Publications by MERI members

Ramirez, A., A. Shakhgildian, A. Rosenberg, and C. J. Baker. Impaired Perception of Isoluminant Contrast Modulation Stimuli: Evidence for a Magnocellular Pathway mechanism. Vol. 26, no. 3, Journal of Vision, 2026, p. Epub PubMed Text.

Dow, C., and Z. Kidess. Proposing Bromo-Epi-Androsterone (BEA) for Perioperative Neurocognitive Disorders With Interleukin-6 As a Druggable target. J Clin Anesth., 2025, p. Epub PubMed Text.

Mukherjee, K., and T. Rogers. Using Drawings and Deep Neural Networks to Characterize the Building Blocks of Human Visual similarity. Mem Cognit, 2025, p. Epub PubMed Text.

Ramakrishnan, G., V. Miskolci, M. Hunter, M. Giese, D. Münch, Y. Hou, K. Eliceiri, M. Lasarev, R. White, and A. Huttenlocher. Real-Time Imaging Reveals a Role for Macrophage Protrusive Motility in Melanoma invasion. J Cell Biol., 2025, p. Epub PubMed Text.

Saxena, S., M. Kabra, A. Abdeen, D. Sinha, M. Zhu, R. Xie, G. Hanstad, M. Zapeda, D. Gamm, B. Pattnaik, S. Gong, and K. Saha. Genome-Wide CRISPR Screening Identifies Cellular Factors Controlling Nonviral Genome Editing Efficiency. bioRxiv, 2025, p. Epub PubMed Text.

Accorinti, M., A. Agarwal, R. Agrawal, M. Altaweel, J. Biswas, A. Fawzi, S. Gangaputra, V. Gupta, A. Invernizzi, D. Jabs, J. Norel, S. Sadda, D. Sarraf, J. Shantha, J. Thorne, E. Tsui, and A. de-la-Torre. Evidence and Consensus-Based Imaging Guidelines in Multifocal Choroiditis With Panuveitis and Punctate Inner Choroiditis – Multimodal Imaging in Uveitis (MUV) Taskforce Report 5. American Journal of Ophthalmology, 2025, p. Epub PubMed Text.

Boff, J., M. Hoon, V. Matveev, N. Rameshkumar, A. Shrestha, T. Vaithianathan, and D. Zenisek. Nanophysiology Approach Reveals Diversity in Calcium Microdomains across Zebrafish Retinal Bipolar Ribbon Synapses. bioRxiv, 2025, p. Epub PubMed Text.

Fisk, D., S. Park, N. Sheibani, Y. Song, and C. Sorenson. Isolation and Characterization of Mouse Choroidal Melanocytes and Their Proinflammatory Characteristics. Cells, 2025, p. Epub PubMed Text.

Gupta, S., M. Hoon, J. Khoussine, B. Pattnaik, A. Sawant, P. Shahi, R. Sinha, and H. Zhai. Divergent Mechanisms of Neural Adaptation and Instability in the Mammalian retina. Current Biology, 2025, pp. Epub

Schildroth, K., J. Chang, T. Nork, J. Gottlieb, M. Wingelaar, P. Boeke, M. Ip, K. Peterson, and M. Altaweel. Intraocular Pressure Control and Long-Term Outcomes With the Reservoir Technique: The Wisconsin Silicone Oil Study (Report 2). Journal of Vitreoretinal Diseases, 2025, p. Epub PubMed Text.

Kiland, J., H. Terhaar, H. Walleck, N. Chen, O. Torné, K. Oikawa, T. Wahl, and G. McLellan. Comparison of Rebound and Applanation Tonometry in Eyes With Focal Corneal Edema. Veterinary Ophthalmology, 2025, p. Epub PubMed Text.

Invernizzi, A., A. Agarwal, S. Gangaputra, M. Airaldi, E. Carreno, M. Munk, F. Pichi, J. Shantha, R. Agrawal, S. Sadda, L. Jampol, J. Smith, D. Jabs, S. Chee, D. Sarraf, V. Gupta, and Multimodal Imaging in Uveitis (MUV) Task Force. Minimum Imaging Sets for Diagnosis, Activity Assessment, and Complications in Noninfectious Posterior Uveitis – Multimodal Imaging in Uveitis (MUV) Task Force Report 9. American Journal of Ophthalmology, 2025, p. Epub PubMed Text.

Dow, C., and L. Obaid. Proposing Bromo-Epi-Androsterone (BEA) for Post-Traumatic Stress Disorder (PTSD). Cells, 2025, p. Epub PubMed Text.

Motevasseli, T., A. Seraj, N. Daftarian, M. Kanav, H. Ahmadieh, and N. Sheibani. Intracellular Signaling Pathways and Their Potential Targeting for Treatment of Ocular Posterior Segment Fibrosis. Journal of Ophthalmic & Vision Research, 2025, p. Epub PubMed Text.

Belecky-Adams, T., N. Sheibani, and C. Sorenson. Editorial: Ocular Fibrosis: Molecular and Cellular Mechanisms and Treatment modalities. Front Ophthalmol (Lausanne), 2024, p. eCollection PubMed Text.

Liang, H., J. Sedillo, S. Schrodi, and A. Ikeda. Structural Variants in Linkage Disequilibrium With GWAS-Significant SNPs. Heliyon, 2024, p. eCollection PubMed Text.

Croft, M., J. Mcdonald, J. Kiland, J. Mattison, G. Roth, D. Ingram, and P. Kaufman. Sex As a Risk Factor Regarding Presbyopia in the Rhesus monkey. PLoS One, 2024, p. eCollection PubMed Text.

Sorenson, C., Z. Gurel, Y. Song, K. Peterson, B. Blodi., and N. Sheibani. Thrombospondin-1, BIM and CFH Polymorphisms and Response to Anti-VEGF Treatment in Neovascular Age- Related Macular Degeneration patients. PLoS One, 2024, p. eCollection PubMed Text.

Maddox, J., G. Ordemann, J. de la Rosa Vázquez, A. Huang, C. Gault, S. Wisner, K. Randall, D. Futagi, N. Salem, R. Mayfield, B. Zemelman, S. DeVries, M. Hoon, and A. Lee. A Non-Conducting Role of the Ca(v)1.4 Ca(2+) Channel Drives Homeostatic Plasticity at the Cone Photoreceptor synapse. bioRxiv, 2024, p. [Preprint] PubMed Text.

Brown, J., B. Aldred, T. Boulter, R. Sullivan, J. Ver Hoeve, B. Pattnaik, and M. Schmitt. A Case Report of Retinal Dystrophy in Patients With PACS1 syndrome. Ophthalmic Genet, 2024, p. PubMed Text.

Heaton, A., N. Burkard, P. Sondel, and M. Skala. Quantifying in Vivo Collagen Reorganization During Immunotherapy in Murine Melanoma With Second Harmonic Generation imaging. Biophotonics Discovery, 2024, p. Epub Full Text.

Liu, B., H. Yang, Y. Song, C. Sorenson, and N. Sheibani. Thrombospondin-1 in Vascular Development, Vascular Function, and Vascular disease. Elsevier, 2024, pp. 32-44 Full Text.

Dow, C., E. Pierce, and L. Sechi. Mycobacterium Paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?. Microorganisms, 2024, p. Epub PubMed Text.

Stevens-Sostre, W., and M. Hoon. Cellular and Molecular Mechanisms Regulating Retinal Synapse Development. Annual Review of Vision Science, 2024, p. Epub PubMed Text.

Sheibani, N., Y. Song, M. Farnoodian, S. Inampudi, B. Hanna, S. Wang, S. Darjatmoko, and C. Sorenson. Bim Expression Influences Choroidal Endothelial Cell Characteristics and Their Response to Therapeutic Intervention. Int J Mol Sci., 2024, p. Epub PubMed Text.

Song, Y., S. Wang, S. Park, B. Hanna, K. Johnson, S. Darjatmoko, M. Saghiri, B. Liu, C. Sorenson, and N. Sheibani. Receptor-Interacting Protein Kinase-3 Expression Impacts Ocular Vascular Development and Pathological Neovascularization. Cells, 2024, p. Epub PubMed Text.

Muench, N., H. Schmitt, C. Schlamp, A. Su, K. Washington, and R. Nickells. Preservation of Murine Whole Eyes With Supplemented UW Cold Storage Solution: Anatomical Considerations. Transl Vis Sci Technol, 2024, p. Epub PubMed Text.

Villanueva, I., N. Li, D. Brossard, T. Jilk, J. Renner, and B. Matre. When Science Meets Art on Instagram: Examining the Effects of Visual Art on Emotions, Interest, and Social Media Engagement. Vol. 46, no. 2, Science Communication, 2024, pp. 210-238 PubMed Text.

Froines, C., J. Pak, E. Agrón, E. Chew, T. Peto, B. Blodi, and A. Domalpally. Longitudinal Assessment of Age-Related Macular Degeneration Using Ultrawidefield Imaging: The Optos Peripheral Retina Follow-up Study. Ophthalmology, 2024, p. Epub PubMed Text.

Domalpally, A., R. Slater, R. Linderman, R. Balaji, J. Bogost, R. Voland, J. Pak, B. Blodi, R. Channa, D. Fong, and E. Chew. Strong Versus Weak Data Labeling for Artificial Intelligence Algorithms in the Measurement of Geographic Atrophy. Ophthalmol Sci, 2024, p. Epub PubMed Text.

Ip, M., I. Scott, P. VanVeldhuisen, N. Oden, and B. Blodi. Month 60 Imaging Findings and Relationship to Treatment Outcomes Following Anti-VEGF Therapy for Macular Edema Due to Central or Hemi-Retinal Vein Occlusion. AM J Ophthalmol., 2024, p. Epub PubMed Text.

Boppart, S., C. Best-Popescu, R. Bartels, and K. Eliceiri. Introducing the Special Issue on Label-Free Quantitative Phase Imaging Honoring Prof. Gabriel Popescu, a Pioneer in Biomedical Optics. J Biomed Opt, 2024, p. Epub PubMed Text.

Erickson-Bhatt, S., B. Cox, E. MacDonald, J. Chacko, P. Begovatz, P. Keely, S. Ponik, K. Eliceiri, and S. Fain. Multi-Modal Investigation of Metabolism in Murine Breast Cancer Cell Lines Using Fluorescence Lifetime Microscopy and Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy. Metabolites, 2024, p. Epub PubMed Text.

Adi, W., B. Rubio Perez, Y. Liu, S. Runkle, K. Eliceiri, and F. Yesilkoy. Machine Learning-Assisted Mid-Infrared Spectrochemical Fibrillar Collagen Imaging in Clinical tissues. J Biomed Opt, 2024, p. Epub PubMed Text.

De Niz, M., R. Escobedo García, C. Ramirez, Y. Pakowski, Y. Abonza, N. Bialy, V. Orr, A. Olivera, V. Abonza, K. Alleva, S. Allodi, M. Almeida, A. Becerril Cuevas, F. Bonnet, A. Solorio, T. Chew, G. Chiabrando, B. Cimini, A. Cleret-Buhot, B. Contreras Jiménez, L. Daza, V. De Sá, N. De Val, D. Delgado-Álvarez, K. Eliceiri, R. Fiolka, H. Grecco, D. Hanein, P. Hernández Herrera, P. Hockberger, H. Hernandez, Y. Hernandez Guadarrama, M. Itano, C. Jacobs, L. Jiménez-García, V. Jiménez Sabinina, A. Kamaid, A. Keppler, A. Kumar, J. Lacoste, A. Lovy, K. Luby-Phelps, A. Mahadevan-Jansen, L. Malacrida, S. Mehta, C. Miller, K. Miranda, J. Moore, A. North, P. O’Toole, M. Olivares Urbano, L. Pietrasanta, R. Portugal, A. Rossi, J. Sanchez Contreras, C. Strambio-De-Castilla, G. Soldevila, B. Vale, D. Vazquez, C. Wood, C. Brown, and A. Guerrero. Building Momentum through Networks: Bioimaging across the Americas. J Microsc, 2024, p. Epub PubMed Text.

Liu, C., J. Smith, Y. Wang, J. Ouellette, J. Rogers, J. Oliner, M. Szulczewski, E. Wait, W. Brown, A. Wax, K. Eliceiri, and J. Rafter. Assessing Cell Viability With Dynamic Optical Coherence microscopy. Biomed Opt Express, 2024, p. Epub PubMed Text.

Sivagurunathan, S., S. Marcotti, C. Nelson, M. Jones, D. Barry, T. Slater, K. Eliceiri, and B. Cimini. Bridging Imaging Users to Imaging Analysis – A Community survey. J Microsc, 2024, p. Epub PubMed Text.

Berson, D., J. Diamond, W. Grimes, M. Hoon, A. Sabnis, R. Sinha, and H. Tian. The retina’S Neurovascular Unit: Müller Glial Sheaths and Neuronal contacts. bioRxiv, 2024, p. Epub PubMed Text.

Malih, S., Y. Song, C. Sorenson, and N. Sheibani. Choroidal Mast Cells and Pathophysiology of Age-Related Macular Degeneration. Cells, 2023, p. PubMed Text.

Saha, A., J. Zuniga, K. Mian, H. Zhai, P. Derr, M. Hoon, and R. Sinha. Regional Variation in the Organization and Connectivity of the First Synapse in the Primate Night Vision pathway. iScience, 2023, p. eCollection PubMed Text.

Diamond, J., W. Grimes, M. Hoon, H. Kolarik, K. Mizerska, A. Saha, R. Sinha, J. Wallin, and S. Wisner. Sensory Deprivation Arrests Cellular and Synaptic Development of the Night-Vision Circuitry in the retina. Current Biology, 2023, p. Epub PubMed Text.

Sauter, M., H. Noel, and C. Brandt. The RLR Intrinsic Antiviral System Is Expressed in Neural Retina and Restricts Lentiviral Transduction of Human Mueller cells. Exp Eye Res, 2023, p. Epub PubMed Text.

Kabra, M., P. Shahi, Y. Wang, D. Sinha, A. Spillane, G. Newby, S. Saxena, Y. Tong, Y. Chang, A. Abdeen, K. Edwards, C. Theisen, D. Liu, D. Gamm, S. Gong, K. Saha, and B. Pattnaik. Nonviral Base Editing of KCNJ13 Mutation Preserves Vision in a Model of Inherited Retinal channelopathy. J Clin Invest, 2023, p. PubMed Text.

Samimi, K., D. Desa, W. Lin, K. Weiss, J. Li, J. Huisken, V. Miskolci, A. Huttenlocher, J. Chacko, A. Velten, J. Rogers, K. Eliceiri, and M. Skala. Light-Sheet Autofluorescence Lifetime Imaging With a Single-Photon Avalanche Diode array. J Biomed Opt, 2023, p. PubMed Text.

Barone, F., J. Amaral, I. Bunea, M. Farnoodian, R. Gupta, R. Gupta, D. Baker, M. Phillips, R. Blanch, A. Maminishkis, D. Gamm, and K. Bharti. A Versatile Laser-Induced Porcine Model of Outer Retinal and Choroidal Degeneration for Preclinical testing. JCI Insight, 2023, p. PubMed Text.

Dow, C., N. Lin, and E. Chan. Sarcoidosis, Mycobacterium Paratuberculosis and Noncaseating Granulomas: Who Moved My Cheese. Microorganisms, 2023, p. PubMed Text.

Ji, M., E. Ward EJ, and C. Green. Realistic and Complex Visual Chasing Behaviors Trigger the Perception of intentionality. PLoS One, 2023, p. PubMed Text.

Goebel, C., Y. Song, I. Zaitoun, S. Wang, H. Potter, C. Sorenson, and N. Sheibani. Adenosine Receptors Expression in Human Retina and Choroid With Age-Related Macular Degeneration. J Ophthalmic Vis Res, 2023, p. PubMed Text.

Song, Y., N. Jamali, C. Sorenson, and N. Sheibani. Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells. Cells, 2023, p. PubMed Text.

Ludwig, A., S. Mayerl, Y. Gao, M. Banghart, C. Bacig, M. Fernandez Zepeda, X. Zhao, and D. Gamm. Re-Formation of Synaptic Connectivity in Dissociated Human Stem Cell-Derived Retinal Organoid cultures. Proc Natl Acad Sci U S A, 2023, p. PubMed Text.

Taparli, O., P. Shahi, N. Cagatay, N. Aycan, B. Ozaydin, S. Yapici, X. Liu, U. Cikla, D. Zafer, J. Eickhoff, P. Ferrazzano, B. Pattnaik, and P. Cengiz. Selectively Compromised Inner Retina Function Following Hypoxic-Ischemic Encephalopathy in Mice: A Noninvasive Measure of Severity of the injury. Neurochem Int, 2023, p. PubMed Text.

Wang, Y., X. Wang, R. Xie, J. Burger, Y. Tong, and S. Gong. Overcoming the Blood-Brain Barrier for Gene Therapy via Systemic Administration of GSH-Responsive Silica Nanocapsules. Adv Mater, 2023, p. Epub PubMed Text.

Kiland, J., H. Terhaar, H. Walleck, N. Chen, K. McDaniel, and G. McLellan. Comparison of the TONOVET Plus®, TonoVet®, and Tono-Pen Vet™ Tonometers in Normal Cats and Cats With glaucoma. Vet Ophthalmol., 2023, p. eCollection PubMed Text.

Schmitz, R., K. Tweed, P. Rehani, K. Samimi, J. Riendeau, I. Jones, E. Maly, E. Guzman, M. Forsberg, A. Shahi, C. Capitini, A. Walsh, and M. Skala. Autofluorescence Lifetime Imaging Classifies Human Lymphocyte Activation and subtype. bioRxiv, 2023, p. Epub Full Text.

Madrigal, A., I. Lee, R. Xie, S. Min, J. Zhu, J. Jin, A. Ludwig, M. Phillips, S. Gong, Z. Ma, and D. Gamm. Incorporation of HPSC-Derived Photoreceptors and RPE Cells into Microfabricated, Honeycomb-Patterned Microscaffolds for Outer Retinal reconstruction. Investigative Ophthalmology & Visual Science, 2023, p. Epub Full Text.

Schoenlein, M., J. Campos, K. Lande, L. Lessard, and K. Schloss. Unifying Effects of Direct and Relational Associations for Visual Communication. IEEE Trans Vis Comput Graph, 2023, p. Epub PubMed Text.

Au, A., M. Ip, B. Blodi, I. Scott, N. Oden, P. VanVeldhuisen, and D. Sarraf. OCT Grading System of Macular Infarction Predicts Vision in Participants With Central Retinal or Hemiretinal Vein Occlusion: A Secondary Analysis of SCORE2. AM J Ophthalmol., 2023, p. Epub PubMed Text.

