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The retinal pigment epithelium (RPE)-dependent visual cycle provides 11-cis-retinal to opsins in the photoreceptor outer segments to generate functional visual pigments that initiate phototransduction in response to light stimuli. Both RPE65 isomerase of the visual cycle and the rhodopsin visual pigment have recently been identified as critical players in mediating lightinduced retinal degeneration. These findings suggest that the expression and function of RPE65 and rhodopsin need to be coordinately controlled to sustain normal vision and to protect the retina from photodamage. However, the mechanism controlling the development of the retinal visual system remains poorly understood. Here, we show that deficiency in ciliary neurotrophic factor (CNTF) up-regulates the levels of rod and cone opsins accompanied by an increase in the thickness of the outer nuclear layers and the lengths of cone and rod outer segments in the mouse retina. Moreover, retinoid isomerase activity, expression levels of RPE65 and lecithin:retinol acyltransferase (LRAT), which synthesizes the RPE65 substrate, were also significantly increased in the Cntf RPE. Rod a-wave and cone b-wave amplitudes of electroretinograms were increased in Cntf mice, but rod b-wave amplitudes were unchanged compared with those in WT mice. Up-regulated RPE65 and LRAT levels accelerated both the visual cycle rate and recovery rate of rod light sensitivity in Cntf mice. Of note, rods and cones in Cntf mice exhibited hypersusceptibility to light-induced degeneration. These results indicate that CNTF is a common extracellular factor that prevents excessive production of opsins, the photoreceptor outer segments, and 11-cis-retinal to protect rods and cones from photodamage. [ABSTRACT FROM AUTHOR]

The present study aimed at observing the effect of a single subconjunctival injection of bevacizumab (BVZ) combined with 5-fluorouracil (5-Fu) or mitomycin C (MMC) on the antiscarring effect of glaucoma filtration surgery (GFS). The inhibitory effect of combined BVZ and 5-Fu in retinal pigment epithelial cells on vascular endothelial growth factor (VEGF) levels was demonstrated through in vitro experiments. Combined BVZ and 5-Fu and combined BVZ and MMC inhibited cell cycle, induced apoptosis, and inhibited human umbilical vein endothelial cell migration. Also, the cytotoxicity of combined BVZ and 5-Fu was lower. In animal experiments, the observation of filtering bleb survival, hematoxylin and eosin and Masson staining of filtering bleb scars, and mRNA expression levels of fibrosis markers in filtering blebs showed that combined BVZ and 5-Fu had a better antiscarring effect compared with single drugs; however, the antiscarring effect of combined BVZ and MMC was not significantly different from MMC. Therefore, the findings of this study provided more reference for the clinical use of adjuncts to inhibit scarring after GFS and helped understand the regulatory effect of combined anti-VEGF antibody BVZ and antimetabolites on wound healing more comprehensively. [ABSTRACT FROM AUTHOR]

Here, we seek to summarize the current understanding of the biochemical and molecular events mediated by visual cycle molecules in the eye. The structures and functions of selected visual cycle proteins and their roles in human retinal diseases are also highlighted. Genetic mutations and malfunctions of these proteins provide etiological evidence that many ocular diseases arise from anomalies of retinoid (vitamin A) metabolism and related visual processes. Genetic retinal disorders such as retinitis pigmentosa, Leber’s congenital amaurosis, and Stargardt’s disease are linked to structural changes in visual cycle proteins. Moreover, recent reports suggest that visual cycle proteins may also play a role in the development of diabetic retinopathy. Basic science has laid the groundwork for finding a cure for many of these blindness-causing afflictions, but much work remains. Some translational research projects have advanced to the clinical trial stage, while many others are still in progress, and more are at the ideas stage and remain yet to be tested. Some examples of these studies are discussed. Recent and future progress in our understanding of the visual cycle will inform intervention strategies to preserve human vision and prevent blindness. [ABSTRACT FROM AUTHOR]

Objectives: T o assess the effects of anti-vascular endothelial growth factor (VEGF) drugs on retinal pigment epithelium cell culture. Materials and Methods: Aflibercept (0.5 mg/mL), bevacizumab (0.3125 mg/mL), and ranibizumab (0.125 mg/mL) were applied to retinal pigment epithelium cell cultures isolated from the enucleated eyes of New Zealand white rabbits. Viability, apoptosis, proliferation, and senescence of the cells were evaluated in control and drug-treated cultures at the end of 72 hours. Results: Cells treated with aflibercept showed increased viability and decreased apoptosis compared to the control culture and both the bevacizumab- and ranibizumab-treated groups (p<0.05). Statistically increased apoptosis and decreased viability were found in the bevacizumab and ranibizumab-treated groups compared with the control group (p<0.05). There were no statistically significant differences in cell proliferation and senescence between the groups (p>0.05). Conclusion: Anti-VEGF drugs did not affect senescence or proliferation of retinal pigment epithelium cells. Aflibercept was found to decrease apoptosis and increase cell viability, while ranibizumab and bevacizumab increased apoptosis and reduced cell viability in retinal pigment epithelium culture. [ABSTRACT FROM AUTHOR]

