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Capture of a photon by an opsin visual pigment isomerizes its 11-cis-retinaldehyde (11cRAL) chromophore to all-trans-retinaldehyde (atRAL), which subsequently dissociates. To restore light sensitivity, the unliganded apo-opsin combines with another 11cRAL to make a new visual pigment. Two enzyme pathways supply chromophore to photoreceptors. The canonical visual cycle in retinal pigment epithelial cells supplies 11cRAL at low rates. The photic visual cycle in Müller cells supplies cones with 11-cis-retinol (11cROL) chromophore precursor at high rates. Although rods can only use 11cRAL to regenerate rhodopsin, cones can use 11cRAL or 11cROL to regenerate cone visual pigments. We performed a screen in zebrafish retinas and identified ZCRDH as a candidate for the enzyme that converts 11cROL to 11cRAL in cone inner segments. Retinoid analysis of eyes from Zcrdh-mutant zebrafish showed reduced 11cRAL and increased 11cROL levels, suggesting impaired conversion of 11cROL to 11cRAL. By microspectrophotometry, isolated Zcrdh-mutant cones lost the capacity to regenerate visual pigments from 11cROL. ZCRDH therefore possesses all predicted properties of the cone 11cROL dehydrogenase. The human protein most similar to ZCRDH is RDH12. By immunocytochemistry, ZCRDH was abundantly present in cone inner segments, similar to the reported distribution of RDH12. Finally, RDH12 was the only mammalian candidate protein to exhibit 11cROL-oxidase catalytic activity. These observations suggest that RDH12 in mammals is the functional ortholog of ZCRDH, which allows cones, but not rods, to regenerate visual pigments from 11cROL provided by Müller cells. This capacity permits cones to escape competition from rods for visual chromophore in daylight-exposed retinas.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

The operation of bacteriorhodopsin (BR) from the archaeon Halobacterium salinarum is based on the photochromic reaction of isomerization of the chromophore group (the retinal protonated Schiff base, RPSB) from the all-trans to the 13-cis form. The ultrafast dynamics of the reverse 13-cis → all-trans photoreaction was studied using femtosecond transient absorption spectroscopy in comparison with the forward photoreaction. The forward photoreaction was initiated by photoexcitation of BR by pulse I (540 nm). The reverse photoreaction was initiated by photoexcitation of the product K590 at an early stage of its formation (5 ps) by pulse II (660 nm). The conversion of the excited K590 to the ground state proceeds at times of 0.19, 1.1, and 16 ps with the relative contributions of ~20/60/20, respectively. All these decay channels lead to the formation of the initial state of BR as a product with a quantum yield of ~1. This state is preceded by vibrationally excited intermediates, the relaxation of which occurs in the 16 ps time range. Likely, the heterogeneity of the excited state of K590 is determined by the heterogeneity of its chromophore center. The forward photoreaction includes two components—0.52 and 3.5 ps, with the relative contributions of 91/9, respectively. The reverse photoreaction initiated from K590 proceeds more efficiently in the conical intersection (CI) region but on the whole at a lower rate compared to the forward photoreaction, due to significant heterogeneity of the potential energy surface. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether more stable electroretinography parameters could be obtained in younger children using skin electrodes placed at the inner canthus and ears compared to using contact lens electrodes. The study included three Japanese patients (two girls and one boy) who presented with epileptic spasms before the age of 3 years. We compared the electroretinography parameters obtained with skin electrodes and contact lens electrodes. We could record reproducible results using skin ERG with a montage of electrodes placed at the inner canthus and the ear in children. Moreover, standard data for younger children were created, enabling the evaluation of electroretinography parameters recorded with skin electrodes in individual pediatric patients. The skin electroretinography using the new montage may be stable parameters for evaluating retinal function in younger children. [ABSTRACT FROM AUTHOR]

