaced by a larger group to raise the histidine pKa>10 and give stereospecific formation of tetrahedral intermediates. The results show that a large increase in the pKa of the active site histidine is not needed for the active site serine hydroxyl group to have an effective molarity of 6000.
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Efficient room-temperature synthesis of a highly strained carbon nanohoop fragment of buckminsterfullerene.
Nat Chem
PUBLISHED: 02-07-2014
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Warped carbon-rich molecules have captured the imagination of scientists across many disciplines. Owing to their promising materials properties and challenging synthesis, strained hydrocarbons are attractive targets that push the limits of synthetic methods and molecular design. Herein we report the synthesis and characterization of [5]cycloparaphenylene ([5]CPP), a carbon nanohoop that can be envisaged as an open tubular fragment of C60, the equator of C70 fullerene and the unit cycle of a [5,5] armchair carbon nanotube. Given its calculated 119 kcal mol(-1) strain energy and severely distorted benzene rings, this synthesis, which employs a room-temperature macrocyclization of a diboronate precursor, single-electron reduction and elimination, is remarkably mild and high yielding (27% over three steps). Single-crystal X-ray diffraction data were obtained to confirm its geometry and previously disputed benzenoid character. First and second pseudoreversible oxidation and reduction events were observed via cyclic voltammetry. The ease of synthesis, high solubility and narrowest optical HOMO/LUMO gap of any para-polyphenylene synthesized make [5]CPP a desirable new material for organic electronics.
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Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 01-15-2014
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Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood.
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Bis{2-[(3,5-diphenyl-1H-pyrrol-2-ylidene-?N)amino]-3,5-diphenylpyrrol-1-ido-?N}palladium(II): a homoleptic four-coordinate tetraphenylazadipyrromethene complex of palladium.
Acta Crystallogr C Struct Chem
PUBLISHED: 01-02-2014
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The structural chemistry of the title compound, [Pd(C32H22N3)2], at 173?K is described. The compound is comprised of two deprotonated (3,5-diphenyl-1H-pyrrol-2-yl)(3,5-diphenylpyrrol-2-ylidene)amine ligands coordinated to a central Pd(II) cation, which lies on an inversion centre and has distorted square-planar geometry. The Pd-N bond lengths range from 2.008?(4) to 2.014?(4)?Å and the bite angle is 84.16?(14)°. The chelate plane makes a dihedral angle of 45.3?(2)° with respect to the central PdN4 plane, giving a stepped conformation to the molecule. The complex displays simple intramolecular C-H···N hydrogen bonds, while the unit cell consists of discrete monomeric Pd(C32H22N3)2 units which display intermolecular C-H···? interactions and limited intra- and intermolecular ?-? stacking.
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Cytoprotective signaling and gene expression in endothelial cells and macrophages-lessons for atherosclerosis.
Microcirculation
PUBLISHED: 11-02-2013
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Atherosclerosis is a chronic inflammatory disease of the medium and large arteries driven in large part by the accumulation of oxidized low-density lipoproteins and other debris at sites rendered susceptible because of the geometry of the arterial tree. As lesions develop, they acquire a pathologic microcirculation that perpetuates lesion progression, both by providing a means for further monocyte and T-lymphocyte recruitment into the arterial wall and by the physical and chemical stresses caused by micro-hemorrhage. This review summarizes work performed in our department investigating the roles of signaling pathways, alone and in combination, that lead to specific programs of gene expression in the atherosclerotic environment. Focusing particularly on cytoprotective responses that might be enhanced therapeutically, the work has encompassed the anti-inflammatory effects of arterial laminar shear stress, mechanisms of induction of membrane inhibitors that prevent complement-mediated injury, homeostatic macrophage responses to hemorrhage, and the transcriptional mechanisms that control the stability, survival, and quiescence of endothelial monolayers. Lastly, while the field has been dominated by investigation into the mechanisms of DNA transcription, we consider the importance of parallel post-transcriptional regulatory mechanisms for fine-tuning functional gene expression repertoires.
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Halonium ion triggered rearrangement of unsaturated benzo-annulated bi- and tricyclic sulfonamides.
J. Org. Chem.
PUBLISHED: 10-04-2013
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The halonium ion mediated 1,2-Wagner-Meerwein-type rearrangement of a series of benzo-fused bi- and tricyclic sulfonamides is reported. During this rearrangement the carbon-carbon bond that migrates was selectively set in the intramolecular Mizoroki-Heck (IHR) synthesis of the starting materials. Consequently, this method constitutes a means to access the regioisomeric series of cyclic sulfonamides not observed during the Mizoroki-Heck reaction.
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Absolute configuration of falcarinol (9Z-heptadeca-1,9-diene-4,6-diyn-3-ol) from Pastinaca sativa.
Nat Prod Commun
PUBLISHED: 10-02-2013
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Falcarinol (9Z-heptadeca-1,9-diene-4,6-diyn-3-ol; (1) is a polyacetylene commonly found in several plant families. The absolute configuration of naturally occurring 1 is not clear and contradictory results have been reported in the literature. Determination of the absolute configuration of 1 from Pastinaca sativa L. was carried out. Isolation of 95% pure 1 was performed via successive fractionation and preparative-HPLC. A racemic mixture comprised of 3R-1 and 3S-1 was synthesized in order to confirm the absolute configuration of the isolated natural product using chiral HPLC. Based on a combination of chiral HPLC and specific rotation, 1 present in P. saliva was found to have a 3R absolute configuration (i.e. (3R, 9Z)-heptadeca-1,9-diene-4,6-diyn-3-ol).