Protein phosphorylation is an abundant molecular switch that regulates a multitude of cellular processes. In contrast to other subfamilies of phosphoprotein phosphatases, the PPEF subfamily is only poorly investigated. Drosophila retinal degeneration C (RDGC) constitutes the founding member of the PPEF subfamily. RDGC dephosphorylates the visual pigment rhodopsin and the ion channel TRP.However, rdgC null mutant flies exhibit rhodopsin and TRP hyperphosphorylation, altered photoreceptor physiology, and retinal degeneration. Here, we report the identification of a third RDGC protein variant and show that the three RDGC isoforms harbor different N‐termini that determine solubility and subcellular targeting due to fatty acylation. Taken together, solubility and subcellular targeting of RDGC splice variants are determined by their N‐termini. [ABSTRACT FROM AUTHOR]

Purpose. As far as we know, during the development of age-related macular degeneration (AMD), the activity of proteasome in retinal pigment epithelium cells (RPE) gradually decreases. And a lot of research has shown that age-related macular degeneration is closely related to inflammation and autoimmune. Moreover, there are many cytokines (CKs) involved in the course of inflammation. In this study, we are going to investigate how the decrease of proteasome activity affects the production of interleukin-6 (IL-6) in human retinal pigment epithelium cells (ARPE-19). Methods. Cultured ARPE-19 was treated with or without MG132, a proteasome inhibitor, and the levels of IL-6 mRNA (messenger ribonucleic acid) in RPE at 1 h, 4 h, 8 h, and IL-6 protein in the culture medium at 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h were measured by real-time polymerase chain reaction (real-time PCR) and enzyme-linked immunosorbent assay (ELISA). The protein levels of MCP-1 (monocyte chemoattractant protein-1) in the culture medium at 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h were also measured by ELISA. Then we tested which of cell signal pathways regulating the production of IL-6 were activated when we added MG132 into the medium by Western blot and electrophoretic mobility shift assays (EMSA). After that, we put the inhibitors of these activated cell signal pathways into the medium individually to see which inhibitor can counteract the effect of upregulating the levels of IL-6 in the culture medium of RPE. Results. MG132 decreased the secretion of MCP-1 in the culture medium of RPE, but it increased the expression of IL-6 mRNA in RPE and IL-6 protein level in the culture medium of RPE. MG132 treatment was also found to enhance the level of phosphorylated p38 mitogen-activated protein kinases (MAPKs) and c-Jun N-terminal Kinase (JNK) by Western blotting. More importantly, the effect of MG132 on upregulating the levels of IL-6 was inhibited by SB203580, an inhibitor of P38 MAP kinases. But the JNK inhibitor, SP600125, cannot prevent the effect of upregulating the levels of IL-6 by MG132 in the RPE culture medium. Conclusions. We concluded that the proteasome inhibitor, MG132, upregulates IL-6 production in RPE cells through the activation of P38 MAPKs. [ABSTRACT FROM AUTHOR]

Purpose. To present new clinical features, multimodal and ultrawide-field imaging characteristics of peripheral cone dystrophy (PCD), and results of laboratory and genetic investigation to decipher the etiology. Methods. Retrospective observational case-series. Results. Three patients with PCD presented with bilateral paracentral scotomas and a mean visual acuity of 20/25. All exhibited confluent macular hyperautofluorescence with a central bull’s eye lesion. Spectral-domain optical coherence tomography revealed loss of outer retinal elements, particularly the inner segment ellipsoid band and external limiting membrane, within the area of macular hyperautofluorescence. This area corresponded with a lightened fundus appearance and variable retinal pigment epithelium (RPE) abnormalities. Full field and multifocal electroretinography distinguished PCD from other photoreceptor dystrophies. Ultrawide-field imaging revealed irregular peripheral retinal lesions in a distribution greater nasally than temporally and not contiguous with the macular lesion. Functional and anatomic testing remained stable over a mean follow-up of 3 years. Laboratory investigation for causes of uveitis was negative. Whole exome sequencing identified rare variants in genes associated with macular or cone dystrophy or degeneration. Conclusions. In contrast to the original description, the funduscopic and fluorescein angiographic appearance of PCD is abnormal, although the defects are subtle. Peripheral lesions may be observed in some patients. Bilateral, symmetric, macular hyperautofluorescence associated with outer retinal atrophy that spares the fovea is a characteristic of PCD. Pathogenic variants in the same gene were not shared across the cohort, suggesting genetic heterogeneity. Further evaluation is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Membrane voltage is an important biophysical signal that underlies intercellular electrical communications. A fluorescent voltage indicator is presented that enables the investigation of electrical signaling at high spatial resolution. The method is built upon the site‐specific modification of microbial rhodopsin proteins with organic fluorophores, resulting in a hybrid indicator scaffold that is one of the most sensitive and fastest orange‐colored voltage indicators developed to date. We applied this technique to optically map electrical connectivity in cultured cells, which revealed gap junction‐mediated long‐range coupling that spanned over hundreds of micrometers. [ABSTRACT FROM AUTHOR]