Globally, eye disorders have been a major issue, especially in developing nations where resources for technology and financing are limited. Due to its tremendous feature learning ability, CNN has obtained remarkable progress in the area of fundus images. Through appropriate analysis and examination of fundus images, computer-aided diagnosis may yield information with a standard value for experts in clinical diagnosis or screening. However, the majority of earlier investigations have focused on the identification of a particular fundus disease, and the accurate fast classification of multiple fundus diseases remains a major challenge. Extremely numerous retinal fundus images must be analyzed to achieve a categorization that is reliable, fast, and precise. As a result, this research aims to propose a novel classification model for eye illnesses based on four major steps: (a) Pre-processing, (b) segmentation of blood vessels, (c) Extracting features and (d) Multi-classification of eye disease. In order to accurately classify the images, it is necessary to extract the essential informational characteristics from the segmented blood vessels. The categorization of eye diseases is carried out using a hybrid classifier that integrates the SqueezeNet and Long-Term Recurrent Convolutional Network (LRCN). We trained and validated our models using tenfold cross-validation tests on a database of fundus images including five categories: Normal, Retinitis Pigmentosa, Pathological Myopia, Maculopathy and Glaucoma. The efficacy of the presented approach is evaluated based on specificity, F1-score, recall, precision and accuracy of 98%, 97.8%, 97.6%, 98.4% and 98% respectively. [ABSTRACT FROM AUTHOR]

Objective: Rhodopsin from the eubacterium Exiguobacterium sibiricum (ESR) performs the lightdependent proton pumping function. The operation of ESR is based on the ultrafast photochemical reaction of isomerization of the retinal chromophore, which triggers dark processes closed in a photocycle. Many parameters of the photocycle are determined by the presence of a hydrogen bond between the primary counterion Asp85 and the chromophore. ESR in detergent micelles pumps protons most efficiently at pH > 9, when such a bond is most probable. Methods: In the present study, the photochemical reaction of ESR at pH 9.5 was investigated by femtosecond laser absorption spectroscopy. Results and Discussion: It was shown that photoisomerization of the chromophore group occurs in 0.51 ps, with the contribution from the reactive excited state being ca. 80%. A comparison with the earlier obtained data for pH 7.4 showed that, at pH 9.5, the reaction proceeds much faster and more efficiently. Conclusions: The present results confirm the important role of the chromophore group counterion in the photoactivated processes of rhodopsins. [ABSTRACT FROM AUTHOR]

Photoisomerization is a key photochemical reaction in microbial and animal rhodopsins. It is well established that such photoisomerization is highly selective; all-trans to 13-cis, and 11-cis to all-trans forms in microbial and animal rhodopsins, respectively. Nevertheless, unusual photoisomerization pathways have been discovered recently in microbial rhodopsins. In an enzymerhodopsin NeoR, the all-trans chromophore is isomerized into the 7-cis form exclusively, which is stable at room temperature. Although, the 7-cis form is produced by illumination of retinal, formation of the 7-cis form was never reported for a protonated Schiff base of all-trans retinal in solution. Present HPLC analysis of retinal oximes prepared by hydroxylamine reaction revealed that all-trans and 7-cis forms cannot be separated from the syn peaks under the standard HPLC conditions, while it is possible by the analysis of the anti-peaks. Consequently, we found formation of the 7-cis form by the photoreaction of all-trans chromophore in solution, regardless of the protonation state of the Schiff base. Upon light absorption of all-trans protonated retinal Schiff base in solution, excited-state relaxation accompanies double-bond isomerization, producing 7-cis, 9-cis, 11-cis, or 13-cis form. In contrast, specific chromophore-protein interaction enforces selective isomerization into the 13-cis form in many microbial rhodopsins, but into 7-cis in NeoR. [ABSTRACT FROM AUTHOR]

