The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD.

Age-related macular degeneration (AMD), the leading cause of geriatric blindness, is a multi-factorial disease with retinal-pigmented epithelial (RPE) cell dysfunction as a central pathogenic driver. With RPE degeneration, lysosomal function is a core process that is disrupted. Transcription factors EB/E3 (TFEB/E3) tightly control lysosomal function; their disruption can cause aging disorders, such as AMD. Here, we show that induced pluripotent stem cells (iPSC)-derived RPE cells with the complement factor H variant [ CFH (Y402H)] have increased AKT2, which impairs TFEB/TFE3 nuclear translocation and lysosomal function. Increased AKT2 can inhibit PGC1α, which downregulates SIRT5, an AKT2 binding partner. SIRT5 and AKT2 co-regulate each other, thereby modulating TFEB-dependent lysosomal function in the RPE. Failure of the AKT2/SIRT5/TFEB pathway in the RPE induced abnormalities in the autophagy-lysosome cellular axis by upregulating secretory autophagy, thereby releasing a plethora of factors that likely contribute to drusen formation, a hallmark of AMD. Finally, overexpressing AKT2 in RPE cells in mice led to an AMD-like phenotype. Thus, targeting the AKT2/SIRT5/TFEB pathway could be a potential therapy for atrophic AMD.

Stable and Reversible Photoluminescence from GaN Nanowires in Solution Tuning by Ionic Concentration.

We report response of photoluminescence (PL) from GaN nanowires without protection in solutions. The distinct response is not only toward pH but toward ionic concentration under same pH. The nanowires appear to be highly stable under aqueous solution with high ionic concentration and low pH value down to 1. We show that the PL has a reversible interaction with various types of acidic and salt solutions. The quantum states of nanowires are exposed to the external environment and have a direct physical interaction which depends on the anions of the acids. As the ionic concentration increases, the PL intensity goes up or down depending on the chemical species. The response results from a competition of change in surface band bending and charge transfer to redox level in solution. That of GaN films is reported for comparison as the effect of surface band bending can be neglected so that there are only slight variations in PL intensity for GaN films. Additionally, such physical interaction does not impact on the PL peaks in acids and salts, whereas there is a red shift on PL when the nanowires are in basic solution, say NH4OH, due to chemical etching occurred on the nanowires.

A 0.5-V multi-channel low-noise readout front-end for portable EEG acquisition.

This article presents a low-noise readout front-end suitable for Electroencephalogram (EEG) acquisition. The chip includes 8-channel fully-differential instrumentation amplifiers, utilizing chopper stabilization technique for reducing the flicker noise, each amplifier with a small Gm-C low-pass filter, a programmable gain amplifier, and a 10-bit successive approximation register (SAR) ADC with a detect logic for DAC switching. The chip is fabricated with the TSMC 90nm CMOS process. The low-noise readout front-end has simulated frequency response from 0.57 Hz to 213 Hz, programmable gain from 54.4 dB to 87.6 dB, integrated input-referred noise of 0.358 µVrms within EEG bandwidth, a noise efficiency factor (NEF) of 2.43, and a power efficiency factor (PEF) of 2.95. The overall system consumes 32.08 µW under 0.5-V supply.