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  • 1
    Language: English
    In: Diabetologia, 2016, Vol.59(12), pp.2503-2506
    Description: Medications approved for diabetes-associated renal and cardiovascular morbidities and candidate drugs currently in development are subject to substantial variability in drug response. Heterogeneity on a molecular phenotype level is not apparent at clinical presentation, which means that inter-individual differences in drug effect at the molecular level are masked. These findings identify the need for optimising patient phenotyping via use of molecular biomarkers for a personalised therapy approach. Molecular diversity may, on the one hand, result from the effect of genetic polymorphisms on drug transport, metabolism and effective target modulation. Equally relevant, differences may be due to molecular pathologies. The presence of distinct molecular phenotypes is suggested by classifiers aimed at modelling progressive disease. Such functions for prognosis incorporate a complex set of clinical variables or a multitude of molecular markers reflecting a diverse set of molecular disease mechanisms. This information on disease pathology and the mechanism of action of the drug needs to be systematically integrated with data on molecular biomarkers to develop an experimental tool for personalising medicine. The large amount of molecular data available for characterising diabetes-associated morbidities allows for elucidation of molecular process model representations of disease pathologies. Selecting biomarker candidates on such grounds and, in turn identifying their association with progressive disease allows for the identification of molecular processes associated with disease progression. The molecular effect of a drug can also be modelled at a molecular process level, and the integration of disease pathology and drug effect molecular models reveals candidate biomarkers for assessing drug response. Such tools serve as enrichment strategies aimed at adding precision to drug development and use.
    Keywords: Biomarker ; Diabetic nephropathy ; Molecular model ; Network ; Pharmacogenomics ; Prediction ; Review
    ISSN: 0012-186X
    E-ISSN: 1432-0428
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  • 2
    Language: English
    In: Archives of toxicology, January 2014, Vol.88(1), pp.5-7
    Description: Byline: Bernd Mayer (1) Author Affiliation: (1) Department of Pharmacology and Toxicology, Karl-Franzens University Graz, Univ.-Platz 2, 8010, Graz, Austria Article History: Registration Date: 05/09/2013 Received Date: 26/08/2013 Accepted Date: 05/09/2013 Online Date: 04/10/2013
    Keywords: Autoexperimentation -- History ; Nicotine -- Administration & Dosage
    ISSN: 03405761
    E-ISSN: 1432-0738
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  • 3
    Language: English
    In: 2012, Vol.7(9), p.e44891
    Description: Novel prognostic markers for progression of kidney disease are needed to distinguish patients who might benefit from a more aggressive nephroprotective therapy. Expression of the proteoglycan versican was evaluated in renal transcriptomics profiles and in an independent set of 74 renal biopsies. Versican levels were correlated to histologic damage scores and to renal outcome, and versican expression and regulation was evaluated in vitro . In transcriptomics profiles of renal tissue versican was positively correlated with (i) histological parameters in kidney biopsies, (ii) progressive decline of renal function in proteinuric kidney diseases, and (iii) impaired renal function and histology scores in diabetic nephropathy. In an independent cohort of 74 biopsies of glomerular diseases renal RNA levels of versican isoforms V0 and V1, but not V2 and V3 correlated significantly with creatinine after a mean follow up time of 53 months. Versican isoforms V0 and V1 together with serum creatinine at time of biopsy and the degree of glomerulosclerosis predicted 20% and 24% of the variability of creatinine at follow up, which was significantly more than serum creatinine and histological parameters alone (16%). However, when patients with acute kidney failure at time of biopsy (n = 5) were excluded, the additive predictive value of versican V1 was only marginally higher (35%) than creatinine and glomerulosclerosis alone (34%). Versican isoforms V0 and V1 were primarily expressed in vitro in proximal tubule cells and in fibroblasts. The results in humans were confirmed in three rodent models of kidney disease, in which renal versican expression was significantly upregulated as compared to corresponding controls. These data show for the first time an association of renal versican isoform V0 and V1 expression with progressive renal disease.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Nephrology ; Computational Biology ; Cell Biology ; Pathology ; Biochemistry
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Biochemistry, 04 March 2014, Vol.53(8), pp.1284-95
    Description: Recombinant neuronal nitric-oxide synthase (nNOS) expressed in baculovirus-infected Sf9 cells contains approximately 1 equiv of tightly bound tetrahydrobiopterin (BH4) per dimer and binds a second equivalent with a dissociation constant in the 10(-7)-10(-6) M range. Less is known about the pterin-binding properties of nNOS originating from expression systems such as Escherichia coli that do not produce BH4. We determined the binding properties of E. coli-expressed nNOS for BH4 and several inhibitory pterins by monitoring their effects on enzyme activity. E. coli-expressed nNOS as isolated was activated by BH4 monophasically with EC50 ≈ 2 × 10(-7) M, demonstrating a lack of tight pterin binding. However, overnight incubation with BH4 resulted in tight binding of one BH4 per dimer, yielding an enzyme that resembled Sf9-expressed nNOS. Tight pterin binding was also induced by preincubation with 4-amino-tetrahydrobiopterin, but not by 7,8-dihydrobiopterin or 4-amino-dihydrobiopterin, suggesting that tight-binding site formation requires preincubation with a fully reduced pteridine. Kinetic experiments showed that tight-binding site formation takes approximately 10 min with 1 μM BH4 (2 min with 1 μM 4-amino-BH4) at 4 °C. Anaerobic preincubation experiments demonstrated that O2 is not involved in the process. Gel electrophoretic studies suggest that tight-binding site formation is accompanied by an increase in the strength of the NOS dimer. We propose that incubation of pterin-free nNOS with BH4 creates one tight pterin-binding site per dimer, leaving the other site unaffected, in a reaction that involves redox chemistry.