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Vinyl sulfone-based peptidomimetics as anti-trypanosomal agents: design, synthesis, biological and computational evaluation.
J. Med. Chem.
PUBLISHED: 09-03-2013
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A series of vinyl sulfone-containing peptidomimetics were rationally designed, synthesized, and evaluated against Trypanosoma brucei brucei . These electrophilic compounds are likely to exert their antitrypanosomal activity via inhibition of trypanosomal cysteine proteases, TbCatB and rhodesain, through alkylation of a key cysteine residue within the protease active site. The series was designed to present complementary groups to naturally recognized peptide substrates while probing tolerance to a range of substitutions at the P1, P1, and P2 positions. The most potent compound, 29 (EC50 = 70 nM, T. b. brucei whole cell assay), displayed minimal toxicity (>785 times selectivity) when assayed for cytotoxicity against the human promyelocytic leukemia (HL-60) cell line. Cells treated with compound 29, as with K777 (2), exhibited an increase in both the number of multinucleated cells and cells with swollen flagellar pockets. Computational analysis revealed a strong correlation between the hypothetical binding mode in TbCatB/rhodesain and trypanocidal activity in vitro.
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Control of tissue morphology by Fasciclin III-mediated intercellular adhesion.
Development
PUBLISHED: 08-14-2013
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Morphogenesis is dependent on the orchestration of multiple developmental processes to generate mature functional organs. However, the signalling pathways that coordinate morphogenesis and the mechanisms that translate these signals into tissue shape changes are not well understood. Here, we demonstrate that changes in intercellular adhesion mediated by the transmembrane protein Fasciclin III (FasIII) represent a key mediator of morphogenesis. Using the embryonic Drosophila hindgut as an in vivo model for organogenesis, we show that the tightening of hindgut curvature that normally occurs between embryonic stage 12 and 15 to generate the characteristic shepherds crook shape is dependent on localised JAK/STAT pathway activation. This localised pathway activity drives the expression of FasIII leading to its subcellular lateralisation at a stage before formation of septate junctions. Additionally, we show that JAK/STAT- and FasIII-dependent morphogenesis also regulates folds within the third instar wing imaginal disc. We show that FasIII forms homophilic intercellular interactions that promote intercellular adhesion in vivo and in cultured cells. To explore these findings, we have developed a mathematical model of the developing hindgut, based on the differential interfacial tension hypothesis (DITH) linking intercellular adhesion and localised surface tension. Our model suggests that increased intercellular adhesion provided by FasIII can be sufficient to drive the tightening of tube curvature observed. Taken together, these results identify a conserved molecular mechanism that directly links JAK/STAT pathway signalling to intercellular adhesion and that sculpts both tubular and planar epithelial shape.
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Radiation exposure associated with dedicated renal mass computed tomography protocol: impact of patient characteristics.
J. Endourol.
PUBLISHED: 08-09-2013
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Renal mass protocol CT (RMP-CT) using multiphase abdomen and pelvis CT imaging is the mainstay for diagnosis, characterization, and follow-up for renal masses; however, it is associated with ionizing radiation to the patient. We sought to quantify the effective dose associated with RMP-CT and to determine how patient factors affect radiation exposure.
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Proteomic analysis of B-cell receptor signaling in chronic lymphocytic leukaemia reveals a possible role for kininogen.
J Proteomics
PUBLISHED: 07-28-2013
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CLL is an incurable disease with variable prognosis. The hyper reactivity of the B-cell receptor (BCR) to unknown antigen ligation plays a pivotal role in CLL-cell survival. We aimed to investigate the BCR signalling pathway using proteomics to identify novel proteins which may have clinical relevance in this disease. Three CLL samples were selected based upon BCR responsiveness, demonstrated by upregulation of phospho-ERK following in vitro stimulation. The differential expression of proteins, upon artificial stimulation of the BCR, was examined in these samples using two-dimensional gel electrophoresis in combination with mass spectrometry. Proteins of interest were subsequently examined using immunoblotting. Proteomic analysis revealed that kininogen, a critical protein of kinin-kallikrein system, was upregulated in all 3 clinical samples upon BCR stimulation. There are 2 forms of kininogen: HMWK and LMWK. The upregulation of LMWK upon BCR stimulation was confirmed by immunoblotting in all 3 of these samples. In a pilot series of 52 unselected CLL samples, 71% demonstrated basal LMWK expression. There was a trend towards shorter median survival in LMWK positive cases (147months versus 253months for LMWK negative cases; p=0.125). Kininogen may be a novel therapeutic target in CLL and the possible association with prognosis warrants further investigation.
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Abdominopelvic and lower extremity deep venous thrombosis: evaluation with contrast-enhanced MR venography with a blood-pool agent.
AJR Am J Roentgenol
PUBLISHED: 06-25-2013
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The purpose of this article is to evaluate contrast-enhanced (CE) MR venography (MRV) with a blood-pool agent for detection of abdominopelvic and lower extremity deep venous thrombosis (DVT) compared with a conventional unenhanced gradient-recalled echo (GRE) MRV technique.
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Structure of the fibrillin-1 N-terminal domains suggests that heparan sulfate regulates the early stages of microfibril assembly.
