Contributions to the Mathematical Systems Medicine of Antimicrobial Therapy and Genotype-Phenotype Inference.

The following summary of my publications describes the main ideas in the corresponding research articles and clarfifies my contribution in multi-author publications. I decided to apply for habilitation according to x2.I.1.(c) of the Habilitationsordnung (this path is usually referred as Kumulative Habilitation"). I selected 13 first- or last author publications for this habilitation that concern contributions to the mathematical systems medicine of antiviral therapy [tMH10, tMS+11, FtK+11, tMMS12, DSt12, DWSt15, Dt16, DSt16, DDKt18, DSD+19, DDKt19], as well as inference of genotype-phenotype associations [SDH+15, SSJ+18]. The selected publications represent my major contributions in this research eld since submitting my doctoral thesis in September 2009

Sie haben mich immer in der Zuruckgesogenheit meiner Lebensart fur isoliert von der welt gehalten; und dooh ist vielleioht niemand inniger damit verbunden als ich

Not Availabl

Absolute Protein Amounts and Relative Abundance of Volume-regulated Anion Channel (VRAC) LRRC8 Subunits in Cells and Tissues Revealed by Quantitative Immunoblotting

The volume-regulated anion channel (VRAC) plays an important role in osmotic cell volume regulation. In addition, it is involved in various physiological processes such as insulin secretion, glia-neuron communication and purinergic signaling. VRAC is formed by hetero-hexamers of members of the LRRC8 protein family, which consists of five members, LRRC8A-E. LRRC8A is an essential subunit for physiological functionality of VRAC. Its obligate heteromerization with at least one of its paralogues, LRRC8B-E, determines the biophysical properties of VRAC. Moreover, the subunit composition is of physiological relevance as it largely influences the activation mechanism and especially the substrate selectivity. However, the endogenous tissue-specific subunit composition of VRAC is unknown. We have now developed and applied a quantitative immunoblot study of the five VRAC LRRC8 subunits in various mouse cell lines and tissues, using recombinant protein for signal calibration. We found tissue-specific expression patterns of the subunits, and generally relative low expression of the essential LRRC8A subunit. Immunoprecipitation of LRRC8A also co-precipitates an excess of the other subunits, suggesting that non-LRRC8A subunits present the majority in hetero-hexamers. With this, we can estimate that in the tested cell lines, the number of VRAC channels per cell is in the order of 10,000, which is in agreement with earlier calculations from the comparison of single-channel and whole-cell currents

Genetic Analysis of the Light Dependence of Courtship in Drosophila subobscura.

uploaded by Plazi from Taxodro

Implementing literature-based curriculum in primary grades

Literature-based reading instruction -- Writing centers -- Library corners

Mathematical Modelling of the Molecular Mechanisms of Interaction of Tenofovir with Emtricitabine against HIV

The combination of the two nucleoside reverse transcriptase inhibitors (NRTI) tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is used in most highly active antiretroviral therapies for treatment of HIV-1 infection, as well as in pre-exposure prophylaxis against HIV acquisition. Administered as prodrugs, these drugs are taken up by HIV-infected target cells, undergo intracellular phosphorylation and compete with natural deoxynucleoside triphosphates (dNTP) for incorporation into nascent viral DNA during reverse transcription. Once incorporated, they halt reverse transcription. In vitro studies have proposed that TDF and FTC act synergistically within an HIV-infected cell. However, it is unclear whether, and which, direct drug–drug interactions mediate the apparent synergy. The goal of this work was to refine a mechanistic model for the molecular mechanism of action (MMOA) of nucleoside analogues in order to analyse whether putative direct interactions may account for the in vitro observed synergistic effects. Our analysis suggests that depletion of dNTP pools can explain apparent synergy between TDF and FTC in HIV-infected cells at clinically relevant concentrations. Dead-end complex (DEC) formation does not seem to significantly contribute to the synergistic effect. However, in the presence of non-nucleoside reverse transcriptase inhibitors (NNRTIs), its role might be more relevant, as previously reported in experimental in vitro studies.Peer Reviewe

Physiologically Based Pharmacokinetic Modelling: A Sub-Compartmentalized Model of Tissue Distribution

We present a sub-compartmentalized model of drug distribution in tissue that extends existing approaches based on the well-stirred tissue model. It is specified in terms of di®erential equations that explicitly account for the drug concentration in erythrocytes, plasma, interstitial and cellular space. Assuming, in addition, steady state drug distribution and by lumping the different sub-compartments, established models to predict tissue-plasma partition coe±cients can be derived in an intriguingly simple way. This direct link is exploited to explicitly construct and parameterize the sub-compartmentalized model for moderate to strong bases, acids, neutrals and zwitterions. The derivation highlights the contributions of the different tissue constituents and provides a simple and transparent framework for the construction of novel tissue distribution models