The spectral absorbance of photoreceptor visual pigments and the opsin gene class of the visual pigments was investigated in Sardinops melanostictus . Microspectrophotometric (MSP) measurements showed that the rod photoreceptors had peak absorbance spectra (λ max ) at 502 nm. The spectral sensitivity of single cones was centered at 393 nm. Double cones had a λ max of 493/522 nm, but a few displayed a red-shifted absorbance of the long-wave member at 542 nm. The mRNAs of six different opsins were isolated from the retina, retrotranscribed, cloned, and sequenced. Three genes encoded opsins in the green-sensitive class (RH2), and three genes encoded opsins in the red-sensitive class (LWS), the ultraviolet (UV)-sensitive (SWS1) class, and the rod class (RH1). A Southern blot analysis showed that the blue-sensitive (SWS2) opsin gene is absent from this species, hence it was concluded that the λ max of 393 nm was generated from the SWS1 opsin. Phylogenetic analyses of S . melanostictus RH1, LWS, and SWS1 sequences placed them with orthologs from other species (e.g., the cyprinids Danio rerio and Carrasius auratus ) in Otomorpha. However, unexpectedly, the RH2 sequences were more similar to orthologs in members of the Euteleosteomorpha (e.g., Oryzias latipes and Takifugu rubripes ) than to cyprinid RH2 opsins. [ABSTRACT FROM AUTHOR]

Visual function in vertebrates critically depends on the continuous regeneration of visual pigments in rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase in the pigment epithelium that regenerates rhodopsin during the rod visual cycle; however, its contribution to the regeneration of cone pigments remains obscure. In this study, we use potent and selective RPE65 inhibitors in rod- and cone-dominant animal models to discern the role of this enzyme in cone-mediated vision. We confirm that retinylamine and emixustat-family compounds selectively inhibit RPE65 over DES1, the putative retinoid isomerase of the intraretinal visual cycle. In vivo and ex vivo electroretinography experiments in Gnat1-/- mice demonstrate that acute administration of RPE65 inhibitors after a bleach suppresses the late, slow phase of cone dark adaptation without affecting the initial rapid portion, which reflects intraretinal visual cycle function. Acute administration of these compounds does not affect the light sensitivity of cone photoreceptors in mice during extended exposure to background light, but does slow all phases of subsequent dark recovery. We also show that cone function is only partially suppressed in cone-dominant ground squirrels and wild-type mice by multiday administration of an RPE65 inhibitor despite profound blockade of RPE65 activity. Complementary experiments in these animal models using the DES1 inhibitor fenretinide show more modest effects on cone recovery. Collectively, these studies demonstrate a role for continuous RPE65 activity in mammalian cone pigment regeneration and provide further evidence for RPE65-independent regeneration mechanisms. [ABSTRACT FROM AUTHOR]

The palm borer moth Paysandisia archon (Castniidae; giant butterfly-moths) has brown dorsal forewings and strikingly orange-coloured dorsal hindwings with white spots surrounded by black margins. Here, we have studied the structure and pigments of the wing scales in the various coloured wing areas, applying light and electron microscopy and (micro)spectrophotometry, and we analysed the spatial reflection properties with imaging scatterometry. The scales in the white spots are unpigmented, those in the black and brown wing areas contain various amounts of melanin, and the orange wing scales contain a blue-absorbing ommochrome pigment. In all scale types, the upper lamina acts as a diffuser and the lower lamina as a thin film interference reflector, with thickness of about 200 nm. Scale stacking plays an important role in creating the strong visual signals: the colour of the white eyespots is created by stacks of unpigmented blue scales, while the orange wing colour is strongly intensified by stacking the orange scales. [ABSTRACT FROM AUTHOR]

We explore the ideas and advances surrounding the genetic basis of pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). As PG is the leading cause of nontraumatic blindness in young adults and current tailored interventions have proven ineffective, a better understanding of the underlying causes of PDS, PG, and their relationship is essential. Despite PDS being a subclinical disease, a large proportion of patients progress to PG with associated vision loss. Decades of research have supported a genetic component both for PDS and conversion to PG. We review the body of evidence supporting a genetic basis in humans and animal models and reevaluate classical mechanisms of PDS/PG considering this new evidence. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a severe micro-vascular complication of diabetes. High glucose (HG)-evoked nitric oxide (NO) production mediated by increased oxidative stress is a key factor in DR pathogenesis. In this study, we examined whether low-intensity ultrasound (LIUS) stimulation can reduce HG-induced NO generation. We determined that LIUS stimulation decreased the HG-induced NO generation possibly via inhibition of reactive oxygen species (ROS) and subsequently diminished the associated pro-inflammatory pathway involving the induced expression of inducible nitric oxide synthase, cyclooxygenase-2 and vascular endothelial growth factor. In addition, we determined that LIUS stimulation reduced the quantity of NO produced by N-acetylcysteine, which was not mediated by ROS. These results indicate that LIUS can inhibit both ROS-dependent and -independent NO generation processes in ARPE-19 cells. We envision LIUS as a potential therapeutic alternative to treat DR. Further studies are required to understand the underlying mechanism of the LIUS-induced reduction of NO generation for DR therapy. [ABSTRACT FROM AUTHOR]

Purpose. To analyze the changes of refraction and metabolism of the retinal cones under monochromatic lights in guinea pigs. Methods. Sixty guinea pigs were randomly divided into a short-wavelength light (SL) group, a middle-wavelength light (ML) group, and a white light (WL) group. Refraction and axial length were measured before and after 10-week illumination. The densities of S-cones and M-cones were determined by retinal cone immunocytochemistry, and the expressions of S-opsins and M-opsins were determined by real-time PCR and Western blot. Results. After 10-week illumination, the guinea pigs developed relative hyperopia in the SL group and relative myopia in the ML group. Compared with the WL group, the density of S-cones and S-opsins increased while M-cones and M-opsins decreased in the SL group (all, p<0.05); conversely, the density of S-cones and S-opsins decreased while M-cones and M-opsins increased in the ML group (all, p<0.05). Increased S-cones/opsins and decreased M-cones/opsins were induced by short-wavelength lights. Decreased S-cones/opsins and increased M-cones/opsins were induced by middle-wavelength lights. Conclusions. Altered retinal cones/opsins induced by monochromatic lights might be involved in the refractive development in guinea pigs. [ABSTRACT FROM AUTHOR]

Vision plays an important role in the development of communication, social interaction, spatial awareness, and the motor skills needed to explore the environment. In the past 2 years, researchers have described the broad spectrum of clinical features that comprise congenital Zika syndrome (CZS). The ocular manifestations are considered 1 important pillar of this new entity. The most characteristic ophthalmic findings include chorioretinal scars and focal pigmentary changes seen in the macular region. Since these findings were first reported, other researchers have validated and extended them, leading to a more complete picture of the spectrum of ocular manifestations related to CZS. In this article, we summarize the current knowledge on the ocular implications of CZS and emphasize the importance of early rehabilitation to enhance visual performance in affected children. [ABSTRACT FROM AUTHOR]

ABSTRACT: Odorant‐binding proteins (OBPs) and chemosensory proteins (CSPs) are regarded as carriers of pheromones and odorants in insect chemoreception. These proteins are typically located in antennae, mouth organs and other chemosensory structures; however, members of both classes of proteins have been detected recently in other parts of the body and various functions have been proposed. The best studied of these non‐sensory tasks is performed in pheromone glands, where OBPs and CSPs solubilise hydrophobic semiochemicals and assist their controlled release into the environment. In some cases the same proteins are expressed in antennae and pheromone glands, thus performing a dual role in receiving and broadcasting the same chemical message. Several reports have described OBPs and CSPs in reproductive organs. Some of these proteins are male specific and are transferred to females during mating. They likely carry semiochemicals with different proposed roles, from inhibiting other males from approaching mated females, to marking fertilized eggs, but further experimental evidence is still needed. Before being discovered in insects, the presence of binding proteins in pheromone glands and reproductive organs was widely reported in mammals, where vertebrate OBPs, structurally different from OBPs of insects and belonging to the lipocalin superfamily, are abundant in rodent urine, pig saliva and vaginal discharge of the hamster, as well as in the seminal fluid of rabbits. In at least four cases CSPs have been reported to promote development and regeneration: in embryo maturation in the honeybee, limb regeneration in the cockroach, ecdysis in larvae of fire ants and in promoting phase shift in locusts. Both OBPs and CSPs are also important in nutrition as solubilisers of lipids and other essential components of the diet. Particularly interesting is the affinity for carotenoids of CSPs abundantly secreted in the proboscis of moths and butterflies and the occurrence of the same (or very similar CSPs) in the eyes of the same insects. A role as a carrier of visual pigments for these proteins in insects parallels that of retinol‐binding protein in vertebrates, a lipocalin structurally related to OBPs of vertebrates. Other functions of OBPs and CSPs include anti‐inflammatory action in haematophagous insects, resistance to insecticides and eggshell formation. Such multiplicity of roles and the high success of both classes of proteins in being adapted to different situations is likely related to their stable scaffolding determining excellent stability to temperature, proteolysis and denaturing agents. The wide versatility of both OBPs and CSPs in nature has suggested several different uses for these proteins in biotechnological applications, from biosensors for odours to scavengers for pollutants and controlled releasers of chemicals in the environment. [ABSTRACT FROM AUTHOR]

Stargardt maculopathy, caused predominantly by mutations in the ABCA4 gene, is characterized by an accumulation of non-degradable visual pigment derivative, lipofuscin, in the retinal pigment epithelium (RPE) - resulting in RPE atrophy. RPE is a monolayer tissue located adjacent to retinal photoreceptors and regulates their health and functioning; RPE atrophy triggers photoreceptor cell death and vision loss in Stargardt patients. Previously, ABCA4 mutations in photoreceptors were thought to be the major contributor to lipid homeostasis defects in the eye. Recently, we demonstrated that ABCA4 loss of function in the RPE leads to cell-autonomous lipid homeostasis defects. Our work underscores that an incomplete understanding of lipid metabolism and lipid-mediated signaling in the retina and RPE are potential causes for lacking treatments for this disease. Here we report altered lipidomic in mouse and human Stargardt models. This work provides the basis for therapeutics that aim to restore lipid homeostasis in the retina and the RPE. [ABSTRACT FROM AUTHOR]

