Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes

Abstract Diabetic retinopathy (DR) is a major cause of blindness in working adults in the industrialized world. In addition to vision loss caused by macular edema and pathological angiogenesis, DR patients often exhibit neuronal dysfunction on electrophysiological testing, suggesting that there may be an independent neuronal phase of disease that precedes vascular disease. Given the tremendous metabolic requirements of the retina and photoreceptors in particular, we hypothesized that derangements in metabolic regulation may accelerate retinal dysfunction in diabetes. As such, we induced hyperglycemia with streptozotocin in mice with monoallelic Nampt deletion from rod photoreceptors, mice lacking SIRT3, and mice lacking SIRT5 and tested multiple components of retinal function with electroretinography. None of these mice exhibited accelerated retinal dysfunction after induction of hyperglycemia, consistent with normal-appearing retinal morphology in hyperglycemic Sirt3 −/− or Sirt5 −/− mice. However, mice lacking both SIRT3 and SIRT5 (Sirt3 −/− Sirt5 −/− mice) exhibited significant evidence of inner retinal dysfunction after induction of hyperglycemia compared to hyperglycemic littermate controls, although this dysfunction was not accompanied by gross morphological changes in the retina. These results suggest that SIRT3 and SIRT5 may be involved in regulating neuronal dysfunction in DR and provide a foundation for future studies investigating sirtuin-based therapies

Short-Wavelength Light-Blocking Eyeglasses Attenuate Symptoms of Eye Fatigue

Purpose: The purpose of this study was to determine whether subjects who wear short wavelength–blocking eyeglasses during computer tasks exhibit less visual fatigue and report fewer symptoms of visual discomfort than subjects wearing eyeglasses with clear lenses.Methods: A total of 36 healthy subjects (20 male; 16 female) was randomized to wearing no-block, low-blocking, or high-blocking eyeglasses while performing a 2-hour computer task. A masked grader measured critical flicker fusion frequency (CFF) as a metric of eye fatigue and evaluated symptoms of eye strain with a 15-item questionnaire before and after computer use.Results: We found that the change in CFF after the computer task was significantly more positive (i.e., less eye fatigue) in the high-block versus the no-block (P = 0.027) and low-block (P = 0.008) groups. Moreover, random assignment to the high-block group but not to the low-block group predicted a more positive change in CFF (i.e., less eye fatigue) following the computer task (adjusted β = 2.310; P = 0.002). Additionally, subjects wearing high-blocking eyeglasses reported significantly less feeling pain around/inside the eye (P = 0.0063), less feeling that the eyes were heavy (P = 0.0189), and less feeling that the eyes were itchy (P = 0.0043) following the computer task, when compared to subjects not wearing high-blocking lenses.Conclusions: Our results support the hypothesis that short-wavelength light-blocking eyeglasses may reduce eye strain associated with computer use based on a physiologic correlate of eye fatigue and on subjects\u27 reporting of symptoms typically associated with eye strain

Understanding the Molecular Pathogenesis of Retinal Neurodegeneration

Retinal degenerative diseases are a major cause of morbidity in modern society because visual impairment significantly decreases the quality of life of patients. A significant challenge in treating retinal degenerative diseases is their genetic and phenotypic heterogeneity. Furthermore, limitations in our understanding of disease pathophysiology have led to reliance on therapies that often treat disease endpoints rather than addressing disease etiology and/or pathophysiology. The long-term goal of my thesis research was to provide molecular and cellular insights into the pathophysiology underlying diverse retinal degenerative diseases, which may lead to much-needed, novel therapeutic approaches. During the first part of my thesis research, I discovered that impaired NAD+ homeostasis is a central feature of diverse retinal degenerative diseases (Chapter 2). For the second part of my thesis research, I found that the central cellular phenotype of aged macrophages, which are known to promote age-related macular degeneration, is impaired cholesterol homeostasis (Chapter 3) and that the transition towards this disease-promoting, aged phenotype is regulated, in part, by microRNA-150 (Chapter 4). Although further research is necessary to translate these findings to the bedside, they have the potential to transform care for patients with retinal degenerative diseases

Coupling Control Variates for Markov Chain Monte Carlo

We show that Markov couplings can be used to improve the accuracy of Markov chain Monte Carlo calculations in some situations where the steady-state probability distribution is not explicitly known. The technique generalizes the notion of control variates from classical Monte Carlo integration. We illustrate it using two models of nonequilibrium transport

Longitudinal Growth Differentiation Factor 15 (GDF15) and Long-term Intraocular Pressure Fluctuation in Glaucoma: A Pilot Study

Purpose: Growth Differentiation Factor 15 (GDF15) was previously identified as a molecular marker of retinal ganglion cell stress in rodent models of glaucoma and was elevated in the aqueous humor (AH) of patients with primary open-angle glaucoma as a possible risk factor for glaucoma progression. The purpose of this study was to determine whether changes in the AH GDF15 levels were associated with intraocular pressure (IOP) changes in eyes undergoing glaucoma surgery. Methods: Here, we performed a prospective, longitudinal pilot study in nine patients to determine whether changes in AH GDF15 levels from surgery to post-surgery follow-up were associated with IOP fluctuation. An initial AH sample was taken from the peripheral corneal paracentesis during planned glaucoma surgery, and a second sample was taken during an outpatient follow-up visit, approximately six months later. Results: There was a statistically significant correlation between GDF15 fold change and IOP standard deviation (r = 0.87, P = 0.003), IOP range (r = 0.87, P = 0.003), and maximum IOP (r = 0.86, P = 0.003). There was no correlation between the GDF15 fold change and baseline IOP (r = 0.50, P = 0.17), final IOP (r = 0.038, P = 0.92), or mean IOP (r = 0.40, P = 0.28). Conclusion: Our findings in this pilot study suggest that longitudinal changes in AH GDF15 may be associated with IOP fluctuation during the postoperative period. Further studies are necessary to corroborate these findings in a larger patient population and to explore the possibility that AH GDF15 may be used not only to improve treatment algorithms but also as a surrogate endpoint in clinical trials

Anharmonicity-induced isostructural phase transition of Zirconium under pressure

We have performed a detailed x-ray diffraction structural study of Zr under pressure and unambiguously identify the existence of a first-order isostructural bcc-to-bcc phase transition near 58 GPa. First-principles quantum molecular dynamics lattice dynamics calculations support the existence of this phase transition, in excellent agreement with experimental results, triggered by anharmonic effects. Our results highlight the potential ubiquity of anharmonically driven isostructural transitions within the periodic table under pressure and calls for follow-up experimental and theoretical studies