Fully automated OCT-based tissue screening system.

This study introduces an innovative optical coherence tomography (OCT) imaging system dedicated to high-throughput screening applications using ex vivo tissue culture. Leveraging OCT's non-invasive, high-resolution capabilities, the system is equipped with a custom-designed motorized platform and tissue detection ability for automated, successive imaging across samples. Transformer-based deep-learning segmentation algorithms further ensure robust, consistent, and efficient readouts meeting the standards for screening assays. Validated using retinal explant cultures from a mouse model of retinal degeneration, the system provides robust, rapid, reliable, unbiased, and comprehensive readouts of tissue response to treatments. This fully automated OCT-based system marks a significant advancement in tissue screening, promising to transform drug discovery, as well as other relevant research fields.

Compensation of inner retina to early-stage photoreceptor degeneration in a RhoP23H/+ mouse model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinal disorder characterized by the degeneration of photoreceptors. RhoP23H/+ mice, which carry a Pro23His mutation in the RHODOPSIN (Rho) gene, are one of the most studied animal models for RP. However, except for the photoreceptors, other retinal neural cells have not been fully investigated in this model. Here, we record the temporal changes of the retina by optical coherence tomography (OCT) imaging of the RhoP23H/+ mice, from early to mid-phase of retinal degeneration. Based on thickness analysis, we identified a natural retinal thickness adaption in wild-type mice during early adulthood and observed morphological compensation of the inner retina layer to photoreceptor degeneration in the RhoP23H/+ mice, primarily on the inner nuclear layer (INL). RhoP23H/+ mice findings were further validated via: histology showing the negative correlation of INL and ONL thicknesses; as well as electroretinogram (ERG) showing an increased b-wave to a-wave ratio. These results unravel the sequential morphologic events in this model and suggest a better understanding of retinal degeneration of RP for future studies.

Fully Automated OCT-based Tissue Screening System.

This study introduces a groundbreaking optical coherence tomography (OCT) imaging system dedicated for high-throughput screening applications using ex vivo tissue culture. Leveraging OCT's non-invasive, high-resolution capabilities, the system is equipped with a custom-designed motorized platform and tissue detection ability for automated, successive imaging across samples. Transformer-based deep learning segmentation algorithms further ensure robust, consistent, and efficient readouts meeting the standards for screening assays. Validated using retinal explant cultures from a mouse model of retinal degeneration, the system provides robust, rapid, reliable, unbiased, and comprehensive readouts of tissue response to treatments. This fully automated OCT-based system marks a significant advancement in tissue screening, promising to transform drug discovery, as well as other relevant research fields.

Oral 8-aminoguanine against age-related retinal degeneration.

Visual decline in the elderly is often attributed to retinal aging, which predisposes the tissue to pathologies such as age-related macular degeneration. Currently, effective oral pharmacological interventions for retinal degeneration are limited. We present a novel oral intervention, 8-aminoguanine (8-AG), targeting age-related retinal degeneration, utilizing the aged Fischer 344 rat model. A low-dose 8-AG regimen (5 mg/kg body weight) via drinking water, beginning at 22 months for 8 weeks, demonstrated significant retinal preservation. This was evidenced by increased retinal thickness, improved photoreceptor integrity, and enhanced electroretinogram responses. 8-AG effectively reduced apoptosis, oxidative damage, and microglial/macrophage activation associated with aging retinae. Age-induced alterations in the retinal purine metabolome, characterized by elevated levels of inosine, hypoxanthine, and xanthine, were partially mitigated by 8-AG. Transcriptomics highlighted 8-AG's anti-inflammatory effects on innate and adaptive immune responses. Extended treatment to 17 weeks further amplified the retinal protective effects. Moreover, 8-AG showed temporary protective effects in the RhoP23H/+ mouse model of retinitis pigmentosa, reducing active microglia/macrophages. Our study positions 8-AG as a promising oral agent against retinal aging. Coupled with previous findings in diverse disease models, 8-AG emerges as a promising anti-aging compound with the capability to reverse common aging hallmarks.

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1.

Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, pyrvinium pamoate reduced tauopathy and alleviated retina degeneration by promoting autophagy and ubiquitin-proteasome system. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.