Novel quaternary structures of the human prion protein globular domain.

Prion disease is caused by the misfolding of the cellular prion protein, PrPC, into a self-templating conformer, PrPSc. Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrPC and the possibility of its dimerization via an interchain disulfide bridge that forms due to domain swap or by non-covalent association of two monomers. On the contrary, PrPSc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrPC with molecules that stabilize the native conformation of its globular domain emerged as a promising approach to develop anti-prion therapies. One of the advantages of this approach is employing structure-based drug discovery methods to PrPC. Thus, it is essential to expand our structural knowledge about PrPC as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrPC that shows a novel dimeric form and a novel oligomeric arrangement. We use molecular dynamics simulations to explore its structural dynamics and stability and discuss potential implications of these new quaternary structures to the conversion process.

Leachability and potential ecotoxic impact of trifluralin-impregnated mulch.

The leachability, potential ecotoxicity, and photolysis of trifluralin-impregnated mulch, a popular retail consumer gardening product, were investigated under environmentally realistic conditions. Leachability of trifluralin from impregnated mulch was low (< 1% of total extractable compound) and in the range of reported values for agricultural soils. No trifluralin transformation products were detected in mulch leachate. Yeast-based estrogenicity and androgenicity screens indicated that aqueous trifluralin is not estrogenic but is moderately androgenic at concentrations ~ 1e - 5 M. Impregnated mulch leachate was not hormonally active, even at undiluted concentrations, but it did exert nonspecific toxicity at dilutions of ~ 1:10. Photolysis of trifluralin was investigated in acetonitrile and water and on mulch surfaces. Degradation on mulch surfaces was diffusion-limited; it was ~ 17 times slower than in aqueous solution, but faster than has been reported on kaolinite. An array of trifluralin transformation products was identified, but in no case did they exceed 10% of the parent compound. Using industry-recommended application guidelines, it is estimated that as much as 1400 µg/m2 of trifluralin may leach from impregnated mulch upon the first rainfall. However, provided that consumers are aware that such mulch products contain trifluralin and are properly educated about its use, the potential for direct ecotoxic impact is likely to be small.