Structure
PUBLISHED: 06-06-2013
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The human extracellular matrix glycoprotein fibrillin-1 is the primary component of the 10- to 12-nm-diameter microfibrils, which perform key structural and regulatory roles in connective tissues. Relatively little is known about the molecular mechanisms of fibrillin assembly into microfibrils. Studies using recombinant fibrillin fragments indicate that an interaction between the N- and C-terminal regions drives head-to-tail assembly. Here, we present the structure of a fibrillin N-terminal fragment comprising the fibrillin unique N-terminal (FUN) and the first three epidermal growth factor (EGF)-like domains (FUN-EGF3). Two rod-like domain pairs are separated by a short, flexible linker between the EGF1 and EGF2 domains. We also show that the binding site for the C-terminal region spans multiple domains and overlaps with a heparin interaction site. These data suggest that heparan sulfate may sequester fibrillin at the cell surface via FUN-EGF3 prior to aggregation of the C terminus, thereby regulating microfibril assembly.
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Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers.
Blood
PUBLISHED: 05-08-2013
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Fetomaternal alloimmune thrombocytopenia, caused by the maternal generation of antibodies against fetal human platelet antigen-1a (HPA-1a), can result in intracranial hemorrhage and intrauterine death. We have developed a therapeutic human recombinant high-affinity HPA-1a antibody (B2G1?nab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fc? receptors. In vitro studies with a range of clinical anti-HPA-1a sera have shown that B2G1?nab blocks monocyte chemiluminescence by >75%. In this first-in-man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1?nab have the same intravascular survival as unsensitized platelets (190 hours), while platelets sensitized with a destructive immunoglobulin G1 version of the antibody (B2G1) are cleared from the circulation in 2 hours. Mimicking the situation in fetuses receiving B2G1?nab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1?nab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1?nab. The efficient clearance of platelets sensitized with B2G1 also opens up the opportunity to carry out studies of prophylaxis to prevent alloimmunization in HPA-1a-negative mothers.
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Genome Sequence of Stenotrophomonas maltophilia Strain AU12-09, Isolated from an Intravascular Catheter.
Genome Announc
PUBLISHED: 05-04-2013
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Stenotrophomonas maltophilia is an opportunistic nosocomial pathogen that is characterized by its high-level intrinsic resistance to a variety of antibiotics and its ability to form biofilms. Here, we report the draft genome sequence of Stenotrophomonas maltophilia AU12-09, isolated from an intravascular catheter tip.
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The effects of stenting on shear stress: relevance to endothelial injury and repair.
Cardiovasc. Res.
PUBLISHED: 04-15-2013
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Stent deployment following balloon angioplasty is used routinely to treat coronary artery disease. These interventions cause damage and loss of endothelial cells (EC), and thus promote in-stent thrombosis and restenosis. Injured arteries are repaired (intrinsically) by locally derived EC and by circulating endothelial progenitor cells which migrate and proliferate to re-populate denuded regions. However, re-endothelialization is not always complete and often dysfunctional. Moreover, the molecular and biomechanical mechanisms that control EC repair and function in stented segments are poorly understood. Here, we propose that stents modify endothelial repair processes, in part, by altering fluid shear stress, a mechanical force that influences EC migration and proliferation. A more detailed understanding of the biomechanical processes that control endothelial healing would provide a platform for the development of novel therapeutic approaches to minimize damage and promote vascular repair in stented arteries.
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Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination.
Circ. Res.
PUBLISHED: 04-05-2013
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Hypoxia followed by reoxygenation promotes inflammation by activating nuclear factor ?B transcription factors in endothelial cells (ECs). This process involves modification of the signaling intermediary tumor necrosis factor receptor-associated factor 6 with polyubiquitin chains. Thus, cellular mechanisms that suppress tumor necrosis factor receptor-associated factor 6 ubiquitination are potential therapeutic targets to reduce inflammation in hypoxic tissues.
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MRI features most often associated with surgically proven tears of the spring ligament complex.
Skeletal Radiol.
PUBLISHED: 04-04-2013
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The authors aim to present the common MRI appearances of surgically proven spring ligament tears as minimal radiological literature exists regarding injury to this increasingly important structure.
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Loss of function of parathyroid hormone receptor 1 induces Notch-dependent aortic defects during zebrafish vascular development.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 04-04-2013
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Coarctation of the aorta is rarely associated with known gene defects. Blomstrand chondrodysplasia, caused by mutations in the parathyroid hormone receptor 1 (PTHR1) is associated with coarctation of the aorta in some cases, although it is unclear whether PTHR1 deficiency causes coarctation of the aorta directly. The zebrafish allows the study of vascular development using approaches not possible in other models. We therefore examined the effect of loss of function of PTHR1 or its ligand parathyroid hormone-related peptide (PTHrP) on aortic formation in zebrafish.
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Double reduction of cyclic aromatic sulfonamides: synthesis of (+)-mesembrine and (+)-mesembranol.
J. Org. Chem.
PUBLISHED: 03-15-2013
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The synthesis of (+)-mesembrine (1) and (+)-mesembranol (2) has been achieved from the monoterpene (S)-(-)-perillyl alcohol. Key transformations include a diastereo- and regioselective Pd-mediated intramolecular Heck reaction, and a double reduction of the resultant cyclic sulfonamide, to afford the cis-3a-aryloctahydroindole skeleton.
