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Article
| Open AccessChain-like gold nanoparticle clusters for multimodal photoacoustic microscopy and optical coherence tomography enhanced molecular imaging
This manuscript presents ultrapure chain-like gold nanoparticle clusters with red shifted absorption and shows their potential for in vivo imaging in living rabbits. The nanoparticles demonstrate a 17-fold increase in photoacoustic microscopy signal and 176% increase in optical coherence tomography signal.
- Van Phuc Nguyen
- , Wei Qian
- & Yannis M. Paulus
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Article
| Open AccessThe TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Here, the authors show that microglia-specific deletion of TSPO and chemical inhibition of TSPO prevent neuroinflammation and vascular damage in a mouse model of AMD.
- Anne Wolf
- , Marc Herb
- & Thomas Langmann
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Article
| Open AccessVascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina
hPSCs in culture acquire a more naïve pluripotent state upon tankyrase inhibition. Here, the authors show that tankyrase inhibitor-regulated naïve hiPSCs from diabetic donors generate more vascular progenitors and more efficient engraftment into mouse retina than conventional PSCs.
- Tea Soon Park
- , Ludovic Zimmerlin
- & Elias T. Zambidis
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Article
| Open AccessIncreased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration
A locus on chromosome 1 encompassing the CFHR genes is highly associated with AMD risk. Here, Cipriani and colleagues investigate the role of CFHR4, encoding FHR-4, and demonstrate a relationship between AMD risk, circulating FHR-4 levels and genetic variants at this locus.
- Valentina Cipriani
- , Laura Lorés-Motta
- & Simon J. Clark
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Article
| Open AccessSustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles
Neovascular age-related macular degeneration and diabetic retinopathy are currently treated with repeated intravitreous injections of VEGF neutralizing proteins. Here the authors develop a microparticle-loaded tyrosine kinase inhibitor therapy, which is effective for six months after a single injection in preclinical models.
- Hiroki Tsujinaka
- , Jie Fu
- & Peter A. Campochiaro
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Article
| Open AccessSingle AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice
Replacing mutant genes with wildtype copies using adeno-associated virus (AAV) has been explored for the treatment of inherited retinopathies, but the low cargo limit restricts its use. Here the authors describe a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end joining.
- Koji M. Nishiguchi
- , Kosuke Fujita
- & Toru Nakazawa
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Article
| Open AccessTRPV1 activity and substance P release are required for corneal cold nociception
The eye shows protective responses to noxious stimuli including cold. Here, the authors show that TRPV1, found co-expressed on TRPM8 + fibres in the cornea, is necessary for cold nociception in the eye.
- Fengxian Li
- , Weishan Yang
- & Qin Liu
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Article
| Open AccessSingle-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration
“Genome-wide association studies have identified variants associated with age-related macular degeneration (AMD); however, other than identifying this as a complement mediated inflammatory disease, little biology has emerged. Here, authors used novel computational tools from the Broad Institute to examine the relationship of single-cell transcriptomics and genome-wide association studies (GWAS) in the human retina and demonstrate that GWAS-associated risk alleles associated with AMD are enriched in glia and vascular cells and that human retinal glia are more diverse than previously thought
- Madhvi Menon
- , Shahin Mohammadi
- & Brian P. Hafler
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Perspective
| Open AccessA systems biology approach towards understanding and treating non-neovascular age-related macular degeneration
No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.
- James T. Handa
- , Cathy Bowes Rickman
- & Lindsay A. Farrer
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Article
| Open AccessA frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy
Genetic variants in RP1 can cause hereditary retinal degeneration (HRD). Here, in a genomic screen of 331 Japanese HRD patients, the authors identify a near-polymorphic RP1 variant that causes Mendelian HRD in trans with an Alu insertion and otherwise is associated with HRD according to a complex model of inheritance.
- Konstantinos Nikopoulos
- , Katarina Cisarova
- & Carlo Rivolta
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Article
| Open AccessAssessment of corneal substrate biomechanics and its effect on epithelial stem cell maintenance and differentiation
The link between how the stiffness of the cornea affects stem cells is unclear. Here, the authors use Brillouin spectro-microscopy to show that mechanical properties of the cornea affect epithelial stem cells and after injury, treating the cornea with collagenase suppresses YAP activation, assisting in regeneration.
- Ricardo M. Gouveia
- , Guillaume Lepert
- & Che J. Connon
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Article
| Open AccessSequence variation at ANAPC1 accounts for 24% of the variability in corneal endothelial cell density
The corneal endothelium is crucial for proper vision. Here, Ivarsdottir et al. perform genome-wide association studies for various corneal endothelial cell measurements and find that an intergenic variant near ANAPC1 explains 24% of the variance of endothelial cell density and associates with corneal hysteresis.
