Featured
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Article
| Open AccessApplying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
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Article
| Open AccessA wireless battery-free eye modulation patch for high myopia therapy
The proper axial length of the eye is crucial for achieving emmetropia. Here, authors introduce a wireless battery-free eye modulation patch designed to correct high myopia and prevent relapse.
- Tianyan Zhong
- , Hangjin Yi
- & Xinyu Xue
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Article
| Open AccessModeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.
- Thomas L. Maurissen
- , Alena J. Spielmann
- & Héloïse Ragelle
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Article
| Open AccessLevels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression
Complement factor H-related 4 protein (FHR-4) has been implicated in the pathophysiology of age-related macular degeneration (AMD). Here, in contrast, the authors find that levels of FHR-4 in plasma or ocular tissue do not appear to influence susceptibility to AMD or its course of progression, questioning whether modulation of FHR-4 is likely to be an effective therapeutic strategy.
- M. A. Zouache
- , B. T. Richards
- & G. S. Hageman
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Article
| Open AccessIntegrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
The molecular and cellular causes of glaucoma are not well understood. Here, the authors integrate GWAS with genetic regulation and single cell expression from multiple eye tissues to identify genes and key cell types that affect glaucoma pathogenesis.
- Andrew R. Hamel
- , Wenjun Yan
- & Ayellet V. Segrè
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Article
| Open AccessLate gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa
Is there a critical period to deliver gene therapies in photoreceptor degeneration? Using a mouse model of retinitis pigmentosa, the authors show that once 70% of rods are lost, gene replacement fails to restore normal retinal output.
- Miranda L. Scalabrino
- , Mishek Thapa
- & Greg D. Field
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Article
| Open AccessA large meta-analysis identifies genes associated with anterior uveitis
Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.
- Sahar Gelfman
- , Arden Moscati
- & Giovanni Coppola
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Article
| Open AccessUncertainty-inspired open set learning for retinal anomaly identification
Failure to recognize samples from unseen classes is a major limitation of AI recognition and classification of retinal anomalies. Here, the authors present the Uncertainty-inspired Open Set learning model that categorises fundus images into pre-trained categories, and provides an uncertainty score that alerts the need for manual inspection when dealing with out-of-distribution images.
- Meng Wang
- , Tian Lin
- & Huazhu Fu
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Article
| Open AccessmRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy
Large genes require dual adeno-associated viral (AAV) vectors for in vivo delivery/expression, but current methods have limitations. Here the authors develop and functionally evaluate REVeRT, an efficient and flexible dual AAV vector technology based on reconstitution via mRNA trans-splicing.
- Lisa Maria Riedmayr
- , Klara Sonnie Hinrichsmeyer
- & Elvir Becirovic
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Article
| Open AccessImproving model fairness in image-based computer-aided diagnosis
Deep learning models can reflect and amplify human bias, potentially resulting inaccurate missed diagnoses. Here, the authors show that by leveraging the marginal pairwise equal opportunity, their model reduces bias in medical image classification by over 35% compared to baseline models, with minimal impact on AUC values.
- Mingquan Lin
- , Tianhao Li
- & Yifan Peng
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Article
| Open AccessStructural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2
BTR1 is an electrogenic H+ transporter belonging to the bicarbonate transporter family. Here, the authors present structures of BTR1 in different conformations and uncover PIP2 as the activator of BTR1.
- Yishuo Lu
- , Peng Zuo
- & Yuxin Yin
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Article
| Open AccessContribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes
A deep understanding of the genetic signatures of neovascular age-related macular degeneration subtypes in Asian patients remains a significant gap. Here the authors pinpoint contributing common and rare variants using GWAS and exome sequencing approaches.
- Qiao Fan
- , Hengtong Li
- & Ching-Yu Cheng
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Article
| Open AccessAAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa
Base editing technology has great potential in treating pathogenic single-nucleotide variations. Using a dual-AAV base editing system, Wu et al. restored visual functions in a mouse model of retinitis pigmentosa.
- Yidong Wu
- , Xiaoling Wan
- & Xueli Zhang
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Article
| Open AccessImbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity
The accumulation of cytotoxic deoxysphingolipids causes retinopathies through unknown mechanisms. Here the authors use retinal organoids to show that photoreceptor toxicity is mediated by unfolded protein response signaling.