Wu, Z., S. Schmitz-Valckenberg, B. Blodi, F. Holz, G. Jaffe, S. Liakopoulos, S. Sadda, M. Bonse, T. Brown, J. Choong, B. Clifton, G. Corradetti, F. Corvi, A. Dieu, V. Dooling, J. Pak, M. Saßmannshausen, C. Skalak, S. Thiele, and R. Guymer. Reticular Pseudodrusen: Interreader Agreement of Evaluation on OCT Imaging in Age-Related Macular Degeneration. Ophthalmol Sci, 2023, p. Epub PubMed Text.

Kymes, S., N. Oden, P. VanVeldhuisen, I. Scott, M. Ip, B. Blodi, and J. King. Cost-Utility Comparison of Bevacizumab and Aflibercept in the Treatment of Central or Hemiretinal Vein Occlusion in the SCORE2 Trial. JAMA Ophthalmol., 2023, p. Epub PubMed Text.

Scott, I., N. Oden, P. VanVeldhuisen, M. Ip, and B. Blodi. SCORE2 Report 20: Relationship of Treatment Discontinuation With Visual Acuity and Central Subfield Thickness Outcomes. AM J Ophthalmol., 2023, p. Epub PubMed Text.

Schmied, C., M. Nelson, S. Avilov, G. Bakker, C. Bertocchi, J. Bischof, U. Boehm, J. Brocher, M. Carvalho, C. Chiritescu, J. Christopher, B. Cimini, E. Conde-Sousa, M. Ebner, R. Ecker, K. Eliceiri, J. Fernandez-Rodriguez, N. Gaudreault, L. Gelman, D. Grunwald, T. Gu, N. Halidi, M. Hammer, M. Hartley, M. Held, F. Jug, V. Kapoor, A. Koksoy, J. Lacoste, S. Le Dévédec, S. Le Guyader, P. Liu, G. Martins, A. Mathur, K. Miura, P. Llopis, R. Nitschke, A. North, A. Parslow, A. Payne-Dwyer, L. Plantard, R. Ali, B. Schroth-Diez, L. Schütz, R. Scott, A. Seitz, O. Selchow, V. Sharma, M. Spitaler, S. Srinivasan, C. Strambio-De-Castillia, D. Taatjes, C. Tischer, and H. Jambor. Community-Developed Checklists for Publishing Images and Image analyses. Nat Methods, 2023, p. Epub PubMed Text.

Cimini, B., K. Eliceiri, and W. Ouyang. Moving Beyond the Desktop: Prospects for Practical Bioimage Analysis via the web. Front Bioinform, 2023, p. Epub PubMed Text.

Carpenter, A., B. Cimini, and K. Eliceiri. Smart Microscopes of the future. Nat Methods, 2023, p. Epub PubMed Text.

Bankhead, P., C. Brideau, B. Cimini, P. Colarusso, B. Diaz-Rohrer, K. Eliceiri, E. Evans, K. Gonzales, N. Jamali, H. Jambor, J. Kirk, P. Llopis, T. Pengo, R. Senft, L. Swift, and V. Uhlmann. A biologist’S Guide to Planning and Performing Quantitative Bioimaging experiments. PLoS Biol, 2023, p. Epub PubMed Text.

Barros, J., J. Chacko, K. Chen, kw Eliceiri, A. Gonzalez Solís, H. Lee, A. Millar, M. Otegui, S. Signorelli, and R. Vierstra. The Autophagy Receptor NBR1 Directs the Clearance of Photodamaged chloroplasts. Elife, 2023, p. Epub PubMed Text.

Eliceiri, K., E. Evans, D. Loeb, S. Romero, N. Sherer, and N. Unchwaniwala. Live Cell Imaging Reveals HBV Capsid Translocation from the Nucleus To the Cytoplasm Enabled by Cell Division. mBio, 2023, p. Epub PubMed Text.

Altaweel, M., A. Burke, J. Dunn, S. Gangaputra, J. Holbrook, D. Jabs, J. Kempen, K. Pepple, R. Stawell, and E. Sugar. Cataract Surgery in Patients With Uveitis Treated With Systemic Therapy in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study: Risk Factors and Outcomes. American Journal of Ophthalmology, 2023, p. Epub PubMed Text.

Mavlyutov, T., J. Li, X. Liu, H. Shen, H. Yang, C. McCurdy, B. Pattnaik, and L. Guo. Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation. Genes (Basel), 2022, p. PubMed Text.

Zaitoun, I., Y. Song, H. Zaitoun, C. Sorenson, and N. Sheibani. Assessment of Choroidal Vasculature and Innate Immune Cells in the Eyes of Albino and Pigmented Mice. Cells, 2022, p. PubMed Text.

Sorenson, C., Y. Song, S. Wang, S. Darjatmoko, M. Saghiri, M. Ranji, and N. Sheibani. Bim Expression Modulates Branching Morphogenesis of the Epithelium and Endothelium. Biomolecules, 2022, p. PubMed Text.

Ripolles-Garcia, A., N. Dolgova, M. Phillips, S. Savina, A. Ludwig, S. Stuedemann, U. Nlebedum, J. Wolfe, O. Garden, A. Maminishkis, J. Amaral, K. Bharti, D. Gamm, G. Aguirre, and W. Beltran. Systemic Immunosuppression Promotes Survival and Integration of Subretinally Implanted Human ESC-Derived Photoreceptor Precursors in dogs. Stem Cell Reports, 2022, p. PubMed Text.

Dow, C., and B. Alvarez. Mycobacterium Paratuberculosis Zoonosis Is a One Health emergency. Ecohealth, 2022, p. PubMed Text.

Beverley, K., P. Shahi, M. Kabra, Q. Zhao, J. Heyrman, J. Steffen, and B. Pattnaik. Kir7.1 Disease Mutant T153I Within the Inner Pore Affects K(+) conduction. American Journal of Physiology, Cell Physiology, 2022, p. PubMed Text.

Croft, M., T. Nork, G. Heatley, J. McDonald, A. Katz, and P. Kaufman. Intraocular Accommodative Movements in Monkeys; Relationship to presbyopia. Exp Eye Res, 2022, p. PubMed Text.

Wang, S., I. Zaitoun, S. Darjatmoko, N. Sheibani, and C. Sorenson. Bim Expression Promotes the Clearance of Mononuclear Phagocytes During Choroidal Neovascularization, Mitigating Scar Formation in Mice. Life (Basel), 2022, p. PubMed Text.

Jiao, X., Z. Ma, J. Lei, P. Liu, X. Cai, P. Shahi, C. Chan, R. Fariss, B. Pattnaik, L. Dong, and J. Fielding Hejtmancik. Retinal Development and Pathophysiology in Kcnj13 Knockout Mice. Frontiers in Cell and Developmental Biology, 2022, p. PubMed Text.

Gundlach, B., M. Frising, A. Shahsafi, G. Vershbow, C. Wan, J. Salman, B. Rokers, L. Lessard, and M. Kats. Author Correction: Design Considerations for the Enhancement of Human Color Vision by Breaking Binocular redundancy. Sci Rep, 2022, p. PubMed Text.

Landowski, M., and C. Rickman. Targeting Lipid Metabolism for the Treatment of Age-Related Macular Degeneration: Insights from Preclinical Mouse Models. J Ocul Pharmacol Ther, 2022, p. PubMed Text.

Gillette, A., R. DeStefanis, S. Pritzl, D. Deming, and M. Skala. Inhibition of B-Cell Lymphoma 2 Family Proteins Alters Optical Redox Ratio, Mitochondrial Polarization, and Cell Energetics Independent of Cell state. Journal of Biomedical Optics, 2022, pp. 056505-056505

Ripolles-Garcia, A., N. Dolgova, M. Phillips, S. Savina, A. Ludwig, S. Stuedemann, J. Wolfe, O. Garden, D. Gamm, G. Aguirre, and W. Beltran. Triple Drug Immunosuppression for Xenotransplantation of Human Photoreceptor Precursor Cells in the Canine retina. Investigative Ophthalmology & Visual Science, 2022, p. Epub Full Text.

Doudlah, R., T. Chang, L. Thompson, B. Kim, A. Sunkara, and A. Rosenberg. Parallel Processing, Hierarchical Transformations, and Sensorimotor Associations Along the ‘where’ Pathway. Elife, 2022, p. Epub PubMed Text.

Mzyk, P., E. Zalog, and C. McDowell. A20 Attenuates the Fibrotic Response in the Trabecular Meshwork. Int J Mol Sci., 2022, p. Epub PubMed Text.

Scott, I., N. Oden, P. VanVeldhuisen, M. Ip, and B. Blodi. Baseline Characteristics and Outcomes After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema in Participants With Hemiretinal Vein Occlusion Compared With Participants With Central Retinal Vein Occlusion: Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Report 18. JAMA Ophthalmol., 2022, p. Epub PubMed Text.

Carpenter, A., B. Cimini, K. Eliceiri, E. Evans, M. Hiner, A. Lucas, M. Pinkert, and C. Rueden. PyImageJ: A Library for Integrating ImageJ and Python. Nat Methods, 2022, p. Epub PubMed Text.

Eliceiri, K., E. Haynes, and T. Ulland. A Model of Discovery: The Role of Imaging Established and Emerging Non-Mammalian Models in Neuroscience. Front Mol Neurosci, 2022, p. Epub PubMed Text.

Wahlin, K., J. Cheng, S. Jurlina, M. Jones, N. Dash, A. Ogata, N. Kibria, S. Ray, K. Eldred, C. Kim, J. Heng, J. Phillips, R. Johnston Jr, D. Gamm, C. Berlinicke, and D. Zack. CRISPR Generated SIX6 and POU4F2 Reporters Allow Identification of Brain and Optic Transcriptional Differences in Human PSC-Derived Organoids. Front Cell Dev Biol, 2021, p. PubMed Text.

Dow, C. Hermon-Taylor: M. Paratuberculosis and Crohn’S Disease-The Book of Revelation According to John. Pathogens, 2021, p. PubMed Text.

Sorenson, C., Y. Song, I. Zaitoun, S. Wang, B. Hanna, S. Darjatmoko, Z. Gurel, D. Fisk, C. McDowell, R. McAdams, and N. Sheibani. Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities. Front Cell Dev Biol, 2021, p. PubMed Text.

Dow, C. Warm, Sweetened Milk at the Twilight of Immunity – Alzheimer’s Disease – Inflammaging, Insulin Resistance, M. Paratuberculosis and Immunosenescence. Front Immunol, 2021, p. PubMed Text.

Schmitt, H., R. Fehrman, M. Maes, H. Yang, L. Guo, C. Schlamp, H. Pelzel, and R. Nickells. Increased Susceptibility and Intrinsic Apoptotic Signaling in Neurons by Induced HDAC3 Expression. Invest Ophthalmol Vis Sci, 2021, p. PubMed Text.

Donahue, R., R. Fehrman, J. Gustafson, and R. Nickells. BCLX(L) Gene Therapy Moderates Neuropathology in the DBA/2J Mouse Model of Inherited glaucoma. Cell Death Dis, 2021, p. PubMed Text.

Muench, N., S. Patel, M. Maes, R. Donahue, A. Ikeda, and R. Nickells. The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease. Cells, 2021, p. PubMed Text.

Zaitoun, I., P. Shahi, A. Suscha, K. Chan, G. McLellan, B. Pattnaik, C. Sorenson, and N. Sheibani. Hypoxic-Ischemic Injury Causes Functional and Structural Neurovascular Degeneration in the Juvenile Mouse retina. Scientific Reports, 2021, p. EPub PubMed Text.

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Zaitoun, I., P. Shahi, A. Suscha, K. Chan, G. McLellan, B. Pattnaik, C. Sorenson, and N. Sheibani. Hypoxic–ischemic Injury Causes Functional and Structural Neurovascular Degeneration in the Juvenile Mouse retina. Scientific Reports, 2021, pp. Epub

Scott, I., N. Oden, P. VanVeldhuisen, M. Ip, and B. Blodi. SCORE2 Report 17: Macular Thickness Fluctuations in Anti-VEGF-Treated Patients With Central or Hemiretinal Vein occlusion. Graefe’s archive for clinical and experimental ophthalmology, 2021, p. Epub PubMed Text.

Huang, J., R. Khurana, A. Ghanekar, P. Wang, B. Day, B. Blodi, A. Domalpally, C. Quezada-Ruiz, and M. Ip. Disease-Modifying Effects of Ranibizumab for Central Retinal Vein occlusion. Graefe’s archive for clinical and experimental ophthalmology, 2021, p. Epub PubMed Text.

Etheridge, T., Z. Liu, M. Nalbandyan, S. Cleland, B. Blodi, J. Mares, S. Bailey, R. Wallace, K. Gehrs, L. Tinker, R. Gangnon, and A. D. Association of Macular Thickness With Age and Age-Related Macular Degeneration in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2), An Ancillary Study of the Women’S Health Initiative. Translational Visual Science & Technology, 2021, p. Epub PubMed Text.

Wu, Z., M. Pfau, B. Blodi, F. Holz, G. Jaffe, S. Liakopoulos, S. Sadda, G. Staurenghi, E. Bjelopera, T. Brown, P. Chang, J. Choong, G. Corradetti, F. Corvi, A. Domalpally, C. Hurtenbach, M. Nittala, A. Olson, J. Pak, J. Pappe, M. Saßmannshausen, C. Skalak, S. Thiele, R. Guymer, and S. Schmitz-Valckenberg. OCT Signs of Early Atrophy in Age-Related Macular Degeneration: Interreader Agreement: Classification of Atrophy Meetings Report 6. Ophthalmology Retina, 2021, p. Epub PubMed Text.

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Ahlquist, R., D. Aytürk, D. Berson, D. Carrera, C. Cepko, J. Diamond, C. Gamlin, W. Grimes, M. Hoon, F. Nadal-Nicolás, A. Nath, F. Rieke, A. Sabnis, R. Wong, and T. Yoshimatsu. A High-Density Narrow-Field Inhibitory Retinal Interneuron With Direct Coupling to Müller Glia. The Journal of Neuroscience, 2021, p. Epub PubMed Text.

Bailey, S., B. Blodi, S. Cleland, A. Domalpally, K. Gehrs, Z. Liu, J. Mares, J. Pak, L. Tinker, and R. Wallace. Reticular Pseudodrusen Characteristics and Associations in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2), an Ancillary Study of the Women’S Health Initiative. Ophthalmology Retina, 2021, p. Epub PubMed Text.

Landowski, M., S. Grindel, P. Shahi, A. Johnson, D. Western, A. Race, F. Shi, J. Benson, M. Gao, E. Santoirre, W. Lee, S. Ikeda, B. Pattnaik, and A. Ikeda. Modulation of Tmem135 Leads to Retinal Pigmented Epithelium Pathologies in Mice. Investigative Ophthalmology & Visual Science, 2020, p. PubMed Text.

Kabra, M., and B. Pattnaik. Sensing through Non-Sensing Ocular Ion Channels. International Journal of Molecular Sciences, 2020, p. PubMed Text.

Maddock, S., R. Nussbaum, J. Day, L. Latta, M. Miller, D. Fisk, M. Wilkinson, S. Rocha, D. Gower, and M. Pfrender. The Roles of Vicariance and Isolation by Distance in Shaping Biotic Diversification across an Ancient Archipelago: Evidence from a Seychelles Caecilian amphibian. BMC Evol Biol, 2020, p. PubMed Text.

Aboualizadeh, E., M. Phillips, J. McGregor, D. DiLoreto, J. Strazzeri, K. Dhakal, B. Bateman, L. Jager, K. Nilles, S. Stuedemann, A. Ludwig, J. Hunter, W. Merigan, D. Gamm, and D. Williams. Imaging Transplanted Photoreceptors in Living Nonhuman Primates With Single-Cell Resolution. Stem Cell Reports, 2020, p. PubMed Text.

Czymmek, K., A. Sawant, K. Goodman, J. Pennington, P. Pedersen, M. Hoon, and M. Otegui. Imaging Plant Cells by High-Pressure Freezing and Serial Block-Face Scanning Electron microscopy. Methods Mol Biol, 2020, p. PubMed Text.

Niemeier, R., Z. Simmons, and J. Rogers. Noise Reduction in Supercontinuum Sources for OCT by Single-Pulse Spectral normalization. Appl Opt, 2020, p. PubMed Text.

Udry, F., S. Decembrini, D. Gamm, N. Déglon, C. Kostic, and Y. Arsenijevic. Lentiviral Mediated RPE65 Gene Transfer in Healthy HiPSCs-Derived Retinal Pigment Epithelial Cells Markedly Increased RPE65 MRNA, But Modestly Protein level. Sci Rep, 2020, p. PubMed Text.

Falero-Perez, J., N. Sheibani, and C. Sorenson. Bim Expression Modulates the Pro-Inflammatory Phenotype of Retinal Astroglial cells. PLoS One, 2020, p. PubMed Text.

Oikawa, K., J. Ver Hoeve, L. Teixeira, K. Snyder, J. Kiland, N. Ellinwood, and G. McLellan. Sub-Region-Specific Optic Nerve Head Glial Activation in Glaucoma. Mol Neurobiol, 2020, p. PubMed Text.

Kallman, A., E. Capowski, J. Wang, A. Kaushik, A. Jansen, K. Edwards, L. Chen, C. Berlinicke, M. Phillips, E. Pierce, J. Qian, T. Wang, D. Gamm, and D. Zack. Investigating Cone Photoreceptor Development Using Patient-Derived NRL Null Retinal organoids. Commun Biol, 2020, p. PubMed Text.

Doebley, A., N. Gruenke, J. Gumperz, E. Henningsen, A. Ikeda, S. Ikeda, E. Jessen, M. Landowski, W. Lee, C. Liu, E. Macke, S. Miller, B. Pattnaik, D. Western, and N. Zumwalde. Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in Skt Mice. Genetics, 2020, p. Epub PubMed Text.

Saghiri, M., A. Suscha, S. Wang, C. Sorenson, and N. Sheibani. Noninvasive Temporal Detection of Early Retinal Vascular Changes During diabetes. Scientific Reports, 2020, pp. Epub

Ludwig, A., J. Phillips, I. Lee, A. Xie, J. Lee, D. Sinha, K. Edwards, S. Gong, J. Ma, and D. Gamm. Ultrathin Micro-Molded Biodegradable Scaffolds for Outer Retina reconstruction. Investigative Ophthalmology & Visual Science, 2020, p. Epub Full Text.

Hendrick, A., P. VanVeldhuisen, I. Scott, J. King, B. Blodi, M. Ip, R. Khurana, and N. Oden. SCORE2 Report 13: Intraretinal Hemorrhage Changes in Eyes With Central or Hemiretinal Vein Occlusion Managed With Aflibercept, Bevacizumab or Observation. Secondary Analysis of the SCORE and SCORE2 Clinical Trials. American Journal of Ophthalmology, 2020, p. Epub PubMed Text.

