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Mimetics
Kinds of Mimetics Selected AbstractsSolvent-Dependent Conformational Behaviour of Model Tetrapeptides Containing a Bicyclic Proline MimeticEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 22 2004Andrea Trabocchi Abstract Two model tetrapeptides containing bicyclic analogues of either D - or L -proline were synthesised and their conformational properties were studied by NMR in different solvent systems and by molecular modelling techniques. Compound 1, with the bicyclic D -proline mimetic in the i+1 position, generated a unique trans isomer, and the peptide showed a well organised structure, in accordance with the tendency of D -proline to act as a good turn inducer with respect to its enantiomer. Peptide 2 displayed structures equilibrating from type I,II to type VI ,-turns, thus confirming the hypothesised relationship between the chirality of BGS/Bgs and proline enantiomers on nucleating compact turns. Moreover, such behaviour suggested a tool for peptidomimetic design of reverse turn peptides containing BGS/Bgs bicyclic proline mimetics, as the choice of chirality might influence the generation either of compact ,- and ,-turns or of flexible equilibrating reverse turn structures. The effect of solvent on conformational behaviour was also studied. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Fracturing Resemblances: Identity and Mimetic Conflict in Melanesia and the West by Simon HarrisonAMERICAN ETHNOLOGIST, Issue 2 2009ALEX GOLUB No abstract is available for this article. [source] ChemInform Abstract: A New Route for the Synthesis of Linezolid Mimetic 3,4-Disubstituted Oxazolidin-2-one Derivatives.CHEMINFORM, Issue 48 2008Fumiko Fujisaki Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Function of an N-Heterocyclic Carbene Ligand Based on Concept of Chiral Mimetic.CHEMINFORM, Issue 17 2007Takafumi Arao Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] An N,Ar Axially Chiral Mimetic.CHEMINFORM, Issue 43 2002A New Approach to Ligand Design for Asymmetric Catalysis. Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Design and Synthesis of a New Sialyl Lewis X Mimetic: How Selective Are the Selectin Receptors?CHEMINFORM, Issue 32 2001Marc De Vleeschauwer Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] National Adoption of International Accounting Standards: An Institutional PerspectiveCORPORATE GOVERNANCE, Issue 3 2010William Judge ABSTRACT Manuscript Type: Empirical Research Question/Issue: Effective corporate governance requires accurate and reliable financial information. Historically, each nation has developed and pursued its own financial standards; however, as financial markets consolidate into a global market, there is a need for a common set of financial standards. As a result, there is a movement towards harmonization of international financial reporting standards (IFRS) throughout the global economy. While there has been considerable research on the effects of IFRS adoption, there has been relatively little systematic study as to the antecedents of IFRS adoption. Consequently, this study seeks to understand why some economies have quickly embraced IFRS standards while others partially adopt IFRS and still others continue to resist. Research Findings/Results: After controlling for market capitalization and GDP growth, we find that foreign aid, import penetration, and level of education achieved within a national economy are all predictive of the degree to which IFRS standards are adopted across 132 developing, transitional and developed economies. Theoretical/Academic Implications: We found that all three forms of isomorphic pressures (i.e., coercive, mimetic, and normative) are predictive of IFRS adoption. Consequently, institutional theory with its emphasis on legitimacy-seeking by social actors was relatively well supported by our data. This suggests that the IFRS adoption process is driven more by social legitimization pressures, than it is by economic logic. Practitioner/Policy Implications: For policy makers, our findings suggest that the institutional pressures within an economy are the key drivers of IFRS adoption. Consequently, policy makers should seek to influence institutional pressures that thwart and/or enhance adoption of IFRS. For executives of multinational firms, our findings provide insights that can help to explain and predict future IFRS adoption within economies where their foreign subsidiaries operate. This ability could be useful for creating competitive advantages for foreign subsidiaries where IFRS adoption was resisted, or avoiding competitive disadvantages for foreign subsidiaries unfamiliar with IFRS standards. [source] Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L -arginine and antioxidantsACTA PHYSIOLOGICA, Issue 4 2007M. P. Koeners Abstract Aim:, Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life-long blood pressure regulation. Methods:, Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar-Kyoto (WKY), prior