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Showing 921–940 of 2058 publications.
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Zheng, Zhaohua; Pinson, Jo Anne; Mountford, Simon J.; Orive, Stephanie L.; Schoenwaelder, Simone M.; Shackleford, David M.; Powell, Andrew K.; Nelson, Erin M.; Hamilton, Justin R.; Jackson, Shaun P.; Jennings, Ian G.; Thompson, Philip E.A series of amino-substituted triazines were developed and examined for PI3K? inhibition and anti-platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3K? selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. The most PI3K? selective inhibitor from the series was studied in detail through a series of invitro and invivo functional studies. MIPS-9922, 10 potently inhibited ADP-induced washed platelet aggregation. It also inhibited integrin ?<inf>IIb</inf>?<inf>3</inf>activation and ?<inf>IIb</inf>?<inf>3</inf>dependent platelet adhesion to immobilized vWF under high shear. It prevented arterial thrombus formation in the invivo electrolytic mouse model of thrombosis without inducing prolonged bleeding or excess blood loss. 2016 Elsevier Masson SAS
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Cook, Naomi L.; Moeke, Cassidy H.; Fantoni, Luca Isaia; Pattison, David I.; Davies, Michael J.Phosphorylation of protein tyrosine residues is critical to cellular processes, and is regulated by kinases and phosphatases (PTPs). PTPs contain a redox-sensitive active site Cys residue, which is readily oxidized. Myeloperoxidase, released from activated leukocytes, catalyzes thiocyanate ion (SCN-) oxidation by H<inf>2</inf>O<inf>2</inf> to form hypothiocyanous acid (HOSCN), an oxidant that targets Cys residues. Dysregulated phosphorylation and elevated MPO levels have been associated with chronic inflammatory diseases where HOSCN can be generated. Previous studies have shown that HOSCN inhibits isolated PTP1B and induces cellular dysfunction in cultured macrophage-like cells. The present study extends this previous work and shows that physiologically-relevant concentrations of HOSCN alter the activity and structure of other members of the wider PTP family (including leukocyte antigen-related PTP, PTP-LAR; T-cell PTP, TC-PTP; CD45 and Src homology phosphatase-1, Shp-1) by targeting Cys residues. Isolated PTP activity, and activity in lysates of human monocyte-derived macrophages (HMDM) was inhibited by 0-100 ?M HOSCN with this being accompanied by reversible oxidation of Cys residues, formation of sulfenic acids or sulfenyl-thiocyanates (detected by Western blotting, and LC-MS as dimedone adducts), and structural changes. LC-MS/MS peptide mass-mapping has provided data on the modified Cys residues in PTP-LAR. This study indicates that inflammation-induced oxidants, and particularly myeloperoxidase-derived species, can modulate the activity of multiple members of the PTP superfamily via oxidation of Cys residues to sulfenic acids. This alteration of the balance of PTP/kinase activity may perturb protein phosphorylation and disrupt cell signaling with subsequent induction of apoptosis at sites of inflammation. 2015 Elsevier Inc.
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Gentile, CarmineEngineering of in vitro three-dimensional cultures of stem cells and their progenies has offered promising alternatives to recapitulate the in vivo microenvironment, or stem cell niche, and has provided more specific cues for proper stem cell differentiation, maintenance and culture. In particular, tissue spheroids are cellular aggregates with defined cellular and extracellular features and have provided optimal conditions for stem cell technology, both in culture and for potential engraftment. Recent studies have focused on spheroid formation and the developmental roles played by cellular and extracellular signals necessary for cellular aggegation into spheroids. This review will provide insights into the factors that regulate in vitro spheroid formation by comparing them with their developmental counterparts in vivo. At the same time, we will identify cellular and extracellular signals that could be used to bioengineer spheroids with improved features according to their application. Finally, this review will provide an overview of the applications to date of spheroid cultures of stem cells and their progenies, providing insights for future studies. 2016 Bentham Science Publishers.