Cleland, S., S. Konda, R. Danis, Y. Huang, D. Myers, B. Blodi, and A. Domalpally. Quantification of Geographic Atrophy Using Spectral Domain OCT in Age-Related Macular Degeneration. Ophthalmology Retina, 2020, p. Epub PubMed Text.

Guymer, R., P. Rosenfeld, C. Curcio, F. Holz, G. Staurenghi, K. Freund, S. Schmitz-Valckenberg, J. Sparrow, R. Spaide, A. Tufail, U. Chakravarthy, G. Jaffe, K. Csaky, D. Sarraf, J. Monés, R. Tadayoni, J. Grunwald, F. Bottoni, S. Liakopoulos, D. Pauleikhoff, W. Pagliarini, E. Chew, F. Viola, M. Fleckenstein, B. Blodi, T. Lim, V. Chong, J. Lutty, A. Bird, and S. Sadda. Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4. Ophthalmology, 2020, p. Epub PubMed Text.

Artemyev, N., S. Baker, L. Della Santina, P. Derr, J. Hagen, M. Hoon, V. Kerov, A. Lee, J. Maddox, K. Randall, B. Williams, and R. Yadav. A Dual Role for Cav1.4 Ca2+ Channels in the Molecular and Structural Organization of the Rod Photoreceptor synapse. eLife, 2020, p. Epub PubMed Text.

Van Grinsven, K., A. Ashtiani, and H. Jiang. Lorentz Force Actuated Tunable-Focus Liquid Lens. Micromachines (Basel), 2019, p. Epub PubMed Text.

Perone, S., and V. Simmering. Connecting the Dots: Finding Continuity Across Visuospatial Tasks and Development. Front Psychol, 2019, p. Epub PubMed Text.

Daniel, S., K. Meyer, M. Anderson, and C. McDowell. Effect of Ocular Hypertension on the Pattern of Retinal Ganglion Cell Subtype Loss in a Mouse Model of Early-Onset glaucoma. Exp Eye Res, 2019, p. Epub PubMed Text.

Yang, H., H. Shen, J. Li, and L. Guo. SIGMAR1/Sigma-1 Receptor Ablation Impairs Autophagosome clearance. Autophagy, 2019, p. PubMed Text.

Capowski, E., K. Samimi, S. Mayerl, M. Phillips, I. Pinilla, S. Howden, J. Saha, A. Jansen, K. Edwards, L. Jager, K. Barlow, R. Valiauga, Z. Erlichman, A. Hagstrom, D. Sinha, V. Sluch, X. Chamling, D. Zack, M. Skala, and D. Gamm. Reproducibility and Staging of 3D Human Retinal Organoids across Multiple Pluripotent Stem Cell lines. Development, 2019, p. PubMed Text.

Telle, M., N. Chen, D. Shinsako, J. Kiland, K. Oikawa, R. Trane, and G. McLellan. Relationship Between Corneal Sensitivity, Corneal Thickness, Corneal Diameter, and Intraocular Pressure in Normal Cats and Cats With Congenital glaucoma. Vet Ophthalmol, 2019, p. PubMed Text.

Sheibani, N., S. Wang, S. Darjatmoko, S. Darjatmoko, D. Fisk, P. Shahi, K. Pawan, B. Pattnaik, C. Sorenson, R. Bhowmick, O. Volpert, D. Albert, I. Melgar-Asensio, and J. Henkin. Novel Anti-Angiogenic PEDF-Derived Small Peptides Mitigate Choroidal neovascularization. Experimental Eye Research, 2019, p. Epub PubMed Text.

Mayerl, S., E. Capowski, D. Sinha, J. Phillips, K. Edwards, and D. Gamm. Characterization of Interphotoreceptor Matrix Proteins Expressed by Human Pluripotent Stem Cell Derived Retinal cells. Investigative Ophthalmology & Visual Science, 2019, p. Epub Full Text.

Scott, I., N. Oden, P. VanVeldhuisen, M. Ip, B. Blodi, and C. Chan. Month 24 Outcomes After Treatment Initiation With Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion: SCORE2 Report 10: A Secondary Analysis of the SCORE2 Randomized Clinical Trial. JAMA Ophthalmology, 2019, p. Epub PubMed Text.

Toh, H., A. Smolentsev, R. Bozadjian, P. Keeley, M. Lockwood, R. Sadjadi, D. Clegg, B. Blodi, P. Coffey, B. Reese, and J. Thomson. Vascular Changes in Diabetic Retinopathy-a Longitudinal Study in the Nile rat. Lab Investigation, 2019, p. Epub PubMed Text.

Peterson, J., K. Rockwell, I. Scott, M. Ip, P. VanVeldhuisen, and B. Blodi. LONG-TERM PHYSICAL STABILITY, STERILITY, AND ANTI-VEGF BIOACTIVITY OF REPACKAGED BEVACIZUMAB IN 2-ML GLASS VIALS. Retina, 2019, p. Epub PubMed Text.

Abdeen, A., G. Chen, S. Gong, B. Pattnaik, S. Robertson, K. Saha, P. Shahi, M. Suzuki, Y. Wang, and R. Xie. A Biodegradable Nanocapsule Delivers a Cas9 Ribonucleoprotein Complex for in Vivo Genome editing. Nature Nanotechnology, 2019, p. Epub PubMed Text.

Falero-Perez, J., S. Gong, O. Mezu-Ndubuisi, J. Schoephoerster, N. Sheibani, Y. Wang, and I. Zaitoun. Intravitreal Delivery of VEGF-A165-Loaded PLGA Microparticles Reduces Retinal Vaso-Obliteration in an In Vivo Mouse Model of Retinopathy of Prematurity. Current Eye Research, 2019, p. Epub PubMed Text.

Blodi, B., A. Domalpally, I. Holmen, S. Konda, K. McDaniel, J. Pak, and K. Stepien. Prevalence and Severity of Artifacts in Optical Coherence Tomographic Angiograms. JAMA Ophthalmology, 2019, p. Epub PubMed Text.

Erratum in Error in Byline. [No authors listed]JAMA Ophthalmol. 2020 Apr 1;138(4):420. doi: 10.1001/jamaophthalmol.2020.0227.PMID: 32105296

Bird, A., R. Bonelli, E. Chew, T. Clemons, A. Dubis, F. Gunnemann, T. Heeren, P. Issa, D. Pauleikhoff, T. Peto, K. Rothaus, and F. Sallo. Progression Characteristics of Ellipsoid Zone Loss in Macular Telangiectasia Type 2. Acta Opthalmolgica, 2019, p. Epub PubMed Text.

Farnoodian, M., C. Sorenson, and N. Sheibani. Negative Regulators of Angiogenesis, Ocular Vascular Homeostasis, and Pathogenesis and Treatment of Exudative AMD. J Ophthalmic Vis Res, 2018, p. PubMed Text.

Jung, Y., M. Phillips, J. Lee, R. Xie, A. Ludwig, G. Chen, Q. Zheng, T. Kim, H. Zhang, P. Barney, J. Min, K. Barlow, S. Gong, D. Gamm, and Z. Ma. 3D Microstructured Scaffolds to Support Photoreceptor Polarization and Maturation. Adv Mater, 2018, p. PubMed Text.

Gundlach, B., M. Frising, A. Shahsafi, G. Vershbow, C. Wan, J. Salman, B. Rokers, L. Lessard, and M. Kats. Design Considerations for the Enhancement of Human Color Vision by Breaking Binocular redundancy. Sci Rep, 2018, p. PubMed Text.

Agbaga, M., D. Merriman, R. Brush, T. Lydic, S. Conley, M. Naash, S. Jackson, A. Woods, G. Reid, J. Busik, and R. Anderson. Differential Composition of DHA and Very-Long-Chain PUFAs in Rod and Cone photoreceptors. J Lipid Res, 2018, p. PubMed Text.

Zaitoun, I., U. Cikla, D. Zafer, E. Udho, R. Almomani, A. Suscha, P. Cengiz, C. Sorenson, and N. Sheibani. Attenuation of Retinal Vascular Development in Neonatal Mice Subjected to Hypoxic-Ischemic Encephalopathy. Sci Rep, 2018, p. PubMed Text.

Kaur, G., and A. Lakkaraju. Early Endosome Morphology in Health and Disease. Adv Exp Med Biol, 2018, p. PubMed Text.

Niemeier, R., S. Etoz, D. Gil, M. Skala, C. Brace, and J. Rogers. Quantifying Optical Properties With Visible and Near-Infrared Optical Coherence Tomography to Visualize Esophageal Microwave Ablation zones. Biomed Opt Express, 2018, p. PubMed Text.

Miller, H., and V. Simmering. Children’S Attention to Task-Relevant Information Accounts for Relations Between Language and Spatial cognition. J Exp Child Psychol, 2018, p. PubMed Text.

Langer, K., S. Ohlemacher, M. Phillips, C. Fligor, P. Jiang, D. Gamm, and J. Meyer. Retinal Ganglion Cell Diversity and Subtype Specification from Human Pluripotent Stem Cells. Stem Cell Reports, 2018, p. PubMed Text.

Gurel, Z., and N. Sheibani. O-Linked β-N-Acetylglucosamine (O-GlcNAc) Modification: A New Pathway to Decode Pathogenesis of Diabetic retinopathy. Clin Sci (Lond), 2018, p. PubMed Text.

Aboualizadeh, E., C. Sorenson, A. Schofield, M. Unger, N. Sheibani, and C. Hirschmugl. Temporal Diabetes-Induced Biochemical Changes in Distinctive Layers of Mouse retina. Sci Rep, 2018, p. PubMed Text.

Lakowski, J., E. Welby, D. Budinger, F. Di Marco, V. Di Foggia, J. Brainbridge, K. Wallace, D. Gamm, R. Ali, and J. Sowden. Isolation of Human Photoreceptor Precursors via a Cell Surface Marker Panel from Stem Cell-Derived Retinal Organoids and Fetal Retinae. Stem Cells, 2018, p. PubMed Text.

Sedykh, I., A. Keller, B. Yoon, L. Roberson, O. Moskvin, and Y. Grinblat. Zebrafish Rfx4 Controls Dorsal and Ventral Midline Formation in the Neural tube. Dev Dyn, 2018, p. PubMed Text.

Adelman, S., D. Shinsako, J. Kiland, V. Yaccarino, N. Ellinwood, G. Ben-Shlomo, and G. McLellan. The Post-Natal Development of Intraocular Pressure in Normal Domestic Cats (Felis Catus) and in Feline Congenital glaucoma. Exp Eye Res, 2018, p. PubMed Text.

Snyder, K., A. Lewin, C. Mans, and G. McLellan. Tonometer Validation and Intraocular Pressure Reference Values in the Normal Chinchilla (Chinchilla lanigera). Vet Ophthalmol, 2018, p. PubMed Text.

Saghiri, M., A. Asatourian, C. Sorenson, and N. Sheibani. Mice Dental Pulp and Periodontal Ligament Endothelial Cells Exhibit Different Proangiogenic properties. Tissue Cell, 2018, p. Epub PubMed Text.

Sinha, D. Mitochondrial Integrity and Function in HPSC-Derived RPE. Investigative Ophthalmology & Visual Science, 2018, p. Epub Full Text.

Sadda, S., R. Guymer, F. Holz, S. Schmitz-Valckenberg, C. Curcio, A. Bird, B. Blodi, F. Bottoni, U. Chakravarthy, E. Chew, K. Csaky, R. Danis, M. Fleckenstein, K. Freund, J. Grunwald, C. Hoyng, G. Jaffe, S. Liakopoulos, J. Monés, D. Pauleikhoff, P. Rosenfeld, D. Sarraf, R. Spaide, R. Tadayoni, A. Tufail, S. Wolf, and G. Staurenghi. Consensus Definition for Atrophy Associated With Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3. Ophthalmology, 2018, p. Epub PubMed Text.

Erratum in Corrigendum.

Gamlin, C., M. Hoon, R. Wong, and W. Yu. Assembly and Maintenance of GABAergic and Glycinergic Circuits in the Mammalian Nervous system. Neural Development, 2018, p. Epub PubMed Text.

Bird, A., B. Blodi, E. Chew, T. Clemons, G. Comer, I. Constable, D. Eliott, S. Farsiu, M. Friedlander, M. Gillies, R. Guymer, J. Hubschman, G. Jaffe, C. Johnson, E. Lad, P. Rosenfeld, L. Singerman, H. Wiley, and J. Yan. Effect of Ciliary Neurotrophic Factor on Retinal Neurodegeneration in Patients With Macular Telangiectasia Type 2: A Randomized Clinical Trial. Ophthalmology, 2018, p. Epub PubMed Text.

Polans, A., J. McAnulty, P. Phelps, S. Darjatmoko, C. Burris, and D. Albert. Pilot Study of a “Large-Eye," Surgically Induced Dry Eye Rabbit Model by Selective Removal of the Harderian, Lacrimal, and Meibomian Glands. Ocul Oncol Pathol, 2017, p. PubMed Text.

Fulvio, J., and B. Rokers. Use of Cues in Virtual Reality Depends on Visual feedback. Sci Rep, 2017, p. PubMed Text.

Ashtiani, A., and H. Jiang. A Liquid Optical Phase Shifter With an Embedded Electrowetting Actuator. J Microelectromech Syst, 2017, p. PubMed Text.

Potential Independent Action of Sigma Receptor Ligands through Inhibition of the Kv2.1 channel. Oncotarget, 2017.

Liu X, Fu Y, Yang H, Mavlyutov T, Li J, McCurdy CR, Guo LW, Pattnaik BR.

Mavlyutov, T., H. Yang, M. Epstein, A. Ruoho, J. Yang, and L. Guo. APEX2-Enhanced Electron Microscopy Distinguishes Sigma-1 Receptor Localization in the Nucleoplasmic reticulum. Oncotarget, 2017, p. PubMed Text.

Galloway, C., S. Dalvi, S. Hung, L. MacDonald, L. Latchney, R. Wong, R. Guymer, D. Mackey, D. Williams, M. Chung, D. Gamm, A. Pébay, A. Hewitt, and R. Singh. Drusen in Patient-Derived HiPSC-RPE Models of Macular dystrophies. Proc Natl Acad Sci U S A, 2017, p. PubMed Text.

Falero-Perez, J., S. Park, C. Sorenson, and N. Sheibani. PEDF Expression Affects Retinal Endothelial Cell Proangiogenic Properties through Alterations in Cell Adhesive mechanisms. Am J Physiol Cell Physiol, 2017, p. PubMed Text.

Sedykh, I., B. Yoon, L. Roberson, O. Moskvin, C. Dewey, and Y. Grinblat. Zebrafish Zic2 Controls Formation of Periocular Neural Crest and Choroid Fissure morphogenesis. Dev Biol, 2017, p. PubMed Text.

Chen, G., X. Shi, B. Wang, R. Xie, L. Guo, S. Gong, and K. Kent. Unimolecular Micelle-Based Hybrid System for Perivascular Drug Delivery Produces Long-Term Efficacy for Neointima Attenuation in Rats. Biomacromolecules, 2017, p. PubMed Text.

Wang, S., I. Zaitoun, R. Johnson, N. Jamali, Z. Gurel, C. Wintheiser, A. Strasser, V. Lindner, N. Sheibani, and C. Sorenson. Bim Expression in Endothelial Cells and Pericytes Is Essential for Regression of the Fetal Ocular vasculature. PLoS One, 2017, p. PubMed Text.

Abstract Apoptosis plays a central role in developmental and pathological angiogenesis and vessel regression. Bim is a pro-apoptotic Bcl-2 family member that plays a prominent role in both developmental and pathological ocular vessel regression, and neovascularization. Endothelial cells (EC) and pericytes (PC) each play unique roles during vascular development, maintenance and regression. We recently showed that germline deletion of Bim results in persistent hyaloid vasculature, increased retinal vascular density and prevents retinal vessel regression in response to hyperoxia. To determine whether retinal vascular regression is attributable to Bim expression in EC or PC we generated mice carrying a conditional Bim allele (BimFlox/Flox) and VE-cadherin-cre (BimEC mice) or Pdgfrb-cre (BimPC mice). BimEC and BimPC mice demonstrated attenuated hyaloid vessel regression and postnatal retinal vascular remodeling. We also observed decreased retinal vascular apoptosis and proliferation. Unlike global Bim -/- mice, mice conditionally lacking Bim in EC or PC underwent hyperoxia-mediated vessel obliteration and subsequent retinal neovascularization during oxygen-induced ischemic retinopathy similar to control littermates. Thus, understanding the cell autonomous role Bim plays in the retinal vascular homeostasis will give us new insight into how to modulate pathological retinal neovascularization and vessel regression to preserve vision.

Raven, M., A. Ringeisen, Y. Yonekawa, M. Stem, L. Faia, and J. Gottlieb. Multi-Modal Imaging and Anatomic Classification of the White Dot syndromes. Int J Retina Vitreous, 2017, p. PubMed Text.

Abstract The white dot syndromes (WDS) are a diverse group of posterior uveitidies that share similar clinical findings but are unique from one another. Multimodal imaging has allowed us to better understand the morphology, the activity and age of lesions, and whether there is CNV associated with these different ocular pathologies. The “white dot syndromes” and their uveitic masqueraders can now be anatomically categorized based on lesion localization. The categories include local uveitic syndromes with choroidal pathology, systemic uveitic syndromes with choroidal pathology, and multifocal choroiditis with outer retinal/choriocapillaris pathology with uveitis and without uveitis. Neoplastic and infectious etiologies are also discussed given their ability to masquerade as WDS. Keywords: Acute posterior multifocal placoid pigment epitheliopathy; Birdshot chorioretinopathy; Multifocal choroiditis with panuveitis; Multiple evanescent white dot syndrome; Punctate inner choroidopathy; Relentless placoid chorioretinitis; Serpiginous choroiditis; Sympathetic ophthalmia; Vogt–Koyanagi–Harada disease; White dot syndromes.

Wang, A., M. Raven, K. Surapaneni, and D. Albert. Studies on the Histopathology of Temporal Arteritis. Ocul Oncol Pathol, 2017, p. PubMed Text.

Abstract Aims: The aim of this paper was to identify the location and to grade the severity of most significant inflammation within positive temporal artery biopsies along with other key clinical and histologic characteristics. Keywords: CD68; Giant cell arteritis; Granulomatous inflammation; Temporal arteritis; Vasculitis.

Guziewicz, K., D. Sinha, N. Gomez, K. Zorych, E. Dutrow, A. Dhingra, R. Mullins, E. Stone, D. Gamm, K. Boesze-Battaglia, and G. Aguirre. Bestrophinopathy: An RPE-Photoreceptor Interface disease. Prog Retin Eye Res, 2017, p. PubMed Text.

Abstract Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies. Keywords: Bestrophinopathies; Canine model; Lipofuscin; Macula; RPE apical microvilli; RPE-Photoreceptor interface; hiPSC-RPE.