to and during i.v. N, -nitro- l -arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). Results:, Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 ± 4 vs. 33 ± 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 ± 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. Conclusion:, Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation. [source] Exenatide: a review from pharmacology to clinical practiceDIABETES OBESITY & METABOLISM, Issue 6 2009R. Gentilella Background:, Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying. Methods:, In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c ,11%), or by thiazolidinediones (with or without metformin) and treated for periods from 16 weeks to 3 years, exenatide (5 ,g b.i.d. s.c. for the first 4 weeks of treatment and 10 ,g b.i.d. s.c. thereafter) reduced HbA1c, fasting and postprandial glucose, and body weight dose dependently, and was similar to insulin glargine and biphasic insulin aspart in reducing HbA1c. Body weight diminished with exenatide, whereas it increased with both insulin preparations. Positive effects on the lipid profile and a reduction in C-reactive protein were also recorded with exenatide. Treatment extensions up to 3 years showed that benefits were maintained in the long term. Adverse events were usually mild to moderate in intensity, and generally the frequency decreased with continued therapy. The most common was nausea (whose incidence may be reduced by gradual dose escalation from 5 ,g b.i.d. to 10 ,g b.i.d.), vomiting, diarrhoea, headache and hypoglycaemia (almost exclusively in patients treated with a sulphonylurea). Results and conclusions:, Exenatide is a new, promising therapeutic option for type 2 diabetic patients inadequately controlled by oral agents, before insulin therapy, offering the added benefits of body weight reduction and tight postprandial glucose control. [source] Effects of exendin-4 on islets from type 2 diabetes patientsDIABETES OBESITY & METABOLISM, Issue 6 2008R. Lupi Exendin-4 is a dipeptidyl peptidase IV (DPP-IV)-resistant glucagon-like peptide1 (GLP-1) mimetic and its synthetic counterpart, exenatide, is being used in the therapy of type 2 diabetes (T2DM). No information, however, is currently available as for the direct action of exendin-4 on human T2DM islets. In the present study, we exposed pancreatic islets prepared from non-diabetic and T2DM subjects to exendin-4 for 48 h and found that the compound had several, direct beneficial actions on insulin secretion and the expression of genes involved in beta-cell function and differentiation. [source] Exenatide effects on glucose metabolism and metabolic disorders common to overweight and obese patients with type 2 diabetesDRUG DEVELOPMENT RESEARCH, Issue 8 2006David M. Webb Abstract The risks of cardiovascular disease (CVD) and type 2 diabetes increase as body mass index increases in overweight (25,30,kg/m2) and obese (>30,kg/m2) individuals. However, these risks can be reduced with even modest weight loss. In patients with established type 2 diabetes, control of both glycemia and body weight are important to minimize the risk of future diabetic complications. Exenatide is a 39-amino-acid peptide incretin mimetic currently approved in the United States for the treatment of type 2 diabetes as an adjunct to sulfonylurea and/or metformin. Phase-3 clinical studies showed exenatide therapy for 30 weeks significantly reduced glycosylated hemoglobin (HbA1c), and fasting and postprandial plasma glucose, while significantly reducing body weight. Open-label extensions from these pivotal trials demonstrated patients treated with exenatide for 2 years had sustained reductions in glycemic control at 30 weeks and a progressive reduction in body weight. Patients treated with exenatide also had improvement in blood pressure, inflammatory markers, and lipid profiles. The glucoregulatory and weight-reducing effects of exenatide are the result of multiple modes of action that mimic several of the glucoregulatory actions of the naturally occurring peptide, glucagon-like peptide-1 (GLP-1). These include restoration of first phase insulin response, enhancement of glucose-dependent insulin secretion, suppression of inappropriate glucagon secretion, slowing of gastric emptying, and affects on satiety leading to reduced food intake. Further research is required to fully understand the role for exenatide to potentially alleviate metabolic disorders associated with type 2 diabetes, including CVD and obesity. Drug Dev. Res. 67:666,676, 2006. © 2006 Wiley-Liss, Inc. [source] Experimental Manipulation of Intraclutch Variation in the Great Reed Warbler Shows No Effect on Rejection of Parasitic EggsETHOLOGY, Issue 1 2003Zsolt Karcza In the continuing arms race between hosts and brood parasites, hosts are expected to reduce variation in the appearance of their own eggs within clutches, as it facilitates recognition of parasitic eggs. At the same time, by increasing interclutch variation, hosts should make it more difficult