Primate color vision is based on two to three cone types in the retina, each expressing a different class of visual pigment, making them the only mammals that possess trichromacy. These pigment classes are the short wavelength-sensitive (SWS1) pigment and the long wavelength-sensitive (LWS) pigment, orthologues of the same pigments found in many other vertebrates, as well as the middle wavelength-sensitive (MWS) pigment, a paralogue to the LWS pigment. Trichromacy was achieved differently in Old World and New World primates. In Old World primates, a duplication of the LWS opsin gene occurred giving rise to a “red-sensitive” or L pigment and a “green-sensitive” or M pigment. Their corresponding L and M genes are adjacent on the X chromosome which, together with their high sequence homology, is the underlying cause for the high frequency of red-green color blindness seen in humans. In New World primates and prosimians, however, the mechanism leading to trichromacy, with one exception, is based on a single polymorphic LWS gene, from which different allelic variants encode pigments with differing spectral peaks. X chromosome inactivation limits expression to just one gene per photoreceptor meaning that trichromacy is only seen in females; while all male are red-green color blind. Despite several leading hypotheses, the reasons for the different evolutionary paths taken by Old and New World primates for trichromacy are still unclear and remain to be confirmed.

Background: The compound eyes of insects allow them to catch photons and convert the energy into electric signals. All compound eyes consist of numerous ommatidia, each comprising a fixed number of photoreceptors. Different ommatidial types are characterized by a specific set of photoreceptors differing in spectral sensitivity. In honey bees, males and females possess different ommatidial types forming distinct retinal mosaics. However, data are lacking on retinal ontogeny and the mechanisms by which the eyes are patterned. In this study, we investigated the intrinsic temporal and circadian expression patterns of the opsins that give rise to the ultraviolet, blue and green sensitive photoreceptors, as well as the morphological maturation of the retina during pupal development of honey bees. Results: qPCR and histological labeling revealed that temporal opsin mRNA expression differs between sexes and correlates with rhabdom elongation during photoreceptor development. In the first half of the pupal stage, when the rhabdoms of the photoreceptors are still short, worker and (dorsal) drone retinae exhibit similar expression patterns with relatively high levels of UV (UVop) and only marginal levels of blue (BLop) and green (Lop1) opsin mRNA. In the second half of pupation, when photoreceptors and rhabdoms elongate, opsin expression in workers becomes dominated by Lop1 mRNA. In contrast, the dorsal drone eye shows high expression levels of UVop and BLop mRNA, whereas Lop1 mRNA level decreases. Interestingly, opsin expression levels increase up to 22-fold during early adult life. We also found evidence that opsin expression in adult bees is under the control of the endogenous clock. Conclusions: Our data indicate that the formation of the sex-specific retinal composition of photoreceptors takes place during the second half of the pupal development, and that opsin mRNA expression levels continue to increase in young bees, which stands in contrast to Drosophila, where the highest expression levels are found during the late pupal stage and remain constant in adults. From an evolutionary perspective, we hypothesize that the delayed retinal maturation during the early adult phase is linked to the delayed transition from indoor to outdoor activities in bees, when vision becomes important. [ABSTRACT FROM AUTHOR]

Background: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties.Objective: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels.Methods: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured.Results: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009).Conclusion: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study. [ABSTRACT FROM AUTHOR]

The light-induced double-bond isomerization of the visual pigment rhodopsin operates a molecular-level optomechanical energy transduction, which triggers a crucial protein structure change. In fact, rhodopsin isomerization occurs according to a unique, ultrafast mechanism that preserves mode-specific vibrational coherence all the way from the reactant excited state to the primary photoproduct ground state. The engineering of such an energy-funnelling function in synthetic compounds would pave the way towards biomimetic molecular machines capable of achieving optimum light-to-mechanical energy conversion. Here we use resonance and off-resonance vibrational coherence spectroscopy to demonstrate that a rhodopsin-like isomerization operates in a biomimetic molecular switch in solution. Furthermore, by using quantum chemical simulations, we show why the observed coherent nuclear motion critically depends on minor chemical modifications capable to induce specific geometric and electronic effects. This finding provides a strategy for engineering vibrationally coherent motions in other synthetic systems. [ABSTRACT FROM AUTHOR]