Background: During neurogenesis, growing axons must navigate through the complex extracellular environment and make correct synaptic connections for the proper functioning of neural circuits. The mechanisms underlying the formation of functional neural networks are still only partially understood. Results: Here we analyzed the role of a novel gene si:ch73‐364h19.1/drish in the neural and vascular development of zebrafish embryos. We show that drish mRNA is expressed broadly and dynamically in multiple cell types including neural, glial, retinal progenitor and vascular endothelial cells throughout the early stages of embryonic development. To study Drish function during embryogenesis, we generated drish genetic mutant using CRISPR/Cas9 genome editing. drish loss‐of‐function mutant larvae displayed defects in early retinal ganglion cell, optic nerve and the retinal inner nuclear layer formation, as well as ectopic motor axon branching. In addition, drish mutant adults exhibited deficient retinal outer nuclear layer and showed defective light response and locomotory behavior. However, vascular patterning and blood circulation were not significantly affected. Conclusions: Together, these data demonstrate important roles of zebrafish drish in the retinal ganglion cell, optic nerve and interneuron development and in spinal motor axon branching. Key Findings: si:ch73‐364h19.1 / drish gene encodes a putative transmembrane protein, which is expressed in neural, glial and vascular endothelial cells in zebrafish embryos.Drish zebrafish mutants show defects in retinal ganglion cell differentiation.Drish mutants exhibit defective branching of motor axons.Drish mutant larvae and adults display reduced swimming activity, a defective light response and deficient prey capture. [ABSTRACT FROM AUTHOR]

Rhodopsin is a seven-helical transmembrane protein with a retinal chromophore covalently bound to a conserved lysine in helix G via a retinal protonated Schiff base (RPSB). Microbial rhodopsins absorb light through chromophore and play a fundamental role in optogenetics. Numerous microbial rhodopsins have been discovered, contributing to diverse functions and colors. Solid-state NMR spectroscopy has been instrumental in elucidating the conformation of chromophores and the three-dimensional structure of microbial rhodopsins. This review focuses on the 15N chemical shift values of RPSB and summarizes recent progress in the field. We displayed the correlation between the 15N isotropic chemical shift values of RPSB and the maximum absorption wavelength of rhodopsin using solid-state NMR spectroscopy. [ABSTRACT FROM AUTHOR]

Animal vision depends on opsins, a category of G protein-coupled receptor (GPCR) that achieves light sensitivity by covalent attachment to retinal. Typically binding as an inverse agonist, 11-cis retinal photoisomerizes to the all-trans isomer and activates the receptor, initiating downstream signaling cascades. Retinal bound to bistable opsins isomerizes back to the 11-cis state after absorption of a second photon, inactivating the receptor. Bistable opsins are essential for invertebrate vision and nonvisual light perception across the animal kingdom. While crystal structures are available for bistable opsins in the inactive state, it has proven difficult to form homogeneous populations of activated bistable opsins either via illumination or reconstitution with all-trans retinal. Here, we show that a nonnatural retinal analog, all-trans retinal 6.11 (ATR6.11), can be reconstituted with the invertebrate bistable opsin, Jumping Spider Rhodopsin-1 (JSR1). Biochemical activity assays demonstrate that ATR6.11 functions as a JSR1 agonist. ATR6.11 binding also enables complex formation between JSR1 and signaling partners. Our findings demonstrate the utility of retinal analogs for biophysical characterization of bistable opsins, which will deepen our understanding of light perception in animals. [ABSTRACT FROM AUTHOR]

The unicellular microalga Euglena gracilis has always been considered the ideal alga to investigate photoreceptive responses and systems, and it has been the subject of hundreds of articles. Moreover, because of its detectable photoreceptor, it has been given a key role in the evolution of photoreception, from single and simple cells to complex visual system of higher organisms. In this article, we report the Raman spectra recorded in vivo on photoreceptors of E. gracilis and Bos taurus retina. The almost perfect superimposability (correlation coefficient r = 0.955) of these spectra states that the Euglena possesses a photoreceptor with the same structural characteristic of a vertebrate photoreceptor, i.e. a stack of membrane layers embedding rhodopsin‐like proteins. Raman spectra recorded in vivo on photoreceptors of E. gracilis after hydroxylamine treatment further confirm our findings, which should lead to a reconsideration of most of the scientific literature on algae photoreception and eye evolution. [ABSTRACT FROM AUTHOR]