- Erna V. Ivarsdottir
- , Stefania Benonisdottir
- & Kari Stefansson
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Article
| Open AccessHomozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly
Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.
- Najim Lahrouchi
- , Aman George
- & Abdelaziz Sefiani
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Article
| Open AccessIntravenous treatment of choroidal neovascularization by photo-targeted nanoparticles
Current treatments of wet age-related macular degeneration require repeated injections of active drugs into the vitreous. Here Wang et al. develop nanoparticles that when injected intravenously can be targeted to the eye by irradiation with blue light, allowing local and enhanced drug release in the back of the eye, and providing an alternative to current delivery strategies.
- Yanfei Wang
- , Chi-Hsiu Liu
- & Daniel S. Kohane
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Article
| Open AccessMineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration
Current treatments for age-related neovascular macular degeneration (nAMD) suffer from limited efficacy. Here, Zhao et al. show that pharmacological inhibition or genetic deletion of the mineralocorticoid receptor (MR) limits choroidal neovascularisation in rodents, and show in a pilot clinical study that targeting the MR pathway may provide clinical benefits in nAMD patiens.
- Min Zhao
- , Irmela Mantel
- & Francine Behar-Cohen
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Article
| Open AccessNCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy
Pericytes are perivascular cells that regulate blood vessel formation and function. Here Dubrac et al. show that pericyte recruitment contributes to pathological neovascularisation in a mouse model of ischemic retinopathy, and that this depends on the regulation of PDGF-B signaling by NCK adaptor proteins.
- Alexandre Dubrac
- , Steffen E. Künzel
- & Anne Eichmann
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Article
| Open AccessA multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci
Primary open-angle glaucoma (POAG) leads to progressive vision loss. Here, Choquet et al. perform genome-wide association analysis for POAG in a multi-ethnic cohort, identify a total of nine novel genetic loci and show relevant function of FMNL2 and LMX1B using cell line and mouse experiments.
- Hélène Choquet
- , Seyyedhassan Paylakhi
- & Eric Jorgenson
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Article
| Open AccessA novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration
Mutations that lead to misfolding of rhodopsin can cause retinitis pigmentosa. Here, the authors carry out a high throughput screen to identify a small molecule chaperone of rod opsin, and show that it protects mouse models of retinitis pigmentosa from retinal degeneration.
- Yuanyuan Chen
- , Yu Chen
- & Krzysztof Palczewski
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Article
| Open AccessCross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
- Adriana I. Iglesias
- , Aniket Mishra
- & Stuart MacGregor
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Article
| Open AccessCRISPR-LbCpf1 prevents choroidal neovascularization in a mouse model of age-related macular degeneration
The CRISPR endonuclease LbCpf1 is reported to have greater efficiency and specificity than Cas9. Here, the authors use LbCpf1 to target the angiogenesis-related genes VEGF and HIF1a, and show that delivery of the nuclease using AAV9 is effective in mouse models of macular degeneration.
- Taeyoung Koo
- , Sung Wook Park
- & Jin-Soo Kim
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Article
| Open AccessCCDC102B confers risk of low vision and blindness in high myopia
Myopic maculopathy is a complication of myopia that often progresses to blindness. Here, in a genome-wide association study, Hosoda et al. find that rs11873439 intronic to CCDC102B is associated with myopic maculopathy, but not with myopia, thus representing a risk factor independent of myopia.
- Yoshikatsu Hosoda
- , Munemitsu Yoshikawa
- & Kenji Yamashiro
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Article
| Open AccessATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration
Age-related macular degeneration (AMD) leads to dysfunctional retinal pigment epithelium (RPE) and vision loss. Here, the authors perform ATAC-seq to study chromatin accessibility and find that differentially accessible regions are enriched for photoreceptor and RPE-specific transcription factors in AMD
- Jie Wang
- , Cristina Zibetti
- & Jiang Qian
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Article
| Open AccessSystems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility
Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.
- Sumana R. Chintalapudi
- , Doaa Maria
- & Monica M. Jablonski
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Article
| Open AccessFoxp3+ Tregs are recruited to the retina to repair pathological angiogenesis
The local immune responses in the eye are attenuated to preserve sight. Surprisingly, Deliyanti et al. show that regulatory T cells (Tregs) take an active role in protecting the eye from neovascularization in oxygen-induced retinopathy, and that interventions that augment the retinal Treg numbers reduce neovascular retinopathy in mice.
- Devy Deliyanti
- , Dean M. Talia
- & Jennifer L. Wilkinson-Berka
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Article
| Open AccessIL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease
IL-12p35 is common to IL-35 and IL-12, which have opposing effects on inflammation. Here the authors show that the IL-12p35 subunit induces regulatory B cells and can be used therapeutically to limit autoimmune uveitis in mice.