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Wain, Louise V.; Shrine, Nick R.G.; Miller, Suzanne; Jackson, Victoria E.; Ntalla, Ioanna; Soler Artigas, Mar; Billington, Charlotte K.; Kheirallah, Abdul Kader; Allen, Richard James; Cook, James P.; Probert, Kelly; Obeidat, Ma'En A.; Boss Yohan; Hao, Ke; Postma, Dirkje S.; Par Peter D.; Ramasamy, Adaikalavan; Mi, Reedik; Mihailov, Evelin; Reinmaa, Eva; Mel, Erik; O'Connell, Jared; Frangou, Elena; Delaneau, Olivier; Freeman, Colin; Petkova, Desislava; McCarthy, Mark I.; Sayers, Ian; Deloukas, Panos; Hubbard, Richard B.; Pavord, Ian Douglas; Hansell, Anna Louise; Thomson, Neil C.; Zeggini, Eleftheria; Morris, Andrew Paul; Marchini, Jonathan L.; Strachan, David P.; Tobin, Martin D.; Hall, Ian P.; Farrall, Martin; Barroso, In E.; Anderson, Carl A.; Botia, Juan A.; Vandrocova, Jana; Guelfi, Sebastian; D'Sa, Karishma; Ryten, Mina; Trabzuni, Daniah; Matar, Mar Del; Hardy, John Anthony; Weale, Michael E.; Varghese, Vibin; Forabosco, P.; Farmer, Anne E.; McGuffin, Peter; Zgaga, Lina; Wilson, James F.; Wild, Sarah Helen; Campbell, Harry; Rudan, Igor; Smith, Colin Nurse Simon; Walker, Robert A.; Liu, Jason Z.; Tozzi, Federica; Muglia, Pierandrea; Waterworth, Dawn M.; Pillai, Sreekumar G.; Yuan, Xin; Mooser, Vincent E.; Middleton, Lefkos T.; Kooner, Jaspal Singh; Chambers, John Campbell; Berrettini, Wade H.; Knouff, Christopher W.; Waeber, Gard; Vollenweider, Peter K.; Preisig, Martin A.; Wareham, Nicholas J.; Zhao, Jinghua; Loos, Ruth J.f.; Khaw, Kay Tee T.; Grundy, Scott M.; Barter, Philip J.; Mahley, Robert W.; Kesaniemi, YrjAntero; McPherson, Ruth M.; Vincent, John B.; Strauss, John S.; Kennedy, James Lowery; Day, Richard; Matthews, Keith; Bakke, Per Sigvald; Gulsvik, Amund; Lucae, Susanne; Ising, Marcus; Brueckl, Tanja M.; Horstmann, Sonja; Wichmann, Heinz Erich; Rawal, Rajesh; Lamina, Claudia; Dahmen, Norbert; Polaek, Ozren; Kolcic, Ivana; Huffman, Jennifer E.; Campbell, Susan; Vitart, Vonique; Hayward, Caroline; Wright, Alan F.; Burnett, Mary Susan; Devaney, Joe M.; Pichard, Augusto Descalzi; Kent, Kenneth M.; Satler, Lowell F.; Lindsay, Joseph M.; Waksman, Ron; Epstein, Stephen E.; Reilly, Muredach P.; Li, Mingyao; Qu, Liming; Wilensky, Robert L.; Matthai, William H.; Honarson, Hon H.; Rader, Daniel J.; Ellinghaus, David; Lieb, Wolfgang; Franke, Andre R.N.; Uda, Manuela; Busonero, Fabio; Terracciano, Antonio; Schlessinger, David; Xiao, Xiangjun; Scheet, Paul A.; St-Clair, David M.; Rujescu, Dan; Abecasis, Gonlo R.; Grabe, Hans Jgen; Teumer, Alexander; Vzke, Henry; Petersmann, Astrid; John, Ulrich; Wright, Benjamin J.; Thompson, John R.; Balmforth, Anthony J.; Hall, Alistair Scott; Samani, Nilesh J.; Ahmad, Tariq; Mathew, Christopher G.; Parkes, Miles; Satsangi, Jack J.; Caulfield, Mark J.; Munroe, Patricia B.; Dominiczak, Anna F.D.; Worthington, Jane E.; Thomson, Wendy; Eyre, Stephen; Barton, Anne C.; Francks, ClydeBackground: Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. Methods: We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV<inf>1</inf>) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV<inf>1</inf>. We also looked for novel variants associated with extremes of FEV<inf>1</inf> and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 10-8. Findings: UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50 008 unique samples: 10 002 individuals with low FEV<inf>1</inf>, 10 000 with average FEV<inf>1</inf>, and 5002 with high FEV<inf>1</inf> from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV<inf>1</inf> between heavy smokers and never smokers (p=229 10-16) and between individuals with and without doctor-diagnosed asthma (p=606 10-11). We discovered six novel genome-wide significant signals of association with extremes of FEV<inf>1</inf>, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV<inf>1</inf>. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. Interpretation: By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. Funding: Medical Research Council. 2015 Wain et al. Open Access article distributed under the terms of CC BY.