Peyer, S., E. Heath-Heckman, and M. McFall-Ngai. Characterization of the Cell Polarity Gene Crumbs During the Early Development and Maintenance of the Squid-Vibrio Light Organ symbiosis. Dev Genes Evol, 2017, p. PubMed Text.

Abstract The protein Crumbs is a determinant of apical-basal cell polarity and plays a role in apoptosis of epithelial cells and their protection against photodamage. Using the squid-vibrio system, a model for development of symbiotic partnerships, we examined the modulation of the crumbs gene in host epithelial tissues during initiation and maintenance of the association. The extracellular luminous symbiont Vibrio fischeri colonizes the apical surfaces of polarized epithelia in deep crypts of the Euprymna scolopes light organ. During initial colonization each generation, symbiont harvesting is potentiated by the biochemical and biophysical activity of superficial ciliated epithelia, which are several cell layers from the crypt epithelia where the symbionts reside. Within hours of crypt colonization, the symbionts induce the cell death mediated regression of the remote superficial ciliated fields. However, the crypt cells directly interacting with the symbiont are protected from death. In the squid host, we characterized the gene and encoded protein during light organ morphogenesis and in response to symbiosis. Features of the protein sequence and structure, phylogenetic relationships, and localization patterns in the eye supported assignment of the squid protein to the Crumbs family. In situ hybridization revealed that the crumbs transcript shows opposite expression at the onset of symbiosis in the two different regions of the light organ: elevated levels in the superficial epithelia were attenuated whereas low levels in the crypt epithelia were turned up. Although a rhythmic association in which the host controls the symbiont population over the day-night cycle begins in the juvenile upon colonization, cycling of crumbs was evident only in the adult organ with peak expression coincident with maximum symbiont population and luminescence. Our results provide evidence that crumbs responds to symbiont cues that induce developmental apoptosis and to symbiont population dynamics correlating with luminescence-based stress throughout the duration of the host-microbe association. Keywords: Apoptosis; Cephalopod; Eye; Photophore; Photoreceptor; Squid vibrio; Symbiosis.

Zhao, L., G. Chen, J. Li, Y. Fu, T. Mavlyutov, A. Yao, R. Nickells, S. Gong, and L. Guo. An Intraocular Drug Delivery System Using Targeted Nanocarriers Attenuates Retinal Ganglion Cell degeneration. Journal of Controlled Release, 2017, p. PubMed Text.

Abstract Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)-polyvalerolactone-poly(ethylene glycol) (PAMAM-PVL-PEG). While the hydrophobic PAMAM-PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity. We conjugated unimNPs with the cholera toxin B domain (CTB) for RGC-targeting and with Cy5.5 for unimNP-tracing. To exploit RGC-protective sigma-1 receptor (S1R), we loaded unimNPs with an endogenous S1R agonist dehydroepiandrosterone (DHEA) as an FDA-approved model drug. These unimNPs produced a steady DHEA release in vitro for over two months at pH7.4. We then co-injected (mice, intraocular) unimNPs with the glutamate analog N-methyl-d-aspartate (NMDA), which is excito-toxic and induces RGC death. The CTB-conjugated unimNPs (i.e., targeted NPs) accumulated at the RGC layer and effectively preserved RGCs at least for 14days, whereas the unimNPs without CTB (i.e., non-targeted NPs) showed neither accumulation at nor protection of NMDA-treated RGCs. Consistent with S1R functions, targeted NPs relative to non-targeted NPs showed markedly better inhibitory effects on apoptosis and oxidative/inflammatory stresses in the RGC layer. Hence, the DHEA-loaded, CTB-conjugated unimNPs represent an RGC/S1R dual-targeted nanoplatform that generates an efficacious template for further development of a sustainable intraocular drug delivery system to protect RGCs, which may be applicable to treatments directed at glaucomatous pathology. Keywords: Cholera toxin B domain; Excitotoxicity; Ganglion cell targeting; Retina; Sigma-1 receptor; Targeted drug delivery; Unimolecular micelles.

Miller, H., H. Vlach, and V. Simmering. Producing Spatial Words Is Not Enough: Understanding the Relation Between Language and Spatial Cognition. Child Dev, 2017, p. PubMed Text.

Abstract Prior research has investigated the relation between children’s language and spatial cognition by assessing the quantity of children’s spatial word production, with limited attention to the context in which children use such words. This study tested whether 4-year-olds children’s (N = 41, primarily white middle class) adaptive use of task-relevant language across contexts predicted their spatial skills. Children were presented with a spatial scene description task, four spatial tasks, and vocabulary assessments. Children’s adaptive use of task-relevant language was more predictive of their spatial skills than demographic and language factors (e.g., quantity of spatial words produced). These findings identify new links between language and spatial cognition and highlight the importance of understanding the quality, not just quantity, of children’s language use.

Clark, P., S. Bhattacharya, A. Elmayan, S. Darjatmoko, B. Thuro, M. Yan, P. van Ginkel, A. Polans, and J. Kuo. Resveratrol Targeting of AKT and p53 in Glioblastoma and Glioblastoma Stem-Like Cells to Suppress Growth and infiltration. J Neurosurg, 2017, p. PubMed Text.

Abstract OBJECTIVE Glioblastoma multiforme (GBM) is an aggressive brain cancer with median survival of less than 2 years with current treatment. Glioblastomas exhibit extensive intratumoral and interpatient heterogeneity, suggesting that successful therapies should produce broad anticancer activities. Therefore, the natural nontoxic pleiotropic agent, resveratrol, was studied for antitumorigenic effects against GBM. METHODS Resveratrol’s effects on cell proliferation, sphere-forming ability, and invasion were tested using multiple patient-derived GBM stem-like cell (GSC) lines and established U87 glioma cells, and changes in oncogenic AKT and tumor suppressive p53 were analyzed. Resveratrol was also tested in vivo against U87 glioma flank xenografts in mice by using multiple delivery methods, including direct tumor injection. Finally, resveratrol was delivered directly to brain tissue to determine toxicity and achievable drug concentrations in the brain parenchyma. RESULTS Resveratrol significantly inhibited proliferation in U87 glioma and multiple patient-derived GSC lines, demonstrating similar inhibitory concentrations across these phenotypically heterogeneous lines. Resveratrol also inhibited the sphere-forming ability suggesting anti-stem cell effects. Additionally, resveratrol blocked U87 glioma and GSC invasion in an in vitro Matrigel Transwell assay at doses similar to those mediating antiproliferative effects. In U87 glioma cells and GSCs, resveratrol reduced AKT phosphorylation and induced p53 expression and activation that led to transcription of downstream p53 target genes. Resveratrol administration via oral gavage or ad libitum in the water supply significantly suppressed GBM xenograft growth; intratumoral or peritumoral resveratrol injection further suppressed growth and approximated tumor regression. Intracranial resveratrol injection resulted in 100-fold higher local drug concentration compared with intravenous delivery, and with no apparent toxicity. CONCLUSIONS Resveratrol potently inhibited GBM and GSC growth and infiltration, acting partially via AKT deactivation and p53 induction, and suppressed glioblastoma growth in vivo. The ability of resveratrol to modulate AKT and p53, as well as reportedly many other antitumorigenic pathways, is attractive for therapy against a genetically heterogeneous tumor such as GBM. Although resveratrol exhibits low bioavailability when administered orally or intravenously, novel delivery methods such as direct injection (i.e., convection-enhanced delivery) could potentially be used to achieve and maintain therapeutic doses in the brain. Resveratrol’s nontoxic nature and broad anti-GBM effects make it a compelling candidate to supplement current GBM therapies. Keywords: CED = convection-enhanced delivery; DMSO = dimethyl sulfoxide; ER = endoplasmic reticulum; GBM = glioblastoma multiforme; GSC = glioblastoma stem-like cell; PBS = phosphate-buffered saline; PCR = polymerase chain reaction; brain tumor; cancer stem-like cells; glioblastoma multiforme; natural products; oncology; resveratrol.

Aboualizadeh, E., M. Ranji, C. Sorenson, R. Sepehr, N. Sheibani, and C. Hirschmugl. Retinal Oxidative Stress at the Onset of Diabetes Determined by Synchrotron FTIR Widefield Imaging: Towards Diabetes pathogenesis. Analyst, 2017, pp. 1061-1072 Full Text.

Abstract Diabetic retinopathy is a microvascular complication of diabetes that can lead to blindness. In the present study, we aimed to determine the nature of diabetes-induced, highly localized biochemical changes in the neuroretina at the onset of diabetes. High-resolution synchrotron Fourier transform infrared (s-FTIR) wide field microscopy coupled with multivariate analysis (PCA–LDA) was employed to identify biomarkers of diabetic retinopathy with spatial resolution at the cellular level. We compared the retinal tissue prepared from 6-week-old Ins2Akita/+ heterozygous (Akita/+, N = 6; a model of diabetes) male mice with the wild-type (control, N = 6) mice. Male Akita/+ mice become diabetic at 4-weeks of age. Significant differences (P < 0.001) in the presence of biomarkers associated with diabetes and segregation of spectra were achieved. Differentiating IR bands attributed to nucleic acids (964, 1051, 1087, 1226 and 1710 cm−1), proteins (1662 and 1608 cm−1) and fatty acids (2854, 2923, 2956 and 3012 cm−1) were observed between the Akita/+ and the WT samples. A comparison between distinctive layers of the retina, namely the photoreceptor retinal layer (PRL), outer plexiform layer (OPL), inner nucleus layer (INL) and inner plexiform layer (IPL) suggested that the photoreceptor layer is the most susceptible layer to oxidative stress in short-term diabetes. Spatially-resolved chemical images indicated heterogeneities and oxidative-stress induced alterations in the diabetic retina tissue morphology compared with the WT retina. In this study, the spectral biomarkers and the spatial biochemical alterations in the diabetic retina and in specific layers were identified for the first time. We believe that the conclusions drawn from these studies will help to bridge the gap in our understanding of the molecular and cellular mechanisms that contribute to the pathobiology of diabetic retinopathy.

Phillips, J., P. Jiang, P. Barney, J. Min, S. Jain, T. Tabassum, K. Barlow, J. Thomson, and D. Gamm. A Simple Approach to Single Cell RNAseq Analysis Facilitates Virtual Cell Sorting of Retinal Cell Subtypes Derived from Human Pluripotent Stem cells. Investigative Ophthalmology & Visual Science, 2017, p. Epub Full Text.

Abstract Purpose To probe the authenticity of human pluripotent stem cell (hPSC)-derived photoreceptors (PRs) and other retinal subtypes generated within 3D hPSC-optic vesicle (OV) like structures using single cell RNA-seq (scRNAseq) analysis. While scRNAseq provides a powerful tool to profile individual cell gene expression, the datasets are challenging to interpret, particularly when profiling heterogenous cell populations. Thus, we sought to develop a straightforward strategy to mine scRNAseq data to extract reliable information on the multitude of cell populations in differentiating hPSC-OVs.

Scott, I., M. Figueroa, N. Oden, M. Ip, B. Blodi, and P. VanVeldhuisen. SCORE2 Report 5: Vision-Related Function in Patients With Macular Edema Secondary to Central Retinal or Hemiretinal Vein Occlusion. AM J Ophthalmol., 2017, p. Epub PubMed Text.

Abstract Purpose: To describe baseline vision-related function, measured with the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), in patients with macular edema secondary to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) in the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2); evaluate the baseline relationship between NEI VFQ-25 scores with visual acuity letter score (VALS) and central retinal thickness; and compare baseline NEI VFQ-25 scores in SCORE2 participants with those in normal-vision reference populations and patients in other retinal vein occlusion trials.

Scott, I., P. VanVeldhuisen, M. Ip, B. Blodi, N. Oden, J. King, A. Antoszyk, M. Peters, and M. Tolentino. Baseline Factors Associated With 6-Month Visual Acuity and Retinal Thickness Outcomes in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Study Report 4. JAMA Ophthalmol., 2017, p. Epub PubMed Text.

Abstract Importance: Macular edema (ME) is the leading cause of decreased visual acuity (VA) associated with retinal vein occlusion (RVO). Identifying factors associated with better outcomes in RVO eyes treated with anti-vascular endothelial growth factor (VEGF) therapy may provide information useful in counseling patients.

Holz, F., S. Sadda, G. Staurenghi, M. Lindner, A. Bird, B. Blodi, F. Bottoni, U. Chakravarthy, E. Chew, K. Csaky, C. Curcio, R. Danis, M. Fleckenstein, K. Freund, J. Grunwald, R. Guymer, C. Hoyng, G. Jaffe, S. Liakopoulos, J. Monés, A. Oishi, D. Pauleikhoff, P. Rosenfeld, D. Sarraf, R. Spaide, R. Tadayoni, A. Tufail, S. Wolf, and S. Schmitz-Valckenberg. Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration: Recommendations from Classification of Atrophy Consensus Meetings. Ophthalmology, 2017, p. Epub PubMed Text.

Abstract Purpose: To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials.

Baudin, J., M. Hoon, H. Okawa, F. Rieke, R. Sinha, and R. Wong. Cellular and Circuit Mechanisms Shaping the Perceptual Properties of the Primate Fovea. Cell, 2017, p. Epub PubMed Text.

Abstract The fovea is a specialized region of the retina that dominates the visual perception of primates by providing high chromatic and spatial acuity. While the foveal and peripheral retina share a similar core circuit architecture, they exhibit profound functional differences whose mechanisms are unknown. Using intracellular recordings and structure-function analyses, we examined the cellular and synaptic underpinnings of the primate fovea. Compared to peripheral vision, the fovea displays decreased sensitivity to rapid variations in light inputs; this difference is reflected in the responses of ganglion cells, the output cells of the retina. Surprisingly, and unlike in the periphery, synaptic inhibition minimally shaped the responses of foveal midget ganglion cells. This difference in inhibition cannot however, explain the differences in the temporal sensitivity of foveal and peripheral midget ganglion cells. Instead, foveal cone photoreceptors themselves exhibited slower light responses than peripheral cones, unexpectedly linking cone signals to perceptual sensitivity.

Gong, S., Y. Jung, M. Kim, Z. Ma, H. Mi, S. Mikael, J. Seo, Z. Xia, K. Zhang, H. Zhou, and W. Zhou. Origami Silicon Optoelectronics for Hemispherical Electronic Eye systems. Nature Communications, 2017, p. Epub PubMed Text.

Abstract Digital image sensors in hemispherical geometries offer unique imaging advantages over their planar counterparts, such as wide field of view and low aberrations. Deforming miniature semiconductor-based sensors with high-spatial resolution into such format is challenging. Here we report a simple origami approach for fabricating single-crystalline silicon-based focal plane arrays and artificial compound eyes that have hemisphere-like structures. Convex isogonal polyhedral concepts allow certain combinations of polygons to fold into spherical formats. Using each polygon block as a sensor pixel, the silicon-based devices are shaped into maps of truncated icosahedron and fabricated on flexible sheets and further folded either into a concave or convex hemisphere. These two electronic eye prototypes represent simple and low-cost methods as well as flexible optimization parameters in terms of pixel density and design. Results demonstrated in this work combined with miniature size and simplicity of the design establish practical technology for integration with conventional electronic devices.

Blodi, B., A. Brucker, E. Chew, T. Clemons, R. Danis, A. Domalpally, M. Elman, G. Fish, G. Gensler, J. Hoskins, G. Hubbard, A. Margherio, M. Rauser, and J. Wells. Treatment of Geographic Atrophy With Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study. Ophthalmology Retina, 2017, p. Epub PubMed Text.

Abstract Objective/purpose: To evaluate efficacy and safety of monthly intravitreal injections of sirolimus, an immunosuppressive drug, for the treatment of age-related macular degeneration associated geographic atrophy (GA).

Broekema, N., I. Larsen, E. Naruzawa, M. Filutowicz, A. Kolb, L. Teixeira, and C. Brandt. A Mouse Model of Multi-Drug Resistant Staphylococcus Aureus-Induced Ocular Disease. J Ocul Biol, 2016, p. PubMed Text.

Abstract Staphylococcus aureus infection of the cornea is a significant threat to vision. The percentage of bacterial isolates resistant to antibiotics is increasing as is the percentage of infections caused by methicillin resistant isolates. There is a critical need for additional therapeutic approaches and their development will require the use of animal models to test efficacy. Two mouse models of S. aureus keratitis have been described but only quantified stromal keratitis (corneal clouding and perforation). We have extended these models using the methicillin resistant S. aureus USA300 LAC strain and show that eyelid inflammation and swelling (blepharitis) and corneal neovascularization can be quantified. This expanded model should prove useful in assessing additional effects of antibacterial therapies and additional pathological mechanisms involved in bacterial ocular infection. Keywords: Bacterial keratitis; MRSA; Mouse model; Ocular disease; Staphylococcus aureus.

Lee, W., H. Higuchi, S. Ikeda, E. Macke, T. Takimoto, B. Pattnaik, C. Liu, L. Chu, S. Siepka, K. Krentz, C. Rubinstein, R. Kalejta, J. Thomson, R. Mullins, J. Takahashi, L. Pinto, and A. Ikeda. Mouse Tmem135 Mutation Reveals a Mechanism Involving Mitochondrial Dynamics That Leads to Age-Dependent Retinal pathologies. eLife, 2016, p. PubMed Text.

Abstract While the aging process is central to the pathogenesis of age-dependent diseases, it is poorly understood at the molecular level. We identified a mouse mutant with accelerated aging in the retina as well as pathologies observed in age-dependent retinal diseases, suggesting that the responsible gene regulates retinal aging, and its impairment results in age-dependent disease. We determined that a mutation in the transmembrane 135 (Tmem135) is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutant Tmem135 as well as Tmem135 overexpressing cells, indicating that TMEM135 is involved in the regulation of mitochondrial dynamics. Additionally, mutant retina showed higher sensitivity to oxidative stress. These results suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protection from environmental stress and controlling the progression of retinal aging. Our study identified TMEM135 as a critical link between aging and age-dependent diseases. Keywords: ENU; age-dependent retinal diseases; aging; cell biology; mitochondrial dynamics; mouse; neuroscience; retina; retinal pigment epithelium.

Chuang, J., E. Ausloos, C. Schwebach, and X. Huang. Integration of Motion Energy from Overlapping Random Background Noise Increases Perceived Speed of Coherently Moving stimuli. J Neurophysiol, 2016, p. PubMed Text.

