Dual AAV-based PCDH15 gene therapy achieves sustained rescue of visual function in a mouse model of Usher syndrome 1F.

Mutations in the PCDH15 gene, encoding protocadherin-15, are among the leading causes of Usher syndrome type 1 (USH1F), and account for up to 12% USH1 cases worldwide. A founder truncating variant of PCDH15 has a ∼2% carrier frequency in Ashkenazi Jews accounting for nearly 60% of their USH1 cases. Although cochlear implants can restore hearing perception in USH1 patients, presently there are no effective treatments for the vision loss due to retinitis pigmentosa. We established a founder allele-specific Pcdh15 knockin mouse model as a platform to ascertain therapeutic strategies. Using a dual-vector approach to circumvent the size limitation of adeno-associated virus, we observed robust expression of exogenous PCDH15 in the retinae of Pcdh15KI mice, sustained recovery of electroretinogram amplitudes and key retinoid oxime, substantially improved light-dependent translocation of phototransduction proteins, and enhanced levels of retinal pigment epithelium-derived enzymes. Thus, our data raise hope and pave the way for future gene therapy trials in USH1F subjects.

Tailoring Lattice Oxygen Binding in Ruthenium Pyrochlores to Enhance Oxygen Evolution Activity.

Ruthenium pyrochlores, that is, oxides of composition A2Ru2O7-δ, have emerged recently as state-of-the-art catalysts for the oxygen evolution reaction (OER) in acidic conditions. Here, we demonstrate that the A-site substituent in yttrium ruthenium pyrochlores Y1.8M0.2Ru2O7-δ (M = Cu, Co, Ni, Fe, Y) controls the concentration of surface oxygen vacancies (VO) in these materials whereby an increased concentration of VO sites correlates with a superior OER activity. DFT calculations rationalize these experimental trends demonstrating that the higher OER activity and VO surface density originate from a weakened strength of the M-O bond, scaling with the formation enthalpy of the respective MOx phases and the coupling between the M d states and O 2p states. Our work introduces a novel catalyst with improved OER performance, Y1.8Cu0.2Ru2O7-δ, and provides general guidelines for the design of active electrocatalysts.

Comparative physiological and biochemical evaluation of salt and nickel tolerance mechanisms in two contrasting tomato genotypes.

Plant tolerance against a combination of abiotic stresses is a complex phenomenon, which involves various mechanisms. Physiological and biochemical analyses of salinity (NaCl) and nickel (Ni) tolerance in two contrasting tomato genotypes were performed in a hydroponics experiment. The tomato genotypes selected were proved to be tolerant (Naqeeb) and sensitive (Nadir) to both salinity and Ni stress in our previous experiment. The tomato genotypes were exposed to combinations of NaCl (0, 75 and 150 mM) and Ni (0, 15, and 20 mg l-1 ) for 28 days. The results revealed that the tolerant and sensitive tomato genotypes showed similar response to NaCl and Ni stress; however, the level of response was significantly different in both genotypes. The tolerant tomato genotype showed less reduction in growth than the sensitive genotype against both NaCl and Ni stress. Root and shoot ionic analysis showed a decrease in Na and increase in K concentration by increasing Ni levels in the growth medium. Moreover, accumulation of Na and Ni in tissues showed a decrease in membrane stability index and an increase in malondialdehyde contents. The activity of superoxide dismutase, catalase, peroxidase and glutathione reductase under NaCl and Ni stress was significantly higher in the tolerant compared to the sensitive genotype. Enhanced activity of many antioxidant enzymes in Naqeeb under stress conditions is among the other mechanisms that enabled the genotype to better detoxify reactive oxygen species and therefore Naqeeb tolerated the stresses better than Nadir.