Topical retinoids continue to be the treatment of choice for healthcare professionals and patients due to their effectiveness in treating several common skincare concerns. In a comprehensive review, Cigdem Kemal Yilmaz discusses the most used topical retinoids: retinyl palmitate, retinol, retinal (retinaldehyde), tretinoin (retinoic acid) and adapalene, and their potential benefits to the skin. This article also addresses the latest EU regulations impacting their use, and the necessity for healthcare professionals to stay informed about advancements and regulatory changes in topical retinoid therapy in order to provide personalised treatment plans for their patients. [ABSTRACT FROM AUTHOR]

Excessive levels of glutamate activity could potentially damage and kill neurons. Glutamate excitotoxicity is thought to play a critical role in many CNS and retinal diseases. Accordingly, glutamate excitotoxicity has been used as a model to study neuronal diseases. Immune proteins, such as major histocompatibility complex (MHC) class I molecules and their receptors, play important roles in many neuronal diseases, while T-cell receptors (TCR) are the primary receptors of MHCI. We previously showed that a critical component of TCR, CD3ζ, is expressed by mouse retinal ganglion cells (RGCs). The mutation of CD3ζ or MHCI molecules compromises the development of RGC structure and function. In this study, we investigated whether CD3ζ-mediated molecular signaling regulates RGC death in glutamate excitotoxicity. We show that mutation of CD3ζ significantly increased RGC survival in NMDA-induced excitotoxicity. In addition, we found that several downstream molecules of TCR, including Src (proto-oncogene tyrosine-protein kinase) family kinases (SFKs) and spleen tyrosine kinase (Syk), are expressed by RGCs. Selective inhibition of an SFK member, Hck, or Syk members, Syk or Zap70, significantly increased RGC survival in NMDA-induced excitotoxicity. These results provide direct evidence to reveal the underlying molecular mechanisms that control RGC death under disease conditions. [ABSTRACT FROM AUTHOR]

For a detailed understanding of chemical processes in nature and industry, we need accurate models of chemical reactions in complex environments. While Eyring transition state theory is commonly used for modeling chemical reactions, it is most accurate for small molecules in the gas phase. A wide range of alternative rate theories exist that can better capture reactions involving complex molecules and environmental effects. However, they require that the chemical reaction is sampled by molecular dynamics simulations. This is a formidable challenge since the accessible simulation timescales are many orders of magnitude smaller than typical timescales of chemical reactions. To overcome these limitations, rare event methods involving enhanced molecular dynamics sampling are employed. In this work, thermal isomerization of retinal is studied using tight‐binding density functional theory. Results from transition state theory are compared to those obtained from enhanced sampling. Rates obtained from dynamical reweighting using infrequent metadynamics simulations were in close agreement with those from transition state theory. Meanwhile, rates obtained from application of Kramers' rate equation to a sampled free energy profile along a torsional dihedral reaction coordinate were found to be up to three orders of magnitude higher. This discrepancy raises concerns about applying rate methods to one‐dimensional reaction coordinates in chemical reactions. [ABSTRACT FROM AUTHOR]

Protein fibrillation is a crucial process in the onset of several neurodegenerative and retinal disorders due to the formation of cytotoxic species. Because of their capacity to prevent protein aggregation, small molecules have the potential to be appointed as therapeutic agents. Here, we examined the inhibitory impacts of the piperonal as a carbaldehyde-derived compound on the fibrillation process of α-synuclein and underlying cytotoxicity against neuron-like (PC12) and human retinal pigment epithelial (RPE) (ARPE-19) cells. The results showed that the values of kapp and lag time of α-synuclein were modulated with piperonal. Moreover, ANS fluorescence intensity analysis indicated that piperonal can inhibit the formation of a molten global (misfolded) state of α-synuclein, which is a necessary step in the formation of protein amyloid fibrils. Congo red absorption and circular dichroism spectroscopy also verified the inhibition of β-sheet structure formation after treatment of α-synuclein with piperonal. Furthermore, theoretical studies displayed that piperonal interacts with VAL40:HN, GLU35:O, VAL40, and LYS43 amino acid residues and forms a complex. In addition, cytotoxicity assays demonstrated that piperonal as a safe small molecule could mitigate the induced cytotoxicity by α-synuclein amyloids in PC12 and ARPE-19 cells through reduction of ROS and Bax/Bcl2 mRNA overexpression. Taken together, these outcomes showed that piperonal as a natural aldehyde compound can inhibit α-synuclein fibrillation and underlying cytotoxicity which may be developed for potential therapeutic applications in vivo.