Abstract The perception of visual motion can be profoundly influenced by visual context. To gain insight into how the visual system represents motion speed, we investigated how a background stimulus that did not move in a net direction influenced the perceived speed of a center stimulus. Visual stimuli were two overlapping random-dot patterns. The center stimulus moved coherently in a fixed direction, whereas the background stimulus moved randomly. We found that human subjects perceived the speed of the center stimulus to be significantly faster than its veridical speed when the background contained motion noise. Interestingly, the perceived speed was tuned to the noise level of the background. When the speed of the center stimulus was low, the highest perceived speed was reached when the background had a low level of motion noise. As the center speed increased, the peak perceived speed was reached at a progressively higher background noise level. The effect of speed overestimation required the center stimulus to overlap with the background. Increasing the background size within a certain range enhanced the effect, suggesting spatial integration. The speed overestimation was significantly reduced or abolished when the center stimulus and the background stimulus had different colors, or when they were placed at different depths. When the center- and background-stimuli were perceptually separable, speed overestimation was correlated with perceptual similarity between the center- and background-stimuli. These results suggest that integration of motion energy from random motion noise has a significant impact on speed perception. Our findings put new constraints on models regarding the neural basis of speed perception. Keywords: center-surround interaction; color cue; neural coding; segmentation; spatiotemporal frequency; speed perception; stereoscopic depth; visual motion processing.

Bohlooli, M., M. Ghaffari-Moghaddam, M. Khajeh, G. Shahraki-Fallah, B. Haghighi-Kekhaiye, and N. Sheibani. The Role of Acetoacetate in Amadori Product Formation of Human Serum albumin. J Photochem Photobiol B, 2016, p. PubMed Text.

Abstract Amadori product is an important and stable intermediate, which is produced during glycation process. It is a marker of hyperglycemia in diabetes mellitus, and its accumulation in the body contributes to microvascular complication of diabetes including diabetic nephropathy and retinopathy. In this study, the effect of acetoacetate on the formation of Amadori products and biophysical properties of human serum albumin (HSA), after incubation with glucose, was investigated using various methods. These included circular dichroism (CD), Fourier transform infrared (FTIR) spectroscopy, and UV-visible and fluorescence spectroscopy. Our results indicated that the production of Amadori products in HSA incubated with glucose (GHSA) was increased in the presence of acetoacetate. We also detected alterations in the secondary and tertiary structure of GHSA, which was increased in the presence of acetoacetate. These changes were attributed to the formation of covalent bonds between the carbonyl group of acetoacetate and the nucleophilic groups (lysine residues) of HSA. Thus, acetoacetate can enhance the production of Amadori products through formation of covalent bonds with biomaterials. Keywords: Acetoacetate; Amadori product; Diabetes mellitus; Glycated HSA; Ketone body; Prolonged incubation.

Tan, L., K. Toops, and A. Lakkaraju. Protective Responses to Sublytic Complement in the Retinal Pigment epithelium. Proc Natl Acad Sci U S A, 2016, p. PubMed Text.

Abstract The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4(-/-) Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4(-/-) mice, indicating that they could be effective therapeutic approaches for macular degenerations. Keywords: cholesterol; drug targets; inflammation; macular degeneration; mitochondria.

Simmering, V., and H. Miller. Developmental Improvements in the Resolution and Capacity of Visual Working Memory Share a Common source. Atten Percept Psychophys, 2016, p. PubMed Text.

Abstract The nature of visual working memory (VWM) representations is currently a source of debate between characterizations as slot-like versus a flexibly-divided pool of resources. Recently, a dynamic neural field model has been proposed as an alternative account that focuses more on the processes by which VWM representations are formed, maintained, and used in service of behavior. This dynamic model has explained developmental increases in VWM capacity and resolution through strengthening excitatory and inhibitory connections. Simulations of developmental improvements in VWM resolution suggest that one important change is the accuracy of comparisons between items held in memory and new inputs. Thus, the ability to detect changes is a critical component of developmental improvements in VWM performance across tasks, leading to the prediction that capacity and resolution should correlate during childhood. Comparing 5- to 8-year-old children’s performance across color discrimination and change detection tasks revealed the predicted correlation between estimates of VWM capacity and resolution, supporting the hypothesis that increasing connectivity underlies improvements in VWM during childhood. These results demonstrate the importance of formalizing the processes that support the use of VWM, rather than focusing solely on the nature of representations. We conclude by considering our results in the broader context of VWM development. Keywords: Development; Memory: Visual working and short-term memory; Neural network modeling.

Shen, A., S. Moran, E. Glover, N. Drinkwater, R. Swearingen, L. Teixeira, and C. Bradfield. Association of a Chromosomal Rearrangement Event With Mouse Posterior Polymorphous Corneal Dystrophy and Alterations in Csrp2bp, Dzank1, and Ovol2 Gene Expression. PLoS One, 2016, p. PubMed Text.

Abstract We have previously described a mouse model of human posterior polymorphous corneal dystrophy (PPCD) and localized the causative mutation to a 6.2 Mbp region of chromosome 2, termed Ppcd1. We now show that the gene rearrangement linked to mouse Ppcd1 is a 3.9 Mbp chromosomal inversion flanked by 81 Kbp and 542 bp deletions. This recombination event leads to deletion of Csrp2bp Exons 8 through 11, Dzank1 Exons 20 and 21, and the pseudogene Znf133. In addition, we identified translocation of novel downstream sequences to positions adjacent to Csrp2bp Exon 7 and Dzank1 Exon 20. Twelve novel fusion transcripts involving Csrp2bp or Dzank1 linked to downstream sequences have been identified. Eight are expressed at detectable levels in PPCD1 but not wildtype eyes. Upregulation of two Csrp2bp fusion transcripts, as well as upregulation of the adjacent gene, Ovol2, was observed. Absence of the PPCD1 phenotype in animals haploinsufficient for Csrp2bp or both Csrp2bp and Dzank1 rules out haploinsufficiency of these genes as a cause of mouse PPCD1. Complementation experiments confirm that PPCD1 embryonic lethality is due to disruption of Csrp2bp expression. The ocular expression pattern of Csrp2bp is consistent with a role for this protein in corneal development and pathogenesis of PPCD1.

Colley, N., and D. Nilsson. Photoreception in Phytoplankton. Integr Comp Biol, 2016, p. PubMed Text.

Abstract In many species of phytoplankton, simple photoreceptors monitor ambient lighting. Photoreceptors provide a number of selective advantages including the ability to assess the time of day for circadian rhythms, seasonal changes, and the detection of excessive light intensities and harmful UV light. Photoreceptors also serve as depth gauges in the water column for behaviors such as diurnal vertical migration. Photoreceptors can be organized together with screening pigment into visible eyespots. In a wide variety of motile phytoplankton, including Chlamydomonas, Volvox, Euglena, and Kryptoperidinium, eyespots are light-sensitive organelles residing within the cell. Eyespots are composed of photoreceptor proteins and typically red to orange carotenoid screening pigments. This association of photosensory pigment with screening pigment allows for detection of light directionality, needed for light-guided behaviors such as positive and negative phototaxis. In Chlamydomonas, the eyespot is located in the chloroplast and Chlamydomonas expresses a number of photosensory pigments including the microbial channelrhodopsins (ChR1 and ChR2). Dinoflagellates are unicellular protists that are ecologically important constituents of the phytoplankton. They display a great deal of diversity in morphology, nutritional modes and symbioses, and can be photosynthetic or heterotrophic, feeding on smaller phytoplankton. Dinoflagellates, such as Kryptoperidinium foliaceum, have eyespots that are used for light-mediated tasks including phototaxis. Dinoflagellates belonging to the family Warnowiaceae have a more elaborate eye. Their eye-organelle, called an ocelloid, is a large, elaborate structure consisting of a focusing lens, highly ordered retinal membranes, and a shield of dark pigment. This complex eye-organelle is similar to multicellular camera eyes, such as our own. Unraveling the molecular makeup, structure and function of dinoflagellate eyes, as well as light-guided behaviors in phytoplankton can inform us about the selective forces that drove evolution in the important steps from light detection to vision. We show here that the evolution from simple photoreception to vision seems to have independently followed identical paths and principles in phytoplankton and animals, significantly strengthening our understanding of this important biological process.

Ghanian, Z., K. Staniszewski, N. Jamali, R. Sepehr, S. Wang, C. Sorenson, N. Sheibani, and M. Ranji. Quantitative Assessment of Retinopathy Using Multi-Parameter Image Analysis. J Med Signals Sens, 2016, p. PubMed Text.

Abstract A multi-parameter quantification method was implemented to quantify retinal vascular injuries in microscopic images of clinically relevant eye diseases. This method was applied to wholemount retinal trypsin digest images of diabetic Akita/+, and bcl-2 knocked out mice models. Five unique features of retinal vasculature were extracted to monitor early structural changes and retinopathy, as well as quantifying the disease progression. Our approach was validated through simulations of retinal images. Results showed fewer number of cells (P = 5.1205e-05), greater population ratios of endothelial cells to pericytes (PCs) (P = 5.1772e-04; an indicator of PC loss), higher fractal dimension (P = 8.2202e-05), smaller vessel coverage (P = 1.4214e-05), and greater number of acellular capillaries (P = 7.0414e-04) for diabetic retina as compared to normal retina. Quantification using the present method would be helpful in evaluating physiological and pathological retinopathy in a high-throughput and reproducible manner. Keywords: Classification; fluorescence microscopy; fractals; image cytometry; retinopathy;

Larsen, I., H. Clausius, A. Kolb, and C. Brandt. Both CD8+ and CD4+ T Cells Contribute to Corneal Clouding and Viral Clearance Following Vaccinia Virus Infection in C57BL/6 Mice. J Virol, 2016, p. PubMed Text.

Abstract Vaccinia virus (VACV) keratitis is a serious complication following smallpox vaccination and can lead to blindness. The pathological mechanisms involved in ocular VACV infection are poorly understood. Previous studies have used rabbits, but the lack of immune reagents and transgenic or knockout animals makes them less suitable for mechanistic studies. We report that infection of C57BL/6 mice with 1 × 10(7) PFU of vaccinia virus strain WR results in blepharitis, corneal neovascularization, and stromal keratitis. The DryVax strain of VACV was completely attenuated. Infection required corneal scarification and replication-competent virus, and the severity of ocular disease was similar in 4- to 6-week-old and 1-year-old mice. Viral titers peaked at approximately 1 × 10(6) PFU on day 5 postinfection, and virus had not cleared by day 13 postinfection. Neutrophils were found in the peripheral cornea on day 1 after infection and then declined, followed by infiltration of both CD4(+) and CD8(+) T cells, which remained peripheral throughout the infection. Blood vessel growth extended 2 to 5 mm into the cornea from the limbus. Infection of CD4(-/-), CD8(-/-), or antibody-depleted mice resulted in similar disease severity and corneal clouding, indicating that both T-cell subsets were involved in the immunopathological response. Depletion of both CD4(+) and CD8(+) T cells resulted in significantly more severe disease and failure to clear the virus. On the basis of our results, the pathology of VACV keratitis is significantly different from that of herpes simplex virus keratitis. Further studies are likely to reveal novel information regarding virulence and immune responses to viral ocular infection.

Nilsson, D., and N. Colley. Comparative Vision: Can Bacteria Really See?. Curr Biol, 2016, p. PubMed Text.

Abstract It has been known for some time that not only animals, but also some advanced unicellular algae possess imaging eyes. Now it seems that even tiny cyanobacteria have what it takes to qualify for the most basic definition of vision.

Kuehn, M., K. Lipsett, M. Menotti-Raymond, S. Whitmore, T. Scheetz, V. David, S. O’Brien, Z. Zhao, J. Jens, E. Snella, N. Ellinwood, and G. McLellan. A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus). PLoS One, 2016, p. PubMed Text.

Erratum in Correction: A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus). Abstract The glaucomas are a group of diseases characterized by optic nerve damage that together represent a leading cause of blindness in the human population and in domestic animals. Here we report a mutation in LTBP2 that causes primary congenital glaucoma (PCG) in domestic cats. We identified a spontaneous form of PCG in cats and established a breeding colony segregating for PCG consistent with fully penetrant, autosomal recessive inheritance of the trait. Elevated intraocular pressure, globe enlargement and elongated ciliary processes were consistently observed in all affected cats by 8 weeks of age. Varying degrees of optic nerve damage resulted by 6 months of age. Although subtle lens zonular instability was a common feature in this cohort, pronounced ectopia lentis was identified in less than 10% of cats examined. Thus, glaucoma in this pedigree is attributed to histologically confirmed arrest in the early post-natal development of the aqueous humor outflow pathways in the anterior segment of the eyes of affected animals. Using a candidate gene approach, significant linkage was established on cat chromosome B3 (LOD 18.38, θ = 0.00) using tightly linked short tandem repeat (STR) loci to the candidate gene, LTBP2. A 4 base-pair insertion was identified in exon 8 of LTBP2 in affected individuals that generates a frame shift that completely alters the downstream open reading frame and eliminates functional domains. Thus, we describe the first spontaneous and highly penetrant non-rodent model of PCG identifying a valuable animal model for primary glaucoma that closely resembles the human disease, providing valuable insights into mechanisms underlying the disease and a valuable animal model for testing therapies.

Kiland, J., A. Voss, and G. McLellan. Effect of Timolol Maleate Gel-Forming Solution on Intraocular Pressure, Pupil Diameter, and Heart Rate in Normal and Glaucomatous cats. Vet Ophthalmol, 2016, p. PubMed Text.

Abstract Objective: To determine the effects of once-daily topical treatment with timolol maleate gel-forming solution (GFS) on intraocular pressure (IOP), pupil diameter (PD), and heart rate (HR) in normal cats and cats with feline primary congenital glaucoma (FCG). Keywords: cat; glaucoma; heart rate; intraocular pressure; pupil diameter; timolol.

Kolb, A., K. Lee, I. Larsen, M. Craven, and C. Brandt. Quantitative Trait Locus Based Virulence Determinant Mapping of the HSV-1 Genome in Murine Ocular Infection: Genes Involved in Viral Regulatory and Innate Immune Networks Contribute to Virulence. PLoS Pathog, 2016, p. PubMed Text.

Abstract Herpes simplex virus type 1 causes mucocutaneous lesions, and is the leading cause of infectious blindness in the United States. Animal studies have shown that the severity of HSV-1 ocular disease is influenced by three main factors; innate immunity, host immune response and viral strain. We previously showed that mixed infection with two avirulent HSV-1 strains (OD4 and CJ994) resulted in recombinants that exhibit a range of disease phenotypes from severe to avirulent, suggesting epistatic interactions were involved. The goal of this study was to develop a quantitative trait locus (QTL) analysis of HSV-1 ocular virulence determinants and to identify virulence associated SNPs. Blepharitis and stromal keratitis quantitative scores were characterized for 40 OD4:CJ994 recombinants. Viral titers in the eye were also measured. Virulence quantitative trait locus mapping (vQTLmap) was performed using the Lasso, Random Forest, and Ridge regression methods to identify significant phenotypically meaningful regions for each ocular disease parameter. The most predictive Ridge regression model identified several phenotypically meaningful SNPs for blepharitis and stromal keratitis. Notably, phenotypically meaningful nonsynonymous variations were detected in the UL24, UL29 (ICP8), UL41 (VHS), UL53 (gK), UL54 (ICP27), UL56, ICP4, US1 (ICP22), US3 and gG genes. Network analysis revealed that many of these variations were in HSV-1 regulatory networks and viral genes that affect innate immunity. Several genes previously implicated in virulence were identified, validating this approach, while other genes were novel. Several novel polymorphisms were also identified in these genes. This approach provides a framework that will be useful for identifying virulence genes in other pathogenic viruses, as well as epistatic effects that affect HSV-1 ocular virulence.

Gosling, A., J. Kiland, L. Rutkowski, A. Hoefs, N. Ellinwood, and G. McLellan. Effects of Topical Corticosteroid Administration on Intraocular Pressure in Normal and Glaucomatous cats. Vet Ophthalmol, 2016, p. PubMed Text.

Abstract Objective: The objective of this study was to determine the effect of topical corticosteroid (CCS) therapy on intraocular pressure (IOP) in normal cats and cats with primary feline congenital glaucoma (FCG). Keywords: cat; corticosteroid; glaucoma; intraocular pressure; steroid-induced ocular hypertension.

Lakkaraju, A., and et al. Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (3rd edition). Autophagy, 2016, p. PubMed Text.

Erratum in Erratum. No abstract availableKeywords: LC3; autolysosome; autophagosome; chaperone-mediated autophagy; flux; lysosome; macroautophagy; phagophore; stress; vacuole.

Bohlooli, M., M. Ghaffari-Moghaddam, M. Khajeh, Z. Aghashiri, N. Sheibani, and A. Moosavi-Movahedi. Acetoacetate Promotes the Formation of Fluorescent Advanced Glycation End Products (AGEs). J Biomol Struct Dyn, 2016, p. PubMed Text.

Abstract Acetoacetate (AA) is an important ketone body, which produces reactive oxygen species (ROS). Advanced glycation end products (AGEs) are defined as final products of glycation process whose production is influenced by the levels of ROS. The accumulation of AGEs in the body contributes to pathogenesis of many diseases including complications of diabetes, and Alzheimer’s and Parkinson’s disease. Here, we evaluated the impact of AA on production of AGEs upon incubation of human serum albumin (HSA) with glucose. The effect of AA on the AGEs formation of HSA was studied under physiological conditions after incubation with glucose for 35 days. The physical techniques including circular dichroism (CD) and fluorescence spectroscopy were used to assess the impact of AA on formation and structural changes of glycated HSA (GHSA). Our results indicated that the secondary and tertiary structural changes of GHSA were increased in the presence of AA. The fluorescence intensity measurements of AGEs also showed an increase in AGEs formation. Acetoacetate has an activator effect in formation of AGEs through ROS production. The presence of AA may result in enhanced glycation in the presence of glucose and severity of complications associated with accumulation of AGEs. Keywords: acetoacetate; advanced glycation end products (AGEs); glycated HSA; prolonged incubation; reactive oxygen species (ROS), Ketone body.

Sinha, D., M. Phillips, and D. Gamm. Mimicking Retinal Development and Disease With Human Pluripotent Stem Cells. Investigative Ophthalmology & Visual Science, 2016, p. Epub Full Text.

Abstract As applications of human pluripotent stem cells (hPSCs) continue to be refined and pursued, it is important to keep in mind that the strengths and weaknesses of this technology lie with its developmental origins. The remarkable capacity of differentiating hPSCs to recapitulate cell and tissue genesis has provided a model system to study stages of human development that were not previously amenable to investigation and experimentation. Furthermore, demonstration of developmentally appropriate, stepwise differentiation of hPSCs to specific cell types offers support for their authenticity and their suitability for use in disease modeling and cell replacement therapies. However, limitations to farming cells and tissues in an artificial culture environment, as well as the length of time required for most cells to mature, are some of the many issues to consider before using hPSCs to study or treat a particular disease. Given the overarching need to understand and modulate the dynamics of lineage-specific differentiation in stem cell cultures, this review will first examine the capacity of hPSCs to serve as models of retinal development. Thereafter, we will discuss efforts to model retinal disorders with hPSCs and present challenges that face investigators who aspire to use such systems to study disease pathophysiology and/or screen for therapeutics. We also refer readers to recent publications that provide additional insight and details on these rapidly evolving topics.