    Keywords: Biopterin -- Analogs & Derivatives ; Nitric Oxide Synthase Type I -- Metabolism
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 5
    Language: English
    In: PLoS ONE, 2011, Vol.6(10), p.e26044
    Description: Understanding the functions of proteins requires information about their protein-protein interactions (PPI). The collective effort of the scientific community generates far more data on any given protein than individual experimental approaches. The latter are often too limited to reveal an interactome comprehensively. We developed a workflow for parallel mining of all major PPI databases, containing data from several model organisms, and to integrate data from the literature for a protein of interest. We applied this novel approach to build the PPI network of the human Hsp90 molecular chaperone machine (Hsp90Int) for which previous efforts have yielded limited and poorly overlapping sets of interactors. We demonstrate the power of the Hsp90Int database as a discovery tool by validating the prediction that the Hsp90 co-chaperone Aha1 is involved in nucleocytoplasmic transport. Thus, we both describe how to build a custom database and introduce a powerful new resource for the scientific community.
    Keywords: Research Article ; Biology ; Computer Science ; Cell Biology ; Computer Science ; Biochemistry
    E-ISSN: 1932-6203
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  • 6
    In: Journal of Applied Polymer Science, 15 July 2017, Vol.134(27), pp.n/a-n/a
    Description: In automotive under‐the‐hood applications, electronics respectively their packaging materials come in contact with automotive fluids. The effect of automatic transmission fluid (ATF) on an anhydride‐cured epoxy was investigated at temperatures up to 180 °C for up to 1000 h. This study has shown that ATF retards the oxidative aging of the epoxy, presumably due to oxygen consumption. Whereas in air the material underwent a thermo‐oxidative aging with a mass loss of up to 4% and a strong broadening of to higher temperatures, in ATF a temperature dependent distinctive drop of from 142 to 126 °C after 1000 h aging at 180 °C, and a mass loss of maximum 1% was observed which might be a thermal decomposition of the epoxy material. A slight broadening of the damping factors might indicate an intrusion of ATF components. A color change of the samples could be observed after aging in air and ATF, with the discoloration in air being more intense. An explanation for the color change might be either a minor amount of oxygen causing an oxidative discoloration reaction or the intrusion of colored ATF degradation products. While the oxidation‐kinetics in air exhibited Arrhenius temperature‐dependence the mechanism in ATF changed above 165 °C. An acceleration of aging tests at temperatures beyond 150 °C is, therefore, not possible. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. , , 44877.
    Keywords: Aging ; Degradation ; Thermosets
    ISSN: 0021-8995
    E-ISSN: 1097-4628
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  • 7
    Language: English
    In: Applied Surface Science, 15 May 2018, Vol.440, pp.1107-1115
    Description: In this paper the distribution of debris generated by a nanosecond UV laser (248 nm) on epoxy resin and the prevention of the corresponding re-deposition effects by parameter selection for a ns-laser scanning process were investigated. In order to understand the mechanisms behind the debris generation, in-situ particle measurements were performed during laser treatment. These measurements enabled the determination of the ablation threshold of the epoxy resin as well as the particle density and size distribution in relation to the applied laser parameters. The experiments showed that it is possible to reduce debris on the surface with an adapted selection of pulse overlap with respect to laser fluence. A theoretical model for the parameter selection was developed and tested. Based on this model, the correct choice of laser parameters with reduced laser fluence resulted in a surface without any re-deposited micro-particles.
