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The dynamic models used for biological and chemical process analysis and design usually include a significant number of uncertain model parameters. Sensitivity analysis is frequently applied to provide quantitative information regarding the influence of the parameters, as well as their uncertainties, on the model output. Various techniques are available in the literature to calculate parameter sensitivities based on local derivatives or changes in dedicated statistical moments of the model output. However, these methods may lead to an inevitable loss of information for a proper sensitivity analysis and are not directly available for problems with correlated model parameters. In this work, we demonstrate the use of a moment-independent sensitivity analysis concept in the presence and absence of parameter correlations and investigate the correlation effect in more detail. Moment-independent sensitivity analysis calculates parameter sensitivities based on changes in the entire probability density distribution of the model output and is formulated independently of whether the parameters are correlated or not. Technically, a single-loop Monte Carlo simulation method in combination with polynomial chaos expansion is implemented to reduce the computational cost significantly. A sampling procedure derived from Gaussian copula formalism is used to generate sample points for arbitrarily correlated uncertain parameters. The proposed concept is demonstrated with a case study of an enzyme-catalyzed reaction network. We observe evident differences in the parameter sensitivities for cases with independent and correlated model parameters.

Die enzymatische Hydrolyse im Rahmen eines Bioraffinerieprozesses spielt eine Schlusselrolle in der Umwandlung lignocellulosehaltiger Biomasse in Zucker, die wiederum als Substrate fur die Fermentation zu Chemikalien oder Kraftstoffen eingesetzt werden. Dabei beschreibt Abschn. 15.1 die Zusammensetzung der Lignocellulose aus Cellulose, Hemicellulose und Lignin und deren Einfluss auf die Hydrolyse. Cellulose wird durch von Pilzen sekretierte Cellulasen in das Monomer Glucose abgebaut (Abschn. 15.2), wahrend Hemicellulose und Lignin durch Hemicellulasen und Ligninasen abgebaut werden (Abschn. 15.3). Die Wahl eines geeigneten Enzymcocktails hangt von der Zusammensetzung der Biomasse ab und diese wiederum von den Vorbehandlungsverfahren (Abschn. 15.4). Abschliesend werden besondere Herausforderungen am Beispiel einer Ethanolbioraffinerie aufgezeigt (Abschn. 15.5).

Background — ADAMs ( A D isintegrin A nd M etalloproteinase) are ectoproteases that have recently been reported to be expressed in cardiac tissue. Although they are known to regulate cell-cell and cell-matrix interactions, their pathophysiological role in various cardiac diseases is unclear. The purpose of the present study was to determine whether structural remodeling of the atria during atrial fibrillation (AF) is associated with altered ADAM expression. Methods and Results — Atrial tissue samples of 30 patients undergoing open-heart surgery were examined. Fifteen patients had persistent AF (≥6 months), and the remaining 15 patients had no history of AF. ADAM9, ADAM10, and ADAM15 expression was analyzed quantitatively at the mRNA and protein levels. ADAM expression was localized by immunohistochemistry. ADAM expression was correlated with amounts of integrins β 1 and β 3 . The amount of ADAM10 protein more than doubled during AF (82±15 versus 36±8 U; P P P P P Conclusions — AF is associated with an increase in the expression of ADAM10 and ADAM15. Enhanced ADAM-dependent disintegrin and metalloproteinase activity may be a molecular mechanism that contributes to the dilation of fibrillating human atria.

Stimulation of human T-cells by pokeweed mitogen (PWM) results in a significant increase of IL-2, IFN-gamma, and DP IV mRNA expression as analyzed by quantitative RT-PCR. Here we show for the first time that the changes observed in cytokine mRNA expression are dose-dependently suppressed by the specific dipeptidyl peptidase IV inhibitor Lys[Z(NO(2))]-thiazolidide. Most interestingly, the inhibition of DP IV activity leads to a decrease in mRNA expression of the enzyme itself. Furthermore, evidence is provided that this suppression is mediated by TGF-beta(1). The presented data fit into the hypothesis that inhibition of DP IV leads to the induction of TGF-beta(1), which in turn provokes an arrest of cell cycle in late G(1).