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Discrimination of liquids by a focal construct X-ray diffraction geometry.
Appl Radiat Isot
PUBLISHED: 03-12-2013
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A novel technique for the discrimination of liquids based upon X-ray diffraction and focal construct technology (FCT) is presented. FCT is a new, high efficiency coherent scatter harvesting technique. In this work, the competence of FCT to discriminate liquids was explored. A variety of liquids relevant to security inspection was analysed by FCT for application to liquid security inspection. Discrimination of potential threat liquids was successfully and reliably achieved even for limited data sets.
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The use of Gore Bio-A in the management of the open abdomen.
BMJ Case Rep
PUBLISHED: 02-27-2013
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Non-permanent, non-woven options for the closure of an open abdomen have previously been limited to biologics such as Permacol or Strattice. Gore Bio-A is constructed from biocompatible synthetic fibres, the use of which has only been described in the repair of inguinal hernia, hiatal hernia and fistula-in-ano. A 60-year-old male underwent emergency laparotomy, partial gastrectomy and formation of a feeding jejunostomy for a strangulated and perforated intrathoracic hiatus hernia. His abdominal wall subsequently dehisced for which he underwent laparostomy and subsequent early closure with a Gore Bio-A mesh, secured in an onlay manner with 2/0 vicryl. Functional and cosmetic outcomes were satisfactory and the patient was discharged home. The use of Gore Bio-A is a safe, feasible and cost effective alternative to traditional biologics for the closure of a laparostomy, deployment of which is safe within a contaminated field. Further prospective data is needed to clarify its role.
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The automated monocyte count is independently predictive of overall survival from diagnosis in chronic lymphocytic leukaemia and of survival following first-line chemotherapy.
Leuk. Res.
PUBLISHED: 02-22-2013
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We conducted an analysis of the effect of monocytosis at diagnosis of CLL on subsequent overall (OS) and treatment-free survival (TFS). Monocyte counts were performed using the Sysmex XE2100 analyser. A monocyte count >0.9 × 10(9)L(-1) at the time of diagnosis was associated with a shortened OS and TFS. Monocytosis at diagnosis was associated with lymphocyte count, deletions of chromosomes 17p and 11q, the extent of IgVH somatic hypermutation and Binet stage. A multivariate analysis model which excluded somatic hypermutation found only monocyte count and age to be independently predictive of OS. The automated monocyte count is predictive of OS and TFS in newly diagnosed CLL.
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FDG-PET/CT characterization of adrenal nodules: diagnostic accuracy and interreader agreement using quantitative and qualitative methods.
Acad Radiol
PUBLISHED: 02-13-2013
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To determine interreader agreement and diagnostic accuracy across varying levels of reader experience using qualitative and quantitative methods of evaluating adrenal nodules using ((18)F)-fluorodeoxyglucose-positron emission tomography/computed tomography.
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The description of Mediorhynchus africanus n. sp. (Acanthocephala: Gigantorhynchidae) from galliform birds in Africa.
Parasitol. Res.
PUBLISHED: 02-06-2013
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Mediorhynchus africanus n. sp. is described from specimens collected from the helmeted guinea fowls, Numida meliagris Linn. 1758 in Kruger National Park and elsewhere in subSaharan Africa from the same and other galliform birds. These specimens were previously assigned to Mediorhynchus gallinarum Bhaleroa (Proc Zool Soc Lond Ser B Syst Morph 107:199-203, 1937) described from chickens, Gallus gallus L. in India and subsequently reported from other Asian countries. The identification of the African forms as M. gallinarum was based on similarities in the structure and measurements of the proboscis, proboscis armature and receptacle, lemnisci, and reproductive organs. A detailed study of specimens from South Africa and descriptions reported from elsewhere in Africa revealed marked differences that clearly distinguish the African material as new species. The African specimens are pseudo-segmented and flattened, the proboscis has two prominent apical pores, sensory pits are prevalent throughout the trunk, the posterior end of the female is broad with dorso-terminal dome-like extension opposite the subterminal gonopore, and the eggs are large. The Asian specimens from Indonesia and elsewhere are cylindrical and non-segmented, the proboscis lacks prominent apical pores, sensory pits are rare on the trunk, the posterior end of the female is pointed with a terminal gonopore, and the eggs are markedly smaller. We used DNA sequence from one mitochondrial gene (cytochrome oxidase subunit I) and one nuclear gene (18S ribosomal RNA) to infer the phylogenetic relationships of M. africanus and M. gallinarum and selected Acanthocephala. Medioryhnchus is monophyletic and M. africanus and M. gallinarum are allopatric sister species (9.7% sequence divergence). All findings indicate that M. africanus should be ranked as a separate species.
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Electronic origin of ultrafast photoinduced strain in BiFeO3.
Phys. Rev. Lett.
PUBLISHED: 01-18-2013
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Above-band-gap optical excitation produces interdependent structural and electronic responses in a multiferroic BiFeO(3) thin film. Time-resolved synchrotron x-ray diffraction shows that photoexcitation can induce a large out-of-plane strain, with magnitudes on the order of half of one percent following pulsed-laser excitation. The strain relaxes with the same nanosecond time dependence as the interband relaxation of excited charge carriers. The magnitude of the strain and its temporal correlation with excited carriers indicate that an electronic mechanism, rather than thermal effects, is responsible for the lattice expansion. The observed strain is consistent with a piezoelectric distortion resulting from partial screening of the depolarization field by charge carriers, an effect linked to the electronic transport of excited carriers. The nonthermal generation of strain via optical pulses promises to extend the manipulation of ferroelectricity in oxide multiferroics to subnanosecond time scales.