Anti-vascular endothelial growth factor (VEGF) reduces choroidal thickness by choroidal hypoperfusion in diabetic macula oedema (DME) patients. Indirect effect of anti-VEGF towards outer retinal layers (ORL) which supplied by choroidal circulation has not been well described. We evaluate the ORL thickness between retinal pigment epithelium (RPE) with inner-segment-outer-segment photoreceptor junction (IS/OS) and RPE with external limiting membrane (ELM) in pre- and postintravitreal Ranibizumab (IVR) treated eyes with central foveal diabetic macula edema. A total of 60 eyes (40 patients) were analysed. ORL thickness measured with optical coherence tomography at pre- and post-injection day 1, week 4 and week 6. Mean thickness of RPE-IS/OS was statistically significant over time (p=0.023) but not for RPE-ELM (p=0.216). Thickness ratio between RPE-IS/OS and RPE-ELM and central subfoveal thickness (CST) both showed statistically significant result over time with p=0.038 and p=0.000, respectively. We observed an initial reduction of ORL thickness at day 1 followed by increased in thickness at week 4 with subsequent reduction at week 6 was observed. ORL is an aspect that can be explore and emphasized further in patients considered for IVR injections. The long-term effects of IVR to the ORL however could not be concluded due to short follow up period. [ABSTRACT FROM AUTHOR]

Background: Morphological divergences of snake retinal structure point to complex evolutionary processes and adaptations. The Colubridae family has a remarkable variety of retinal structure that can range from all-cone and all-rod to duplex (cone/rod) retinas. To explore whether nocturnal versus diurnal activity is responsible for constraints on molecular evolution and plays a role in visual opsin spectral tuning of colubrids, we carried out molecular evolution analyses of the visual opsin genes LWS, RH1 and SWS1 from 17 species and performed morphological analyses. Results: Phylogenetic reconstructions of the RH1 and LWS recovered major clades characterized by primarily diurnal or primarily nocturnal activity patterns, in contrast with the topology for SWS1, which is very similar to the species tree. We found stronger signals of purifying selection along diurnal and nocturnal lineages for RH1 and SWS1, respectively. A blue-shift of the RH1 spectral peak is associated with diurnal habits. Spectral tuning of cone opsins did not differ among diurnal and nocturnal species. Retinas of nocturnal colubrids had many rows of photoreceptor nuclei, with large numbers of rods, labeled by wheat germ agglutinin (WGA) and two types of cones: large cones sensitive to long/medium wavelengths (L/M) and small cones sensitive to ultra-violet/violet wavelengths (UV/VS). In contrast, retinas of diurnal species had only one row of photoreceptor nuclei, with four types of cones: large and double L/M cones, small UV/VS cones and a second group of small cones, labeled by WGA. Conclusions: For LWS gene, selection tests did not confirm different constraints related to activity pattern. For SWS1, stronger purifying selection in nocturnal lineages indicates divergent evolutionary pressures related to the activity pattern and the importance of the short wavelength sensitivity at low light condition. Activity pattern has a clear influence on the signatures of selection and spectral tuning of RH1, with stronger purifying selection in diurnal lineages, which indicates selective pressure to preserve rhodopsin structure and function in pure-cone retinas. We suggest that the presence of four cone types in primarily diurnal colubrids might be related to the gain of color discrimination capacity. [ABSTRACT FROM AUTHOR]

Sensory systems provide valuable insight into the evolution of molecular mechanisms underlying organismal anatomy, physiology, and behaviour. Visual pigments, which mediate the first step in visual transduction, offer a unique window into the relationship between molecular variation and visual performance, and enhance our understanding of how ecology, life history, and physiology may shape genetic variation across a variety of organisms. Here we review recent work investigating vertebrate visual pigments from a number of perspectives. Opsin gene duplication, loss, differential expression, structural variation, and the physiological context in which they operate, have profoundly shaped the visual capabilities of vertebrates adapting to novel environments. We note the importance of conceptual frameworks in investigating visual pigment diversity in vertebrates, highlighting key examples including evolutionary transitions between different photic environments, major shifts in life history evolution and ecology, evolutionary innovations in visual system anatomy and physiology, as well as shifts in visually mediated behaviours and behavioural ecology. We emphasize the utility of studying visual pigment evolution in the context of these different perspectives, and demonstrate how the integrative approaches discussed in this review contribute to a better understanding of the underlying molecular processes mediating adaptation in sensory systems, and the contexts in which they occur. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the effect of partial ablation of melanopsin-containing retinal ganglion cells (mcRGCs) on nonimage-forming (NIF) visual functions in rd mice lacking rods. Methods. The rd mice were intravitreally injected with different doses (100 ng/μl, 200 ng/μl, and 400 ng/μl) of immunotoxin melanopsin-SAP. And then, the density of ipRGCs was examined. After establishing the animal models with different degrees of ipRGC damage, a wheel-running system was used to evaluate their reentrainment response. Results. Intravitreal injection of melanopsin-SAP led to partial ablation of ipRGCs in a dose-dependent manner. The survival rates of ipRGCs in the 100 ng/μl, 200 ng/μl, and 400 ng/μl groups were 74.14% ± 4.15%, 39.25% ± 2.29%, and 38.38% ± 3.74%, respectively. The wheel-running experiments showed that more severe ipRGC loss was associated with a longer time needed for reentrainment. When the light/dark cycle was delayed by 8 h, the rd mice in the PBS control group took 4.67 ± 0.79 days to complete the synchronization with the shifted cycle, while those in the 100 ng/μl and 200 ng/μl groups required 7.90 ± 0.55 days and 11.00 ± 0.79 days to complete the synchronization with the new light/dark cycle, respectively. Conclusion. Our study indicates that the regulation of some NIF visual functions is dependent on a certain minimal number of intact functional ipRGCs. [ABSTRACT FROM AUTHOR]