Min, J., J. Phillips, W. Daly, W. Murphy, and D. Gamm. Evaluating the Effects of ECM and Elastic Modulus on Human Pluripotent Stem Cell-Derived Photoreceptor enrichment. Investigative Ophthalmology & Visual Science, 2016, p. Epub Full Text.

Abstract Purpose Human pluripotent stem cell (hPSC)-based photoreceptor replacement strategies require efficient generation and isolation of photoreceptors, as well as the removal of proliferative retinal progenitor cells (RPCs). Extrinsic factors such as the extracellular matrix (ECM), as well as the stiffness (elastic modulus) of the extracellular environment are known to modulate cellular adherence, differentiation, and maturation. The purpose of this study was to determine the potential of these extrinsic factors to promote photoreceptor enrichment while reducing the number of RPCs.

Scott, I., P. VanVeldhuisen, M. Ip, B. Blodi, N. Oden, and M. Figueroa. SCORE2 Report 1: Techniques to Optimize Recruitment in Phase III Clinical Trials of Patients With Central Retinal Vein Occlusion. AM J Ophthalmol., 2016, p. Epub PubMed Text.

Abstract Purpose: To investigate recruitment rates of patients with central retinal vein occlusion (CRVO) into phase III clinical trials evaluating intravitreal pharmacotherapy for treatment of macular edema in the United States, describe recruitment techniques in the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2), and assess which SCORE2 recruitment techniques were most useful to principal investigators and clinical coordinators.

Della Santina, L., M. Hoon, S. Kuo, H. Okawa, F. Rieke, S. Suzuki, K. Tsuboyama, R. Wong, and T. Yoshimatsu. Glutamatergic Monopolar Interneurons Provide a Novel Pathway of Excitation in the Mouse Retina. Current Biology, 2016, p. Epub PubMed Text.

Abstract Excitatory and inhibitory neurons in the CNS are distinguished by several features, including morphology, transmitter content, and synapse architecture [1]. Such distinctions are exemplified in the vertebrate retina. Retinal bipolar cells are polarized glutamatergic neurons receiving direct photoreceptor input, whereas amacrine cells are usually monopolar inhibitory interneurons with synapses almost exclusively in the inner retina [2]. Bipolar but not amacrine cell synapses have presynaptic ribbon-like structures at their transmitter release sites. We identified a monopolar interneuron in the mouse retina that resembles amacrine cells morphologically but is glutamatergic and, unexpectedly, makes ribbon synapses. These glutamatergic monopolar interneurons (GluMIs) do not receive direct photoreceptor input, and their light responses are strongly shaped by both ON and OFF pathway-derived inhibitory input. GluMIs contact and make almost as many synapses as type 2 OFF bipolar cells onto OFF-sustained A-type (AOFF-S) retinal ganglion cells (RGCs). However, GluMIs and type 2 OFF bipolar cells possess functionally distinct light-driven responses and may therefore mediate separate components of the excitatory synaptic input to AOFF-S RGCs. The identification of GluMIs thus unveils a novel cellular component of excitatory circuits in the vertebrate retina, underscoring the complexity in defining cell types even in this well-characterized region of the CNS.

Chu, U., T. Mavlyutov, M. Chu, H. Yang, A. Schulman, C. Mesangeau, C. McCurdy, L. Guo, and A. Ruoho. The Sigma-2 Receptor and Progesterone Receptor Membrane Component 1 Are Different Binding Sites Derived From Independent Genes. EBioMedicine, 2015, p. PubMed Text.

Abstract The sigma-2 receptor (S2R) is a potential therapeutic target for cancer and neuronal diseases. However, the identity of the S2R has remained a matter of debate. Historically, the S2R has been defined as (1) a binding site with high affinity to 1,3-di-o-tolylguanidine (DTG) and haloperidol but not to the selective sigma-1 receptor ligand (+)-pentazocine, and (2) a protein of 18-21 kDa, as shown by specific photolabeling with [(3)H]-Azido-DTG and [(125)I]-iodoazido-fenpropimorph ([(125)I]-IAF). Recently, the progesterone receptor membrane component 1 (PGRMC1), a 25 kDa protein, was reported to be the S2R (Nature Communications, 2011, 2:380). To confirm this identification, we created PGRMC1 knockout NSC34 cell lines using the CRISPR/Cas9 technology. We found that in NSC34 cells devoid of or overexpressing PGRMC1, the maximum [(3)H]-DTG binding to the S2R (Bmax) as well as the DTG-protectable [(125)I]-IAF photolabeling of the S2R were similar to those of wild-type control cells. Furthermore, the affinities of DTG and haloperidol for PGRMC1 (KI = 472 μM and 350 μM, respectively), as determined in competition with [(3)H]-progesterone, were more than 3 orders of magnitude lower than those reported for the S2R (20-80 nM). These results clarify that PGRMC1 and the S2R are distinct binding sites expressed by different genes. Keywords: Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 knockout; Progesterone receptor membrane component-1 (PGRMC1); Sigma-2 receptor (S2R); [125I]-Iodoazido-fenpropimorph ([125I]-IAF); [3H]-1,3-Di-o-tolylguanidine ([3H]-DTG).

Yi, J., W. Liu, S. Chen, V. Backman, N. Sheibani, C. Sorenson, A. Fawzi, R. Linsenmeier, and H. Zhang. Visible Light Optical Coherence Tomography Measures Retinal Oxygen Metabolic Response to Systemic oxygenation. Light Sci Appl, 2015, p. PubMed Text.

Abstract The lack of capability to quantify oxygen metabolism noninvasively impedes both fundamental investigation and clinical diagnosis of a wide spectrum of diseases including all the major blinding diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Using visible light optical coherence tomography (vis-OCT), we demonstrated accurate and robust measurement of retinal oxygen metabolic rate (rMRO2) noninvasively in rat eyes. We continuously monitored the regulatory response of oxygen consumption to a progressive hypoxic challenge. We found that both oxygen delivery, and rMRO2 increased from the highly regulated retinal circulation (RC) under hypoxia, by 0.28 ± 0.08 μL min-1 (p < 0.001), and 0.20 ± 0.04 μL min-1 (p < 0.001) per 100 mmHg systemic pO2 reduction, respectively. The increased oxygen extraction compensated for the deficient oxygen supply from the poorly regulated choroidal circulation. Results from an oxygen diffusion model based on previous oxygen electrode measurements corroborated our in vivo observations. We believe that vis-OCT has the potential to reveal the fundamental role of oxygen metabolism in various retinal diseases. Keywords: oxygen metabolism; retinal circulation; visible light optical coherence tomography.

Zaitoun, I., R. Johnson, N. Jamali, R. Almomani, S. Wang, N. Sheibani, and C. Sorenson. Endothelium Expression of Bcl-2 Is Essential for Normal and Pathological Ocular Vascularization. PLoS One, 2015, p. PubMed Text.

Abstract Bcl-2 is an anti-apoptotic protein with important roles in vascular homeostasis and angiogenesis. Mice globally lacking Bcl-2 (Bcl-2 -/-) are small in stature and succumb to renal failure shortly after weaning as a result of renal hypoplasia/cystic dysplasia. We have shown that Bcl-2 -/- mice displayed attenuated retinal vascular development and neovascularization. In vitro studies indicated that in addition to modulating apoptosis, Bcl-2 expression also impacts endothelial and epithelial cell adhesion, migration and extracellular matrix production. However, studies delineating the cell autonomous role Bcl-2 expression plays in the endothelium during vascular development, pruning and remodeling, and neovascularization are lacking. Here we generated mice carrying a conditional Bcl-2 allele (Bcl-2Flox/Flox) and VE-cadherin-cre (Bcl-2EC mice). Bcl-2EC mice were of normal stature and lifespan and displayed some but not all of the retinal vascular defects previously observed in global Bcl-2 deficient mice. Bcl-2EC mice had decreased numbers of endothelial cells, decreased retinal arteries and premature primary branching of the retinal vasculature, but unlike the global knockout mice, spreading of the retinal superficial vascular layer proceeded normally. Choroidal neovascularization was attenuated in Bcl-2EC mice, although retinal neovascularization accompanying oxygen-induced ischemic retinopathy was not. Thus, Bcl-2 expression in the endothelium plays a significant role during postnatal retinal vascularization, and pathological choroidal but not retinal neovascularization, suggesting vascular bed specific Bcl-2 function in the endothelium.

McLellan, G., and L. Teixeira. Feline Glaucoma. Vet Clin North Am Small Anim Pract, 2015, p. PubMed Text.

Abstract Feline glaucoma is often insidious in onset and slowly progressive with very subtle clinical signs. As a consequence, it is likely that the disease in cats is underdiagnosed. As cats typically present late in the course of disease, prognosis for long-term maintenance of vision is poor. Patient and owner compliance with frequent application of topical medications can be a limiting factor, and represents a serious clinical challenge. This review outlines the clinical features, classification, and pathophysiology of the feline glaucomas and provides current evidence on which to base the selection of appropriate treatment strategies for cats with glaucoma. Keywords: Cat; Congenital glaucoma; Feline; Neoplasia; Primary glaucoma; Secondary glaucoma; Treatment; Uveitis.

Wright, L., I. Pinilla, J. Saha, J. Clermont, J. Lien, K. Borys, E. Capowski, M. Phillips, and D. Gamm. VSX2 and ASCL1 Are Indicators of Neurogenic Competence in Human Retinal Progenitor Cultures. PLoS One, 2015, p. PubMed Text.

Abstract Three dimensional (3D) culture techniques are frequently used for CNS tissue modeling and organoid production, including generation of retina-like tissues. A proposed advantage of these 3D systems is their potential to more closely approximate in vivo cellular microenvironments, which could translate into improved manufacture and/or maintenance of neuronal populations. Visual System Homeobox 2 (VSX2) labels all multipotent retinal progenitor cells (RPCs) and is known to play important roles in retinal development. In contrast, the proneural transcription factor Acheate scute-like 1 (ASCL1) is expressed transiently in a subset of RPCs, but is required for the production of most retinal neurons. Therefore, we asked whether the presence of VSX2 and ASCL1 could gauge neurogenic potential in 3D retinal cultures derived from human prenatal tissue or ES cells (hESCs). Short term prenatal 3D retinal cultures displayed multiple characteristics of human RPCs (hRPCs) found in situ, including robust expression of VSX2. Upon initiation of hRPC differentiation, there was a small increase in co-labeling of VSX2+ cells with ASCL1, along with a modest increase in the number of PKCα+ neurons. However, 3D prenatal retinal cultures lost expression of VSX2 and ASCL1 over time while concurrently becoming refractory to neuronal differentiation. Conversely, 3D optic vesicles derived from hESCs (hESC-OVs) maintained a robust VSX2+ hRPC population that could spontaneously co-express ASCL1 and generate photoreceptors and other retinal neurons for an extended period of time. These results show that VSX2 and ASCL1 can serve as markers for neurogenic potential in cultured hRPCs. Furthermore, unlike hESC-OVs, maintenance of 3D structure does not independently convey an advantage in the culture of prenatal hRPCs, further illustrating differences in the survival and differentiation requirements of hRPCs extracted from native tissue vs. those generated entirely in vitro.

Saghiri, M., A. Asatourian, J. Orangi, C. Sorenson, and N. Sheibani. Functional Role of Inorganic Trace Elements in Angiogenesis-Part II: Cr, Si, Zn, Cu, and S. Crit Rev Oncol Hematol, 2015, p. PubMed Text.

Abstract Trace elements play critical roles in angiogenesis events. The effects of nitrogen, iron, selenium, phosphorus, gold, and calcium were discussed in part I. In part II, we evaluated the effect of chromium, silicon, zinc, copper, and sulfur on different aspects of angiogenesis, with critical roles in healing and regeneration processes, and undeniable roles in tumor growth and cancer therapy. This review is the second of series that serves as an overview of the role of inorganic elements in regulation of angiogenesis and vascular function. The methods of exposure, structure, mechanism, and potential activity of these trace elements are briefly discussed. An electronic search was performed on the role of these trace elements in angiogenesis from January 2005 to April 2014. The recent aspects of the relationship between five different trace elements and their role in regulation of angiogenesis, and homeostasis of pro- and anti-angiogenic factors were assessed. Many studies have investigated the effects and importance of these elements in angiogenesis events. Both stimulatory and inhibitory effects on angiogenesis are observed for the evaluated elements. Chromium can promote angiogenesis in pathological manners. Silicon as silica nanoparticles is anti-angiogenic, while in calcium silicate extracts and bioactive silicate glasses promote angiogenesis. Zinc is an anti-angiogenic agent acting on important genes and growth factors. Copper and sulfur compositions have pro-angiogenic functions by activating pro-angiogenic growth factors and promoting endothelial cells migration, growth, and tube formation. Thus, utilization of these elements may provide a unique opportunity to modulate angiogenesis under various setting. Keywords: Angiogenesis; Endothelial cells; Trace elements; Wound healing.

Kushner, B., and D. Gamm. Eye Muscle Surgery for Recurrent Nystagmus Related to Head Tilt After Prior Torsional surgery. J AAPOS, 2015, p. PubMed Text.

Abstract Purpose: To describe the usefulness of anterior nasal transposition of the inferior oblique muscle in the fixing eye to treat nystagmus-mediated head tilt recurring after prior torsional surgery.

Zhao, Y., C. Sorenson, and N. Sheibani. Cytochrome P450 1B1 and Primary Congenital Glaucoma. J Ophthalmic Vis Res, 2015, p. PubMed Text.

Abstract Cytochrome P450 1B1 (Cyp1b1) belongs to the CYP450 superfamily of heme-binding mono-oxygenases which catalyze oxidation of various endogenous and exogenous substrates. The expression of Cyp1b1 plays an important role in the modulation of development and functions of the trabecular meshwork (TM). Mutations in Cyp1b1 have been reported in patients with primary congenital glaucoma (PCG). Mice lacking Cyp1b1 also exhibit developmental defects in the TM similar to those reported in congenital glaucoma patients. However, how Cyp1b1 deficiency contributes to TM dysgenesis remains unknown. In the present review, we will address the significance of Cyp1b1 expression and/or its function in anterior segment development. Cyp1b1-deficient (Cyp1b1 (-/-)) mice are discussed as a promising model for an oxidative stress-induced model of PCG, in which Cyp1b1 activity is revealed as an important modulator of oxidative homeostasis contributing to the development and structural function of the TM. This conclusion suggests a possible clinical intervention for individuals who are genetically at high risk of developing PCG. Keywords: Anterior Chamber; Cyp1b1; Oxidative Stress; Periostin; Trabecular Meshwork.

Rajala, A., R. Jenison, and L. Populin. Decision Making: Effects of Methylphenidate on Temporal Discounting in Nonhuman primates. J Neurophysiol, 2015, p. PubMed Text.

Abstract Decisions are often made based on which option will result in the largest reward. When given a choice between a smaller but immediate reward and a larger delayed reward, however, humans and animals often choose the smaller, an effect known as temporal discounting. Dopamine (DA) neurotransmission is central to reward processing and encodes delayed reward value. Impulsivity, the tendency to act without forethought, is associated with excessive discounting of rewards, which has been documented in patients with attention deficit hyperactivity disorder (ADHD). Both impulsivity and temporal discounting are linked to the dopaminergic system. Methylphenidate (MPH), which blocks the DA transporter and increases extracellular levels of DA in the basal ganglia and prefrontal cortex, is a primary treatment for ADHD and, at low doses, ameliorates impulsivity in both humans and animals. This study tested the hypothesis that low doses of MPH would decrease the discounting rate of rhesus monkeys performing an intertemporal choice task, suggesting a reduction in impulsivity. The results support this hypothesis and provide further evidence for the role of DA in temporal discounting and impulsive behavior. Keywords: hyperbolic; impulsivity; methylphenidate; monkey; temporal discounting.

Lee, K., A. Kolb, Y. Sverchkov, J. Cuellar, M. Craven, and C. Brandt. Recombination Analysis of Herpes Simplex Virus 1 Reveals a Bias Toward GC Content and the Inverted Repeat Regions. J Virol, 2015, p. PubMed Text.

Abstract Herpes simplex virus 1 (HSV-1) causes recurrent mucocutaneous ulcers and is the leading cause of infectious blindness and sporadic encephalitis in the United States. HSV-1 has been shown to be highly recombinogenic; however, to date, there has been no genome-wide analysis of recombination. To address this, we generated 40 HSV-1 recombinants derived from two parental strains, OD4 and CJ994. The 40 OD4-CJ994 HSV-1 recombinants were sequenced using the Illumina sequencing system, and recombination breakpoints were determined for each of the recombinants using the Bootscan program. Breakpoints occurring in the terminal inverted repeats were excluded from analysis to prevent double counting, resulting in a total of 272 breakpoints in the data set. By placing windows around the 272 breakpoints followed by Monte Carlo analysis comparing actual data to simulated data, we identified a recombination bias toward both high GC content and intergenic regions. A Monte Carlo analysis also suggested that recombination did not appear to be responsible for the generation of the spontaneous nucleotide mutations detected following sequencing. Additionally, kernel density estimation analysis across the genome found that the large, inverted repeats comprise a recombination hot spot.

Huang, H., G. Jing, J. Wang, N. Sheibani, and S. Zhang. ATF4 Is a Novel Regulator of MCP-1 in Microvascular Endothelial cells. J Inflamm (Lond), 2015, p. PubMed Text.

Abstract Background: Monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that recruits monocyte/macrophage to the site of tissue injury and plays a critical role in microvascular complications of diabetes. However, the mechanisms underlying the regulation of MCP-1 are not fully understood. The present study aims to explore the role of activating transcription factor 4 (ATF4), an ER stress-inducible transcription factor, in regulation of MCP-1 expression and production in brain and retinal microvascular endothelial cells. Keywords: Activating transcription factor 4; Microvascular endothelial cells; Monocyte chemoattractant protein 1.

Sechi, L., and C. Dow. Mycobacterium Avium Ss. Paratuberculosis Zoonosis – The Hundred Year War – Beyond Crohn’S Disease. Front Immunol, 2015, p. PubMed Text.

Abstract The factitive role of Mycobacterium avium ss. paratuberculosis (MAP) in Crohn’s disease has been debated for more than a century. The controversy is due to the fact that Crohn’s disease is so similar to a disease of MAP-infected ruminant animals, Johne’s disease; and, though MAP can be readily detected in the infected ruminants, it is much more difficult to detect in humans. Molecular techniques that can detect MAP in pathologic Crohn’s specimens as well as dedicated specialty labs successful in culturing MAP from Crohn’s patients have provided strong argument for MAP’s role in Crohn’s disease. Perhaps more incriminating for MAP as a zoonotic agent is the increasing number of diseases with which MAP has been related: Blau syndrome, type 1 diabetes, Hashimoto thyroiditis, and multiple sclerosis. In this article, we debate about genetic susceptibility to mycobacterial infection and human exposure to MAP; moreover, it suggests that molecular mimicry between protein epitopes of MAP and human proteins is a likely bridge between infection and these autoimmune disorders. Keywords: Crohn’s; MAP; autoimmune; autoimmune thyroiditis; molecular mimicry; multiple sclerosis; paratuberculosis; type 1 diabetes.

