Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf.LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet-and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.age-related macular degeneration | glycemic index | advanced glycation end-product | gut microbiome | metabolomics A ge-related macular degeneration (AMD) is the leading cause of irremediable blindness in the industrialized world, with 200 million cases projected by 2020, at a cost of $300 billion (1, 2). Dry AMD accounts for the great majority of cases and is associated with photoreceptor cell loss, often preceded by compromise to the retina pigment epithelium (RPE) cells that nourish and remove waste from the photoreceptors. The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.Recently, we and others observed in epidemiologic studies that, in addition to micronutrients (4-6), macronutrient quality [e.g., consuming a diet with a high glycemic index (GI)] is a significant risk factor for AMD onset and/or progress in nondiabetic humans (7)(8)(9). The GI appears to be an attractive dietary intervention target, because simple replacement of small amounts of high-index foods (such as white bread) with lower-index foods (such as wholegrain bread) can significantly reduce glycemic peaks without requiring ...

Background CC-Cruiser is an artificial intelligence (AI) platform developed for diagnosing childhood cataracts and providing risk stratification and treatment recommendations. The high accuracy of CC-Cruiser was previously validated using specific datasets. The objective of this study was to compare the diagnostic efficacy and treatment decision-making capacity between CC-Cruiser and ophthalmologists in real-world clinical settings. Methods This multicentre randomized controlled trial was performed in five ophthalmic clinics in different areas across China. Pediatric patients (aged ≤ 14 years) without a definitive diagnosis of cataracts or history of previous eye surgery were randomized (1:1) to receive a diagnosis and treatment recommendation from either CC-Cruiser or senior consultants (with over 5 years of clinical experience in pediatric ophthalmology). The experts who provided a gold standard diagnosis, and the investigators who performed slit-lamp photography and data analysis were blinded to the group assignments. The primary outcome was the diagnostic performance for childhood cataracts with reference to cataract experts' standards. The secondary outcomes included the evaluation of disease severity and treatment determination, the time required for the diagnosis, and patient satisfaction, which was determined by the mean rating. This trial is registered with ClinicalTrials.gov ( NCT03240848 ). Findings Between August 9, 2017 and May 25, 2018, 350 participants (700 eyes) were randomly assigned for diagnosis by CC-Cruiser (350 eyes) or senior consultants (350 eyes). The accuracies of cataract diagnosis and treatment determination were 87.4% and 70.8%, respectively, for CC-Cruiser, which were significantly lower than 99.1% and 96.7%, respectively, for senior consultants ( p < 0.001, OR = 0.06 [95% CI 0.02 to 0.19]; and p < 0.001, OR = 0.08 [95% CI 0.03 to 0.25], respectively). The mean time for receiving a diagnosis from CC-Cruiser was 2.79 min, which was significantly less than 8.53 min for senior consultants ( p < 0.001, mean difference 5.74 [95% CI 5.43 to 6.05]). The patients were satisfied with the overall medical service quality provided by CC-Cruiser, typically with its time-saving feature in cataract diagnosis. Interpretation CC-Cruiser exhibited less accurate performance comparing to senior consultants in diagnosing childhood cataracts and making treatment decisions. However, the medical service provided by CC-Cruiser was less time-consuming and achieved a high level of patient satisfaction. CC-Cruiser has the capacity to assist human doctors in clinical practice in its current state. Funding National Key R&D Program of China (2018YFC0116500) and the Key Research Plan for the National Natural Science Foundation of China in Cultivation P...

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Although the ocular lens shares many features with other tissues, it is unique in that it retains its cells throughout life, making it ideal for studies of differentiation/development. Precipitation of proteins results in lens opacification, or cataract, the major blinding disease. Lysines on ubiquitin (Ub) determine fates of Ub-protein substrates. Information regarding ubiquitin proteasome systems (UPSs), specifically of K6 in ubiquitin, is undeveloped. We expressed in the lens a mutant Ub containing a K6W substitution (K6W-Ub). Protein profiles of lenses that express wild-type ubiquitin (WT-Ub) or K6W-Ub differ by only ∼2%. Despite these quantitatively minor differences, in K6W-Ub lenses and multiple model systems we observed a fourfold Ca2+ elevation and hyperactivation of calpain in the core of the lens, as well as calpain-associated fragmentation of critical lens proteins including Filensin, Fodrin, Vimentin, β-Crystallin, Caprin family member 2, and tudor domain containing 7. Truncations can be cataractogenic. Additionally, we observed accumulation of gap junction Connexin43, and diminished Connexin46 levels in vivo and in vitro. These findings suggest that mutation of Ub K6 alters UPS function, perturbs gap junction function, resulting in Ca2+ elevation, hyperactivation of calpain, and associated cleavage of substrates, culminating in developmental defects and a cataractous lens. The data show previously unidentified connections between UPS and calpain-based degradative systems and advance our understanding of roles for Ub K6 in eye development. They also inform about new approaches to delay cataract and other protein precipitation diseases.