Kevin Fung, George Hoppe, Andrew Benos, Demiana Hanna, Ke Jiang, Jonathan E Sears
{"title":"Maternal Vertical Transmission Provides a Mitochondrial Basis for ROP Susceptibility.","authors":"Kevin Fung, George Hoppe, Andrew Benos, Demiana Hanna, Ke Jiang, Jonathan E Sears","doi":"10.1167/iovs.67.12.78","DOIUrl":"https://doi.org/10.1167/iovs.67.12.78","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to link strain-based susceptibility to mitochondria.</p><p><strong>Methods: </strong>Crosses between susceptible and protected strains of mice were analyzed for oxygen-induced retinopathy (OIR). Oxygen consumption and extracellular acidification of retina explants from individual strains were quantified. Expression and protein concentrations of key metabolic proteins were measured. Isotopic based metabolomics was used to measure transformations of glycolytic carbon.</p><p><strong>Results: </strong>A/J mice were protected from OIR compared to C57Bl/6 mice, having a 5-fold reduction in the ratio of vaso-obliteration (P = 1*10-5) and a 20-fold reduction in neovascularization (P = 0.002). Mapping among A/J, Balb/C, and C57Bl/6 mice showed a maternal inheritance pattern of protection that implicated mitochondria. A/J and C57Bl/6 mitochondrial functions showed a reduction in the basal respiration rates of A/J ex vivo retina (P = 4*10-9) and a two-fold reduction in the carboxyethyl pyrrole oxidative stress marker of A/J mice retinas with OIR (P = 0.007) compared with C57Bl/6 mice. Placed in hyperoxia, A/J mice retina demonstrated reduced levels of respiratory proteins, as well as expression of subunit IVi1 of cytochrome c oxidase in comparison to C57Bl/6 (P = 3*10-6). To support the hypothesis that a reduction in oxidative phosphorylation was protective, C57Bl/6 mice were injected with the mitochondrial uncoupler 2,4 dinitrophenylhydrazine (DNP) during the hyperoxia phase of OIR; DNP created reduced levels of vaso-obliteration (P = 1.5*10-5) and neovascularization (P = 8*10-6). Isotopic metabolomics demonstrated that A/J aortic endothelium increased glutamine (Gln) synthesis from glycolytic carbon in comparison to C57Bl/6 with upregulation of Hmox1 expression.</p><p><strong>Conclusions: </strong>Strain-specific susceptibility or protection may involve vertical maternal transmission.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"78"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149297534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martine J Jager, Sarah E Coupland, Hans E Grossniklaus
{"title":"Introducing Geeta K. Vemuganti: The 2025 Recipient of the Weisenfeld Award.","authors":"Martine J Jager, Sarah E Coupland, Hans E Grossniklaus","doi":"10.1167/iovs.67.12.12","DOIUrl":"https://doi.org/10.1167/iovs.67.12.12","url":null,"abstract":"","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"12"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Age-Related Lens Membrane Composition and N101D Deamidation Modulate αA-Crystallin Membrane Interactions Relevant to Cataract.","authors":"Preston Hazen, Jordyn Anderson, Navdeep Kalkat, Binod Aryal, Nawal K Khadka, Laxman Mainali","doi":"10.1167/iovs.67.12.18","DOIUrl":"10.1167/iovs.67.12.18","url":null,"abstract":"<p><strong>Purpose: </strong>αA-crystallin (αAc), the predominant subunit comprising α-crystallin (αABc), becomes increasingly deamidated and membrane bound with cataract formation. Furthermore, the lens lipids and cholesterol (Chol) composition significantly change with age and cataract formation. Despite this, the relationship between αAc deamidation and lens membrane composition in cataractogenesis remains unclear. To address this, we analyzed the role of N101 deamidation and membrane composition in the membrane interactions of αAc.</p><p><strong>Methods: </strong>Experimentation involved using electron paramagnetic resonance (EPR) to analyze wild-type (WT) and N101D-αAc membrane binding and its physical effects on the membrane properties of 60-year-old (yo) and 20-yo model human lens lipid (MHLL) membranes containing 2 mol% cholestane spin label and increasing Chol concentrations.</p><p><strong>Results: </strong>Without Chol, WT-αAc and N101D-αAc do not significantly differ in their 60-yo MHLL membrane binding, but N101D deamidation significantly diminishes αAc binding in 20-yo MHLL membranes. With Chol, the binding of WT-αAc and N101D-αAc to 60-yo and 20-yo MHLL membranes is significantly reduced. However, N101D-αAc consistently binds less and with a lower affinity than WT-αAc to both membranes at all Chol contents. Additionally, both WT-αAc and N101D-αAc membrane binding decreases 60-yo and 20-yo MHLL membrane mobility while increasing hydrophobicity and order near the headgroup region.</p><p><strong>Conclusions: </strong>These data indicate that lens membrane composition significantly modulates the membrane association of WT-αAc and N101D-αAc while N101D deamidation generally diminishes αAc membrane binding regardless of membrane composition. Consequently, it appears that N101D deamidation may synchronously function with the membrane composition alterations to diminish αAc membrane binding throughout life and prevent cataract formation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"18"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