Ohlemacher, S., C. Iglesias, A. Sridhar, D. Gamm, and J. Meyer. Generation of Highly Enriched Populations of Optic Vesicle-Like Retinal Cells from Human Pluripotent Stem cells. Curr Protoc Stem Cell Biol, 2015, p. PubMed Text.

Abstract The protocol outlined below is used to differentiate human pluripotent stem cells (hPSCs) into retinal cell types through a process that faithfully recapitulates the stepwise progression observed in vivo. From pluripotency, cells are differentiated to a primitive anterior neural fate, followed by progression into two distinct populations of retinal progenitors and forebrain progenitors, each of which can be manually separated and purified. The hPSC-derived retinal progenitors are found to self-organize into three-dimensional optic vesicle-like structures, with each aggregate possessing the ability to differentiate into all major retinal cell types. The ability to faithfully recapitulate the stepwise in vivo development in a three-dimensional cell culture system allows for the study of mechanisms underlying human retinogenesis. Furthermore, this methodology allows for the study of retinal dysfunction and disease modeling using patient-derived cells, as well as high-throughput pharmacological screening and eventually patient-specific therapies. Keywords: development; differentiation; human pluripotent stem cells (hPSCs); optic vesicle; retina.

Halbach, P., D. Pillers, N. York, M. Asuma, M. Chiu, W. Luo, S. Tokarz, I. Bird, and B. Pattnaik. Oxytocin Expression and Function in the Posterior Retina: A Novel Signaling pathway. Investigative Ophthalmology & Visual Science, 2015, p. PubMed Text.

Abstract Purpose: Oxytocin (OXT) is recognized as an ubiquitously acting nonapeptide hormone that is involved in processes ranging from parturition to neural development. Its effects are mediated by cell signaling that occurs as a result of oxytocin receptor (OXTR) activation. We sought to determine whether the OXT-OXTR signaling pathway is also expressed within the retina. Keywords: GPCR; cell-calcium; neuropeptide; oxytocin receptor; retinal pigment epithelium; signaling.

Fotouhi, L., S. Yousefinejad, N. Salehi, A. Saboury, N. Sheibani, and A. Moosavi-Movahedi. Application of Merged Spectroscopic Data Combined With Chemometric Analysis for Resolution of Hemoglobin Intermediates During Chemical unfolding. Spectrochim Acta A Mol Biomol Spectrosc, 2015, p. PubMed Text.

Abstract Using tetradecyltrimethylammonium bromide (TTAB) as a surfactant denaturant, and augmentation of different spectroscopic data, helped to detect the intermediates of hemoglobin (Hb) during unfolding process. UV-vis, fluorescence, and circular dichroism spectroscopy were used simultaneously to monitor different aspects of hemoglobin species from the tertiary or secondary structure points of view. Application of the multivariate curve resolution-alternating least square (MCR-ALS), using the initial estimates of spectral profiles and appropriate constraints on different parts of augmented spectroscopic data, showed good efficiency for characterization of intermediates during Hb unfolding. These results indicated the existence of five protein species, including three intermediate-like compounds in this process. The unfolding pathway in the presence of TTAB included conversion of oxyhemoglobin into deoxyhemoglobin, and then ferrylhemoglobin, ferrihemoglobin or aquamethemoglobin, which finally transformed into hemichrome. This is the first application of chemometric analysis on the merged spectroscopic data related to chemical denaturation of a protein. These types of analysis in multisubunit proteins not only increase the domain of information, but also can reduce the ambiguities of the obtained results. Keywords: Chemical unfolding; Chemometrics; Curve resolution; Folding intermediate; Hemoglobin; Spectroscopy.

Toops, K., L. Tan, Z. Jiang, R. Radu, and A. Lakkaraju. Cholesterol-Mediated Activation of Acid Sphingomyelinase Disrupts Autophagy in the Retinal Pigment epithelium. Mol Biol Cell, 2015, p. PubMed Text.

Abstract Autophagy is an essential mechanism for clearing damaged organelles and proteins within the cell. As with neurodegenerative diseases, dysfunctional autophagy could contribute to blinding diseases such as macular degeneration. However, precisely how inefficient autophagy promotes retinal damage is unclear. In this study, we investigate innate mechanisms that modulate autophagy in the retinal pigment epithelium (RPE), a key site of insult in macular degeneration. High-speed live imaging of polarized adult primary RPE cells and data from a mouse model of early-onset macular degeneration identify a mechanism by which lipofuscin bisretinoids, visual cycle metabolites that progressively accumulate in the RPE, disrupt autophagy. We demonstrate that bisretinoids trap cholesterol and bis(monoacylglycero)phosphate, an acid sphingomyelinase (ASMase) cofactor, within the RPE. ASMase activation increases cellular ceramide, which promotes tubulin acetylation on stabilized microtubules. Live-imaging data show that autophagosome traffic and autophagic flux are inhibited in RPE with acetylated microtubules. Drugs that remove excess cholesterol or inhibit ASMase reverse this cascade of events and restore autophagosome motility and autophagic flux in the RPE. Because accumulation of lipofuscin bisretinoids and abnormal cholesterol homeostasis are implicated in macular degeneration, our studies suggest that ASMase could be a potential therapeutic target to ensure the efficient autophagy that maintains RPE health.

Meyers, K., Z. Liu, A. Millen, S. Iyengar, B. Blodi, E. Johnson, D. Snodderly, M. Klein, K. Gehrs, L. Tinker, G. Sarto, J. Robinson, R. Wallace, and J. Mares. Joint Associations of Diet, Lifestyle, and Genes With Age-Related Macular Degeneration. Ophthalmology, 2015, p. Epub PubMed Text.

Abstract Purpose: Unhealthy lifestyles have been associated with increased odds for age-related macular degeneration (AMD). Whether this association is modified by genetic risk for AMD is unknown and was investigated.

Diamond, J., C. Graydon, W. Grimes, M. Hoon, F. Rieke, H. Tian, and J. Zhang. Complex Inhibitory Microcircuitry Regulates Retinal Signaling Near Visual threshold. Journal of Neurophysiology, 2015, p. Epub PubMed Text.

Abstract Neuronal microcircuits, small, localized signaling motifs involving two or more neurons, underlie signal processing and computation in the brain. Compartmentalized signaling within a neuron may enable it to participate in multiple, independent microcircuits. Each A17 amacrine cell in the mammalian retina contains within its dendrites hundreds of synaptic feedback microcircuits that operate independently to modulate feedforward signaling in the inner retina. Each of these microcircuits comprises a small (<1 μm) synaptic varicosity that typically receives one excitatory synapse from a presynaptic rod bipolar cell (RBC) and returns two reciprocal inhibitory synapses back onto the same RBC terminal. Feedback inhibition from the A17 sculpts the feedforward signal from the RBC to the AII, a critical component of the circuitry mediating night vision. Here, we show that the two inhibitory synapses from the A17 to the RBC express kinetically distinct populations of GABA receptors: rapidly activating GABA(A)Rs are enriched at one synapse while more slowly activating GABA(C)Rs are enriched at the other. Anatomical and electrophysiological data suggest that macromolecular complexes of voltage-gated (Cav) channels and Ca(2+)-activated K(+) channels help to regulate GABA release from A17 varicosities and limit GABA(C)R activation under certain conditions. Finally, we find that selective elimination of A17-mediated feedback inhibition reduces the signal to noise ratio of responses to dim flashes recorded in the feedforward pathway (i.e., the AII amacrine cell). We conclude that A17-mediated feedback inhibition improves the signal to noise ratio of RBC-AII transmission near visual threshold, thereby improving visual sensitivity at night. Keywords: GABA; amacrine; feedback; microcircuit; retina.

Shin, E., C. Sorenson, and N. Sheibani. Diabetes and Retinal Vascular dysfunction. J Ophthalmic Vis Res, 2014, p. PubMed Text.

Abstract Diabetes predominantly affects the microvascular circulation of the retina resulting in a range of structural changes unique to this tissue. These changes ultimately lead to altered permeability, hyperproliferation of endothelial cells and edema, and abnormal vascularization of the retina with resulting loss of vision. Enhanced production of inflammatory mediators and oxidative stress are primary insults with significant contribution to the pathogenesis of diabetic retinopathy (DR). We have determined the identity of the retinal vascular cells affected by hyperglycemia, and have delineated the cell autonomous impact of high glucose on function of these cells. We discuss some of the high glucose specific changes in retinal vascular cells and their contribution to retinal vascular dysfunction. This knowledge provides novel insight into the molecular and cellular defects contributing to the development and progression of diabetic retinopathy, and will aid in the development of innovative, as well as target specific therapeutic approaches for prevention and treatment of DR. Keywords: Diabetes; Inflammation; Oxidative Stress; Retinal vasculature; Thrombospondins.

Dow, C. M. Paratuberculosis and Parkinson’S Disease–Is This a trigger. Med Hypotheses, 2014, p. PubMed Text.

Abstract Genetic linkage studies and genome wide analysis have provided insights into complex medical diseases. Mycobacterium avium ss. paratuberculosis (MAP) causes Johne’s disease, an important enteric inflammatory disease mostly studied in ruminant animals. MAP is also the putative cause of Crohn’s disease. Moreover, MAP has been linked to other inflammatory diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis and multiple sclerosis. Genetic studies reveal an association between Parkinson’s disease (PD), leprosy and Crohn’s disease and since discovered, these findings have been considered “surprising”. Autophagy and ubiquitin-proteosome systems are cellular systems that both fight intracellular pathogens (xenophagy) and maintain cellular protein quality control. PD is a common neurodegenerative disease that manifests clinically as a profound movement disorder. The recognized genetic defects of PD create disruption of cellular homeostasis that result in protein folding abnormalities of PD called Lewy bodies. Those same genetic defects are associated with susceptibility to intracellular pathogens, including mycobacteria. It is now understood that PD Lewy body pathology starts in the enteric nervous system and “spreads” to the brain in a retrograde fashion via the vagus nerve. This is the same process by which prions affect the brain. Lewy body pathology of the enteric nervous system predates the Lewy body pathology of the central nervous system (CNS) by years or even decades. This article proposes that genetic defects associated with PD also result in a permissive environment for MAP infection–ineffective xenophagy. It postulates that beginning as an enteric infection, MAP–via the vagus nerve–initiates a pathologic process that results in a targeted neuroinvasion of the CNS. The article proposes that MAP infection and resultant PD pathology are due, in the genetically at-risk and age dependant, to the consumptive exhaustion of the protein quality control systems.

Brandt, C. Peptide Therapeutics for Treating Ocular Surface infections. J Ocul Pharmacol Ther, 2014, p. PubMed Text.

Abstract Microbial pathogens-bacteria, viruses, fungi, and parasites-are significant causes of blindness, particularly in developing countries. For bacterial and some viral infections a number of antimicrobial drugs are available for therapy but there are fewer available for use in treating fungal and parasitic keratitis. There are also problems with current antimicrobials, such as limited efficacy and the presence of drug-resistant microbes. Thus, there is a need to develop additional drugs. Nature has given us an example of 1 potential source of new antimicrobials: antimicrobial peptides and proteins that are either present in bodily fluids and tissues constitutively or are induced upon infection. Given the nature of peptides, topical applications are the most likely use to be successful and this is ideal for treating keratitis. Such peptides would also be active against drug-resistant pathogens and might act synergistically if used in combination therapy. Hundreds of peptides with antimicrobial properties have been isolated or synthesized but only a handful have been tested against ocular pathogens and even fewer have been tested in animal models. This review summarizes the currently available information on the use of peptides to treat keratitis, outlines some of the problems that have been identified, and discusses future studies that will be needed. Most of the peptides that have been tested have shown activity at concentrations that do not warrant further development, but 1 or 2 have promising activity raising the possibility that peptides can be developed to treat keratitis.

Shin, E., Q. Huang, Z. Gurel, C. Sorenson, and N. Sheibani. High Glucose Alters Retinal Astrocytes Phenotype through Increased Production of Inflammatory Cytokines and Oxidative stress. PLoS One, 2014, p. PubMed Text.

Abstract Astrocytes are macroglial cells that have a crucial role in development of the retinal vasculature and maintenance of the blood-retina-barrier (BRB). Diabetes affects the physiology and function of retinal vascular cells including astrocytes (AC) leading to breakdown of BRB. However, the detailed cellular mechanisms leading to retinal AC dysfunction under high glucose conditions remain unclear. Here we show that high glucose conditions did not induce the apoptosis of retinal AC, but instead increased their rate of DNA synthesis and adhesion to extracellular matrix proteins. These alterations were associated with changes in intracellular signaling pathways involved in cell survival, migration and proliferation. High glucose conditions also affected the expression of inflammatory cytokines in retinal AC, activated NF-κB, and prevented their network formation on Matrigel. In addition, we showed that the attenuation of retinal AC migration under high glucose conditions, and capillary morphogenesis of retinal endothelial cells on Matrigel, was mediated through increased oxidative stress. Antioxidant proteins including heme oxygenase-1 and peroxiredoxin-2 levels were also increased in retinal AC under high glucose conditions through nuclear localization of transcription factor nuclear factor-erythroid 2-related factor-2. Together our results demonstrated that high glucose conditions alter the function of retinal AC by increased production of inflammatory cytokines and oxidative stress with significant impact on their proliferation, adhesion, and migration.

Sauter, M., J. Gauger, and C. Brandt. Oligonucleotides Designed to Inhibit TLR9 Block Herpes Simplex Virus Type 1 Infection at Multiple steps. Antiviral Res, 2014, p. PubMed Text.

Abstract Herpes simplex virus type 1 (HSV-1) is an important human pathogen which requires activation of nuclear factor-kappa B (NFκB) during its replication cycle. The persistent nature of HSV-1 infection, and the emergence of drug-resistant strains, highlights the importance of research to develop new antiviral agents. Toll-like receptors (TLRs) play a prominent role during the early antiviral response by recognizing viral nucleic acid and gene products, activating NFκB, and stimulating the production of inflammatory cytokines. We demonstrate a significant effect on HSV-1 replication in ARPE-19 and Vero cells when oligonucleotides designed to inhibit TLR9 are added 2h prior to infection. A greater than 90% reduction in the yield of infectious virus was achieved at oligonucleotide concentrations of 10-20 μM. TLR9 inhibitory oligonucleotides prevented expression of essential immediate early herpes gene products as determined by immunofluorescence microscopy and Western blotting. TLR9 oligonucleotides also interfered with viral attachment and entry. A TLR9 inhibitory oligonucleotide containing five adjacent guanosine residues (G-ODN) exhibited virucidal activity and inhibited HSV-1 replication when added post-infection. The antiviral effect of the TLR9 inhibitory oligonucleotides did not depend on the presence of TLR9 protein, suggesting a mechanism of inhibition that is not TLR9 specific. TLR9 inhibitory oligonucleotides also reduced NFκB activity in nuclear extracts. Studies using these TLR inhibitors in the context of viral infection should be interpreted with caution. Keywords: ARPE-19; Herpes simplex virus; ICP4; NFκB; Retinal pigment epithelium; TLR9.

Toops, K., L. Tan, and A. Lakkaraju. A Detailed Three-Step Protocol for Live Imaging of Intracellular Traffic in Polarized Primary Porcine RPE monolayers. Exp Eye Res, 2014, p. PubMed Text.

Abstract The retinal pigment epithelium (RPE) performs numerous functions that are indispensable for photoreceptor health and vision. This monolayer of cells is also a major site of insult in inherited and age-related macular degenerations. In vitro models of primary RPE such as human fetal and adult RPE cultures have been invaluable for dissecting disease pathways at the cellular and molecular level. However, numerous studies show that it takes over four weeks for human RPE cell monolayers to become fully polarized after plating on semipermeable membrane supports. Poor persistence of transgene expression over this time period critically limits the applicability of human RPE cultures for live imaging studies required to follow dynamic processes like intracellular trafficking and organelle transport that occur over timescales of milliseconds. Here, we provide a detailed three-step protocol for live imaging of polarized primary RPE using high-speed spinning disk confocal microscopy. Step 1: establish porcine RPE monolayers that undergo differentiation within one week after plating on semipermeable membrane supports; step 2: transfect or transduce RPE using either of two different protocols that result in prolonged transgene expression; and step 3: perform multicolor high-speed live imaging of organelle transport in polarized RPE monolayers. Porcine RPE cells and photoreceptor outer segments were isolated from freshly harvested eyes and plated on collagen-coated Transwell® filters to generate polarized monolayers. After seven days, RPE monolayers were highly pigmented, had TER values ≥ 200 Ω.cm2 and cleared outer segments within 5 hours after phagocytosis. These cells expressed RPE65, localized ZO-1 to the tight junction, Na+,K+-ATPase to the apical membrane and acetylated tubulin to the primary cilium. There was an inverse relationship between initial plating density and the time to differentiation. We used nucleofection to express fluorescently tagged genes in RPE cells prior to plating on filters or baculovirus fusion constructs to transfect polarized monolayers. Both these methods resulted in transfection efficiencies over 40% and transgene expression lasted up to 8 days after plating. These filters were imaged by high-speed spinning disk microscopy to follow tubulovesicular trafficking of lysosomes and actin dynamics in the RPE. Four-dimensional image analysis performed using commercially available software was used to analyze live imaging data. In conclusion, this 3-step protocol describes a powerful method to investigate organelle trafficking and function in real time in the RPE that can be used for answering fundamental questions of RPE cell biology and pathobiology. Keywords: age-related macular degeneration; culture protocol; gene expression; live imaging; organelle traffic; polarized monolayers; retinal diseases; retinal pigment epithelium.

Teixeira, L., K. Buhr, O. Bowie, F. Duke, T. Nork, R. Dubielzig, and G. McLellan. Quantifying Optic Nerve Axons in a Cat Glaucoma Model by a Semi-Automated Targeted Counting method. Mol Vis, 2014, p. PubMed Text.

Abstract Purpose: To describe and validate a semi-automated targeted sampling (SATS) method for quantifying optic nerve axons in a feline glaucoma model.

Phillips, M., E. Perez, J. Martin, S. Reshel, K. Wallace, E. Capowski, R. Singh, L. Wright, E. Clark, P. Barney, R. Stewart, S. Dickerson, M. Miller, E. Percin, J. Thomson, and D. Gamm. Modeling Human Retinal Development With Patient-Specific Induced Pluripotent Stem Cells Reveals Multiple Roles for Visual System Homeobox 2. Stem Cells, 2014, p. PubMed Text.