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Thompson, Peter Lindsay; Macdonald, Peter Simon[No abstract available]
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Wakelin, Edgar A.; Fathi, Ali; Kracica, Masturina; Yeo, Giselle C.; Wise, Steven G.; Weiss, Anthony Steven; McCulloch, Dougal G.; Dehghani, Fariba; McKenzie, David R.; Bilek, Marcela M.M.Plasma immersion ion implantation (PIII) is used to modify the surface properties of polyether ether ketone for biomedical applications. Modifications to the mechanical and chemical properties are characterized as a function of ion fluence (treatment time) to determine the suitability of the treated surfaces for biological applications. Young's modulus and elastic recovery were found to increase with respect to treatment time at the surface from 4.4 to 5.2 MPa and from 0.49 to 0.68, respectively. The mechanical properties varied continuously with depth, forming a graded layer where the mechanical properties returned to untreated values deep within the layer. The treated surface layer exhibited cracking under cyclical loads, associated with an increased modulus due to dehydrogenation and cross-linking; however, it did not show any sign of delamination, indicating that the modified layer is well integrated with the substrate, a critical factor for bioactive surface coatings. The oxygen concentration remained unchanged at the surface; however, in contrast to ion implanted polymers containing only carbon and hydrogen, the oxygen concentration within the treated layer was found to decrease. This effect is attributed to UV exposure and suggests that PIII treatments can modify the surface to far greater depths than previously reported. Protein immobilization on PIII treated surfaces was found to be independent of treatment time, indicating that the surface mechanical properties can be tuned for specific applications without affecting the protein coverage. Our findings on the mechanical properties demonstrate such treatments render PEEK well suited for use in orthopedic implantable devices. 2015 American Chemical Society.
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Bobek, Gabriele; Surmon, Laura; Colafella, Katrina Mirabito; Makris, Angela; Hennessy, AnnemarieProblem: Increased levels of inflammatory cytokines are demonstrated in the serum of women with pre-eclampsia. TNF-? infusion in animal models induces proteinuric hypertension similar to human pre-eclampsia. The effect of TNF-? on regulation of the immune and hypoxic pathways in the developing placenta and their relationship with experimental pre-eclampsia remains unexamined. Method of Study: TNF-? was infused into pregnant mice, and the effects on maternal hypertension, proteinuria, circulating levels of sFlt-1 and corresponding placental changes in molecules responding to inflammation (TLR-3 and TLR-4) and hypoxia (HIF-1?) were examined. Results: TNF-? infusion resulted in maternal hypertension and proteinuria. Molecular changes in the placenta involved upregulation of TLR-3, TLR-4 and HIF-1?. Serum levels of sFlt-1 were high in pregnant animals, but not further upregulated by TNF-? infusion. Conclusion: A role for maladaptive regulation of TLR and HIF-1? induced by an imbalance in inflammatory cytokines is implicated in the pathogenesis of pre-eclampsia. 2015 John Wiley & Sons A/S.
