A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks

Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug–drug, or drug–metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach

Rückwirkungsfreie Motordrehzahlerfassung für friseurtechnische Geräte

Zusammenfassung: Die vorliegende Studienarbeit wurde in Zusammenarbeit mit der Firma Wella, einem Hersteller professioneller Geräte für den Friseurbedarf, durchgeführt. Aufgabenstellung war die Entwicklung eines Verfahrens zur Messung der Motordrehzahl eines Föns o.ä. ohne Beeinflussung des Volumenstroms. Das Ergebnis soll auf einem PC zur Verfügung stehen und an ein vorhandenes Basic-Programm übergeben werden können. Bei dem entwickelten Verfahren wird die Unwucht des rotierenden Systems Motor-Lüfterrad genutzt und die Vibrationen am Gehäuse mit Hilfe eines Körperschallmikrofones (Beschleunigungsaufnehmer) aufgenommen. Zur Aufbereitung und Auswertung des Signals wurde eine Lösung realisiert, bei der das Signal eines Körperschallmikrofons mittels einer 'Soundblasterkarte' digitalisiert und mit Methoden der digitalen Signalverarbeitung gefiltert und ausgewertet wird. Vorteile dieses Verfahrens sind seine geringen Kosten, die Genauigkeit der gelieferten Ergebnisse und seine Flexibilität hinsichtlich der Anpassung an den Geräteprüfling

Using expression data for quantification of active processes in physiologically based pharmacokinetic modeling. Drug Metabolism and Disposition 40(5): 892–901

ABSTRACT: Active processes involved in drug metabolization and distribution mediated by enzymes, transporters, or binding partners mostly occur simultaneously in various organs. However, a quantitative description of active processes is difficult because of limited experimental accessibility of tissue-specific protein activity in vivo. In this work, we present a novel approach to estimate in vivo activity of such enzymes or transporters that have an influence on drug pharmacokinetics. Tissue-specific mRNA expression is used as a surrogate for protein abundance and activity and is integrated into physiologically based pharmacokinetic (PBPK) models that already represent detailed anatomical and physiological information. The new approach was evaluated using three publicly available databases: whole-genome expression microarrays from ArrayExpress, reverse transcription-polymerase chain reaction-derived gene expression estimates collected from the literature, and expressed sequence tags from UniGene. Expression data were preprocessed and stored in a customized database that was then used to build PBPK models for pravastatin in humans. These models represented drug uptake by organic anion-transporting polypeptide 1B1 and organic anion transporter 3, active efflux by multidrug resistance protein 2, and metabolization by sulfotransferases in liver, kidney, and/or intestine. Benchmarking of PBPK models based on gene expression data against alternative models with either a less complex model structure or randomly assigned gene expression values clearly demonstrated the superior model performance of the former. Besides accurate prediction of drug pharmacokinetics, integration of relative gene expression data in PBPK models offers the unique possibility to simultaneously investigate drug-drug interactions in all relevant organs because of the physiological representation of protein-mediated processes

Using expression data for quantification of active processes in physiologically based pharmacokinetic modeling. Drug Metabolism and Disposition 40(5): 892–901

Number of text pages 21 Number of tables 3 Number of figures 4 Number of references 40 Number of words in the abstract 244 DMD #43174 3 Tissue specific mRNA expression is used as a surrogate for protein abundance and activity and is integrated into physiologically-based pharmacokinetic (PBPK) models which already represent detailed anatomical and physiological information. The new approach was evaluated using three publicly available databases: Whole genome expression microarrays from ArrayExpress, RT-PCR derived gene expression estimates collected from literature, and expressed sequence tags (EST) from UniGene. Expression data were preprocessed and stored in a c ustomized database that was then used to build PBPK models for p ravastatin in humans. These models represented drug uptake by OATP1B1 and OAT3, active efflux by MRP2, and metabolization by sulfotransferases in either liver, kidney and/or intestine. Bench-marking of PBPK models based on gene expression data against alternative models with either less complex model structure or randomly assigned gene expression values clearly demonstrated the superior model performance of the former. Besides an accurate prediction of drug pharmacokinetics, integration of relative gene expression data in PBPK models offers the unique possibility to simultaneously investigate drug-drug interactions in all relevant organs due to the physiological representation of protein mediated processes. Number of words in the introduction 715 Number of words in the discussion 1192 List of nonstandard abbreviations DMD #43174

A Novel Superfamily of Transporters for Allantoin and Other Oxo Derivatives of Nitrogen Heterocyclic Compounds in Arabidopsis

A wide spectrum of soil heterocyclic nitrogen compounds are potential nutrients for plants. Here, it is shown that Arabidopsis plants are able to use allantoin as sole nitrogen source. By functional complementation of a yeast mutant defective in allantoin uptake, an Arabidopsis transporter, AtUPS1 ( Arabidopsis thaliana ureide permease 1 ), was identified. AtUPS1 belongs to a novel superfamily of plant membrane proteins with five open reading frames in Arabidopsis (identity, 64 to 82%). UPS proteins have 10 putative transmembrane domains with a large cytosolic central domain containing a “Walker A” motif. Transport of 14 C-labeled allantoin by AtUPS1 in yeast exhibited saturation kinetics ( K m ∼ 52 μM), was dependent on Glc and a proton gradient, and was stimulated by acidic pH. AtUPS1 transports uric acid and xanthine, besides allantoin, but not adenine. Protons are cosubstrates in allantoin transport by AtUPS1, as demonstrated by expression in Xenopus laevis oocytes. In plants, AtUPS1 gene expression was dependent on the nitrogen source. Therefore, AtUPS1 presumably is involved in the uptake of allantoin and other purine degradation products when primary sources are limiting

The lifestyle of Corynebacterium urealyticum derived from its complete genome sequence established by pyrosequencing

Tauch A, Trost E, Tilker A, et al. The lifestyle of Corynebacterium urealyticum derived from its complete genome sequence established by pyrosequencing. Journal of Biotechnology. 2008;136(1-2):11-21

Runoff extremity in the Upper Lužnice catchment area

Thesis subject is the evaluation of runoff and flood regime of rivers Lužnice and Skřemelice at the closing profiles just before their confluences. The results are compared with findings from the profile Pilař, which were published in the past by other authors. More attention is paid to the evaluation of the hydrological year 2013 and in detail is described the flood in June of the same year. Daily flow data from the years 1971 - 2014 were used for evaluating of runoff conditions. The assessment of the runoff regime in terms of daily, monthly and annual flows were compared with the runoff regime in Pilař gauge station. The source regions with dominating influence on the resulting runoff were discovered. Analysis of the flood regime confirmed that spring floods in Lužnice came mainly from upland and hilly parts of catchment and large summer floods have main source area in the catchment of Lužnice river itself, before the confluence of the Lužnice river and Skřemelic river. When assessing flood in 2013, the main source areas of flood flows that hit Lužnice river basin were founded. The flood extremity was compared in each closing profiles