    Keywords: Uv-Excimer Laser ; Epoxy Resin ; Laser Ablation ; Pre-Treatment ; Debris ; Fiber Reinforced Polymers ; Engineering
    ISSN: 0169-4332
    E-ISSN: 1873-5584
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  • 8
    Language: English
    In: 2015, Vol.10(1), p.e0116404
    Description: Muscle invasive bladder carcinoma is a complex, multifactorial disease caused by disruptions and alterations of several molecular pathways that result in heterogeneous phenotypes and variable disease outcome. Combining this disparate knowledge may offer insights for deciphering relevant molecular processes regarding targeted therapeutic approaches guided by molecular signatures allowing improved phenotype profiling. The aim of the study is to characterize muscle invasive bladder carcinoma on a molecular level by incorporating scientific literature screening and signatures from omics profiling. Public domain omics signatures together with molecular features associated with muscle invasive bladder cancer were derived from literature mining to provide 286 unique protein-coding genes. These were integrated in a protein-interaction network to obtain a molecular functional map of the phenotype. This feature map educated on three novel disease-associated pathways with plausible involvement in bladder cancer, namely Regulation of actin cytoskeleton, Neurotrophin signalling pathway and Endocytosis. Systematic integration approaches allow to study the molecular context of individual features reported as associated with a clinical phenotype and could potentially help to improve the molecular mechanistic description of the disorder.
    Keywords: Research Article
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: PLoS ONE, 2015, Vol.10(5), pp.urn:issn:1932-6203
    Description: Objective We aimed to identify a novel panel of biomarkers predicting renal function decline in type 2 diabetes, using biomarkers representing different disease pathways speculated to contribute to the progression of diabetic nephropathy. Research Design and Methods A systematic data integration approach...
    Keywords: Chronic Kidney-Disease ; Glomerular-Filtration-Rate ; Endothelial Dysfunction ; Nephropathy ; Mellitus ; Plasma ; Microalbuminuria ; Albuminuria ; Progression ; Inflammation
    ISSN: 1932-6203
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  • 10
    Language: English
    In: The Journal of biological chemistry, 09 October 2015, Vol.290(41), pp.24932-44
    Description: Citrulline formation by both human neuronal nitric-oxide synthase (nNOS) and mouse macrophage inducible NOS was inhibited by the hydrogen sulfide (H2S) donor Na2S with IC50 values of ∼2.4·10(-5) and ∼7.9·10(-5) m, respectively, whereas human endothelial NOS was hardly affected at all. Inhibition of nNOS was not affected by the concentrations of l-arginine (Arg), NADPH, FAD, FMN, tetrahydrobiopterin (BH4), and calmodulin, indicating that H2S does not interfere with substrate or cofactor binding. The IC50 decreased to ∼1.5·10(-5) m at pH 6.0 and increased to ∼8.3·10(-5) m at pH 8.0. Preincubation of concentrated nNOS with H2S under turnover conditions decreased activity after dilution by ∼70%, suggesting irreversible inhibition. However, when calmodulin was omitted during preincubation, activity was not affected, suggesting that irreversible inhibition requires both H2S and NO. Likewise, NADPH oxidation was inhibited with an IC50 of ∼1.9·10(-5) m in the presence of Arg and BH4 but exhibited much higher IC50 values (∼1.0-6.1·10(-4) m) when Arg and/or BH4 was omitted. Moreover, the relatively weak inhibition of nNOS by Na2S in the absence of Arg and/or BH4 was markedly potentiated by the NO donor 1-(hydroxy-NNO-azoxy)-l-proline, disodium salt (IC50 ∼ 1.3-2.0·10(-5) m). These results suggest that nNOS and inducible NOS but not endothelial NOS are irreversibly inhibited by H2S/NO at modest concentrations of H2S in a reaction that may allow feedback inhibition of NO production under conditions of excessive NO/H2S formation.
    Keywords: Enzyme Inactivation ; Hydrogen Sulfide ; Nitric Oxide ; Nitric-Oxide Synthase ; Reactive Nitrogen Species (Rns) ; Enzyme Inhibitors -- Pharmacology ; Hydrogen Sulfide -- Pharmacology ; Nitric Oxide -- Pharmacology ; Nitric Oxide Synthase Type I -- Antagonists & Inhibitors ; Nitric Oxide Synthase Type II -- Antagonists & Inhibitors
    ISSN: 00219258
    E-ISSN: 1083-351X
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