Klaus Lindauer - Academia.edu (original) (raw)

Papers by Klaus Lindauer

CPT: Pharmacometrics & Systems Pharmacology

Toxicologic Pathology

Reliable detection and measurement of cell proliferation are essential in the preclinical assessm... more Reliable detection and measurement of cell proliferation are essential in the preclinical assessment of carcinogenic risk of therapeutics. In this context, the assessment of mitogenic potential on mammary glands is crucial in the preclinical safety evaluation of novel insulins. The existing manual counting is time-consuming and subject to operator bias. To standardize the processes, make it faster, and resistant to errors, we developed a semiautomated image analysis system (CEPA software, which is open-source) for counting of proliferating cells in photomicrographs of mammary gland sections of rats labeled with Ki-67. We validated the software and met the predefined targets for specificity, accuracy, and reproducibility. In comparison to manual counting, the respective mean differences in absolute labeling indices (LIs) for CEPA software were 3.12% for user 1 and 3.05% for user 2. The respective regression analysis revealed a good correlation between the CEPA software user and manua...

Int. Journal of Clinical Pharmacology and Therapeutics

BMC Bioinformatics, 2015

The concept of Petri nets (PN) is widely used in systems biology and allows modeling of complex b... more The concept of Petri nets (PN) is widely used in systems biology and allows modeling of complex biochemical systems like metabolic systems, signal transduction pathways, and gene expression networks. In particular, PN allows the topological analysis based on structural properties, which is important and useful when quantitative (kinetic) data are incomplete or unknown. Knowing the kinetic parameters, the simulation of time evolution of such models can help to study the dynamic behavior of the underlying system. If the number of involved entities (molecules) is low, a stochastic simulation should be preferred against the classical deterministic approach of solving ordinary differential equations. The Stochastic Simulation Algorithm (SSA) is a common method for such simulations. The combination of the qualitative and semi-quantitative PN modeling and stochastic analysis techniques provides a valuable approach in the field of systems biology. Here, we describe the implementation of stochastic analysis in a PN environment. We extended MONALISA - an open-source software for creation, visualization and analysis of PN - by several stochastic simulation methods. The simulation module offers four simulation modes, among them the stochastic mode with constant firing rates and Gillespie&amp;#39;s algorithm as exact and approximate versions. The simulator is operated by a user-friendly graphical interface and accepts input data such as concentrations and reaction rate constants that are common parameters in the biological context. The key features of the simulation module are visualization of simulation, interactive plotting, export of results into a text file, mathematical expressions for describing simulation parameters, and up to 500 parallel simulations of the same parameter sets. To illustrate the method we discuss a model for insulin receptor recycling as case study. We present a software that combines the modeling power of Petri nets with stochastic simulation of dynamic processes in a user-friendly environment supported by an intuitive graphical interface. The program offers a valuable alternative to modeling, using ordinary differential equations, especially when simulating single-cell experiments with low molecule counts. The ability to use mathematical expressions provides an additional flexibility in describing the simulation parameters. The open-source distribution allows further extensions by third-party developers. The software is cross-platform and is licensed under the Artistic License 2.0.

The increase in eosinophils at the site of antigen challenge has been used as evidence to suggest... more The increase in eosinophils at the site of antigen challenge has been used as evidence to suggest that this cell type plays a role in the pathophysiology of asthma. Aberrant production of sev- eral different cytokines, particularly interleukin (IL)-5, has been shown to result in eosinophilia. IL-5 influences the develop- ment and maturation of eosinophils in a number of different

Theoretical Chemistry Accounts: Theory, Computation, and Modeling (Theoretica Chimica Acta), 1999

Small molecule studies indicate that C

Protein Engineering Design and Selection, 2001

The structure of human Janus kinase 2 (JAK2) comprising the two C-terminal domains (JH1 and JH2) ... more The structure of human Janus kinase 2 (JAK2) comprising the two C-terminal domains (JH1 and JH2) was predicted by application of homology modelling techniques. JH1 and JH2 represent the tyrosine kinase and tyrosine kinase-like domains, respectively, and are crucial for function and regulation of the protein. A comparison between the structures of the two domains is made and structural differences are highlighted. Prediction of the relative orientation of JH1 and JH2 was aided by a newly developed method for the detection of correlated amino acid mutations. Analysis of the interactions between the two domains led to a model for the regulatory effect of JH2 on JH1. The predictions are consistent with available experimental data on JAK2 or related proteins and provide an explanation for inhibition of JH1 tyrosine kinase activity by the adjacent JH2 domain. Keywords: amino acid interactions/comparative sequence analysis/homology modelling/JAK2/tyrosine kinase

Osteoarthritis and Cartilage, 2004

Objective: Cultures of primary articular chondrocytes for studying chondrocyte biology are notori... more Objective: Cultures of primary articular chondrocytes for studying chondrocyte biology are notoriously difficult to handle. One alternative is the use of chondrocytic cell lines. Because the HCS-2/8 cells are the most widely used cell line in cartilage research, we investigated the molecular phenotype of these cells by mRNA-expression profiling.

Bioinformatics, 1996

The program HBexplore is a new tool for identifying and analysing H-bonding patterns in biologica... more The program HBexplore is a new tool for identifying and analysing H-bonding patterns in biological macromolecules. It selects all potential H-bonds according to geometrical criteria. The H-bond table can then be subjected to further automatic or interactive analysis tools. These tools include the calculation of mean values and distributions of geometrical H-bond parameters for parts of a single structure, for complete single structures and for structure sets, the classification of each H-bond according to the participation of backbone, side chain or base, ligand and water parts of nucleic acids or proteins, identification of Watson-Crick nucleotide pairs and of H-bonded pairs of equal nucleotides, the calculation of the mean number of H-bonds per residue, and of the fraction of potential donor and acceptor atoms involved in H-bonds. HBexplore further generates automatically a H-bond residue interaction table. This table lists for all residues of the structure the other residues, ligands or water molecules directly connected via a H-bond. By means of a binary tree search algorithm, this table is then converted into a H-bond cluster table. Clusters are understood here as an uninterrupted network of H-bonded residues. For nucleic acids, secondary structures and tertiary interactions are automatically derived from the H-bonding pattern. HBexplore is applied to two example RNA structures: a pseudoknot and a hairpin. It provides a comprehensive listing of individual H-bonds and statistical information for larger structure sets. In addition, it can identify interesting new H-bond motifs. One example is a pentanucleotide base-base H-bond interaction motif in the RNA pseudoknot. HBexplore is intended to contribute both to the elucidation of general principles of the architecture of biological macromolecules, and to the prediction and refinement of single structures. ) Oxford University Press

Journal of Immunological Methods, 2001

Microarrays of oligonucleotides or cDNAs can be used to establish the expression profiles of nume... more Microarrays of oligonucleotides or cDNAs can be used to establish the expression profiles of numerous genes in a single experiment. We have established a microarray platform to identify genes in a number of different pathological conditions, particularly those with an inflammation component. This platform utilised the output of an eosinophil sequencing project in which 1069 sequences were identified that were not represented in the public domain. An eosinophil model cell line, AML14.3D10, was used to investigate cell adhesion. The transcription profile of adhered and non-adhered AML 14.3D10 cells was shown to be both technically and biologically reproducible. A number of genes were found differentially expressed in the adhered vs. non-adhered populations. In the adhered population, the expression of these genes was restricted compared to brain, lung, kidney and especially bone marrow. However, the differentially regulated genes were not among those genes most restricted to eosinophils. We discuss the implications of transcription profiling on gene annotation and its potential utility for the identification of targets for drug intervention.