José A Matamoros, Santiago Milla-Navarro, Elena Salobrar-García, José A Fernández-Albarral, Víctor Paleo-García, Marta Cantero, Inés López-Cuenca, Lorena Elvira-Hurtado, Francisco J Germain, Lluis Montoliu, Rosa de Hoz, Juan José Salazar, Pedro de la Villa, Ana I Ramírez
{"title":"Spontaneous Achromatopsia-Like Phenotype in Albino Swiss CD-1 Mice: Retinocortical Dysfunction, Neurovascular Remodeling, and Glial Activation.","authors":"José A Matamoros, Santiago Milla-Navarro, Elena Salobrar-García, José A Fernández-Albarral, Víctor Paleo-García, Marta Cantero, Inés López-Cuenca, Lorena Elvira-Hurtado, Francisco J Germain, Lluis Montoliu, Rosa de Hoz, Juan José Salazar, Pedro de la Villa, Ana I Ramírez","doi":"10.1167/iovs.67.12.20","DOIUrl":"10.1167/iovs.67.12.20","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize the functional, structural, vascular, genetic, and histologic correlates of spontaneous retinal electrophysiological phenotypes in male CD-1 mice to ensure accurate phenotyping in vision research.</p><p><strong>Methods: </strong>Baseline full-field flash ERG (ffERG) was recorded in 205 male CD-1 mice. Subsets were evaluated using visual evoked potentials (VEP; n = 12), optical coherence tomography/optical coherence tomography angiography (OCT/OCTA) (n = 17), Gnat2 genotyping (n = 8), and quantitative immunohistochemistry (n = 5-6/phenotype) for cone arrestin, rhodopsin, PKCα (bipolar cells), Brn3a (ganglion cells), Iba1 (microglia), and GFAP (macroglia).</p><p><strong>Results: </strong>FfERG identified three phenotypes: normal (n = 74), cone dysfunction (n = 126), and severe retinal dysfunction (n = 5). FfERG and VEP showed absent cone responses in cone dysfunction mice and complete response abolition in the severe group. OCT/OCTA revealed outer retinal thinning and deep capillary plexus remodeling in severe dysfunction, whereas the cone dysfunction mice retained overall structure. Genotyping confirmed Gnat2 mutations in affected groups. Histology confirmed isolated cone loss in cone dysfunction and combined rod-cone loss in severe dysfunction, both with increased glial activation. Brn3a+ ganglion cells were significantly reduced in both affected groups compared to in normal mice.</p><p><strong>Conclusions: </strong>Spontaneous Gnat2-associated retinal dysfunction is common in CD-1 mice, causing photoreceptor loss, neuroinflammation, and ganglion cell reduction. Baseline electrophysiological screening is crucial when using this strain for vision research.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"20"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Luye An, Mario A Robledo, Seyyed Vahid Niknezhad, Wendy Ko, Beryl Zhang, Yu Ting Chen, Nancy A McNamara, Sarah M Knox
{"title":"Immune Landscape and Intercellular Crosstalk in the Cornea of an Autoimmune-Mediated Dry Eye Disease.","authors":"Luye An, Mario A Robledo, Seyyed Vahid Niknezhad, Wendy Ko, Beryl Zhang, Yu Ting Chen, Nancy A McNamara, Sarah M Knox","doi":"10.1167/iovs.67.12.32","DOIUrl":"10.1167/iovs.67.12.32","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to comprehensively characterize the identity and signaling profiles of resident and infiltrating immune cells, and their interactions with non-immune cells, in a spontaneous mouse model of autoimmune-mediated dry eye disease (DED).</p><p><strong>Methods: </strong>Corneal tissues from wild-type (WT) and autoimmune regulator-deficient (Aire-/-) mice were analyzed by whole-mount immunofluorescence to define immune cell composition and spatial distribution within the limbus and central cornea. Immune cell identities and cell-cell communication were further characterized using single-cell RNA sequencing (scRNA-seq). Intercellular signaling pathways among immune cells, epithelial, and stromal cells were analyzed using CellChat.