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Kozor, Rebecca A.; Callaghan, Fraser M.; Nelson, Gregory I.C.; Figtree, Gemma A.; Grieve, Stuart M.[No abstract available]
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Bisoendial, Radjesh J.; Tabet, Fatiha; Tak, Paul Peter; Petrides, Francine; Torres, Luisa Cuesta; Hou, Liming; Cook, Adam; Barter, Philip J.; Weninger, Wolfgang Peter; Rye, Kerry AnneObjective-Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF. Approach and Results-TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice. Conclusions-ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature. 2015 American Heart Association, Inc.
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Clayton, Zoe E.; Vickers, Mark Hedley; Bernal, Angelica B.; Yap, Cassandra; Sloboda, Deborah MagdalenaAim: Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation. Methods: Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR. Results: Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1? mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes. Conclusions: Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may point to impaired immune sensing. 2015 Clayton et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Di Bartolo, Belinda Ann; Cartland, Si; Prado-Louren, Leonel; Griffith, Thomas Scott; Gentile, Carmine; Ravindran, Jayant; Azahri, Nor Saadah Muhammad; Thai, Thuan; Yeung, Amanda W.S.; Thomas, Shane R.; Kavurma, Mary M.Background-Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to inhibit angiogenesis by inducing endothelial cell death, as well as being able to promote pro-angiogenic activity in vitro. These seemingly opposite effects make its role in ischemic disease unclear. Using Trail-/- and wildtype mice, we sought to determine the role of TRAIL in angiogenesis and neovascularization following hindlimb ischemia. Methods and Results-Reduced vascularization assessed by real-time 3-dimensional Vevo ultrasound imaging and CD31 staining was evident in Trail-/- mice after ischemia, and associated with reduced capillary formation and increased apoptosis. Notably, adenoviral TRAIL administration significantly improved limb perfusion, capillary density, and vascular smooth-muscle cell content in both Trail-/- and wildtype mice. Fibroblast growth factor-2, a potent angiogenic factor, increased TRAIL expression in human microvascular endothelial cell-1, with fibroblast growth factor-2-mediated proliferation, migration, and tubule formation inhibited with TRAIL siRNA. Both fibroblast growth factor-2 and TRAIL significantly increased NADPH oxidase 4 (NOX4) expression. TRAILinducible angiogenic activity in vitro was inhibited with siRNAs targeting NOX4, and consistent with this, NOX4 mRNA was reduced in 3-day ischemic hindlimbs of Trail-/- mice. Furthermore, TRAIL-induced proliferation, migration, and tubule formation was blocked by scavenging H<inf>2</inf>O<inf>2</inf>, or by inhibiting nitric oxide synthase activity. Importantly, TRAIL-inducible endothelial nitric oxide synthase phosphorylation at Ser-1177 and intracellular human microvascular endothelial cell-1 cell nitric oxide levels were NOX4 dependent. Conclusions-This is the first report demonstrating that TRAIL can promote angiogenesis following hindlimb ischemia in vivo. The angiogenic effect of TRAIL on human microvascular endothelial cell-1 cells is downstream of fibroblast growth factor-2, involving NOX4 and nitric oxide signaling. These data have significant therapeutic implications, such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with cardiovascular disease and diabetes. 2015 The Authors.
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Ju, Lining Arnold; Lou, Jizhong; Chen, Yunfeng; Li, Zhenhai; Zhu, ChengLeucine-rich repeat (LRR) is a versatile motif widely present in adhesive proteins and signal-transducing receptors. The concave structure formed by a group of LRRs is thought to facilitate binding to globular protein domains with increased affinities. However, little is known about the conformational dynamics of LRRs in such a structure, e.g., whether and how force induces conformational changes in LRRs to regulate protein binding and signal transduction. Here we investigated the platelet glycoprotein Ib? (GPIb?), a demonstrated mechanoreceptor with known crystal structures for the N-terminal domain (GPIb?N), as a model for LRR-containing proteins using a combined method of steered molecular dynamics simulations and single-molecule force spectroscopy with a biomembrane force probe. We found that force-induced unfolding of GPIb?N starts with LRR2-4 and propagates to other LRRs. Importantly, force-dependent lifetimes of individual VWF-A1 bonds with GPIb? are prolonged after LRR unfolding. Enhancement of protein-protein interactions by force-induced LRR unfolding may be a phenomenon of interest in biology. 2015 Biophysical Society.