Hyperfluorescence (HF) and reduced autofluorescence (RA) are important biomarkers in fundus autofluorescence images (FAF) for the assessment of health of the retinal pigment epithelium (RPE), an important indicator of disease progression in geographic atrophy (GA) or central serous chorioretinopathy (CSCR). Autofluorescence images have been annotated by human raters, but distinguishing biomarkers (whether signals are increased or decreased) from the normal background proves challenging, with borders being particularly open to interpretation. Consequently, significant variations emerge among different graders, and even within the same grader during repeated annotations. Tests on in-house FAF data show that even highly skilled medical experts, despite previously discussing and settling on precise annotation guidelines, reach a pair-wise agreement measured in a Dice score of no more than 63–80% for HF segmentations and only 14–52% for RA. The data further show that the agreement of our primary annotation expert with herself is a 72% Dice score for HF and 51% for RA. Given these numbers, the task of automated HF and RA segmentation cannot simply be refined to the improvement in a segmentation score. Instead, we propose the use of a segmentation ensemble. Learning from images with a single annotation, the ensemble reaches expert-like performance with an agreement of a 64–81% Dice score for HF and 21–41% for RA with all our experts. In addition, utilizing the mean predictions of the ensemble networks and their variance, we devise ternary segmentations where FAF image areas are labeled either as confident background, confident HF, or potential HF, ensuring that predictions are reliable where they are confident (97% Precision), while detecting all instances of HF (99% Recall) annotated by all experts. [ABSTRACT FROM AUTHOR]

Background: Retinal microvascular anomalies have been identified in patients with cardiovascular conditions such as arterial hypertension, diabetes mellitus, and carotid artery disease. We conducted a systematic review and meta-analysis (PROSPERO registration number CRD42024506589) to explore the potential of retinal vasculature as a biomarker for diagnosis and monitoring of patients with coronary artery disease (CAD) through optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). Methods: We systematically examined original articles in the Pubmed, Embase, and Web of Science databases from their inception up to November 2023, comparing retinal microvascular features between patients with CAD and control groups. Studies were included if they reported sample mean with standard deviation or median with range and/or interquartile range (which were computed into mean and standard deviation). Review Manager 5.4 (The Cochrane Collaboration, 2020) software was used to calculate the pooled effect size with weighted mean difference and 95% confidence intervals (CI) by random-effects inverse variance method. Results: Eleven studies meeting the inclusion criteria were incorporated into the meta-analysis. The findings indicated a significant decrease in the retinal nerve fiber layer (WMD −3.11 [−6.06, −0.16]), subfoveal choroid (WMD −58.79 [−64.65, −52.93]), and overall retinal thickness (WMD −4.61 [−7.05, −2.17]) among patients with CAD compared to controls (p < 0.05). Furthermore, vascular macular density was notably lower in CAD patients, particularly in the superficial capillary plexus (foveal vessel density WMD −2.19 [−3.02, −1.135], p < 0.0001). Additionally, the foveal avascular zone area was statistically larger in CAD patients compared to the control group (WMD 52.73 [8.79, 96.67], p = 0.02). Heterogeneity was significant (I2 > 50%) for most features except for subfoveal choroid thickness, retina thickness, and superficial foveal vessel density. Conclusion: The current meta-analysis suggests that retinal vascularization could function as a noninvasive biomarker, providing additional insights beyond standard routine examinations for assessing dysfunction in coronary arteries. [ABSTRACT FROM AUTHOR]