Resetting of G-protein-coupled receptors (GPCRs) from their active state back to their biologically inert ground state is an integral part of GPCR signaling. This "on-off" GPCR cycle is regulated by reversible phosphorylation. Retinal rod and cone photoreceptors arguably represent the best-understood example of such GPCR signaling. Their visual pigments (opsins) are activated by light, transduce the signal, and are then inactivated by a GPCR kinase and arrestin. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain unknown. Here, we show that protein phosphatase 2A (PP2A) acts as opsin phosphatase in both rods and cones. Elimination of PP2A substantially slows pigment dephosphorylation, visual chromophore recycling, and ultimately photoreceptor dark adaptation. These findings demonstrate that visual pigment dephosphorylation regulates the dark adaptation of photoreceptors and provide insights into the role of this reaction in GPCR signaling. [ABSTRACT FROM AUTHOR]

Stomatopods (mantis shrimps) possess one of the most complex eyes in the world with photoreceptors detecting up to 12 different colors. It is not yet understood why stomatopods have almost four times the number of spectral photoreceptors compared with most other animals. It has, however, been suggested that these seemingly redundant photoreceptors could encode color through a new mechanism. Here we compare the spectral sensitivities across five species of stomatopods within the superfamily Gonodactyloidea using intracellular electrophysiological recordings. The results show that the spectral sensitivities across species of stomatopods are remarkably similar apart from some variation in the long-wavelength receptors. We relate these results to spectral sensitivity estimates previously obtained using microspectrophotometry and discuss the variation in the spectral sensitivity maxima (λmax) of the long-wavelength receptors in regard to the previous findings that stomatopods are able to tune their spectral sensitivities according to their respective light environment. We further discuss the similarities of the spectral sensitivities across species of stomatopods in regard to how color information might be processed by their visual systems. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/ malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSCRPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich "drusen- like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSCRPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface. [ABSTRACT FROM AUTHOR]

Ciliary and rhabdomeric opsins are employed by different kinds of photoreceptor cells, such as ciliary vertebrate rods and cones or protostome microvillar eye photoreceptors, that have specialized structures and molecular physiologies. We report unprecedented cellular co-expression of rhabdomeric opsin and a visual pigment of the recently described xenopsins in larval eyes of a mollusk. The photoreceptors bear both microvilli and cilia and express proteins that are orthologous to transporters in microvillar and ciliary opsin trafficking. Highly conserved but distinct gene structures suggest that xenopsins and ciliary opsins are of independent origin, irrespective of their mutually exclusive distribution in animals. Furthermore, we propose that frequent opsin gene loss had a large influence on the evolution, organization and function of brain and eye photoreceptor cells in bilaterian animals. The presence of xenopsin in eyes of even different design might be due to a common origin and initial employment of this protein in a highly plastic photoreceptor cell type of mixed microvillar/ciliary organization. [ABSTRACT FROM AUTHOR]

Visual pigments, each composed of an opsin protein covalently bound to a chromophore molecule, confer light sensitivity for vision. The eyes of some species of stomatopod crustaceans, or mantis shrimp, can express dozens of different opsin genes. The opsin diversity, along with spectral filters and unique tripartite eye structure, bestow upon stomatopods unusually complex visual systems. Although opsins are found in tissues outside typical image-forming eyes in other animals, extraocular opsin expression in stomatopods, animalswell known for their diversity of opsins, was unknown. Caudal photoreception in the central nervous system of decapod crustaceans, a group closely related to stomatopod crustaceans, is thought to be opsin based. However, electrophysiological data suggest that stomatopods do not have caudal photoreceptors. In this study, we identified mRNAs that could encode four different opsins and several components of a potential Gq-mediated phototransduction pathway in the central nervous system of the Caribbean mantis shrimp Neogonodactylus oerstedii. The four opsins are abundantly expressed in the cerebral ganglion, or brain, with little or no expression in the remainder of the ventral nerve cord. Our data suggest that there are previously undiscovered cerebral photoreceptors in stomatopods. [ABSTRACT FROM AUTHOR]

The conversion of light energy into ion gradients across biological membranes is one of the most fundamental reactions in primary biological energy transduction. Recently, the structure of the first light-activated Na+ pump, Krokinobacter eikastus rhodopsin 2 (KR2), was resolved at atomic resolution [Kato HE, et al. (2015) Nature 521:48-53]. To elucidate its molecular mechanism for Na+ pumping, we perform here extensive classical and quantum molecular dynamics (MD) simulations of transient photocycle states. Our simulations show how the dynamics of key residues regulate water and ion access between the bulk and the buried light-triggered retinal site. We identify putative Na+ binding sites and show how protonation and conformational changes gate the ion through these sites toward the extracellular side. We further show by correlated ab initio quantum chemical calculations that the obtained putative photocycle intermediates are in close agreement with experimental transient optical spectroscopic data. The combined results of the ion translocation and gating mechanisms in KR2 may provide a basis for the rational design of novel light-driven ion pumps with optogenetic applications. [ABSTRACT FROM AUTHOR]