for parasites to evolve perfectly mimetic eggs. In this study, we experimentally manipulated intraclutch variation in the great reed warbler, Acrocephalus arundinaceus, in Hungary, where this species is heavily (c. 64%) parasitized by the common cuckoo, Cuculus canorus. We placed artificial cuckoo eggs, which appeared moderately mimetic to humans, in two groups of nests; in one group we increased variability of egg appearance within clutches by exchanging host eggs among nests. These clutches showed a significantly higher intraclutch variability than natural clutches, which we used as a control group. Our results indicate that it has no effect on rejection behaviour in this species, neither when variation was increased experimentally, nor within the natural range of variation displayed by our population. We suggest that when parasitism is high, selection for reduced intraclutch variation may be less important than frequency-dependent selection for increased variation between individuals within a host population. [source] C-Disaccharides as Probes for Carbohydrate Recognition , Investigation of the Conformational Requirements for Binding of Disaccharide Mimetics of Sialyl Lewis XEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 4 2007Richard W. Denton Abstract A set of C-disaccharide analogs was designed to probe the recognition of a known O-disaccharide mimetic of sialyl Lewis X, to P-selectin. The synthesis of the C-glycosides centered on the de novo construction of the galactose residue via an oxocarbenium ion/enol ether cyclization. Conformational analysis was performed by a combination of NMR spectroscopy and molecular mechanics (MM) and molecular dynamics (MD) calculations. The inhibition of P-selectin binding was evaluated in a P-selectin Biacore assay. At 12 mM, the O-glycoside showed 48,% inhibition of binding, while the C-glycoside analogs exhibited between 25,31,% inhibition. This data is discussed within the context of the active conformation of sLex and the conformational behavior of these ligands. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Solvent-Dependent Conformational Behaviour of Model Tetrapeptides Containing a Bicyclic Proline MimeticEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 22 2004Andrea Trabocchi Abstract Two model tetrapeptides containing bicyclic analogues of either D - or L -proline were synthesised and their conformational properties were studied by NMR in different solvent systems and by molecular modelling techniques. Compound 1, with the bicyclic D -proline mimetic in the i+1 position, generated a unique trans isomer, and the peptide showed a well organised structure, in accordance with the tendency of D -proline to act as a good turn inducer with respect to its enantiomer. Peptide 2 displayed structures equilibrating from type I,II to type VI ,-turns, thus confirming the hypothesised relationship between the chirality of BGS/Bgs and proline enantiomers on nucleating compact turns. Moreover, such behaviour suggested a tool for peptidomimetic design of reverse turn peptides containing BGS/Bgs bicyclic proline mimetics, as the choice of chirality might influence the generation either of compact ,- and ,-turns or of flexible equilibrating reverse turn structures. The effect of solvent on conformational behaviour was also studied. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Targeting leukocyte trafficking to inflamed skin , still an attractive therapeutic approach?EXPERIMENTAL DERMATOLOGY, Issue 1 2007Thomas M. Zollner Abstract:, Research into leukocyte trafficking and its therapeutic exploitation appears to be a multistep process, just like the trafficking cascade itself. The initial euphoria evoked by an early understanding of the trafficking steps was followed by considerable disappointment following the clinical failure of the first selectin antagonist Cylexin (CY-1503), a sialyl LewisX mimetic. The research area recovered and identified additional attractive pharmacological targets such as chemokine receptors and integrins. However, after lack of efficacy in anti-chemokine trials and the fatalities associated with anti VLA-4 therapy (Tysabri), the question arose again whether targeting leukocyte trafficking is really promising or whether such a complex, multistep process with many redundant and/or functionally overlapping molecules is simply too challenging to deal with. In this article, we delineate some pros and cons of this approach followed by a brief update on where we stand in the field and where we might move in the future. [source] A mutagenic analysis of the RNase mechanism of the bacterial Kid toxin by mass spectrometryFEBS JOURNAL, Issue 17 2009Elizabeth Diago-Navarro Kid, the toxin of the parD (kis, kid) maintenance system of plasmid R1, is an endoribonuclease that preferentially cleaves RNA at the 5, of A in the core sequence 5,-UA(A/C)-3,. A model of the Kid toxin interacting with the uncleavable mimetic 5,-AdUACA-3, is available. To evaluate this model, a significant