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Molecular diversity of the foregut bacteria community in the dromedary camel (Camelus dromedarius).
Environ. Microbiol.
PUBLISHED: 09-14-2011
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The molecular diversity of the foregut bacterial community in the dromedary camel (Camelus dromedarius) in Central Australia was investigated through comparative analyses of 16S rRNA gene sequences prepared from the foregut contents of 12 adult feral camels fed on native vegetation. A total of 267 full-length 16S rRNA gene clones were examined, with 151 operational taxonomic units (OTUs) identified at a 99% species-level identity cut-off criterion. The prediction of actual diversity in the foregut of the dromedary camel using the Chaol approach was 238 OTUs, while the richness and evenness of the diversity estimated using Shannon index was 4.84. The majority of bacteria in the current study were affiliated with the bacterial phylum Firmicutes (67% of total clones) and were related to the classes Clostridia, Bacilli and Mollicutes, followed by the Bacteroidetes (25%) that were mostly represented by the family Prevotellaceae. The remaining phyla were represented by Actinobacteria, Chloroflexi, Cynophyta, Lentisphaerae, Planctomycetes, Proteobacteria and Sphirochaetes. Moreover, 11 clones of cultivated bacteria were identified as Brevundimonas sp., Butyrivibrio fibrisolvens, Prevotella sp. and Ruminococcus flavefaciens. The novelty in this foregut environment is remarkable where 97% of the OTUs were distantly related to any known sequence in the public database.
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Heme induces heme oxygenase 1 via Nrf2: role in the homeostatic macrophage response to intraplaque hemorrhage.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 08-27-2011
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Intraplaque hemorrhage (IPH) is an important progression event in advanced atherosclerosis, in large part because of the delivery of prooxidant hemoglobin in erythrocytes. We have previously defined a novel macrophage phenotype (hemorrhage-associated-mac) in human advanced plaques with IPH. These may be atheroprotective in view of raised heme oxygenase 1 (HO-1), CD163, and interleukin-10 expression and suppressed oxidative stress.
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Point-of-care electronic prompts: an effective means of increasing compliance, demonstrating quality, and improving outcome.
Anesth. Analg.
PUBLISHED: 07-25-2011
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Incentives based on quality indicators such as the Surgical Care Improvement Project core measures (SCIP 1) encourage implementation of evidence-based guidelines consistently into clinical practice. Information systems with point-of-care electronic prompts (POCEPs) can facilitate adoption of processes and benchmark performance. We evaluated the effectiveness of POCEPs on rates of antibiotic administration within 60 minutes of surgical incision and effect on outcome in a prospective observational trial.
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Structural consequences of ferroelectric nanolithography.
Nano Lett.
PUBLISHED: 07-05-2011
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Domains of remnant polarization can be written into ferroelectrics with nanoscale precision using scanning probe nanolithography techniques such as piezoresponse force microscopy (PFM). Understanding the structural effects accompanying this process has been challenging due to the lack of appropriate structural characterization tools. Synchrotron X-ray nanodiffraction provides images of the domain structure written by PFM into an epitaxial Pb(Zr,Ti)O(3) thin film and simultaneously reveals structural effects arising from the writing process. A coherent scattering simulation including the superposition of the beams simultaneously diffracted by multiple mosaic blocks provides an excellent fit to the observed diffraction patterns. Domains in which the polarization is reversed from the as-grown state have a strain of up to 0.1% representing the piezoelectric response to unscreened surface charges. An additional X-ray microdiffraction study of the photon-energy dependence of the difference in diffracted intensity between opposite polarization states shows that this contrast has a crystallographic origin. The sign and magnitude of the intensity contrast between domains of opposite polarization are consistent with the polarization expected from PFM images and with the writing of domains through the entire thickness of the ferroelectric layer. The strain induced by writing provides a significant additional contribution to the increased free energy of the written domain state with respect to a uniformly polarized state.
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Nanosecond dynamics of ferroelectric/dielectric superlattices.
Phys. Rev. Lett.
PUBLISHED: 04-15-2011
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The nanosecond response of a PbTiO(3)/SrTiO(3) ferroelectric/dielectric superlattice to applied electric fields is closely linked to the dynamics of striped domains of the remnant polarization. The intensity of domain satellite reflections observed with time-resolved x-ray microdiffraction decays in 5-100 ns depending on the magnitude of the electric field. The piezoelectric response of the superlattice within stripe domains is strongly suppressed due to electromechanical clamping between adjacent regions of opposite polarization. Regions of the superlattice that have been switched into a uniform polarization state by the applied electric field, however, exhibit piezoelectricity during the course of the switching process. We propose a switching model different from previous models of the switching of superlattices, based instead on a spatially heterogeneous transformation between striped and uniform polarization states.
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Combined X-ray diffraction and kinetic depth effect imaging.
Opt Express
PUBLISHED: 04-01-2011
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In this preliminary study we present a depth resolved transmission image sequence of an object combined with the materials discriminating ability of angular dispersive X-ray diffraction. Volumes within the object giving rise to diffraction patterns matched to a library of specific materials have been encoded visually within the images. The intensity of these highlighted areas has been weighted based on the certainty of the match. Both the theory and experimental proof of principle have been demonstrated. Considerations pertaining to a "scaled up" version of this technique are also discussed.
