Integrating Pharmacogenetic Decision Support into a Clinical Information System

Pharmacogenetic testing can prevent adverse drug events but has rarely found its way into clinical routine. One reason is the lack of tools for smooth and automatable integration of pharmacogenetic knowledge into existing processes. Especially, electronic medical records (EMR) represent a suitable environment for such tools. We developed a modular service-oriented prototype of a pharmacogenetic decision support system within an EMR system of the Bern University Hospital. Here, we present the component architecture of our system and discuss issues required for generalizing our results

Cluster-based density-functional approach to quantum transport through molecular and atomic contacts

We present a cluster-based density-functional approach to model charge transport through molecular and atomic contacts. The electronic structure of the contacts is determined in the framework of density functional theory, and the parameters needed to describe transport are extracted from finite clusters. A similar procedure, restricted to nearest-neighbor interactions in the electrodes, has been presented by Damle et al. [Chem. Phys. 281, 171 (2002)]. Here, we show how to systematically improve the description of the electrodes by extracting bulk parameters from sufficiently large metal clusters. In this way we avoid problems arising from the use of nonorthogonal basis functions. For demonstration we apply our method to electron transport through Au contacts with various atomic-chain configurations and to a single-atom contact of Al.Comment: 18 pages, 13 figure

PARP1 catalytic variants reveal branching and chain length-specific functions of poly(ADP-ribose) in cellular physiology and stress response

Poly(ADP-ribosyl)ation regulates numerous cellular processes like genome maintenance and cell death, thus providing protective functions but also contributing to several pathological conditions. Poly(ADP-ribose) (PAR) molecules exhibit a remarkable heterogeneity in chain lengths and branching frequencies, but the biological significance of this is basically unknown. To unravel structure-specific functions of PAR, we used PARP1 mutants producing PAR of different qualities, i.e. short and hypobranched (PARP1\G972R), short and moderately hyperbranched (PARP1\Y986S), or strongly hyperbranched PAR (PARP1\Y986H). By reconstituting HeLa PARP1 knockout cells, we demonstrate that PARP1\G972R negatively affects cellular endpoints, such as viability, cell cycle progression and genotoxic stress resistance. In contrast, PARP1\Y986S elicits only mild effects, suggesting that PAR branching compensates for short polymer length. Interestingly, PARP1\Y986H exhibits moderate beneficial effects on cell physiology. Furthermore, different PARP1 mutants have distinct effects on molecular processes, such as gene expression and protein localization dynamics of PARP1 itself, and of its downstream factor XRCC1. Finally, the biological relevance of PAR branching is emphasized by the fact that branching frequencies vary considerably during different phases of the DNA damage-induced PARylation reaction and between different mouse tissues. Taken together, this study reveals that PAR branching and chain length essentially affect cellular functions, which further supports the notion of a ‘PAR code’

Nucleon-nucleon elastic scattering analysis to 2.5 GeV

A partial-wave analysis of NN elastic scattering data has been completed. This analysis covers an expanded energy range, from threshold to a laboratory kinetic energy of 2.5 GeV, in order to include recent elastic pp scattering data from the EDDA collaboration. The results of both single-energy and energy-dependent analyses are described.Comment: 23 pages of text. Postscript files for the figures are available from ftp://clsaid.phys.vt.edu/pub/said/n