collection of mutants in some of the key residues proposed to be involved in RNA binding (T46, A55, T69 and R85) or RNA cleavage (R73, D75 and H17) were analysed by mass spectrometry in RNA binding and cleavage assays. A pair of substrates, 5,-AUACA-3,, and its uncleavable mimetic 5,-AdUACA-3,, used to establish the model and structure of the Kid,RNA complex, were used in both the RNA cleavage and binding assays. A second RNA substrate, 5,-UUACU-3, efficiently cleaved by Kid both in vivo and in vitro, was also used in the cleavage assays. Compared with the wild-type protein, mutations in the residues of the catalytic site abolished RNA cleavage without substantially altering RNA binding. Mutations in residues proposed to be involved in RNA binding show reduced binding efficiency and a corresponding decrease in RNA cleavage efficiency. The cleavage profiles of the different mutants were similar with the two substrates used, but RNA cleavage required much lower protein concentrations when the 5,-UUACU-3, substrate was used. Protein synthesis and growth assays are consistent with there being a correlation between the RNase activity of Kid and its inhibitory potential. These results give important support to the available models of Kid RNase and the Kid,RNA complex. [source] Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and IIIFEBS JOURNAL, Issue 16 2009Klara Hlouchova Glutamate carboxypeptidase III (GCPIII) is a metalloenzyme that belongs to the transferrin receptor/glutamate carboxypeptidase II (GCPII; EC 3.4.17.21) superfamily. GCPIII has been studied mainly because of its evolutionary relationship to GCPII, an enzyme involved in a variety of neuropathologies and malignancies, such as glutamatergic neurotoxicity and prostate cancer. Given the potential functional and pharmacological overlap between GCPIII and GCPII, studies addressing the structural and physiological properties of GCPIII are crucial for obtaining a deeper understanding of the GCPII/GCPIII system. In the present study, we report high-resolution crystal structures of the human GCPIII ectodomain in a ,pseudo-unliganded' state and in a complex with: (a) l -glutamate (a product of hydrolysis); (b) a phosphapeptide transition state mimetic, namely (2S,3,S)-{[(3,-amino-3,-carboxy-propyl)-hydroxyphosphinoyl]methyl}-pentanedioic acid; and (c) quisqualic acid, a glutamate biostere. Our data reveal the overall fold and quaternary arrangement of the GCPIII molecule, define the architecture of the GCPIII substrate-binding cavity, and offer an experimental evidence for the presence of Zn2+ ions in the bimetallic active site. Furthermore, the structures allow us to detail interactions between the enzyme and its ligands and to characterize the functional flexibility of GCPIII, which is essential for substrate recognition. A comparison of these GCPIII structures with the equivalent GCPII complexes reveals differences in the organization of specificity pockets, in surface charge distribution, and in the occupancy of the co-catalytic zinc sites. The data presented here provide information that should prove to be essential for the structurally-aided design of GCPIII-specific inhibitors and might comprise guidelines for future comparative GCPII/GCPIII studies. [source] Synthesis and structural characterization of a mimetic membrane-anchored prion proteinFEBS JOURNAL, Issue 6 2006Matthew R. Hicks During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP,GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP,GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP. [source] The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human plateletsFEBS JOURNAL, Issue 8 2000Carol Dangelmaier U46619, a thromboxane A2 mimetic, but not ADP, caused activation of p38 mitogen activated protein (MAP) kinase in aspirin-treated platelets. In nonaspirinated human platelets ADP activated p38 MAP kinase in both a time-and concentration-dependent manner, suggesting that ADP-induced p38 MAP kinase activation requires generation of thromboxane A2. However, neither a thromboxane A2/prostaglandin H2 receptor antagonist SQ29548 and a thromboxane synthase inhibitor, furegrelate, either alone or together, nor indomethacin blocked ADP-induced p38 kinase activation in nonaspirinated platelets. Other cycloxygenase products, PGE2, PGD2, and PGF2,, failed to activate p38 kinase in aspirin-treated platelets. Hence, ADP must be generating an agonist, other than thromboxane A2, via an aspirin-sensitive pathway, which is capable of activating p38 kinase. AR-C66096, a P2TAC (platelet ADP receptor coupled to inhibition of adenylate cyclase) antagonist, did not inhibit ADP-induced p38 MAP kinase activation. The P2X receptor selective agonist, ,,,-methylene ATP, failed to activate p38 MAP kinase. On the other hand, the P2Y1 receptor selective antagonist, adenosine-2,-phosphate-5,-phosphate inhibited ADP-induced p38 kinase activation in a concentration-dependent manner, indicating that the P2Y1 receptor alone mediates ADP-induced generation