- Jessica D. Rosarda
- , Sarah Giles
- & Kevin T. Eade
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Article
| Open AccessA randomized non-inferiority trial of therapeutic strategy with immunosuppressants versus biologics for Vogt-Koyanagi-Harada disease
Different classes of biologic therapeutics have been assessed in the context of Vogt-Koyanagi-Harada disease. Here the authors compared cyclosporine immunosuppression or adalimumab in a randomised clinical trial for the treatment of patients with Vogt-Koyanagi-Harada disease and found non-inferiority upon treatment with cyclosporine.
- Zhenyu Zhong
- , Lingyu Dai
- & Peizeng Yang
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Article
| Open AccessSnowflake-inspired and blink-driven flexible piezoelectric contact lenses for effective corneal injury repair
The cornea is susceptible to various injuries with a complicated repair process. Here, the authors propose a snowflake-inspired, blink-driven flexible piezoelectric contact lens for corneal injury repair.
- Guang Yao
- , Xiaoyi Mo
- & Yuan Lin
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Article
| Open AccessGrowth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation
Endocrine factors have been shown to alter functions of pathogenic Th17 cells that are involved in autoimmunity. Here the authors study the influence of growth hormone releasing hormone receptor and show that this receptor is found on Th17 cells and promotes ocular autoimmunity.
- Lin Du
- , Bo Man Ho
- & Wai Kit Chu
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Article
| Open AccessAntibody blockade of Jagged1 attenuates choroidal neovascularization
Current treatment for neovascular age-related macular degeneration (nAMD) does not help all patients. Here, the authors show that using antibodies to block Jagged1 reduces disease burden in a model of nAMD, which could enable new treatment options.
- Torleif Tollefsrud Gjølberg
- , Jonas Aakre Wik
- & Eirik Sundlisæter
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Article
| Open AccessPlasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank
Primary open-angle glaucoma is a leading cause of blindness. Here, the authors report higher plasma levels of diglycerides and triglycerides in samples collected prior to diagnosis, particularly in cases presenting with vision loss near fixation.
- Oana A. Zeleznik
- , Jae H. Kang
- & Louis R. Pasquale
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Article
| Open AccessA visual opsin from jellyfish enables precise temporal control of G protein signalling
Jellyfish see light in a similar way that vertebrates smell odours. Here, Michiel van Wyk and Sonja Kleinlogel show how jellyfish has adapted this slow signal detection pathway to support sophisticated vision, and use a similar method to restore vision in blind mice.
- Michiel van Wyk
- & Sonja Kleinlogel
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Article
| Open AccessThe protective role of conjunctival goblet cell mucin sialylation
Conjunctival goblet cells secrete mucins that are heavily glycosylated. Here, the authors show that sialylation of mucins is essential for capturing and encapsulates allergen particles and thus reduces the risk for developing allergic conjunctivitis.
- Moe Matsuzawa
- , Tomoaki Ando
- & Jiro Kitaura
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Article
| Open AccessThe usherin mutation c.2299delG leads to its mislocalization and disrupts interactions with whirlin and VLGR1
The c.2299delG mutation in usherin causes loss of hearing and vision. Here, the authors show in a mouse model of this disease that the expression of mutant usherin leads to retinitis pigmentosa and structural defects in the photoreceptor cilium associated with mislocalization of VLGR1 and WHRN.
- Lars Tebbe
- , Maggie L. Mwoyosvi
- & Muna I. Naash
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Article
| Open AccessPerfluorodecalin-based oxygenated emulsion as a topical treatment for chemical burn to the eye
Chemical injuries to the eye are medical emergencies with limited acute treatment options and can cause permanent vision loss. Here, the authors show that perfluorodecalin-based supersaturated oxygen emulsion is a safe and effective topical therapeutic in treating acute ocular chemical burn by reducing tissue hypoxia and inflammation.
- Sanming Li
- , Kunpeng Pang
- & Jia Yin
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Article
| Open AccessWhole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma
Elevated intraocular pressure is a risk factor for glaucoma. Here, the authors performed an exome-wide association study for intraocular pressure, demonstrating the power of rare variants in gene discovery and uncovering potential therapeutic targets for glaucoma.
- Xiaoyi Raymond Gao
- , Marion Chiariglione
- & Alexander J. Arch
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Article
| Open AccessWireless theranostic smart contact lens for monitoring and control of intraocular pressure in glaucoma
Glaucoma is an irreversible ocular disease that may lead to vision loss. Here the authors develop a theranostic smart contact lens with an intraocular pressure sensor, a flexible drug delivery system, wireless power and communication systems and an application specific integrated circuit chip for both monitoring and control of intraocular pressure in glaucoma induced rabbits.