We report a rare case of subconjunctival, optic nerve head and retinal haemorrhages secondary to immune thrombocytopenia (ITP) associated with coronavirus disease 2019 (COVID-19). A previously healthy 17-year-old male presented with a 2-day history of generalized rash, dysphagia and redness of right eye. Physical examination revealed diffuse petechiae, peritonsillar mucosal bleeding and subconjunctival haemorrhage in right eye. Investigations revealed anaemia with severe thrombocytopenia, and patient was COVID-19 positive. Ophthalmic evaluation during hospital course revealed subconjunctival haemorrhage in right eye and extensive haemorrhages over the optic nerve head and retinal nerve fibre layer in both eyes. A diagnosis of subconjunctival and retinal haemorrhages secondary to COVID-19-induced immune thrombocytopenia was made. Patient was managed conservatively, and spontaneous resolution was noted at follow-up. COVID-19-induced ITP can rarely present with ocular manifestations. Systemic treatment and correction of hematologic parameters lead to resolution and a successful outcome.

Retinal Optical Coherence Tomography (OCT) is a non-invasive cross-sectional scan of the eye that provides qualitative 3D visualization of the retinal anatomy. It is used to study the retinal structure and the presence of pathogens. The advent of retinal OCT has transformed ophthalmology and is currently paramount for the diagnosis, monitoring, and treatment of many eye diseases, including macular edema, which impairs vision severely, and glaucoma, which can cause irreversible blindness. However, the quality of OCT images can vary among device manufacturers. Deep learning methods have been successful in the medical image segmentation community, but it is not yet clear if the level of success can be generalized across images collected from different device vendors. In this study, we provide a comprehensive review of current deep learning segmentation methods applied to OCT images. Furthermore, to investigate the problem of variant of data sources from OCT device vendors, we analyse a selection of the most representative methods to address this problem, including those on the top of the RETOUCH competition such as nnUNet and its variant nnUNet_RASPP, SAM and its variant SAMedOCT, IAUNet_SPP_CL, alongside other state-of-the-art algorithms. The algorithms were validated on the RETOUCH challenge dataset, which was acquired from three device vendors across three medical centers from patients suffering from two retinal disease types. Experimental results show that for several tasks of segmentation, detection and generalisation performance from the retinal images, while fine-tuned large foundation models such as SAMedOCT have demonstrated promising performance, the specifically designed and trained models such as nnUNet and nnUNet_RASPP still offer a slight advantage overall. Also, the nnUNet_RASPP obtained the best performance of 82.3% of mean Dice score for fluid segmentation.

The operation of bacteriorhodopsin (BR) from the archaeon Halobacterium salinarum is based on the photochromic reaction of isomerization of the chromophore group (the retinal protonated Schiff base, RPSB) from the all-trans to the 13-cis form. The ultrafast dynamics of the reverse 13-cis → all-trans photoreaction was studied using femtosecond transient absorption spectroscopy in comparison with the forward photoreaction. The forward photoreaction was initiated by photoexcitation of BR by pulse I (540 nm). The reverse photoreaction was initiated by photoexcitation of the product K590 at an early stage of its formation (5 ps) by pulse II (660 nm). The conversion of the excited K590 to the ground state proceeds at times of 0.19, 1.1, and 16 ps with the relative contributions of ~20/60/20, respectively. All these decay channels lead to the formation of the initial state of BR as a product with a quantum yield of ~1. This state is preceded by vibrationally excited intermediates, the relaxation of which occurs in the 16 ps time range. Likely, the heterogeneity of the excited state of K590 is determined by the heterogeneity of its chromophore center. The forward photoreaction includes two components—0.52 and 3.5 ps, with the relative contributions of 91/9, respectively. The reverse photoreaction initiated from K590 proceeds more efficiently in the conical intersection (CI) region but on the whole at a lower rate compared to the forward photoreaction, due to significant heterogeneity of the potential energy surface.

