NMNAT2 is downregulated in glaucomatous RGCs, and RGC-specific gene therapy rescues neurodegeneration and visual function.

The lack of neuroprotective treatments for retinal ganglion cells (RGCs) and optic nerve (ON) is a central challenge for glaucoma management. Emerging evidence suggests that redox factor NAD+ decline is a hallmark of aging and neurodegenerative diseases. Supplementation with NAD+ precursors and overexpression of NMNAT1, the key enzyme in the NAD+ biosynthetic process, have significant neuroprotective effects. We first profile the translatomes of RGCs in naive mice and mice with silicone oil-induced ocular hypertension (SOHU)/glaucoma by RiboTag mRNA sequencing. Intriguingly, only NMNAT2, but not NMNAT1 or NMNAT3, is significantly decreased in SOHU glaucomatous RGCs, which we confirm by in situ hybridization. We next demonstrate that AAV2 intravitreal injection-mediated overexpression of long half-life NMNAT2 mutant driven by RGC-specific mouse γ-synuclein (mSncg) promoter restores decreased NAD+ levels in glaucomatous RGCs and ONs. Moreover, this RGC-specific gene therapy strategy delivers significant neuroprotection of both RGC soma and axon and preservation of visual function in the traumatic ON crush model and the SOHU glaucoma model. Collectively, our studies suggest that the weakening of NMNAT2 expression in glaucomatous RGCs contributes to a deleterious NAD+ decline, and that modulating RGC-intrinsic NMNAT2 levels by AAV2-mSncg vector is a promising gene therapy for glaucomatous neurodegeneration.

Effect of pretreatments on the metal-ceramic bonding strength of a Pd-Ag alloy.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of surface treatments on the bonding properties between a metal and ceramic. METHODS: Sixty metal specimens were divided equally into four groups of 15 samples each. These groups received different treatments (Gr1: 250µm Al2O3+preoxidation; Gr2: 250µm Al2O3+degassing; Gr3: 120µm Al2O3+preoxidation; Gr4: 120µm Al2O3+degassing). Bond strengths were evaluated using a three-point bending test. The results were analyzed using 2-way ANOVA and Tukey's test. Scanning electron microscopy and energy dispersive spectroscopy were used to observe the microscopic features, elemental compositions and distributions, and diffusion in the specimens. Mechanical profiler was used to measure the roughness of metal surface. RESULTS: The bond strengths of the four groups ranged from 45.00±3.63MPa to 51.61±5.91MPa, with significant differences (P<.05). The specimen that received the pretreatment of 250µm Al2O3 air-particle abrasion+degassing had the highest bond strength. Heating under different oxygen partial pressures caused the final Pd-Ag alloys to have varying degrees of internal oxidation and different quantities of metallic nodules. None of the elements in either the ceramic or the Pd-Ag alloy layer diffused into the other layer. CONCLUSIONS: The metal-ceramic specimen subjected to air-particle abrasion with 250µm Al2O3 and degassed before porcelain firing had significantly higher bond strength than specimens treated differently.