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Samson, Andre L.; Ju, Lining Arnold; Kim, Hyun Ah; Zhang, Shenpeng R.; Lee, Jessica A.; Sturgeon, Sharelle A.; Sobey, C. G.; Jackson, Shaun P.; Schoenwaelder, Simone M.The Open Field (OF) test is one of the most commonly used assays for assessing exploratory behaviour and generalised locomotor activity in rodents. Nevertheless, the vast majority of researchers still rely upon costly commercial systems for recording and analysing OF test results. Consequently, our aim was to design a freely available program for analysing the OF test and to provide an accompanying protocol that was minimally invasive, rapid, unbiased, without the need for specialised equipment or training. Similar to commercial systems, we show that our software - called MouseMove - accurately quantifies numerous parameters of movement including travel distance, speed, turning and curvature. To assess its utility, we used MouseMove to quantify unilateral locomotor deficits in mice following the filament-induced middle cerebral artery occlusion model of acute ischemic stroke. MouseMove can also monitor movement within defined regions-of-interest and is therefore suitable for analysing the Novel Object Recognition test and other field-related cognitive tests. To the best of our knowledge, MouseMove is the first open source software capable of providing qualitative and quantitative information on mouse locomotion in a semi-automated and high-throughput fashion, and hence MouseMove represents a sound alternative to commercial movement analysis systems.
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Degendorfer, Georg; Chuang, Christine Y.; Hammer, Astrid; Malle, Ernst; Davies, Michael J.Basement membranes (BM) are specialized extracellular matrices underlying endothelial cells in the artery wall. Laminin, the most abundant BM glycoprotein, is a structural and biologically active component. Peroxynitrous acid (ONOOH), a potent oxidizing and nitrating agent, is formed in vivo at sites of inflammation from superoxide and nitric oxide radicals. Considerable data supports ONOOH formation in human atherosclerotic lesions, and an involvement of this oxidant in atherosclerosis development and lesion rupture. These effects may be mediated, at least in part, via extracellular matrix damage. In this study we demonstrate co-localization of 3-nitrotyrosine (a product of tyrosine damage by ONOOH) and laminin in human atherosclerotic lesions. ONOOH-induced damage to BM was characterized for isolated murine BM, and purified murine laminin-111. Exposure of laminin-111 to ONOOH resulted in dose-dependent loss of protein tyrosine and tryptophan residues, and formation of 3-nitrotyrosine, 6-nitrotryptophan and the cross-linked material di-tyrosine, as detected by amino acid analysis and Western blotting. These changes were accompanied by protein aggregation and fragmentation as detected by SDS-PAGE. Endothelial cell adhesion to isolated laminin-111 exposed to 10 ?M or higher levels of ONOOH was significantly decreased (~25%) compared to untreated controls. These data indicate that laminin is oxidized by equimolar or greater concentrations of ONOOH, with this resulting in structural and functional changes. These modifications, and resulting compromised cell-matrix interactions, may contribute to endothelial cell dysfunction, a weakening of the structure of atherosclerotic lesions, and an increased propensity to rupture. 2015 Elsevier Inc. All rights reserved.