of the p38 kinase-activating factor. These results demonstrate that ADP causes the generation of a factor in human platelets, which can activate p38 kinase, and that this response is mediated by the P2Y1 receptor. Neither the P2TAC receptor nor the P2X1 receptor has any significant role in this response. [source] Vascular reactivity to angiotensin II alone or combined with a thromboxane A2 mimetic in the isolated perfused kidney of Lyon hypertensive ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2002Valérie Oréa The aim of this study was to evaluate whether thromboxane A2 -prostaglandin H2 (TP) receptor activation potentiates the renal vasoconstrictor effect of Angiotensin II (Ang II) in genetically hypertensive rats of the Lyon strain (LH). Concentration-response curves (CRCs) to Ang II (5 pM to 10 nM), to the specific TP receptor agonist U46619 (7.5,960 nM) and to a mixture of Ang II + U46619 (fixed molar ratio of 1 : 9) were obtained in single-pass perfused kidneys isolated from 8 week-old LH and low blood pressure (LL) control rats. Baseline vascular resistance was significantly increased in LH compared to LL kidneys. Comparison of the CRCs obtained for Ang II and U46619 showed that, in both strains, Ang II was about 100 times more potent than U46619. For both drugs, the pD2 or slope values did not differ among the two strains. Co-activation of TP receptors, analyzed with the method of Pöch and Holzmann, tended to potentiate the effects of Ang II in LH but not in LL kidneys. In conclusion, isolated perfused kidneys of LH rat did not exhibit an increased vascular sensitivity to acute infusion of Ang II or U46619 compared to control LL ones. In addition, the results suggest that the interactions between Ang II and TP receptor agonist may differ among the two strains. [source] Synthesis of Polymerizable Superoxide Dismutase Mimetics to Reduce Reactive Oxygen Species Damage in Transplanted Biomedical Devices,ADVANCED FUNCTIONAL MATERIALS, Issue 20 2008Charles Y. Cheung Abstract A new polymerizable superoxide dismutase (SOD) mimetic metalloporphyrin macromer was synthesized to minimize inflammatory damage associated with tissue transplantation and biomaterial implantation, such as the use of encapsulated pancreatic islets for the treatment of type I diabetes mellitus (TIDM). This functional SOD mimetic, Mn(III) Tetrakis[1-(3-acryloxy-propyl)-4-pyridyl] porphyrin (MnTPPyP-Acryl), was copolymerized and crosslinked with poly(ethylene glycol) diacrylate (PEGDA) to form hydrogel networks that may actively reduce reactive oxygen species (ROS) damage associated with biomaterial implantation. Solution phase activity assays with MnTPPyP-Acryl macromers showed comparable SOD activity to MnTMPyP, a non-polymerizable commercially available SOD mimetic. This work also describes the development of a new, simple, and inexpensive solid phase assay system that was developed to assess the activity of MnTPPyP-Acryl macromers polymerized within PEGDA hydrogels, which has the potential to fulfill an existing void with the biochemical tools available for testing other immobilized ROS antagonists. With this new assay system, hydrogels containing up to 0.25,mol% MnTPPyP-Acryl showed significantly higher levels of SOD activity, whereas control hydrogels polymerized with inactive TPPyP-Acryl macromers showed only background levels of activity. The potential for repeated use of such hydrogel devices to consistently reduce superoxide anion concentrations was demonstrated upon retention of ,100% SOD activity for at least 72,h post-polymerization. These results demonstrate the potential that polymerizable SOD mimetics may have for integration into medical devices for the minimization of inflammatory damage upon transplantation, such as during the delivery of encapsulated pancreatic islets. [source] The impact of managed competition on diversity, innovation and creativity in the delivery of home-care servicesHEALTH & SOCIAL CARE IN THE COMMUNITY, Issue 4 2008Glen E. Randall PhDArticle first published online: 28 JUN 200 Abstract Reforming publicly funded healthcare systems by introducing elements of competition, often by allowing for-profit providers to compete with not-for-profit providers, is a strategy that has become commonplace in Western democracies. It is widely thought that the competitive forces of the marketplace will lead to greater efficiency, diversity and even innovation in the delivery of services. Between 1997 and 2000, a model of ,managed competition' was introduced as a major reform to the delivery of home-care services in Ontario, Canada. It was expected that by allowing greater competition within the home-care sector, this model would constrain costs and encourage provider agencies to become more innovative and creative in meeting service delivery needs. The purpose of this case study is to explore the impact of the managed competition reform on the for-profit and the not-for-profit organisations that provided rehabilitation home-care services, and, more