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An investigation into the one-pot Heck olefination-hydrogenation reaction.
J. Org. Chem.
PUBLISHED: 03-07-2011
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Herein is described an operationally simple process concerning the observation that, following either inter-, or intramolecular Heck olefination, stirring of the so formed substituted alkenyl product under an atmosphere of hydrogen efficiently effects alkene hydrogenation. Overall this two-operation, one-pot "reductive Heck" sequence is notable since direct reductive Heck processes, using additives such as formate salts, are restricted to a limited range of substrates. In total 25 examples are reported (yields ranging from 0 to 95%), which were selected in order to probe the scope and limitations of this method. Finally, the utility of this sequence was demonstrated in a short synthesis of the calcimimetic agent, cinacalcet.
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The role of blood flow in determining the sites of atherosclerotic plaques.
F1000 Med Rep
PUBLISHED: 03-01-2011
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Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells along the inner walls of arteries, and is an underlying cause of cardiovascular disease. Atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow, which exerts low/oscillatory shear stress on the vessel wall. This mechanical environment alters endothelial cell physiology by enhancing inflammatory activation. In contrast, regions of the arterial tree that are exposed to uniform, unidirectional blood flow and experience high shear stress are protected from inflammation and lesion development. Shear stress is sensed by the endothelium via mechanoreceptors and is subsequently transduced into biochemical signals resulting in modulation of proinflammatory signaling pathways. In this article, we address the molecular mechanisms behind the spatial localization of vascular inflammation and atherosclerosis, with particular focus on studies by our own group of two key proinflammatory signaling pathways, the mitogen-activated protein kinase pathway and the nuclear factor-kappa-B pathway.
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Review of qualitative approaches for the construction industry: designing a risk management toolbox.
Saf Health Work
PUBLISHED: 02-28-2011
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This paper presents the framework and protocol design for a construction industry risk management toolbox. The construction industry needs a comprehensive, systematic approach to assess and control occupational risks. These risks span several professional health and safety disciplines, emphasized by multiple international occupational research agenda projects including: falls, electrocution, noise, silica, welding fumes, and musculoskeletal disorders. Yet, the International Social Security Association says, "whereas progress has been made in safety and health, the construction industry is still a high risk sector."
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Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-?B regulation that promotes arterial inflammation.
Circ. Res.
PUBLISHED: 02-24-2011
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The nuclear factor (NF)-?B pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-?B are defined, the mechanisms that regulate the expression levels of NF-?B transcription factors are uncertain.
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Do miniaturized extracorporeal circuits confer significant clinical benefit without compromising safety? A meta-analysis of randomized controlled trials.
ASAIO J.
PUBLISHED: 01-27-2011
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Miniaturized extracorporeal circulation (mECC) attempts to reduce the adverse effects of conventional extracorporeal circulation (CECC) bypass. However, the potential benefits remain unclear and safety concerns persist. A systematic literature review identified 29 studies incorporating 2,355 patients: 1,181 (50.1%) who underwent cardiac surgery with CECC and 1,174 (49.9%) with mECC. These were meta-analyzed using random effects modeling. Heterogeneity, subgroup analysis, and risk of bias were assessed. Primary endpoints were 30-day mortality, neurovascular compromise, and end organ dysfunction. Secondary endpoints were length of stay and transfusion burden. Miniaturized extracorporeal circulation significantly reduced postoperative arrhythmias (p = 0.03), but no significant difference in 30-day mortality, neurocognitive disturbance, cerebrovascular events, renal failure, or myocardial infarction was identified. Miniaturized extracorporeal circulation also significantly reduced mean blood loss (p < 0.00001) and number of patients transfused (p < 0.00001); however, duration of hospitalization, units transfused per patient, chest tube drainage, and revision for rebleeding remained unchanged. Subgroup analysis of larger studies (10 studies, n ? 31) showed mECC to significantly reduce ventilation period, hospital stay, and intensive care unit (ICU) stay. Similarly, a significant reduction in neurocognitive disturbance was seen in studies with closely matched demographic groups. Miniaturized extracorporeal circulation is not associated with increased cerebrovascular injury and may confer an advantage, reducing postoperative arrhythmia, blood loss, and transfusion burden.
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Dexamethasone arterializes venous endothelial cells by inducing mitogen-activated protein kinase phosphatase-1: a novel antiinflammatory treatment for vein grafts?
Circulation
PUBLISHED: 01-24-2011
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Vein grafting in coronary artery surgery is complicated by a high restenosis rate resulting from the development of vascular inflammation, intimal hyperplasia, and accelerated atherosclerosis. In contrast, arterial grafts are relatively resistant to these processes. Vascular inflammation is regulated by signaling intermediaries, including p38 mitogen-activated protein (MAP) kinase, that trigger endothelial cell (EC) expression of chemokines (eg, interleukin-8, monocyte chemotactic protein-1) and other proinflammatory molecules. Here, we have tested the hypothesis that p38 MAP kinase activation in response to arterial shear stress (flow) may occur more readily in venous ECs, leading to greater proinflammatory activation.
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The influence of sulforaphane on vascular health and its relevance to nutritional approaches to prevent cardiovascular disease.