</p><p><strong>Results: </strong>Immunofluorescence revealed extensive infiltration of CD3⁺ and CD4⁺ T cells, CD45R⁺ B-cells, and IBA1⁺ macrophages in Aire-/- cornea compared with WT controls. The scRNA-seq identified diverse immune subsets, including cytotoxic T cells, γδ17 cells, regulatory T cells, NK T cells, B-cells, plasma cells, and multiple macrophage subtypes. Monocyte-derived macrophages demonstrated distinct transcriptional programs, including pro-inflammatory and antigen-presenting phenotypes, with CD40 to CD40L signaling linking T cells, B-cells, and macrophages. CellChat analysis revealed coordinated upregulation of signaling pathways associated with immune activation, inflammation, apoptosis, and loss of immune tolerance. Additionally, epithelial cells and keratocytes in Aire-/- corneas upregulated antigen-presenting and pro-inflammatory gene signatures, suggesting active participation of non-immune cells in immune activation and recruitment.</p><p><strong>Conclusions: </strong>Single-cell transcriptomics reveals a complex, multicellular inflammatory environment in the Aire-/- cornea involving diverse immune subsets and activated resident epithelial and stromal cells. These findings suggest that non-T cell mechanisms contribute to chronic dry eye pathogenesis and may underlie the limited efficacy of currently US Food and Drug Administration (FDA)-approved T cell-targeted therapies. Further characterization of these multi-cellular interactions and signaling pathways may inform the development of broader therapeutic strategies for autoimmune-mediated dry eye disease.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"32"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Seeing the Bias: Hemifield‑Dependent Remapping of Sensory, Sighting, and Acuity Eye Dominance.","authors":"Lujia Jian, Dorita H F Chang","doi":"10.1167/iovs.67.12.66","DOIUrl":"https://doi.org/10.1167/iovs.67.12.66","url":null,"abstract":"<p><strong>Purpose: </strong>Eye dominance may refer to sensory, sighting, and acuity dominance, yet their correspondence across the visual field is unclear. Here, we indexed these three dominance metrics across 17 visual field locations: the fovea and 16 locations at 3° and 6° eccentricities along eight polar angles.</p><p><strong>Methods: </strong>Forty-three visually normal adults were tested. Sensory dominance was indexed with a dichoptic signal-in-noise motion coherence threshold task, sighting dominance with a Porta-derived pointing alignment task, and acuity dominance with a grating acuity task. Peripheral stimuli across all tasks were size scaled according to the cortical magnification function.</p><p><strong>Results: </strong>Along the horizontal and oblique meridians, both sensory and sighting dominance shifted from foveal dominance toward the left eye in the left hemifield and toward the right eye in the right hemifield. There were no shifts in sensory or sighting dominance along the vertical meridian. Sensory and sighting dominance were thus spatially well matched. Within subjects, sensory dominance significantly predicted sighting dominance across the visual field, and this correspondence was selective to the meridians exhibiting hemifield asymmetries. In contrast, acuity dominance was weak in magnitude and spatially invariant, with weak, nonsignificant correlations with the other two metrics.</p><p><strong>Conclusions: </strong>Sensory and sighting eye dominance are not uniform across the visual field. We speculate that both tap into binocular combination processes at the primary visual cortex (V1), where the contralateral eye is weighted more strongly due to structural asymmetries across the visual pathway. In contrast, acuity dominance likely reflects monocular optical and retinal factors independent of binocular interactions, explaining its spatial invariance and weak correlations with other dominance metrics. Our results suggest that the clinical convention of relying on a single foveal test (e.g., hole-in-the-card or Porta) cannot capture an individual's dominant eye across the visual field or across sensory, sighting, and acuity dimensions.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"66"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Introducing Aaron Y. Lee and Cecilia S. Lee, the 2026 Recipients of the Cogan Award.","authors":"Emily Y Chew","doi":"10.1167/iovs.67.12.71","DOIUrl":"https://doi.org/10.1167/iovs.67.12.71","url":null,"abstract":"","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"71"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149286819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuta Kitamura, Kazuhiko Namekata, Xiaoli Guo, Youichi Shinozaki, Sari Honda, Euido Nishijima, Takahiko Noro, Chikako Harada, Takayuki Harada