specifically, to assess the extent to which the goal of greater diversity, innovation and creativity was achieved following implementation of the reform. A purposive sample of 49 key informants were selected for in-depth interviews, and a survey of the 36 organisations that provided rehabilitation home-care services and the 43 community care access centres that purchased services from these provider agencies was conducted. Data were collected between November 2002 and May 2003. Findings demonstrate that a combination of coercive, mimetic and normative isomorphic pressures have constrained diversity, innovation and creativity within the home-care sector. The implication is that the features that have traditionally distinguished for-profit and not-for-profit provider agencies from each other are rapidly disappearing, and a new hybrid organisational structure is evolving. [source] The Evolution of the Standard Unqualified Auditor's Report in Canada / L'ÉVOLUTION DU RAPPORT TYPE DU VÉRIFICATEUR AU CANADAACCOUNTING PERSPECTIVES, Issue 1 2006MICHAEL MAINGOT ABSTRACT This study examines the historical development of the auditor's report in Canada. The auditor's report has been significantly influenced by British and U.S. legislation and practices. The English Joint Stock Companies Act of 1844 required compulsory audits and the British audit report was introduced in North America shortly after the introduction of this Act. The legislature prescribed an audit but it did not determine the form and content of the auditor's report; these were left to the individual practitioner. The British influence was strong in Canada up to the 1930s. However, from this time onward, the U.S. influence began to grow. The impact of the landmark case of Ultramares v. Touche on third-party liability and consequent change in the auditor's report is analyzed. The paper uses institutional theory to explore reasons for the similarities of the auditor's report under British influence and under American influence. Specifically, the paper examines how the mechanisms of mimetic, coercive, and normative isomorphism led to institutional change in the accounting profession as organizations adapted their auditors' reports to achieve greater legitimacy. [source] Novel glycosaminoglycan mimetic (RGTA, RGD120) contributes to enhance skeletal muscle satellite cell fusion by increasing intracellular Ca2+ and calpain activityJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2005M. Zimowska Glycosaminoglycans (GAG) are classes of molecules that play an important role in cellular processes. The use of GAG mimetics called regenerating agent (RGTA) represents a tool to investigate the effect of GAG moiety on cellular behavior. A first member of the RGTA family (RG1192), a dextran polymers with defined amounts of sulfate, carboxymethyl, as well as hydrophobic groups (benzylamide), was shown to stimulate skeletal muscle repair after damage and myoblast differentiation. To obtain a comprehensive insight into the mechanism of action of GAG mimetics, we investigated the effect on myoblast differentiation of a novel RGTA, named RGD120, which was devoid of hydrophobic substitution and had ionic charge similar to heparin. Myoblasts isolated from adult rat skeletal muscles and grown in primary cultures were used in this study. We found that chronic treatment with RGD120 increased the growth of adult myoblasts and induced their precocious fusion into myotubes in vitro. It also partially overcame the inhibitory effect of the calpain inhibitor N -acetyl-leu-leu-norleucinal (ALLN) on these events. Western blot and zymography analyses revealed that milli calpain was slightly increased by RGD120 chronic treatment. In addition, using fluorescent probes (Indo-1 and Boc-leu-met-MAC), we demonstrated that RGD120 added to prefusing myoblast cultures accelerates myoblast fusion into myotubes, induced an increase of cytosolic free calcium concentration, and concomitantly an increase of intracellular calpain protease activity. Altogether, these results suggested that the efficiency of RGD120 in stimulating myogenesis might be in part explained through its effect on calcium mobilization as well as on the calpain amount and activity. © 2005 Wiley-Liss, Inc. [source] Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stressAGING CELL, Issue 3 2010Catarina Rippe Summary To determine if short-term calorie restriction reverses vascular endothelial dysfunction in old mice, old (O, n = 30) and young (Y, n = 10) male B6D2F1 mice were fed ad libitum (AL) or calorie restricted (CR, approximately 30%) for 8 weeks. Ex vivo carotid artery endothelium-dependent dilation (EDD) was impaired in old ad libitum (OAL) vs. young ad libitum (YAL) (74 ± 5 vs. 95 ± 2% of maximum dilation, P < 0.05), whereas old calorie-restricted (OCR) and YCR did not differ (96 ± 1 vs. 94 ± 3%). Impaired EDD in OAL was mediated by reduced nitric oxide (NO) bioavailability associated with decreased endothelial NO synthase expression (aorta) (P < 0.05), both of which