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Wise, Steven G.; Michael, Praveesuda Lorwattanapongsa; Waterhouse, Anna; Santos, Miguel; Filipe, Elysse C.; Hung, Juichien; Kondyurin, Alexey V.; Bilek, Marcela M.M.; Ng, Martin K.C.Components of many vascular prostheses including endovascular stents, heart valves and ventricular assist devices are made using metal alloys. In these blood contacting applications, metallic devices promote blood clotting, which is managed clinically by profound platelet suppression and/or anticoagulation. Here it is proposed that the localized immobilization of bioactive plasmin, a critical mediator of blood clot stability, may attenuate metallic prosthesis-induced thrombus formation. Previously described approaches to covalently immobilize biomolecules on implantable materials have relied on complex chemical linker chemistry, increasing the possibility of toxic side effects and reducing bioactivity. We utilize a plasma deposited thin film platform to covalently immobilize biologically active plasmin on stainless steel substrates, including stents. A range of in vitro whole blood assays demonstrate striking reductions in thrombus formation. This approach has profound potential to improve the efficacy of a wide range of metallic vascular implants. 2015 Elsevier B.V.
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Storkey, Corin M.; Pattison, David I.; Ignasiak, Marta Teresa; Schiesser, Cart H.; Davies, Michael J.Peroxynitrite (the physiological mixture of ONOOH and its anion, ONOO-) is a powerful biologically-relevant oxidant capable of oxidizing and damaging a range of important targets including sulfides, thiols, lipids, proteins, carbohydrates and nucleic acids. Excessive production of peroxynitrite is associated with several human pathologies including cardiovascular disease, ischemic-reperfusion injury, circulatory shock, inflammation and neurodegeneration. This study demonstrates that low-molecular-mass selenols (RSeH), selenides (RSeR') and to a lesser extent diselenides (RSeSeR') react with peroxynitrite with high rate constants. Low molecular mass selenols react particularly rapidly with peroxynitrite, with second order rate constants k<inf>2</inf> in the range 5.105-1.906 M-1 s-1, and 250-830 fold faster than the corresponding thiols (RSH) and many other endogenous biological targets. Reactions of peroxynitrite with selenides, including selenosugars are approximately 15-fold faster than their sulfur homologs with k<inf>2</inf> approximately 2.503 M-1 s-1. The rate constants for diselenides and sulfides were slower with k<inf>2</inf> 0.72-1.303 M-1 s-1 and approximately 2.102 M-1 s-1 respectively. These studies demonstrate that both endogenous and exogenous selenium-containing compounds may modulate peroxynitrite-mediated damage at sites of acute and chronic inflammation, with this being of particular relevance at extracellular sites where the thiol pool is limited. 2015 Elsevier Inc. All rights reserved.
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Outcomes of Patients Undergoing Balloon Aortic Valvuloplasty in the TAVI Era: A Multicenter RegistryMoretti, Claudio; Chandran, Sujay Subash; Vervueren, Paul Louis; DAscenzo, Fabrizio; Barbanti, Marco; Weerackody, Roshan P.; Boccuzzi, Giacomo Giovanni; Lee, Daehyun; de la Torre, JosMar; Omed Pierluigi; Nijenhuis, Vincent Johan; Igbineweka, Norris E.; Lim, Patrick R.; Berg, Ten; Carri Didier; Hildick-Smith, David J.R.; Gulino, Simona; Cannata, Stefano; Gargiulo, Giuseppe; Tamburino, Corrado; Conrotto, Federico; Meynet, Ilaria; Quadri, Giorgio; Marangoni, Ludovica; Taha, Salma M.; Biondi-Zoccai, Giuseppe G.L.; Salizzoni, Stefano; Marra, Sebastiano; Gaita, FiorenzoBACKGROUND: Few clinical data about indications and prognoses of patients undergoing balloon aortic valvuloplasty (BAV) in the transcatheter aortic valve implantation (TAVI) era have been reported. METHODS: Data from all consecutive patients undergoing BAV in seven European centers from 2006 to 2013 were collected. Acute results and long-term outcomes were assessed. RESULTS: A total of 811 patients aged 82 9 years were included; 416 patients (51%) underwent BAV as palliative destination therapy, 320 patients (40%) as bridge to TAVI, and 75 patients (9%) as bridge to surgical aortic valve replacement (SAVR). Patients undergoing BAV as destination therapy had a higher risk profile (logistic EuroSCORE, 20 17 vs 22 14 vs 11 8, respectively; P<.001). Post procedure, peak gradient decreased from 87 22 mm Hg to 66 22 mm Hg (P<.001) and aortic valve area increased from 0.61 0.2 cm2 to 0.8 0.2 cm2 (P<.001). At 30 days, the all-cause death rate (6.5% vs 6.2% vs 7.4%, respectively; P?.56) and the rate of life-threatening and major bleedings (8.0% vs 5.7% vs 6.0%, respectively) did not differ between groups. After a mean follow-up of 318 days (range, 116-500 days), rates of all-cause death were similar (30% vs 34% vs 31%, respectively; P>.99), although patients undergoing BAV as bridge to SAVR showed a lower cardiovascular death rate (11% vs 11% vs 3%, respectively; P?.04). CONCLUSION: In the TAVI era, BAV may represent a reasonable option for patients with severe aortic stenosis and temporary contraindications to definite therapy. Given the mortality rates at 30 days, patients should be carefully selected, while events at follow-up are deeply influenced by the decision of whether or not subsequent interventions are performed.
