Synergistic gold-copper detoxification at the core of gold biomineralisation in Cupriavidus metallidurans

The bacterium Cupriavidus metallidurans is capable of reducing toxic Au(i/iii)-complexes into metallic gold (Au) nano-particles, thereby mediating the (trans)formation of Au nuggets in Earth surface environments. In this study we describe a novel detoxification pathway, which prevents synergistic copper (Cu)/Au-toxicity. Gold-complexes and Cu-ions exert cooperative toxicity, because cellular uptake of Au(i/iii)-complexes blocks Cu(i) export from the cytoplasm by the Cu-efflux pump CupA. Using a combination of micro-analytical and biochemical methods we show that inducible resistance to these Cu/Au mixtures is mediated by the periplasmic Cu(i)-oxidase CopA, which functions as an oxygen-consuming Au(i)-oxidase. With high Au-complex loads the enzymatic activity of CopA detoxifies the reduction pathway of Au(iii)-complexes via Au(i)-intermediates to Au(0) nanoparticles in the periplasm. Thereby the concentration of highly toxic Au(i) in the cytoplasm is diminished, while allowing direct reduction of Au(iii) to Au nanoparticles in the periplasm. This permits C. metallidurans to thrive in Au-rich environments and biomineralise metallic Au.L. Bütof, N. Wiesemann, M. Herzberg, M. Altzschner, A. Holleitner, F. Reithc and D. H. Nie

Precise image-guided irradiation of small animals: a flexible non-profit platform.

Preclinical in vivo studies using small animals are essential to develop new therapeutic options in radiation oncology. Of particular interest are orthotopic tumour models, which better reflect the clinical situation in terms of growth patterns and microenvironmental parameters of the tumour as well as the interplay of tumours with the surrounding normal tissues. Such orthotopic models increase the technical demands and the complexity of preclinical studies as local irradiation with therapeutically relevant doses requires image-guided target localisation and accurate beam application. Moreover, advanced imaging techniques are needed for monitoring treatment outcome. We present a novel small animal image-guided radiation therapy (SAIGRT) system, which allows for precise and accurate, conformal irradiation and x-ray imaging of small animals. High accuracy is achieved by its robust construction, the precise movement of its components and a fast high-resolution flat-panel detector. Field forming and x-ray imaging is accomplished close to the animal resulting in a small penumbra and a high image quality. Feasibility for irradiating orthotopic models has been proven using lung tumour and glioblastoma models in mice. The SAIGRT system provides a flexible, non-profit academic research platform which can be adapted to specific experimental needs and therefore enables systematic preclinical trials in multicentre research networks

High-precision image-guided proton irradiation of mouse brain sub-volumes.

Proton radiotherapy offers the potential to reduce normal tissue toxicity. However, clinical safety margins, range uncertainties, and varying relative biological effectiveness (RBE) may result in a critical dose in tumor-surrounding normal tissue. To assess potential adverse effects in preclinical studies, image-guided proton mouse brain irradiation and analysis of DNA damage repair was established