The dipeptidyl peptidase IV is an activation marker on T, B and NK cells. Specific inhibitors of DP IV suppress DNA synthesis, as well as cytokine protein production. Here, we describe for the first time the quantitative changes of mRNA expression of IFN-gamma, IL-2, IL-12 and DP IV after inhibition of DP IV. Due to the stimulation of human peripheral blood mononuclear cells (PBMC) with pokeweed mitogen (PWM) both cytokine as well as DP IV mRNA expression is increased significantly. Treatment with DP IV inhibitor suppresses dose-dependently these changes. Importantly, mRNA expression of DP IV itself was inhibited. The presented data are fully compatible with our hypothesis that inhibition of DP IV leads to cell cycle arrest in late G1 due to enhanced TGF-beta 1 expression.

Inhibition of alanyl-aminopeptidase gene expression or enzymatic activity compromises T cell proliferation and function. Molecular mechanisms mediating theseeffects are not known as yet. Applying the cDNA array technique we identified the proto-oncogen Wnt-5a strongly affected by APN-inhibition Wnt-5a and other members of the Wnt family of secreted factors are implicated in cell growth and differentiation. Wnt-5a was moderately expressed in resting T cells, but stronglydown-regulated in response to activation by OKT3/IL-4/IL-9. Actinonin increased Wnt-5a-mRNA contents as confirmed by RT-PCR. In addition, expression of GSK-s an inherent component of the Wnt-pathway, was found to be increased in response to activation, but suppressed by actinonin at both the mRNA and protein level. These findings may provide a rationale for the strong growth inhibitory effects resulting from an inhibition of alanylaminopeptidase expression or activity.

Inhibition of alanyl-aminopeptidase (APN, CD13) gene expression or enzymatic activity compromises T cell proliferation and function. Molecular mechanisms mediating these effects are not known as yet. Recently, we found the expression of the proto-oncogen Wnt-5a to be strongly affected by APN-inhibition. Wnt-5a and other members of the Wnt family of secreted factors are implicated in cell growth and differentiation. Here, we analyzed by quantitative RT-PCR and immunoblotting the expression in mitogen-activated T cells of a major constituent of the Wnt-5a pathway, glycogen synthase kinase-3beta (GSK-3beta). T cell activation by phytohaemagglutinin or pokeweed mitogen results in a strong increase of GSK-3beta mRNA amounts. At the protein level, we observed an up-regulation of both GSK-3beta and phosphorylated GSK-3beta. This induction-dependent increase of GSK-3beta is markedly reduced in response to inhibitors of alanyl-aminopeptidase, actinonin, leuhistin, and RB3014. These findings may provide a rational for the growth inhibition resulting from a diminished expression or activity of alanyl aminopeptidase.

Background —Previous studies have suggested that atrial fibrillation (AF) is associated with the activation of the atrial angiotensin system. However, it is not known whether the expression of angiotensin II receptors changes during AF. The purpose of this study was to determine the atrial expression of angiotensin II type 1 and type 2 receptors (AT 1 -R and AT 2 -R) in patients with AF. Methods and Results —Atrial tissue samples from 30 patients undergoing open heart surgery were examined. Eleven patients had chronic persistent AF (≥6 months; cAF), 8 patients had paroxysmal AF (pAF), and 11 patients were in sinus rhythm. AT 1 -R and AT 2 -R were localized in the atrial tissue by immunohistochemistry and quantified at the protein and mRNA level by Western blotting and quantitative polymerase chain reaction. Both types of AT-R were predominantly expressed in atrial myocytes in all groups. The amount of AT 1 -R was reduced to 34.9% during cAF ( P P 2 -R was increased during cAF (246%; P =NS) and pAF (505%; P 1 -R/AT 2 -R mRNA content was similar in all groups. Conclusions —AF is associated with the down-regulation of atrial AT 1 -R and the up-regulation of AT 2 -R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria.