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"Marion, Kenneth M."
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Dark destiny
\"It's the meeting of the trinities, as the six aforementioned heroes must save DC's Dark Trinity--Red Hood, Artemis and Bizarro! As these three antiheroes are sacrificed into the depths of the Pandora Pits by Circe and Ra's al Ghul, will Superman, Batman and Wonder Woman be able to save their demonically possessed allies?\"-- Provided by publisher.
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Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration
The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA–induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.
Journal Article
Subretinal injection in mice to study retinal physiology and disease
Subretinal injection (SRI) is a widely used technique in retinal research and can be used to deliver nucleic acids, small molecules, macromolecules, viruses, cells or biomaterials such as nanobeads. Here we describe how to undertake SRI of mice. This protocol was adapted from a technique initially described for larger animals. Although SRI is a common procedure in eye research laboratories, there is no published guidance on the best practices for determining what constitutes a ‘successful’ SRI. Optimal injections are required for reproducibility of the procedure and, when carried out suboptimally, can lead to erroneous conclusions. To address this issue, we propose a standardized protocol for SRI with ‘procedure success’ defined by follow-up examination of the retina and the retinal pigmented epithelium rather than solely via intraoperative endpoints. This protocol takes 7–14 d to complete, depending on the reagent delivered. We have found, by instituting a standardized training program, that trained ophthalmologists achieve reliable proficiency in this technique after ~350 practice injections. This technique can be used to gain insights into retinal physiology and disease pathogenesis and to test the efficacy of experimental compounds in the retina or retinal pigmented epithelium.
Mice undergo subretinal injection, with successful injection confirmed by follow-up examination of the retina and the retinal pigmented epithelium.
Journal Article
Impact of mydriasis in fluorescence lifetime imaging ophthalmoscopy
Fluorescence lifetime imaging ophthalmoscopy (FLIO) is a novel technique that measures in vivo autofluorescence intensity decay over time of endogenous fluorophores in the retina. The Heidelberg Engineering FLIO system was used to obtain two 30 degree scans centered on the fovea of both eyes. The FLIO system uses a 473nm blue scanning laser light source and the emitted fluorescence is detected in two wavelengths channels, short and long spectral channels (SSC, LSC). Since the mydriatic status influence the FLIO result, the impact of mydriasis on FLIO need to be clarified. In this prospective, observational study, the impact of mydriasis on measurements from fluorescence lifetime imaging ophthalmoscope (FLIO) images in normal subjects were evaluated. 12 healthy participants (24 eyes) were volunteered and all subjects were scanned twice and the mean fluorescence lifetime (τm) values were computed with dilation and without dilation on different days. Intraclass correlation coefficients (ICC) and coefficients of variation (CV) were calculated from the measured τm in dilated, nondilated and between the dilated and non-dilated setting. Test duration was also compared and correlated with lifetimes in both settings. Repeatability was excellent for both the dilation and non-dilation settings (ICC; 0.967-0.996; 0.926-0.986, respectively). The agreement between the dilation and non-dilation settings, however, were lower (ICC; 0.688-0.970). The τm in the non-dilation setting was significantly longer than in the dilation setting for the SSC (P<0.05). The FLIO test duration in the non-dilation setting was significantly longer than with dilation for the SSC (P <0.05). Although good repeatability in τm measurements between imaging sessions were observed both with and without dilation, the agreement was not as good when comparing dilated with non-dilated measurements. Since FLIO without mydriasis results in longer τm in the SSC and takes a longer time for image acquisition, maximal dilation is recommended for FLIO testing.
Journal Article
Comparison of Iridocorneal Angle Assessments in Open-Angle Glaucoma and Ocular Hypertension Patients: Anterior Segment Optical Coherence Tomography and Gonioscopy
To quantitatively compare iridocorneal angle assessments using gonioscopy and anterior segment optical coherence tomography (AS-OCT).
US and Chinese patients with open-angle glaucoma (OAG) and/or ocular hypertension (OHT).
Analysis was pooled from 2 multicenter, noninterventional studies conducted in the US and China. Gonioscopy Shaffer grade and an AS-OCT method that approximates the angle width relative to local morphologic variations were compared by measuring the same iridocorneal angles. A third, separate, single-center, noninterventional study was conducted to verify results observed from the pooled analysis.
From the pooled studies, a total of 239 eyes were measured using Shaffer grade and AS-OCT. Of these, 6 were Shaffer grade 2, 37 in Shaffer grade 3, and 196 in Shaffer grade 4. There was a trend of increasing Shaffer grade with increasing AS-OCT angle width. Open iridocorneal angles, Shaffer grade ≥3, had a ~98% sensitivity and 88% positive predictive value for identifying AS-OCT angle width ≥300 µm, using the AS-OCT method. To verify these results, a total of 28 right eyes were imaged for the third study. A trend of increasing Shaffer grade with increasing AS-OCT angle width was observed, and angles with Shaffer grade ≤2 had AS-OCT angle width <300 µm.