- Ivy M. Dambuza
- , Chang He
- & Charles E. Egwuagu
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Article
| Open AccessEndothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis
Pathological angiogenesis in the retina is a major cause of blindness. Here the authors show that adenosine receptor A2A drives pathological angiogenesis in the oxygen-induced retinopathy mouse model by promoting glycolysis in endothelial cells via the ERK/Akt/HIF-1α pathway, thereby suggesting new therapeutic targets for disease treatment.
- Zhiping Liu
- , Siyuan Yan
- & Yuqing Huo
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Article
| Open AccessGelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models
Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin.
- Roly Megaw
- , Hashem Abu-Arafeh
- & Charles ffrench-Constant
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Article
| Open AccessGenome editing abrogates angiogenesis in vivo
Abnormal angiogenesis causes many ocular diseases. Here the authors employ CRISPR/Cas9 gene editing technology to silence VEGFR2, a major regulator of angiogenesis, in retinal endothelium and abrogate angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization.
- Xionggao Huang
- , Guohong Zhou
- & Hetian Lei
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Article
| Open AccessPseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1
LOXL1 is a genetic risk factor for pseudoexfoliation syndrome of the eye but a causal variant has not been identified. Here, Pasutto et al., find intronic LOXL1 risk variants influence transcription factor binding and alternative splicing of LOXL1 in affected tissues reducing levels of LOXL1mRNA.
- Francesca Pasutto
- , Matthias Zenkel
- & Ursula Schlötzer-Schrehardt
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Article
| Open AccessPlastic roles of pericytes in the blood–retinal barrier
Blood-retinal barrier (BRB) is composed of tightly connected endothelium and supporting pericytes and glia. Here, the authors show that pericytes are crucial for BRB buildup during retinal development and its maintenance in adult retinas in response to VEGF-A-induced endothelial sensitization by regulating the Tie2/FOXO1/Ang2 axis.
- Do Young Park
- , Junyeop Lee
- & Gou Young Koh
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Article
| Open AccessCataract-associated P23T γD-crystallin retains a native-like fold in amorphous-looking aggregates formed at physiological pH
Aggregation of eye lens proteins leads to cataracts, a major cause of blindness. Here the authors use solid state NMR to probe the structure of γD-crystallin eye lens proteins aggregates, which are found to retain a native-like conformation.
- Jennifer C. Boatz
- , Matthew J. Whitley
- & Patrick C. A. van der Wel
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Article
| Open AccessGenome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy
Fuchs endothelial corneal dystrophy (FECD) is one of the most common reasons for corneal transplantation, and is known to cluster in families. Here, the authors discover new genetic loci associated with FECD with sex-specific effects and implications for disease mechanism.
- Natalie A. Afshari
- , Robert P. Igo Jr
- & Sudha K. Iyengar
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Article
| Open AccessNrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice
Retinitis pigmentosa is mainly caused by mutations that initially affect survival of rod photoreceptors, leading to secondary loss of cones. Here the authors use gene editing to prevent rod degeneration, leading to survival of cones and improved vision in mice.
- Wenhan Yu
- , Suddhasil Mookherjee
- & Zhijian Wu
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Article
| Open AccessIn vivo genome editing with a small Cas9 orthologue derived from Campylobacter jejuni
The amount of genetic material that can be packaged in AAV vectors used for genome editing is limited. Here the authors show that the smallest known Cas9 orthologue, cjCas9, can be packaged in a single AAV vector along with sgRNA and a marker gene, and demonstrate efficient gene editing in mice.
- Eunji Kim
- , Taeyoung Koo
- & Jin-Soo Kim
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Article
| Open AccessPACAP suppresses dry eye signs by stimulating tear secretion
Dry eye disease is a complex condition with limited treatments. Here the authors show that mice lacking a multi-functional peptide PACAP develop dry eye-like signs that can be topically treated with PACAP peptide that stimulates tearing in mice, suggesting a possible therapy in humans with dry eyes.
- Tomoya Nakamachi
- , Hirokazu Ohtaki
- & Seiji Shioda
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Article
| Open AccessFOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1
Peter's Anomaly is a developmental disorder of the eye and has been linked to mutations in a range of genes, including the transcription factor FOXE3. Here the authors use next-generation RNA sequencing and mass spectrometry to identify an autophagy-associated protein, DNAJB1 as the transcriptional target of FOXE3.
- Shahid Y. Khan
- , Shivakumar Vasanth
- & S. Amer Riazuddin
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Article
| Open AccessMeta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error
This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.