were restored in OCR. Nitrotyrosine, a cellular marker of oxidant modification, was markedly elevated in OAL (P < 0.05), whereas OCR was similar to Y. Aortic superoxide production was 150% greater in OAL vs. YAL (P < 0.05), but normalized in OCR, and TEMPOL, a superoxide dismutase (SOD) mimetic that restored EDD in OAL (to 97 ± 2%), had no effect in Y or OCR. OAL had increased expression and activity of the oxidant enzyme, NADPH oxidase, and its inhibition (apocynin) improved EDD, whereas NADPH oxidase in OCR was similar to Y. Manganese SOD activity and sirtuin1 expression were reduced in OAL (P < 0.05), but restored to Y in OCR. Inflammatory cytokines were greater in OAL vs. YAL (P < 0.05), but unaffected by CR. Carotid artery endothelium-independent dilation did not differ among groups. Short-term CR initiated in old age reverses age-associated vascular endothelial dysfunction by restoring NO bioavailability, reducing oxidative stress (via reduced NADPH oxidase,mediated superoxide production and stimulation of anti-oxidant enzyme activity), and upregulation of sirtuin-1. [source] New species of Moenkhausia Eigenmann (Characiformes: Characidae) from Rio Xingu and Rio Tapajós basins, Brazil, with comments on a putative case of polymorphic Batesian mimicryJOURNAL OF FISH BIOLOGY, Issue 10 2009A. M. Zanata A new species of Moenkhausia is described from Rio Xingu and Rio Tapajós basins, Brazil. The new species is distinguished from its congeners, except from Moenkhausia moisae, by having more scales in the lateral series, 43,47 (v. 23,41 in the remaining congeners). The new species is distinguished from M. moisae by its colour pattern, which consists of a dark midlateral stripe, and an asymmetrical caudal blotch (inconspicuous or faded in specimens from the Rio Arinos) continuous with the midlateral stripe (v. narrow dark midlateral line and conspicuous, regularly rounded and symmetrical blotch not continuous with the midlateral line). The new species is putatively assumed to be mimetic to Jupiaba apenima, in the Rio Xingu and Rio Teles Pires drainages, and to Jupiaba yarina in the Rio Arinos. The two species of Jupiaba are sympatric and remarkably similar in size, general external morphology and colouration to the new species. A small difference occurs in the colouration between the two species of Jupiaba and is also observed in the two respectively sympatric morphotypes of the new species of Moenkhausia. The occurrence of polymorphic Batesian mimicry is therefore discussed for neotropical freshwater fishes. [source] Stimulation of choline acetyltransferase by C3d, a neural cell adhesion molecule ligandJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2009Alison Burgess Abstract Septal cholinergic neurons project to the hippocampus and release acetylcholine, a neurotransmitter involved in learning and memory. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing acetylcholine. Promoting ChAT activity and acetylcholine release can lead to new treatments for neurodegenerative diseases with cholinergic deficits, such as Alzheimer's disease. We present evidence that the synthetic molecule C3d, which is a peptide mimetic of the neural cell adhesion molecule (NCAM), promotes ChAT activity in cultures of rat embryonic septal neurons. Our data demonstrate that ChAT activity triggered by C3d is dependent on the fibroblast growth factor receptor (FGFR) and the mitogen-activated protein kinase (MAPK) pathway. C3d did not affect the number of cholinergic neurons in culture, indicating that NCAM homophilic binding enhances ChAT activity, without affecting cholinergic cell survival. In conclusion, the NCAM mimetic peptide C3d promotes ChAT activity in septal neurons through FGFR and MAPK. These findings are relevant to the design of new strategies aimed at stimulating cholinergic function and improving cognition in disorders such as Alzheimer's disease. © 2008 Wiley-Liss, Inc. [source] ETHANOL-INDUCED SUPEROXIDE RADICALS IN FETAL CORTICAL NEURONS: CELLULAR ROS NETWORKALCOHOLISM, Issue 2008Amina E Jamali Alcohol exposure to the developing brain compromises both neurons and glial functions. While neurons are considered the primary targets, microglia may play a neurotoxic role in this process. Previous studies demonstrated that neuron death is due to oxidative stress and mitochondrially mediated (Intrinsic). These studies showed a rapid increase (within minutes) in reactive oxygen species (ROS). Due to the diffusive nature of ethanol and multiple sources of free radicals, we sought to determine the primary source of superoxide targeted by ethanol. Confocal studies of neurons suggest that the superoxide radicals may originate from the mitochondria. Using whole neurons in a luminol-based chemiluminescence assay (Diogenes) we detected superoxide radicals in the extracellular mileu. We observed a two-three fold transient increase in the steady state generation of superoxide radicals between 20 minutes to one hour of ethanol exposure (4mg/ml). However, the presence of