Clinical research continues to provide an increasing number of studies that reveal an association between macular pigment optical density (MPOD) and both visual function and ocular health. As a result, there is a growing need for repeatable, accurate measures of MPOD that can describe peak optical density as well as spatial distribution. Measurement of MPOD in a research setting has an established history encompassing a number of both objective and subjective techniques. Transition of these techniques to a clinical setting has produced an array of commercial devices using three primary methods: heterochromatic flicker photometry, fundus autofluorescence and fundus reflectometry. The inherent differences among the techniques create difficulty in making direct comparisons between MPOD measurement devices. Understanding the limitations of each technique is critical in the clinical interpretation of MPOD results. Here, both the objective and subjective methods of MPOD measurement are reviewed with emphasis on the commercially available devices used in clinical settings. [ABSTRACT FROM AUTHOR]

Colubridae is the largest and most diverse family of snakes, with visual systems that reflect this diversity, encompassing a variety of retinal photoreceptor organizations. The transmutation theory proposed by Walls postulates that photoreceptors could evolutionarily transition between cell types in squamates, but few studies have tested this theory. Recently, evidence for transmutation and rod-like machinery in an all-cone retina has been identified in a diurnal garter snake (Thamnophis), and it appears that the rhodopsin gene at least may be widespread among colubrid snakes. However, functional evidence supporting transmutation beyond the existence of the rhodopsin gene remains rare. We examined the all-cone retina of another colubrid, Pituophis melanoleucus, thought to be more secretive/burrowing than Thamnophis. We found that P. melanoleucus expresses two cone opsins (SWS1, LWS) and rhodopsin (RH1) within the eye. Immunohistochemistry localized rhodopsin to the outer segment of photoreceptors in the all-cone retina of the snake and all opsin genes produced functional visual pigments when expressed in vitro. Consistent with other studies, we found that P. melanoleucus rhodopsin is extremely blue-shifted. Surprisingly, P. melanoleucus rhodopsin reacted with hydroxylamine, a typical cone opsin characteristic. These results support the idea that the rhodopsincontaining photoreceptors of P. melanoleucus are the products of evolutionary transmutation from rod ancestors, and suggest that this phenomenon may be widespread in colubrid snakes. We hypothesize that transmutationmay beanadaptation for diurnal, brighter-light vision, which could result in increased spectral sensitivity and chromatic discrimination with the potential for colour vision. [ABSTRACT FROM AUTHOR]

The spectral sensitivity and complement of the retinal photoreceptors of the Asiatic smelt from the Sea of Japan were studied by microspectrophotometry and light microscopy. Apart from rods, one type of single cones and one type of unequal double cones were found in major parts of the retina. The dominant type of the cone pattern (mosaic) is a row pattern consisting of various linear arrangements of separate single and double cones. The absorbance maxima of rods and a majority of singe cones and double cones equaled 516, 425 and 514/565 nm, respectively. It has been established that all of the pigments are based on retinal. The findings are compared with data on the osmerid retina from the literature and discussed with respect to the adaptations to light conditions, peculiarities of behavior, and seasonal migrations of smelts. [ABSTRACT FROM AUTHOR]

Key points Following substantial bleaching of the visual pigment, the desensitization of the rod photovoltage is not as substantial as the desensitization of the rod outer segment photocurrent., The block of cation conductances during the internal dialysis of Cs+ further desensitizes the photovoltage thereby eliminating its difference in desensitization with the rod outer segment photocurrent., Bleached visual pigment produced an acceleration of the rod photovoltage with respect to the outer segment photocurrent, which is eliminated upon internal dialysis of Cs+., Abstract A majority of our visual experience occurs during the day when a substantial fraction of the visual pigment in our photoreceptor cells is bleached. Under these conditions it is widely believed that rods are saturated and do not contribute substantially to downstream signalling. However, behavioural experiments on subjects with only rod function reveals that these individuals unexpectedly retain substantial vision in daylight. We sought to understand this discrepancy by characterizing the sensitivity of rod photoresponses following exposure to bright bleaching light. Measurements of the rod outer segment photocurrent in transgenic mice, which have only rod function, revealed the well-studied reduction in the sensitivity of rod photoresponses following pigment bleaching. However, membrane voltage measurements showed that the desensitization of the photovoltage was considerably less than that of the outer segment photocurrent following equivalent pigment bleaching. This discrepancy was largely eliminated during the blockade of cation channels due to the internal dialysis of Cs+, which increased the bleach-induced desensitization of the photovoltage and slowed its temporal characteristics. Thus, sensitization of the photovoltage by rod inner segment conductances appears to extend the operating range of rod phototransduction following pigment bleaching. [ABSTRACT FROM AUTHOR]