- Qiao Fan
- , Virginie J. M. Verhoeven
- & Kari Matti Mäkelä
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Article
| Open AccessTransplanted neurons integrate into adult retinas and respond to light
Replacing lost retinal ganglion cells is a potential treatment for optic neuropathies such as glaucoma. Here, the authors show that transplanted donor RGCs can successfully integrate into a mature host retina in vivo, projecting axons along the intact visual pathway and responding to light stimuli.
- Praseeda Venugopalan
- , Yan Wang
- & Jeffrey L. Goldberg
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Article
| Open AccessGuanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases
IMP dehydrogenase (IMPDH) plays essential roles in purine metabolism and cell proliferation. Here Buey et al. describe a guanine nucleotides regulated molecular mechanism for allosteric communication between the regulatory and catalytic domains of IMPDH.
- Rubén M. Buey
- , Rodrigo Ledesma-Amaro
- & José L. Revuelta
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Article |
A short N-terminal domain of HDAC4 preserves photoreceptors and restores visual function in retinitis pigmentosa
Retinitis pigmentosa is an inherited form of blindness caused by the progressive loss of rod and cone photoreceptors. Here, Guo et al.show that expression of a short amino-terminal domain of the histone deacetylase HDAC4 prolongs cone survival in mouse models, helping to partially restore vision.
- Xinzheng Guo
- , Shao-Bin Wang
- & Bo Chen
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Article
| Open AccessIL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis
Pathological neovascularization causes blinding eye disease. Here the authors show that IL10 activates STAT3 signalling in the macrophages in the ageing eye, promoting their polarization towards a pro-angiogenic phenotype; interfering with this pathway reverses the pathology in a mouse model.
- Rei Nakamura
- , Abdoulaye Sene
- & Rajendra S. Apte
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Article |
Multisensory training reverses midbrain lesion-induced changes and ameliorates haemianopia
Failure to attend to visual cues is a common consequence of visual cortical injury. Here, the authors demonstrate that auditory–visual cross-modal behavioural training leads to neural plasticity and reinstatement of visuomotor competency in animals rendered unilaterally blind by visual cortical removal.
- Huai Jiang
- , Barry E. Stein
- & John G. McHaffie
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Article |
Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations
Age-related macular degeneration is a prominent cause of irreversible blindness among the elderly. Here Huang et al.identify a novel missense variant in UBE3D that sheds new light on the pathogenesis of the disease.
- Lv-Zhen Huang
- , Ying-Jie Li
- & Xiao-Xin Li
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Article |
Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia
Myopia is a significant and increasing public health concern. Here Miyake et al. conduct a genome-wide association study and identify WNT7Bas a susceptibility gene across different ethnic groups, suggesting a possible role in the development of myopia.
- Masahiro Miyake
- , Kenji Yamashiro
- & Nagahisa Yoshimura
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Article |
EphrinB2 controls vessel pruning through STAT1-JNK3 signalling
Pruning of newly formed blood vessels is an important and yet poorly understood aspect of angiogenesis. Here the authors show that endothelial phosphotyrosine-dependent EphrinB2 signalling represses JNK3 function via STAT1, and identify JNK3 as an effector of endothelial cell death and vessel pruning in mice.
- Ombretta Salvucci
- , Hidetaka Ohnuki
- & Giovanna Tosato
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Article
| Open AccessAdiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival
Docosahexaenoic acid is a major and important retinal fatty acid that is recruited and retained in the photoreceptor membrane via an unknown mechanism. Here, Rice et al. show that adiponectin receptor 1 is a key molecular switch for docosahexaenoic acid membrane homeostasis and photoreceptor cell function.
- Dennis S. Rice
- , Jorgelina M. Calandria
- & Nicolas G. Bazan
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Article
| Open AccessGene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179
The rd1 mouse is the most widely used model to study retinal degeneration. Here, the authors identify a wide-spread mutation in these mice that may explain the failure of previous gene therapeutic approaches and show that long-lasting restoration of vision is possible in rd1 mice without this mutation.
- Koji M. Nishiguchi
- , Livia S. Carvalho
- & Robin R. Ali
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Article |
Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. Here the authors link mutations in the gene PNPLA6 with childhood blindness in seven families with retinal degeneration and show that the gene plays a role in photoreceptor survival in Drosophila.
- S. Kmoch
- , J. Majewski
- & R. K. Koenekoop
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Article |
Unencapsulated Streptococcus pneumoniae from conjunctivitis encode variant traits and belong to a distinct phylogenetic cluster
Pneumococci can cause a variety of bacterial infections including conjunctivitis. Here, Valentino et al.show that most conjunctivitis-causing pneumococci belong to a closely related group of strains that possess a unique set of putative virulence factors.
- Michael D. Valentino
- , Abigail Manson McGuire
- & Michael S. Gilmore
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