{"title":"Acute Loss of TrkB Signaling Impairs the Survival of Mature Retinal Ganglion Cells and Retinal Function.","authors":"Yuta Kitamura, Kazuhiko Namekata, Xiaoli Guo, Youichi Shinozaki, Sari Honda, Euido Nishijima, Takahiko Noro, Chikako Harada, Takayuki Harada","doi":"10.1167/iovs.67.12.75","DOIUrl":"https://doi.org/10.1167/iovs.67.12.75","url":null,"abstract":"<p><strong>Purpose: </strong>To determine whether acute loss of tropomyosin receptor kinase B (TrkB) signaling in mature retinal ganglion cells (RGCs) induces RGC degeneration and retinal functional impairment in the adult mouse retina.</p><p><strong>Methods: </strong>TrkB deletion was induced in adult TrkBflox/flox mice by intravitreal administration of adeno-associated virus serotype 2 (AAV2)-Cre. AAV2-Cre tropism was examined using tdTomato reporter mice and retinal cell markers. TrkB, RNA-binding protein with multiple splicing (RBPMS), calretinin, glutamine synthetase, and recoverin protein levels were assessed by western blotting. RGC survival was evaluated by RBPMS immunostaining of retinal flatmounts. Retinal function was assessed by analyzing the second-order kernel of multifocal electroretinography. Acute TrkB deletion was compared with developmental TrkB deletion in TrkBflox/flox;c-kit-Cre mice.</p><p><strong>Results: </strong>AAV2-Cre predominantly transduced RBPMS-positive RGCs, with little overlap with calretinin-positive amacrine cells, glutamine synthetase-positive Müller glia, or recoverin-positive photoreceptors. AAV2-Cre administration at 7 weeks of age reduced TrkB protein levels. RBPMS protein levels and RBPMS-positive RGC density were significantly decreased 5 weeks after AAV2-Cre administration at 12 weeks of age, whereas calretinin, glutamine synthetase, and recoverin protein levels were unchanged. Retinal responses of the second-order kernel were also significantly reduced. In contrast, RGC density was not significantly altered in TrkBflox/flox;c-kit-Cre mice at 12 weeks of age.</p><p><strong>Conclusions: </strong>Acute TrkB deletion in the adult retina induces RGC degeneration and impairs retinal function, whereas no significant reduction in RGC density was detected following developmental TrkB deletion at 12 weeks of age. These findings indicate that endogenous TrkB signaling is required for mature RGC maintenance and suggest that reduced TrkB signaling may contribute to glaucomatous RGC degeneration.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"75"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149286782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Integrative Genomic Analyses Prioritize CETP-Related Lipid Traits in Age-Related Macular Degeneration.","authors":"Changzhong Xu, Qiulin Yan, Chao Feng, Yanzi Li, Xiangyun Li, Rui Zhang, Junwen He, Jianhua Wu","doi":"10.1167/iovs.67.12.54","DOIUrl":"10.1167/iovs.67.12.54","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize the genetically supported candidate gene landscape of age-related macular degeneration (AMD), identify robust candidate genes, and evaluate the potential roles of cholesteryl ester transfer protein (CETP)-related lipid traits in AMD susceptibility and progression.</p><p><strong>Methods: </strong>Large-scale AMD genome-wide association study discovery and replication cohorts were analyzed using an integrative framework combining single-tissue and cross-tissue transcriptome-wide association studies (TWASs) with MAGMA gene-based analysis. Candidate genes were further evaluated using GTEx expression quantitative trait loci data with summary-data-based Mendelian randomization (SMR) and colocalization analyses. Mendelian randomization (MR), multivariable MR (MVMR), and MR-Bayesian model averaging (MR-BMA) were used to assess CETP-related lipid traits in AMD risk and progression.</p><p><strong>Results: </strong>Integrated evidence from TWASs and MAGMA prioritized seven AMD-associated genes, including CFH, CETP, PLEKHA1, RDH5, HTRA1, AFF1, and ZBTB41. Two-sample MR indicated that genetically predicted CETP-related high-density lipoprotein cholesterol (HDL-C) was associated with increased AMD risk (odds ratio = 1.51; 95% confidence interval, 1.40-1.62; P = 7.0 × 10-27). In MVMR analyses, CETP-related HDL-C retained an independent association, and MR-BMA ranked it as the lipid trait with the highest posterior support. Exploratory analyses suggested that genetically predicted CETP-related HDL-C was associated with AMD progression, including choroidal neovascularization and geographic atrophy.</p><p><strong>Conclusions: </strong>Across discovery and replication cohorts, this multi-cohort, multi-method study prioritized CETP as a genetically supported candidate effector gene for AMD and implicates HDL-C-related genetic variation at the CETP locus in AMD susceptibility and exploratory progression outcomes. These findings support the potential relevance of CETP-related lipid biology but require further mechanistic validation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"67 12","pages":"54"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}