In spite of recent advances in describing the health outcomes of exposure to nanoparticles (NPs), it still remains unclear how exactly NPs interact with their cellular targets. Size, surface, mass, geometry, and composition may all play a beneficial role as well as causing toxicity. Concerns of scientists, politicians and the public about potential health hazards associated with NPs need to be answered. With the variety of exposure routes available, there is potential for NPs to reach every organ in the body but we know little about the impact this might have. The main objective of the FP7 NanoTEST project ( www.nanotest-fp7.eu ) was a better understanding of mechanisms of interactions of NPs employed in nanomedicine with cells, tissues and organs and to address critical issues relating to toxicity testing especially with respect to alternatives to tests on animals. Here we describe an approach towards alternative testing strategies for hazard and risk assessment of nanomaterials, highlighting the adaptation of standard methods demanded by the special physicochemical features of nanomaterials and bioavailability studies. The work has assessed a broad range of toxicity tests, cell models and NP types and concentrations taking into account the inherent impact of NP properties and the effects of changes in experimental conditions using well-characterized NPs. The results of the studies have been used to generate recommendations for a suitable and robust testing strategy which can be applied to new medical NPs as they are developed.
The life histories of many species depend first on dispersal to local sites and then on establishment. After dispersal, density-independent and density-dependent mortalities modify propagule supply, determining the number of individuals that establish. Because multiple factors influence recruitment, the dichotomy of propagule versus establishment limitation is best viewed as a continuum along which the strength of propagule or establishment limitation changes with propagule input. To evaluate the relative importance of seed and establishment limitation for plants, we (1) describe the shape of the recruitment function and (2) use limitation and elasticity analyses to quantify the sensitivity of recruitment to perturbations in seed limitation and density-independent and density-dependent mortality. Using 36 seed augmentation studies for 18 species, we tested four recruitment functions against one another. Although the linear model (accounting for seed limitation and density-independent mortality) fitted the largest number of studies, the nonlinear Beverton-Holt model (accounting for density-dependent mortality) performed better at high densities of seed augmentation. For the 18 species, seed limitation constrained population size more than other sources of limitation at ambient conditions. Seedling density reached saturation with increasing seed density in many studies, but at such high densities that seedling density was primarily limited by seed availability rather than microsite availability or density dependence.
The two-pore domain potassium selective (K2P) ion-channels TREK-1, TREK-2, and TRAAK essential mechanical stimulation sensors, and TREK-1/2 also targets for the antidepressant Nor-fluoxetine (Prozac). They respond directly to membrane tension by moving from the down to up conformation, a transition that is associated with a rise in open-probability. However, the mechanosensitive K2P (mK2P) channels can also open while occupying the down conformation, and although these channels are mostly closed, all structural models represent seemingly open conformations. To understand the dynamics between open/closed and up/down states and determine how membrane tension influences transitions between specific conformations, we use a novel method to analyze tension-driven activation of single purified and reconstituted TREK-2 channels. We screen a panel of prospective schemes to find the mechanism that best accounts for specific TREK-2 characteristics as tension-driven activation, suppression by Nor-fluoxetine, and single-channel kinetics. To adequately describe TREK-2 behavior, mechanistic schemes require two separate tension-sensitive transitions, one that occurs between distinct down conformations and one that moves the channel between down and up states. As membrane tension activates TREK-2, it is a transition within the structural down conformations that account for the major increase in open-probability (> 100 fold); the move from down to up further promotes channel opening, but with much lower potency (~3 fold activation).
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