Abstract Human induced pluripotent stem cells (hiPSCs) have been shown to differentiate along the retinal lineage in a manner that mimics normal mammalian development. Under certain culture conditions, hiPSCs form optic vesicle-like structures (OVs), which contain proliferating progenitors capable of yielding all neural retina (NR) cell types over time. Such observations imply conserved roles for regulators of retinogenesis in hiPSC-derived cultures and the developing embryo. However, whether and to what extent this assumption holds true has remained largely uninvestigated. We examined the role of a key NR transcription factor, visual system homeobox 2 (VSX2), using hiPSCs derived from a patient with microphthalmia caused by an R200Q mutation in the VSX2 homeodomain region. No differences were noted between (R200Q)VSX2 and sibling control hiPSCs prior to OV generation. Thereafter, (R200Q)VSX2 hiPSC-OVs displayed a significant growth deficit compared to control hiPSC-OVs, as well as increased production of retinal pigmented epithelium at the expense of NR cell derivatives. Furthermore, (R200Q)VSX2 hiPSC-OVs failed to produce bipolar cells, a distinctive feature previously observed in Vsx2 mutant mice. (R200Q)VSX2 hiPSC-OVs also demonstrated delayed photoreceptor maturation, which could be overcome via exogenous expression of wild-type VSX2 at early stages of retinal differentiation. Finally, RNAseq analysis on isolated hiPSC-OVs implicated key transcription factors and extracellular signaling pathways as potential downstream effectors of VSX2-mediated gene regulation. Our results establish hiPSC-OVs as versatile model systems to study retinal development at stages not previously accessible in humans and support the bona fide nature of hiPSC-OV-derived retinal progeny. Keywords: Homeobox genes; Neurogenesis; Retina; Transcription factors; VSX2 protein; human induced pluripotent stem cells.

Meyers, K., J. Mares, R. Igo Jr, B. Truitt, Z. Liu, A. Millen, M. Klein, E. Johnson, C. Engelman, C. Karki, B. Blodi, K. Gehrs, L. Tinker, R. Wallace, J. Robinson, E. LeBlanc, G. Sarto, P. Bernstein, J. SanGiovanni, and S. Iyengar. Genetic Evidence for Role of Carotenoids in Age-Related Macular Degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Invest Ophthalmol Vis Sci, 2014, p. PubMed Text.

Abstract Purpose: We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Keywords: carotenoids; genes; macular degeneration.

Dharmarajan, S., Z. Gurel, S. Wang, C. Sorenson, N. Sheibani, and T. Belecky-Adams. Bone Morphogenetic Protein 7 Regulates Reactive Gliosis in Retinal Astrocytes and Müller glia. Mol Vis, 2014, p. eCollection PubMed Text.

Abstract Purpose: The focus of this study was to determine whether bone morphogenetic proteins (BMPs) trigger reactive gliosis in retinal astrocytes and/or Müller glial cells.

Kumar, M., and B. Pattnaik. Focus on Kir7.1: Physiology and channelopathy. Channels, 2014, p. Epub PubMed Text.

Abstract Genetic studies have linked alterations in Kir7.1 channel to diverse pathologies. We summarize functional relevance of Kir7.1 channel in retinal pigment epithelium (RPE), regulation of channel function by various cytoplasmic metabolites, and mutations that cause channelopathies. At the apical membrane of RPE, K(+) channels contribute to subretinal K(+) homeostasis and support Na(+)/K(+) pump and Na(+)-K(+)-2Cl(-) cotransporter function by providing a pathway for K(+) secretion. Electrophysiological studies have established that barium- and cesium-sensitive inwardly rectifying K(+) (Kir) channels make up a major component of the RPE apical membrane K(+) conductance. Native human RPE expresses transcripts for Kir1.1, Kir2.1, Kir2.2, Kir3.1, Kir3.4, Kir4.2, and Kir6.1, albeit at levels at least 50-fold lower than Kir7.1. Kir7.1 is structurally similar to other Kir channels, consisting of 2 trans-membrane domains, a pore-forming loop that contains the selectivity filter, and 2 cytoplasmic polar tails. Within the cytoplasmic structure, clusters of amino acid sequences form regulatory domains that interact with cellular metabolites and control the opening and closing of the channel. Recent evidence indicated that intrinsic sequence motifs present in Kir7.1 control surface expression. Mutant Kir7.1 channels are associated with inherited eye pathologies such as Snowflake Vitreoretinal Degeneration (SVD) and Lebers Congenital Amaurosis (LCA16). Based on the current evidence, mutations implicated in channelopathies have the potential to be used for genetic testing to diagnose blindness due to Kir7.1. Keywords: LCA; SVD; channelopathy; potassium channel; retinal degeneration; retinal pigment epithelium.

Briggman, K., W. Grimes, M. Hoon, F. Rieke, and R. Wong. Cross-Synaptic Synchrony and Transmission of Signal and Noise across the Mouse retina. eLife, 2014, p. Epub PubMed Text.

Abstract Cross-synaptic synchrony–correlations in transmitter release across output synapses of a single neuron–is a key determinant of how signal and noise traverse neural circuits. The anatomical connectivity between rod bipolar and A17 amacrine cells in the mammalian retina, specifically that neighboring A17s often receive input from many of the same rod bipolar cells, provides a rare technical opportunity to measure cross-synaptic synchrony under physiological conditions. This approach reveals that synchronization of rod bipolar cell synapses is near perfect in the dark and decreases with increasing light level. Strong synaptic synchronization in the dark minimizes intrinsic synaptic noise and allows rod bipolar cells to faithfully transmit upstream signal and noise to downstream neurons. Desynchronization in steady light lowers the sensitivity of the rod bipolar output to upstream voltage fluctuations. This work reveals how cross-synaptic synchrony shapes retinal responses to physiological light inputs and, more generally, signaling in complex neural networks. Keywords: mouse; neuroscience; signal processing; synaptic transmission; synchronization.

Lu, Y., H. Tu, Y. Xu, and H. Jiang. Tunable Dielectric Liquid Lens on Flexible substrate. Appl Phys Lett, 2013, p. PubMed Text.

Abstract We demonstrate the fabrication of a tunable-focus dielectric liquid lens (DLL) on a flexible substrate made of polydimethylsiloxane, which was wrapped onto a goggle surface to show its functionality. As a positive meniscus converging lens, the DLL has the focal length variable from 14.2 to 6.3 mm in 1.3 s when the driving voltage increases to 125 Vrms. The resolving power of the DLL is 17.95 line pairs per mm. The DLL on a flexible, curvilinear surface is promising for expanded field of view covered as well as in reconfigurable optical systems.

Sorenson, C., S. Wang, R. Gendron, H. Paradis, and N. Sheibani. Thrombospondin-1 Deficiency Exacerbates the Pathogenesis of Diabetic Retinopathy. J Diabetes Metab, 2013, p. PubMed Text.

Abstract Diabetic retinopathy is a leading cause of blindness in the United States. Access to new animal models that exhibit retinal vasculopathies with short duration of diabetes, are vital for understanding the underlying mechanisms and examining the efficacy of new treatment modalities. Our previous studies demonstrated decreased expression of Thrombospondin-1 (TSP1), an endogenous inhibitor of angiogenesis, in eyes from both patients and rodents with diabetes. Here we examined whether TSP1 deficiency could exacerbate diabetic retinal vasculopathies. Akita/+ male mice reproducibly develop diabetes by 4 weeks of age. These mice demonstrated the early non-proliferative stages of diabetic retinopathy, including decreased numbers of pericytes and increased glial cell activation. However, Akita/+ male mice deficient in TSP1 (Akita/+; TSP1-/-) demonstrated more advanced stages of diabetic retinopathy with a 4-fold increase in acellular capillaries and increased fibronectin and GFAP expression. These vascular changes were not attributable to aberrant retinal vascular development in the absence of TSP1, since down-regulation of TSP1 postnatally in the endothelium also resulted in more severe retinopathy. In addition, lack of another endogenous inhibitor of angiogenesis, pigment epithelium derived factor (PEDF), also enhanced diabetic retinopathy in Akita/+ mice. Akita/+; PEDF-/- male mice demonstrated increased numbers of acellular capillaries compared to controls but at a level lower than that observed in Akita/+; TSP1-/- mice. Thus, the exacerbation of diabetic retinopathy in Akita/+; TSP1-/- mice will allow the study of retinal vasculopathies with a shorter duration of diabetes and facilitate future testing of treatment modalities that protect the retinal vasculature and preserve sight. Keywords: Angiogenesis inhibitors; Diabetic retinopathy; PEDF; Thrombospondin-1.

Toops, K., and A. Lakkaraju. Let’S Play a Game of Chutes and Ladders: Lysosome Fusion With the Epithelial Plasma membrane. Commun Integr Biol, 2013, p. e24474, PubMed Text.

Abstract In non-polarized cells, calcium-induced exocytosis of “conventional” lysosomes is important in diverse processes like membrane repair after exposure to pore-forming toxins and clearance of cellular debris. Resealing of torn membranes is especially critical for barrier epithelia that directly interact with pathogens and toxins, which can result in membrane microdisruptions and lesions. However, whether lysosomes participate in membrane repair in polarized epithelia has been an open question. We recently reported that in polarized Madin-Darby canine kidney (MDCK) cells, localized influx of calcium induces lysosomes to fuse with the basolateral membrane. This spatial segregation of exocytosis depends on an intact actin cytoskeleton, membrane cholesterol and restricted distribution of fusion machinery such as the t-SNARE syntaxin 4. Our data show that the polarity of syntaxin 4 (which is regulated by the clathrin adaptor protein AP-1) dictates whether lysosomes parachute down to the basolateral membrane or take a ladder up to the apical membrane. Here, we speculate about additional machinery (such as the lysosomal calcium sensor synaptotagmin VII and the v-SNARE VAMP7) that could be involved in polarized fusion of lysosomes with the epithelial membrane. We also discuss the potential importance of lysosome exocytosis in maintaining membrane integrity in the retinal pigment epithelium, the primary tissue affected in blinding diseases such as age-related macular degeneration. Keywords: SNAREs; age-related disease; fusion machinery; membrane repair; polarized epithelia; retinal pigment epithelium; synaptotagmins.

Gamm, D., and L. Wright. From Embryonic Stem Cells to Mature photoreceptors. Nat Biotechnol, 2013, p. PubMed Text.

No abstract available

Colley, N., and J. Dowling. Spotlight on the Evolution of vision. Vis Neurosci, 2013, p. PubMed Text.

No abstract available

Euler, T., M. Hoon, P. Lukasiewicz, T. Schubert, and R. Wong. Developmental Regulation and Activity-Dependent Maintenance of GABAergic Presynaptic Inhibition onto Rod Bipolar Cell Axonal terminals. Neuron, 2013, p. Epub PubMed Text.

Abstract Presynaptic inhibition onto axons regulates neuronal output, but how such inhibitory synapses develop and are maintained in vivo remains unclear. Axon terminals of glutamatergic retinal rod bipolar cells (RBCs) receive GABAA and GABAC receptor-mediated synaptic inhibition. We found that perturbing GABAergic or glutamatergic neurotransmission does not prevent GABAergic synaptogenesis onto RBC axons. But, GABA release is necessary for maintaining axonal GABA receptors. This activity-dependent process is receptor subtype specific: GABAC receptors are maintained, whereas GABAA receptors containing α1, but not α3, subunits decrease over time in mice with deficient GABA synthesis. GABAA receptor distribution on RBC axons is unaffected in GABAC receptor knockout mice. Thus, GABAA and GABAC receptor maintenance are regulated separately. Although immature RBCs elevate their glutamate release when GABA synthesis is impaired, homeostatic mechanisms ensure that the RBC output operates within its normal range after eye opening, perhaps to regain proper visual processing within the scotopic pathway.

Capowski, E., D. Gamm, S. Howden, J. Martin, J. Meyer, B. Pattnaik, I. Pinilla, R. Stewart, J. Thomson, S. Tian, A. Verhoeven, K. Wallace, and L. Wright. Optic Vesicle-Like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease treatment. Stem Cells, 2011, pp. 1206-18 PubMed Text.

Abstract Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine.

Hughes, B., and B. Pattnaik. Regulation of Kir Channels in Bovine Retinal Pigment Epithelial Cells by Phosphatidylinositol 4,5-bisphosphate. American Journal of Physiology, Cell Physiology, 2009, p. Epub PubMed Text.

Abstract The inwardly rectifying K+ (Kir) current in mammalian retinal pigment epithelial (RPE) cells, which is largely mediated by Kir7.1 channels, is stable in cells dialyzed with MgATP but runs down when intracellular ATP is depleted. A potential mechanism for this rundown is a decrease in phosphatidylinositol 4,5-bisphosphate (PIP2) regeneration by ATP-dependent lipid kinases. Here, we used the whole cell voltage-clamp technique to investigate the membrane PIP2 dependence of Kir channels in isolated bovine RPE cells. When RPE cells were dialyzed with ATP-free solution containing PIP2 (25-50 microM), rundown persisted but was markedly reduced. Removal of Mg2+ from the pipette solution also slowed rundown, indicating that elevated intracellular Mg2+ concentration contributes to rundown. Cell dialysis with the PIP2 scavenger neomycin in MgATP solution diminished Kir current in a voltage-dependent manner, suggesting that it acted at least in part by blocking the Kir channel. Kir current in MgATP-loaded cells was partially inhibited by bath application of quercetin (100 microM), phenylarsine oxide (100 microM), or wortmannin (50 microM), inhibitors of phosphatidylinositol (PI) kinases, and was completely inhibited by cell dialysis with 2 mM adenosine, a PI4 kinase inhibitor. Both LY-294002 (100 microM), an inhibitor of PI3 kinases, and its inactive analog LY-303511 (100 microM) rapidly and reversibly inhibited Kir current, suggesting that these compounds act as direct channel blockers. We conclude that the activity of Kir channels in the RPE is critically dependent on the regeneration of membrane PIP2 by PI4 kinases and that this may explain the dependence of these channels on hydrolyzable ATP.

A Combined RNA-Seq and Whole Genome Sequencing Approach for Identification of Non-Coding Pathogenic Variants in Single families. Hum Mol Genet.

Bronstein R, Capowski EE, Mehrotra S, Jansen AD, Navarro-Gomez D, Maher M, Place E, Sangermano R, Bujakowska KM, Gamm DM, Pierce EA.

Using Eye-Tracking to Understand Relations Between Visual Attention and Language in children’S Spatial skills. Cogn Psychol.

Miller HE, Kirkorian HL, Simmering VR.

The Programmed Death Pathway in Ocular Adnexal Sebaceous Carcinoma. Ophthalmic Plast Reconstr Surg.

Bowen RC, Lawson BM, Jody NM, Potter HD, Lucarelli MJ.

Van Grinsven, K., A. Ashtiani, and H. Jiang. Flexible Electrowetting-on-Dielectric Microlens Array Sheet. Micromachines (Basel), p. PubMed Text.

Abstract We have fabricated a fully-flexible, focus-tunable microlens array on a sheet and demonstrated its imaging capabilities. Each liquid lens of the array is individually tunable via electrowetting on dielectric (EWOD) actuation and is situated on a polydimethylsiloxane (PDMS) substrate, which allows the lens array to operate as a reconfigurable optical system. In particular, we observed a significant increase in the field of view (FOV) of the system to 40.4° by wrapping it on a cylindrical surface as compared to the FOV of 21.5° obtained by the array on a planer surface. We also characterized the liquid lenses of the system, observing a range of focus length from 20.2 mm to 9.2 mm as increased voltage was applied to each EWOD lens. A Shack-Hartmann wavefront sensor (SHWS) was used to measure the wavefront of the lens as it was actuated, and the aberrations of the lens were assessed by reporting the Zernike coefficients of the wavefronts. Keywords: electrowetting-on-dielectric; flexible; large field of view; tunable lens array; tunable liquid lens.

Gamm, D., E. Clark, E. Capowski, and R. Singh. The Role of FGF9 in the Production of Neural Retina and RPE in a Pluripotent Stem Cell Model of Early Human Retinal Development. Am J Ophthalmol, p. PubMed Text.

Abstract Purpose: To investigate the role of fibroblast growth factors (FGFs) in the production of neural retina (NR) and retinal pigmented epithelium (RPE) in a human pluripotent stem cell model of early retinal development.

Grinblat, Y., and R. Lipinski. A Forebrain Undivided: Unleashing Model Organisms to Solve the Mysteries of holoprosencephaly. Dev Dyn, p. PubMed Text.

Abstract Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and abnormal. Standard genetic approaches, particularly useful in understanding monogenic diseases, are no longer sufficient as research attention shifts toward multifactorial outcomes. Here, we examine this progression through the lens of holoprosencephaly (HPE), a common human malformation involving incomplete forebrain division, and a classic example of an etiologically complex outcome. We relate the basic underpinning of HPE pathogenesis to critical cell-cell interactions and signaling molecules discovered through embryological and genetic approaches in multiple model organisms, and discuss the role of the mouse model in functional examination of HPE-linked genes. We then outline the most critical remaining gaps to understanding human HPE, including the conundrum of incomplete penetrance/expressivity and the role of gene-environment interactions. To tackle these challenges, we outline a strategy that leverages new and emerging technologies in multiple model systems to solve the puzzle of HPE. Keywords: HPE; Hh signaling; Zic2; forebrain; gene-environment.

Gallego-Lopez, G., E. Guzman, L. Knoll, and M. Skala. Metabolic Changes to Host Cells With Toxoplasma Gondii infection. bioRxiv, p. Epub PubMed Text.

Abstract Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular parasite that infects warm-blooded vertebrates across the world. In humans, seropositivity rates of T. gondii range from 10% to 90%. Despite its prevalence, few studies address how T. gondii infection changes the metabolism of host cells. Here, we investigate how T. gondii manipulates the host cell metabolic environment by monitoring metabolic response over time using non-invasive autofluorescence lifetime imaging of single cells, seahorse metabolic flux analysis, reactive oxygen species (ROS) production, and metabolomics. Autofluorescence lifetime imaging indicates that infected host cells become more oxidized and have an increased proportion of bound NAD(P)H with infection. These findings are consistent with changes in mitochondrial and glycolytic function, decrease of intracellular glucose, fluctuations in lactate and ROS production in infected cells over time. We also examined changes associated with the pre-invasion “kiss and spit” process using autofluorescence lifetime imaging, which similarly showed a more oxidized host cell with an increased proportion of bound NAD(P)H over 48 hours. Glucose metabolic flux analysis indicated that these changes are driven by NADH and NADP+ in T. gondii infection. In sum, metabolic changes in host cells with T. gondii infection were similar during full infection, and kiss and spit. Autofluorescence lifetime imaging can non-invasively monitor metabolic changes in host cells over a microbial infection time-course.

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