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Deng, Wei; Farnham, M. M. J.; Goldys, Ewa M.; Mohammed, Suja; Pilowsky, Paul M.For the first time the efficiency of gene knockdown of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 1 (PAC1R) is demonstrated by employing gold nanocomplexes. This gene knockdown subsequently affects the action of PACAP on neurite outgrowth in PC12 cells. These nanocomplexes comprise cholera toxin B (CTB)-gold nanoparticle conjugates loaded with double-stranded morpholinos (MOs) (photo MO and antisense MO). Nanocomplexes are introduced into cells via lipid raft-dependent endocytosis. After UV light exposure, the photolinker in the photo MO is cleaved, bisecting the photo MO and releasing the antisense MO from the conjugate. The antisense MO then binds the PAC1R mRNA and decreases gene expression. The maximal efficiency of gene knockdown is observed after 24 hours, resulting in a 65% 12 reduction of the protein level. This reduction in PAC1R impairs the responsiveness of cells to PACAP exposure. Following PAC1R gene knockdown, only 10%8 and 11%9 of cells exhibit neurite outgrowth after 4-day exposure to PACAP-38 and PACAP-27, respectively. These results demonstrate an efficient PAC1R gene knockdown and noticeable difference in response to PACAP action on neural cell differentiation, adding an extra dimension to determine the involvement of PACAP and its PAC1R in the neurotropic effect to PC12 cells. 2015 American Scientific Publishers. All rights reserved.
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Robinson, Tracy Elizabeth; Rankin, Nicole M.; Janssen, Anna B.; McGregor, Deborah M.; Grieve, Stuart M.; Shaw, Tim J.Background: Collaborative research networks are often touted as a solution for enhancing the translation of knowledge, but questions remain about how to evaluate their impact on health service delivery. This pragmatic scoping study explored the enabling factors for developing and supporting a collaborative imaging network in a metropolitan university in Australia. Methods: An advisory group was established to provide governance and to identify key informants and participants. Focus group discussions (n = 2) and semi-structured interviews (n = 22) were facilitated with representatives from a broad range of disciplines. In addition, a survey, a review of relevant websites (n = 15) and a broad review of the literature were undertaken to elicit information on collaborative research networks and perceived needs and factors that would support their involvement in a multi-disciplinary collaborative research network. Findings were de-identified and broad themes were identified. Results: Participants identified human factors as having priority for developing and sustaining a collaborative research network. In particular, leadership, a shared vision and a communication plan that includes social media were identified as crucial for sustaining an imaging network in health research. It is important to develop metrics that map relationships between network members and the role that communication tools can contribute to this process. Conclusions: This study confirms that human factors remain significant across a range of collaborative endeavours. The use of focus group discussions, interviews, and literature and website reviews means we can now strongly recommend the primacy of human factors. More work is needed to identify how the network operates and what specific indicators or metrics help build the capacity of clinicians and scientists to participate in translational research. 2015 Robinson et al.
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Schoenwaelder, Simone M.; Jackson, Shaun P.[No abstract available]