- Tae Yeon Kim
- , Jee Won Mok
- & Sei Kwang Hahn
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Article
| Open AccessMaprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells
ER stress is associated with various neurodegenerative diseases. This study found that FDA approved drug, maprotiline, inhibits histamine receptor H1-mediated ER stress and provides significant neuroprotection in mouse glaucoma model.
- Wei Chen
- , Pingting Liu
- & Yang Hu
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Article
| Open AccessElectronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats
Retinal prosthetics has shown its promise in restoring vision, despite limited acuity. Here, the authors demonstrate a high-resolution prosthetic vision that enables grating acuity matching the natural visual resolution in rats, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.
- Bing-Yi Wang
- , Zhijie Charles Chen
- & Daniel Palanker
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Article
| Open AccessThe inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision
Motile and non-motile cilia have distinct functions and protein complexes associated with them. Here, the authors show the conserved protein CFAP20 is important for both motile and non-motile cilia and is distinct from other ciliopathy-associated domains or macromolecular complexes.
- Paul W. Chrystal
- , Nils J. Lambacher
- & Michel R. Leroux
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Article
| Open AccessReducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy
Retinal pigment epithelium (RPE) plays an important role in diabetic retinopathy (DR) progression. Here, the authors show AKT1 and AKT2 are reciprocally regulated in the RPE of DR donor tissue and diabetic mice, reducing Akt2 in RPE causing a compensatory increase in Akt1 and attenuating DR.
- Haitao Liu
- , Nadezda A. Stepicheva
- & Debasish Sinha
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Article
| Open AccessScleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes
he underlying mechanism of myopic axial elongation of the eyes has long been unknown. Here, the authors show that endoplasmic reticulum stress in the sclera and its sensor proteins, PERK and ATF6, are involved in myopic axial elongation
- Shin-ichi Ikeda
- , Toshihide Kurihara
- & Kazuo Tsubota
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Article
| Open AccessHigh-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci
The genome-wide high-resolution chromatin contact of the human retina identifies genetic control of cell-type specific gene expression pattern, missing heritability in retinopathies, and candidate genes/variants for diseases including AMD and glaucoma.
- Claire Marchal
- , Nivedita Singh
- & Anand Swaroop
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Article
| Open AccessAllosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration
The protease HTRA1 is a genetic risk factor for geographic atrophy. Here, Gerhardy et al. describe its inhibition by a clinical Fab, whose binding locks it in an inactive state. The mechanism identifies an essential function of LoopA with this protease family.
- Stefan Gerhardy
- , Mark Ultsch
- & Daniel Kirchhofer
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Article
| Open AccessTranscriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of vision loss, and there is no approved treatment for AMD with geographic atrophy. Here, the authors used transcriptomic and proteomic analyses of patient induced pluripotent stem cell-derived retinal pigment epithelium to better understand disease mechanisms.
- Anne Senabouth
- , Maciej Daniszewski
- & Alice Pébay
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Article
| Open AccessTargeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
Gomez-Sintes et al. have developed small molecules that selectively activate chaperone-mediated autophagy by stabilizing the interaction between retinoic acid receptor alpha and its co-repressor N-CoR1. They demonstrate the protective effect of boosting chaperone-mediated autophagy against retinal degeneration.
- Raquel Gomez-Sintes
- , Qisheng Xin
- & Ana Maria Cuervo
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Article
| Open AccessThe contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.
- Vincent Michaud
- , Eulalie Lasseaux
- & Panagiotis I. Sergouniotis
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Article
| Open AccessA proteogenomic signature of age-related macular degeneration in blood
Age related macular degeneration is a common cause of visual impairment in the elderly, but the etiology is not fully understood. Here, the authors use genetic data, serum proteomics, and AMD phenotypic data from a large Icelandic cohort to discover proteins altered in, causally related to AMD or signifying progression of advanced AMD.
- Valur Emilsson
- , Elias F. Gudmundsson
- & Tony E. Walshe
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Article
| Open AccessSimultaneous perception of prosthetic and natural vision in AMD patients
Atrophic age-related macular degeneration (AMD) results in visual impairment. Here the authors report interim analysis of open-label single group feasibility trial using a wireless photovoltaic subretinal implant in patients with atrophic AMD, and report that the patients exhibited prosthetic visual perception with acuity closely matching the pixel size during the 18-24 month follow-up period.
- D. Palanker
- , Y. Le Mer
- & J. A. Sahel
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Article
| Open AccessRetinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of blindness and is characterised by the accumulation of lipid deposits, called drusen. Here, the authors show that mice lacking chloride intracellular channel 4 in retinal pigment epithelium have defective lipid processing in the eye and pathological features mirroring human AMD, including drusen formation.