EPMA J
PUBLISHED: 01-17-2011
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Oxidation of low-density lipoproteins (LDL) promotes atherosclerosis by enhancing vascular inflammation and foam cell formation. The corollary is that diets that stimulate endogenous anti-oxidants may protect against atherosclerosis. This review focuses on sulforaphane, an isothiocyanate derived from green vegetables, which induces multiple anti-oxidant enzymes via activation of a transcription factor called Nrf2. Although studies of cultured cells and experimental animals revealed that sulforaphane can suppress inflammatory activation of vascular cells, the potential beneficial effects of sulforaphane in atherosclerosis have not been studied directly. A deeper understanding of vascular responses to sulforaphane may inform nutritional approaches to prevent vascular inflammation and atherosclerosis.
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Benefit of computed tomography enterography in Crohns disease: effects on patient management and physician level of confidence.
Inflamm. Bowel Dis.
PUBLISHED: 01-14-2011
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Computed tomographic enterography (CTE) has been shown to have a high sensitivity and specificity for active small bowel inflammation. There are only sparse data on the effect of CTE results on Crohns disease (CD) patient care.
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Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia.
Br. J. Haematol.
PUBLISHED: 11-18-2010
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Defects in the DNA damage response pathway [e.g. del(17p)] are associated with drug-resistant B-cell chronic lymphocytic leukaemia (CLL). We previously demonstrated that over-expression of DNA-dependent protein kinase (DNA-PK) correlates with chemo-resistance and that inhibition of DNA-PK sensitizes CLL cells to chemotherapeutics. Here, we investigated expression of DNA-PK and other proteins that impact on drug resistance, and evaluated the effects of a DNA-PK inhibitor (NU7441) on mitoxantrone-induced cytotoxicity in CLL cells. NU7441 sensitized cells from 42/49 CLL samples to mitoxantrone, with sensitization ranging from 2- to 200-fold Co-culture of CLL cells in conditioned stromal medium increased chemoresistance but did not reduce sensitization by NU7441. Mitoxantrone treatment induced ?H2AX foci and NU7441 increased their longevity (24?h). NU7441 prevented mitoxantrone-induced autophosphorylation of the DNA-PK catalytic subunit (DNA-PKcs) at Ser 2056, confirming that DNA-PK participates in repair of mitoxantrone-induced DNA damage. del(17p) cases were more resistant to mitoxantrone than del(13q) cases, but were resensitized (7-16?fold) by co-incubation with NU7441. Expression of DNA-PKcs, Ku80, P-glycoprotein and topoisomerase II? were significantly higher in del(17p) cases. PRKDC mRNA levels correlated with DNA-PKcs protein expression, which predicted shorter survival. These data confirm the potential of DNA-PK as a therapeutic target in poor prognosis CLL.
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The transcription factor Erg inhibits vascular inflammation by repressing NF-kappaB activation and proinflammatory gene expression in endothelial cells.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 10-21-2010
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To test whether ETS-related gene (Erg) inhibits tumor necrosis factor (TNF)-?-dependent endothelial activation and inflammation.
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Thalidomide enhances cyclophosphamide and dexamethasone-mediated cytotoxicity towards cultured chronic lymphocytic leukaemia cells.
Oncol. Rep.
PUBLISHED: 09-30-2010
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Numerous chemotherapeutic regimens exist for the treatment of symptomatic or progressive chronic lymphocytic leukaemia (CLL). However, once the disease becomes refractory to nucleoside-based therapy the prognosis is poor. In this study we investigated the cytotoxicity of thalidomide in combination with dexamethasone, fludarabine and cyclophosphamide. Cells from a cohort of 25 CLL patients were incubated for 72 h with each of these three agents, at 3 concentrations, both with and without thalidomide. Cell viability was assessed using the Annexin V:FITC assay. Fludarabine was highly toxic to the cells, producing very high levels of cell death; however, thalidomide did not increase this effect. Cyclophosphamide combined with thalidomide showed a small, non-significant improvement in toxicity compared with monotherapy. Median cell death for 5 µM dexamethasone monotherapy and for combination with thalidomide was 15% [interquartile range (IQR) 0-38%] and 17% (IQR 0-54%), respectively (Wilcoxon Signed Rank analysis, p=0.034). Cell death for 10 µM dexamethasone monotherapy was 15% (IQR 0-45%) and 16% (IQR 0-62%) in combination with thalidomide (Wilcoxon Signed Rank analysis, p=0.035). At the highest doses tested 11 of 25 cases displayed an enhancement of cyclophosphamide-mediated cytotoxicity, and 14 of 25 cases showed enhanced dexamethasone-mediated cytotoxicity in the presence of thalidomide. Some CLL cells in which dexamethasone-mediated killing was enhanced were derived from patients with poor prognostic markers, including p53 mutations and unmutated IgVH genes. In summary, thalidomide enhances cyclophosphamide- and dexamethasone-mediated cytotoxicity of CLL cells in vitro in a proportion of cases.
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GE-145, a new low-osmolar dimeric radiographic contrast medium.
Acta Radiol
PUBLISHED: 09-21-2010
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Contrast-induced nephrotoxicity is a significant risk when using radiographic contrast media clinically, especially in high risk patients. Consequently, there is a need for a new contrast agent with improved clinical safety with regards to nephrotoxicity.
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Inhibition of NF-?B signaling in human dendritic cells by the enteropathogenic Escherichia coli effector protein NleE.
