ICAR: endoscopic skull‐base surgery

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Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence

Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells’ oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells’ hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress

Development of cyclometallated iridium(III) complexes for light-emitting electrochemical cells

This chapter gives an overview of the development of cyclometallated iridium(III) complexes for application in light-emitting electrochemical cells (LECs) and highlights the ligand-design strategies employed to enhance device stability, operating efficiency and (critically for LECs in which the ion mobilities are typically low) turn-on times. Typical iridium-containing ionic transtion metal complexes (Ir-iTMCs) belong to the family of [Ir(C^N) 2 (N^N)] + complexes in which H(C^N) is a cyclometallating ligand and N^N is a diimine or related chelating ligand. The partitioning of Ir/C^N vs N^N character in the HOMO and LUMO of a [Ir(C^N) 2 (N^N)] + complex, respectively, lends itself to a ligand-functionalization driven method of varying the band-gap allowing emission-colour tuning. An important development in addressing device stability has been the design of ligands that can protect the iridium(III) centre through intra-cation π-stacking interactions, and progress in this area is discussed in detail. The need for deep-blue emitters has been addressed by introducing fluoro-substituents into the cyclometallating domain; however this can lead to lower stability of the LECs and alternative means of shifting the emission into the blue are discussed. Finally, we discuss how a move away from singly-charged, cationic Ir-iTMCs can be used to shorten the turn-on times of LEC