Daniel Faller

Simulation Methods for Optimal Experimental Design in Systems Biology

To obtain a systems-level understanding of a biological system, the authors conducted quantitative dynamic experiments from which the system structure and the parameters have to be deduced. Since biological systems have to cope with different environmental conditions, certain properties are often robust with respect to variations in some of the parameters. Hence, it is important to use optimal experimental design considerations in advance of the experiments to improve the information content of the measurements. Using the MAP-Kinase pathway as an example, the authors present a simulation study investigating the application of different optimality criteria. It is demonstrated that experimental design significantly improves the parameter estimation accuracy and also reveals difficulties in parameter estimation due to robustness.

Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF-E2

The molecular aetiology of polycythaemia vera (PV) remains unknown and the differential diagnosis between PV and secondary erythrocytosis (SE) can be challenging. Gene expression profiling can identify candidates involved in the pathophysiology of PV and generate a molecular signature to aid in diagnosis. We thus performed cDNA microarray analysis on 40 PV and 12 SE patients. Two independent data sets were obtained: using a two‐step training/validation design, a set of 64 genes (class predictors) was determined, which correctly discriminated PV from SE patients. Separately 253 genes were identified to be upregulated and 391 downregulated more than 1·5‐fold in PV compared with healthy controls (P < 0·01). Of the genes overexpressed in PV, 27 contained Sp1 sites: we therefore propose that altered activity of Sp1‐like transcription factors may contribute to the molecular aetiology of PV. One Sp1 target, the transcription factor NF‐E2 [nuclear factor (erythroid‐derived 2)], is overexpressed 2‐ to 40‐fold in PV patients. In PV bone marrow, NF‐E2 is overexpressed in megakaryocytes, erythroid and granulocytic precursors. It has been shown that overexpression of NF‐E2 leads to the development of erythropoietin‐independent erythroid colonies and that ectopic NF‐E2 expression can reprogram monocytic cells towards erythroid and megakaryocytic differentiation. Transcription factor concentration may thus control lineage commitment. We therefore propose that elevated concentrations of NF‐E2 in PV patients lead to an overproduction of erythroid and, in some patients, megakaryocytic cells/platelets. In this model, the level of NF‐E2 overexpression determines both the severity of erythrocytosis and the concurrent presence or absence of thrombocytosis.

Expression profiling on chronically rejected transplant kidneys.

Background. Chronic transplant nephropathy remains a poorly defined inflammatory process that limits the survival rate of most renal transplants. We analyzed the gene profile of chronically rejected kidney transplants to identify candidate genes that characterize chronic transplant nephropathy. Methods. To distinguish genes present in normal renal tissue or specific for end-stage renal failure, we compared the gene profiles of 13 chronically rejected kidney transplants with 16 normal kidneys and 12 end-stage polycystic kidneys using a 7K human cDNA microarray. After elimination of genes with signals close to background, 2,190 genes were available for statistical analysis. Results. More than 20% of the examined genes were significantly regulated when compared with the expression level of normal renal tissue (P <0.0003). Hierarchic clustering based on 571 genes differentiated normal and transplant tissue, and transplant and polycystic kidney tissue. Most of these genes encoded proteins involved in cellular metabolism, transport, signaling, transcriptional activation, adhesion, and the immune response. Notably, comprehensive gene profiling of chronically rejected kidneys revealed two distinct subsets of chronically rejected transplants. Neither clinical data nor histology could explain this genetic heterogeneity. Conclusions. Microarray analysis of rejected kidneys may help to define different entities of transplant nephropathy, reflecting the multifactorial cause of chronic rejection.

Real-time monitoring of ethene/1-hexene copolymerizations: determination of catalyst activity, copolymer composition and copolymerization parameters

High-throughput development of catalysts, initiators, and polymeric materials combines automated parallel catalyst synthesis and automated polymerization reactors. The reactors can be additionally equipped with on-line monitoring (ReactIR from Mettler) based on ATR-FT-IR technique. This powerful tool has proven to be a very valuable probe for high-throughput experiments. During copolymerizations of ethene and 1-hexene monomers, the ReactIR was used to monitor the 1-hexene conversion as well as polymer formation, polymer concentration, and polymer composition. This gives access to information on catalyst activity, activation and deactivation times of the catalyst, polymerization kinetics, copolymerization parameters, and the degree of homogeneity of the resulting copolymers. The technology is especially useful for solution copolymerization. The spectrometer can be applied in the lab as well as in pilot plants and production facilities where rapid on-line analyses are useful for product quality control.

A master equation approach to option pricing

A master equation approach to the numerical solution of option pricing models is developed. The basic idea of the approach is to consider the Black–Scholes equation as the macroscopic equation of an underlying mesoscopic stochastic option price variable. The dynamics of the latter is constructed and formulated in terms of a master equation. The numerical efficiency of the approach is demonstrated by means of stochastic simulation of the mesoscopic process for both European and American options.

An Open Source Protein Gel Documentation System for Proteome Analyses

Data organization and data mining represents one of the main challenges for modern high throughput technologies in pharmaceutical chemistry and medical chemistry. The presented open source documentation and analysis system provides an integrated solution (tutorial, setup protocol, sources, executables) aimed at substituting the traditionally used lab-book. The data management solution provided incorporates detailed information about the processing of the gels and the experimental conditions used and includes basic data analysis facilities which can be easily extended. The sample database and User-Interface are available free of charge under the GNU license from http://webber.physik.uni-freiburg.de/~fallerd/tutorial.htm.

Non-Markovian dynamics in continuous-wave atom lasers

The non-Markovian dynamics of a continuous-wave atom laser model including gravitational effects and interactions inside the Bose-Einstein condensate is studied. A generalization of the time-convolutionless projection operator technique presented in this article enables a correct modeling of memory effects in the atom laser which takes into account correlations in the initial state of the combined atom-reservoir system. This generalization allows the computation of both the occupation number of the condensate and the spectrum of the atoms coupled out of the condensate. The non-Markovian evolution is shown to yield substantial deviations from results obtained in the Born-Markov approximation.