- Jen-Zen Chuang
- , Nan Yang
- & Ching-Hwa Sung
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Article
| Open AccessStructural basis for transthyretin amyloid formation in vitreous body of the eye
Systemic ATTR amyloidosis causes the abnormal accumulation of ATTR fibrils formed from the human plasma protein transthyretin (TTR) in multiple organs including the eye. Here, the authors present a 3.2 Å cryo-EM structure of an ATTR fibril isolated from the vitreous body of an ATTR patient’s eye and discuss the mechanism for the structural conversion of TTR into a fibrillar form.
- Irina Iakovleva
- , Michael Hall
- & A. Elisabeth Sauer-Eriksson
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Article
| Open AccessCellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies
Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1, or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.
- Benjamin R. Thomson
- , Pan Liu
- & Susan E. Quaggin
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Article
| Open AccessCryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease
ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidenephosphatidylethanolamine (N-Ret-PE) to the cytoplasmic leaflet of photoreceptor membranes. ABCA4 mutations are associated with loss of vision. Here, structures of ABCA4 with and without substrate bound provide insight into N-Ret-PE binding and suggest a lateral access mechanism.
- Jessica Fernandes Scortecci
- , Laurie L. Molday
- & Robert S. Molday
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Article
| Open AccessMirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa
Rhodopsin-related dominant retinitis pigmentosa is a degenerative disease of the retina of the eye for which there is no current treatment. In this study, the authors use a novel form of RNA-interference- artificial mirtrons- to slow retinal degeneration in a mouse model of the disease.
- Harry O. Orlans
- , Michelle E. McClements
- & Robert E. MacLaren
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Article
| Open AccessGLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans
Dysfunction of the trabecular meshwork (TM) is the chief cause of elevated intraocular pressure, the major risk factor of glaucoma. Here, the authors identify the transcription factor, GLIS1, as a critical regulator of TM maintenance and intraocular pressure, and as a glaucoma risk gene.
- K. Saidas Nair
- , Chitrangda Srivastava
- & Anton M. Jetten
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Article
| Open AccessAutomatic detection of 39 fundus diseases and conditions in retinal photographs using deep neural networks
Systems for automatic detection of a single disease may miss other important conditions. Here, the authors show a deep learning platform can detect 39 common retinal diseases and conditions.
- Ling-Ping Cen
- , Jie Ji
- & Mingzhi Zhang
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Article
| Open AccessPreventing corneal blindness caused by keratitis using artificial intelligence
Keratitis is the main cause of corneal blindness worldwide, but most vision loss caused by keratitis can be avoidable via early detection and treatment, which are challenging in resource-limited settings. Here, the authors develop a deep learning system for the automated classification of keratitis and other cornea abnormalities.
- Zhongwen Li
- , Jiewei Jiang
- & Wei Chen
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Article
| Open AccessA large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects
The genetic basis of cataract is not well understood. Here, the authors perform a genome-wide association multiethnic meta-analysis of cataract, finding 37 new loci and replicating known and new loci. They additionally perform sex-specific analyses, identifying new associations specific to women.
- Hélène Choquet
- , Ronald B. Melles
- & Eric Jorgenson
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Article
| Open AccessA deep learning system for detecting diabetic retinopathy across the disease spectrum
As the leading cause of vision loss in working-age adults, diabetic retinopathy requires routinely retinal screening. Here the authors develop a deep learning system that can facilitate the screening by providing real-time image quality assessment, lesions detection, and grades across the disease spectrum.
- Ling Dai
- , Liang Wu
- & Weiping Jia
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Article
| Open AccessQki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency
Eye lens cells are highly enriched in cholesterol that sustains lens transparency, and disruption of cholesterol biosynthesis leads to cataracts. The authors show that cholesterol biosynthesis regulated by Qki is essential for maintenance of membrane integrity of lens cells and proper protein folding.
- Seula Shin
- , Hao Zhou
- & Jian Hu
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Article
| Open AccessAberrant TGF-β1 signaling activation by MAF underlies pathological lens growth in high myopia
High myopia is associated with lens changes, but the underlying mechanisms are unclear. Here, the authors show increased equatorial diameter of the lens in subjects affected by high myopia, and find that these changes are associated with an increase in crystallin expression driven by the transcription factor MAF and TGF-β1 signaling.
- Xiangjia Zhu
- , Yu Du
- & Yi Lu
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