J. Immunol.
PUBLISHED: 09-10-2010
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Intestinal dendritic cells (DCs) send processes between epithelial cells into the gut lumen to sample pathogens. Noninvasive enteropathogenic Escherichia coli (EPEC) colonize the gut using a type three secretion system (T3SS) to inject effector proteins into epithelial cells. We hypothesized that EPEC might also inject proteins into DC processes to dampen immune recognition. Using a T3SS-linked fluorescence resonance energy transfer-based system we show that EPEC injects effectors into in vitro grown human myeloid DCs. Injected cells emit a blue signal due to cleavage of the green fluorescence resonance energy transfer-based substrate CCF2/AM by ?-lactamase. When cultured with a mutant EPEC unable to translocate effector proteins, myeloid DCs show rapid activation of NF-?B, secrete large amounts of proinflammatory cytokines and increase expression of CD80, CD83, and CD86, whereas wild-type EPEC barely elicits cytokine production and shuts off nuclear translocation of NF-?B p65. By deleting effector protein genes, we identified NleE as being critical for this effect. Expression of NleE in HeLa cells completely prevented nuclear p65 accumulation in response to IL1-?, and luciferase production in an NF-?B reporter cell line. DCs cocultured with wild-type EPEC or NleE-complemented strains were less potent at inducing MLR. EPEC was also able to inject effectors into DCs sending processes through model gut epithelium in a transwell system and into Peyers patch myeloid DCs. Thus, EPEC translocate effectors into human DCs to dampen the inflammatory response elicited by its own pathogen-associated molecular patterns.
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Predicting cardiotoxicity propensity of the novel iodinated contrast medium GE-145: Ventricular fibrillation during left coronary arteriography in pigs.
Acta Radiol
PUBLISHED: 08-31-2010
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Severe side effects caused by iodinated radiographic contrast media (CM) are rare, but can occur in high risk patients and during percutaneous coronary intervention. To minimize this risk a new nonionic CM with low inherent osmolality has been designed, giving room for a relatively high concentration of favorable electrolytes in the isotonic formulation.
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Position determination of scatter signatures--a novel sensor geometry.
Talanta
PUBLISHED: 07-07-2010
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A novel diffraction sensor geometry able to provide the diffraction pattern of a suspect material without prior knowledge of the samples location is introduced. The sensor geometry can also resolve diffraction patterns originating from multiple unknown materials overlapped along the primary X-ray beam path. This is achieved through tracking Bragg peak maxima that linearly propagate from the inspection volume at a series of X-ray detector positions. A series of simulations and experiments have been performed to verify this technique and provide an insight into its characteristics. Such a technique could have widespread appeal in the security industry. Areas of most relevance include the materials characterisation of volumes such as those prevalent in an airport screening environment or equally the rapid screening for illicit drugs trafficked through the postal system.
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Stereocontrolled synthesis of the PPAR-gamma agonist 10-nitrolinoleic acid.
J. Org. Chem.
PUBLISHED: 07-03-2010
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The naturally occurring PPAR-gamma ligand 10-nitrooctadeca-9(E),12(Z)-dienoic acid (10-nitrolinoleic acid) (2a) was prepared as a single regio- and geometrical isomer in a practical eight-step, convergent sequence. The synthetic route featured a nitro aldol reaction between 9-oxononanoic acid methyl ester (3) and 1-nitronon-3(Z)-ene (4) in the key carbon-carbon bond forming step. The ability of 2a (and its methyl ester 9) to bind to PPAR-gamma in a ligand-binding assay is reported.
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Piezoelectricity in the dielectric component of nanoscale dielectric-ferroelectric superlattices.
Phys. Rev. Lett.
PUBLISHED: 05-19-2010
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The origin of the functional properties of complex oxide superlattices can be resolved using time-resolved synchrotron x-ray diffraction into contributions from the component layers making up the repeating unit. The CaTiO3 layers of a CaTiO3/BaTiO3 superlattice have a piezoelectric response to an applied electric field, consistent with a large continuous polarization throughout the superlattice. The overall piezoelectric coefficient at large strains, 54??pm/V, agrees with first-principles predictions in which a tetragonal symmetry is imposed on the superlattice by the SrTiO3 substrate.
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Role of nuclear factor kappaB in cardiovascular health and disease.
Clin. Sci.
PUBLISHED: 02-24-2010
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Cardiovascular pathologies are still the primary cause of death worldwide. The molecular mechanisms behind these pathologies have not been fully elucidated. Unravelling them will bring us closer to therapeutic strategies to prevent or treat cardiovascular disease. One of the major transcription factors that has been linked to both cardiovascular health and disease is NF-kappaB (nuclear factor kappaB). The NF-kappaB family controls multiple processes, including immunity, inflammation, cell survival, differentiation and proliferation, and regulates cellular responses to stress, hypoxia, stretch and ischaemia. It is therefore not surprising that NF-kappaB has been shown to influence numerous cardiovascular diseases including atherosclerosis, myocardial ischaemia/reperfusion injury, ischaemic preconditioning, vein graft disease, cardiac hypertrophy and heart failure. The function of NF-kappaB is largely dictated by the genes that it targets for transcription and varies according to stimulus and cell type. Thus NF-kappaB has divergent functions and can protect cardiovascular tissues from injury or contribute to pathogenesis depending on the cellular and physiological context. The present review will focus on recent studies on the function of NF-kappaB in the cardiovascular system.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.