Rotenone (mitochondrial complex I inhibitor) and DPI (an inhibitor of all flavinoids) blocked the release of these superoxide radicals. Interestingly, cortical microglia treated identically with ethanol, showed a greater than five fold increase in superoxide generation with a maximum at one hour. Moreover, since ethanol is known to induce hydrogen peroxide generation, it was used as a mimetic. Hydrogen peroxide also induced the production of superoxide different time kinetics. Thus, together these data demonstrate that ethanol induces the steady state production of superoxide radicals in the extracellular mileu in a mitochondrial dependent manner. Since NOX2 an NADPH oxidase is expressed in neurons, it is a potential candidate for the secondary sites of superoxide generation. The ROS network between mitochondria and the plasma membrane highlights new therapeutical targets to counter ethanol toxicity. [source] Review article: optimizing SVR and management of the haematological side effects of peginterferon/ribavirin antiviral therapy for HCV , the role of epoetin, G-CSF and novel agentsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2010R. MAC NICHOLAS Aliment Pharmacol Ther,31, 929,937 Summary Background, Chronic hepatitis C is one of the leading causes for chronic liver disease globally. The past two decades have seen many advances in hepatitis C treatment. Despite these advances, side effects of treatment are common. Haematological complications of treatment can result in treatment cessation and suboptimal results. Recent data have suggested a role for epoetin/granulocyte colony stimulating factor (G-CSF) in optimizing sustained virological response (SVR). Aim, To investigate the nature, frequency and management of haematological side effects in the treatment of chronic hepatitis C infection. Methods, The terms hepatitis C, hepatitis C virus (HCV), treatment, side effects, interferon, peginterferon, ribavirin, anaemia, haemoglobin, neutropenia, thrombocytopenia, haematological, growth factor, erythropoietin and G-CSF were searched on MEDLINE for the period 1991,2009. References from selected articles were also included. Results, Haematological side effects such as anaemia, neutropenia and thrombocytopenia are frequent in anti-HCV treatment. The off-label use of haematological growth factors is common and effective. Conclusions, Erythropoietic agents are effective in treating anaemia, preventing ribavirin dose reduction, improving patients' quality of life, but the effect on SVR is not fully elucidated. G-CSF is effective in raising absolute neutrophil count; however, neutropenic HCV-infected patients on combination treatment may not experience increased bacterial infections. Eltrombopag, a new oral thrombopoietin mimetic, may allow combination treatment in patients with thrombocytopenia. [source] Mimicry in coral reef fishes: ecological and behavioural responses of a mimic to its modelJOURNAL OF ZOOLOGY, Issue 1 2004Janelle V. Eagle Abstract Mimicry is a widely documented phenomenon in coral reef fishes, but the underlying relationships between mimics and models are poorly understood. Juveniles of the surgeonfish Acanthurus pyroferus mimic the coloration of different pygmy angelfish Centropyge spp. at different locations throughout the geographic range of the surgeonfish, while adopting a common species-specific coloration as adults. This study examines the ecological and behavioural relationships between A pyroferus and one of its models, Centropyge vroliki, in Papua New Guinea. Surgeonfish underwent a transition from the juvenile (mimetic) coloration to the adult (non-mimetic) coloration when they reached the maximum size of the angelfish. As typical of mimic,model relationships, mimic surgeonfish were always less abundant than their model. Spatial variation in the abundance of mimics was correlated with models, while the abundance of adults was not. We show that juvenile surgeonfish gain a foraging advantage by mimicking the angelfish. Mimic surgeonfish were always found within 1,2 m of a similar-sized individual of C. vroliki with which they spent c. 10% of their time in close association. When in association with angelfish, juvenile surgeonfish exhibited an increase of c. 10% in the amount of time spent feeding compared to when they were alone. This foraging benefit seems to be explained by reduced aggression by the territorial damselfish Plectroglyphidon lacrymatus, which dominates the reef crest habitat. While adult A. pyroferus and all other surgeonfish were aggressively displaced from damselfish territories, mimic surgeonfish and their models were attacked less frequently and were not always displaced. Stomach contents analysis showed that the diet of C. vroliki differed substantially from P. lacrymatus, while that of A. pyroferus was more similar to the damselfish. We hypothesize that mimics deceive damselfish as to their diet in order to gain access to food supplies in defended areas. 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