The AS-OCT method can determine the space in the anterior chamber and can potentially identify angles that are the appropriate size for certain glaucoma devices. Information gathered from AS-OCT can provide additional comprehensive and quantitative assessment to gonioscopy.
Journal Article
Analysis of ocular inflammation in anterior chamber—involving uveitis using swept-source anterior segment OCT
PurposeTo evaluate the utility of swept-source (SS) optical coherence tomography (OCT) to objectively analyze the degree of anterior chamber (AC) inflammation.MethodsThirty-eight eyes of 32 patients with uveitis and 20 control eyes were enrolled. SS OCT B-scans were obtained, and the number of cells in the B-scans was counted using two methods: (1) manual grading by Point Picker plug-in of Image J (http://bigwww.epfl.ch/thevenaz/pointpicker/) and (2) automated grading by the Image J Particle Analysis algorithm (http://imagej.net/Particle_Analysis). The automated and manual AC cell counts were correlated with the Standardization of Uveitis Nomenclature score.ResultsThe average numbers of AC inflammatory cells counted by the automated method were 8 ± 4.0, 18 ± 3.0, 42 ± 14.0, 81 ± 32.0, 117 ± 57.0, and 275 ± 67.0 cells/mm2 for grades 0, 0.5 + , 1 + , 2 + , 3 + , and 4 + , respectively. For the same clinical categories, the average manual cell counts were 6 ± 4.0, 18 ± 3.0, 34 ± 14.0, 72 ± 32.0, 92 ± 43.0, and 168 ± 65.0 cells/mm2, respectively. Zero cells were detected in the AC of healthy eyes. The automated and manual methods were highly correlated (R = 0.98, p < 0.001) and showed good correlation with the clinical grading (R = 0.88, p < 0.001). A mean AC particle size of 117.4 ± 108.8 μm was obtained by the automated method.ConclusionsQuantification of the AC cells imaged by SS AS-OCT shows good correlation with categorical clinical severity assessments in uveitis eyes. This approach may provide a more objective method for monitoring uveitis and response to uveitis therapy.
Journal Article
Evaluation of retinal vessel quantity within individual retinal structural layers using optical coherence tomography angiography
PurposeTo evaluate retinal vessel quantity within various retinal structural layers using optical coherence tomography angiography (OCTA).MethodsIn this IRB-approved study, 22 normal eyes (from 22 subjects) were imaged using the Spectralis OCT2, with a 15 × 15 degree OCTA scan centered on fovea and two additional 15 × 5 degree OCTA scans, displaced temporally and nasally by 15 degrees along the fovea-Bruch’s membrane opening (BMO) axis. Following projection artifact removal (PAR), vessel quantity (i.e., amount of flow signal) within each retinal nuclear and plexiform layer was assessed across the scan and was plotted as a vessel quantity profile over this fovea-BMO axis. Vessel quantity was correlated against the retinal layer thickness at the corresponding locations using the Spearman correlation.ResultsFor the nerve fiber layer (NFL), the vessel quantity was highest nasally and declined towards the fovea and was near zero temporal to the fovea with or without PAR. For all other retinal layers, the retinal vessel quantities were greatest in the parafoveal retina, peaking approximately 5 degrees from the foveal center. Before PAR, the parafoveal vessel quantity was highest in the inner plexiform layer (IPL). Following PAR, the vessel quantity in the IPL decreased but was relatively unchanged in the other layers. The vessel quantity correlated moderately well with retinal layer thickness (r = 0.432 to 0.511; P < 0.05 among the various layers).ConclusionsRetinal vessel quantity varies significantly among the various structural layers, with significant regional variability. Projection artifact can significantly impact retinal vessel quantity in the deeper layers, but the effect appears to be most pronounced in the IPL.
Journal Article
Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-β induced retinal pigmented epithelium degeneration
Nonfibrillar amyloid-β oligomers (AβOs) are a major component of drusen, the sub-retinal pigmented epithelium (RPE) extracellular deposits characteristic of age-related macular degeneration (AMD), a common cause of global blindness. We report that AβOs induce RPE degeneration, a clinical hallmark of geographic atrophy (GA), a vision-threatening late stage of AMD that is currently untreatable. We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7, an upstream mediator of NLRP3 inflammasome activation, is required for AβO-induced RPE degeneration. Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors (NRTIs) and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration. These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.
Journal Article
cGAS drives noncanonical-inflammasome activation in age-related macular degeneration
Degeneration of the retinal pigment epithelium is a hallmark of geographic atrophy, a type of age-related macular degeneration. Kerur
et al
. show that this degeneration results from a multistep pathway in which mitochondrial dysfunction in RPE cells, triggered by accumulation of Alu RNA, leads to activation of the noncanonical inflammasome via a cGAS–STING–IRF3 signaling axis.
Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous
Alu
-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D–dependent interleukin-18 secretion. Decreased DICER1 levels or
Alu
-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.
Journal Article
Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration
Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1–reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493–0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.
Journal Article