Compared to a fold-change MRS 2578 screen, this process compensates automatically for the variance of each spot. This excludes automatically spots with a high coefficient of variation, but enables to take into account small but reproducible changes when the coefficient of variation is low, thus avoiding the arbitrary exclusion of small changes that can be biologically meaningful. In order to take into account the multiple testing issue, the metrics are shown on S4Fig. Only the nanoparticles induced significant changes compared to the control cells. Indeed, several proteins were modulated by the treatment with copper oxide nanoparticles, but none of these proteins was modulated when the cells were treated with an equivalent concentration of copperion, which is in line with the difference of toxicity of nanoparticles compared to the ion. Oppositely, titanium dioxide nanoparticles induced a very limited modulation of protein expression, which is consistent with the Pridinol Methanesulfonate recently published transcriptomic analyses on similar cell types. This also allowed us to use titaniumdi oxide nanoparticles as a negative control under our conditions of exposure. As both nanoparticles are internalized this shows that the protein modulations observed upon treatment with copper oxide nanoparticles shall not beat tribute to the phagocytosis event perse, but to specific effects induced by copperoxide nanoparticles. Thus, if the homeostatichypothesisis verified, the induction of GCLM should represent a mechanism by which cells increase their concentration of glutathione to buffer the copper that has entered the cytoplasm. It is then necessary to determine whether this response is critical for cell survival or whether it belongs to the fitness response. To this purpose, we inhibited the glutamate cysteine ligase with buthionine sulfoximine and checked the effect of this inhibition on cell survival upon treatment with copper. The results, shown in Fig5, demonstrate that inhibition of glutamatecysteineligase dramatically increases the sensitivity of the cells to copper oxide nanoparticles, but not to copper ion, except at high concentrations.