In the retina, retinoids involved in vision are under constant threat of oxidation, and their oxidation products exhibit deleterious properties. Using pulse radiolysis, this study determined that the bimolecular rate constants of scavenging cation radicals of retinoids by taurine are smaller than 2 × 107 M−1s−1 whereas lutein scavenges cation radicals of all three retinoids with the bimolecular rate constants approach the diffusion-controlled limits, while zeaxanthin is only 1.4–1.6-fold less effective. Despite that lutein exhibits greater scavenging rate constants of retinoid cation radicals than other antioxidants, the greater concentrations of ascorbate in the retina suggest that ascorbate may be the main protectant of all visual cycle retinoids from oxidative degradation, while α-tocopherol may play a substantial role in the protection of retinaldehyde but is relatively inefficient in the protection of retinol or retinyl palmitate. While the protection of retinoids by lutein and zeaxanthin appears inefficient in the retinal periphery, it can be quite substantial in the macula. Although the determined rate constants of scavenging the cation radicals of retinol and retinaldehyde by dopa-melanin are relatively small, the high concentration of melanin in the RPE melanosomes suggests they can be scavenged if they are in proximity to melanin-containing pigment granules. [ABSTRACT FROM AUTHOR]

There is a need to shift the absorbance of biomolecules to the optical transparency window of tissue for applications in optogenetics and photo-pharmacology. There are a few strategies to achieve the so-called red shift of the absorption maxima. Herein, a series of 11 merocyanine dyes were synthesized and employed as chromophores in place of retinal in bacteriorhodopsin (bR) to achieve a bathochromic shift of the absorption maxima relative to bR's λ max a of 568 nm. Assembly with the apoprotein bacterioopsin (bO) led to stable, covalently bound chromoproteins with strongly bathochromic absorbance bands, except for three compounds. Maximal red shifts were observed for molecules 9, 2, and 8 in bR where the λ max a was 766, 755, and 736 nm, respectively. While these three merocyanines have different end groups, they share a similar structural feature, namely, a methyl group which is located at the retinal equivalent position 13 of the polyene chain. The absorption and fluorescence data are also presented for the retinal derivatives in their aldehyde, Schiff base (SB), and protonated SB (PSB) forms in solution. According to their hemicyanine character, the PSBs and their analogue bRs exhibited fluorescence quantum yields (Φf) several orders of magnitude greater than native bR (Φf 0.02 to 0.18 versus 1.5 × 10–5 in bR) while also exhibiting much smaller Stokes shifts than bR (400 to 1000 cm−1 versus 4030 cm−1 in bR). The experimental results are complemented by quantum chemical calculations where excellent agreement between the experimental λ max a and the calculated λ max a was achieved with the second-order algebraic-diagrammatic construction [ADC(2)] method. In addition, quantum mechanics/molecular mechanics (QM/MM) calculations were employed to shed light on the origin of the bathochromic shift of merocyanine 2 in bR compared with native bR. [ABSTRACT FROM AUTHOR]

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Ocular neovascularization is the leading cause of blindness in clinical settings. Pathological angiogenesis of the eye can be divided into corneal neovascularization (CoNV), retinal neovascularization (RNV, including diabetic retinopathy and retinopathy of prematurity), and choroidal neovascularization (CNV) based on the anatomical location of abnormal neovascularization. Although anti-Vascular endothelial growth factor (VEGF) agents have wide-ranging clinical applications and are an effective treatment for neovascular eye disease, many deficiencies in this treatment strategy remain. Recently, emerging evidence has demonstrated that macrophages are vital during the process of physiological and pathological angiogenesis. Monocyte-macrophage lineage is diverse and plastic, they can shift between different activation modes and have different functions. Due to the obvious regulatory effect of macrophages on inflammation and angiogenesis, macrophages have been increasingly studied in the field of ophthalmology. Here, we detail how macrophage activated and the role of different subtypes of macrophages in the pathogenesis of ocular neovascularization. The complexity of macrophages has recently taken center stage owing to their subset diversity and tightly regulated molecular and metabolic phenotypes. In this review, we reveal the functional and phenotypic characterization of macrophage subsets associated with ocular neovascularization, more in-depth research is needed to explore the specific mechanisms by which macrophages regulate angiogenesis as well as macrophage polarization. Targeted regulation of macrophage differentiation based on their phenotype and function could be an effective approach to treat and manage ocular neovascularization in the future.

Excessive levels of glutamate activity could potentially damage and kill neurons. Glutamate excitotoxicity is thought to play a critical role in many CNS and retinal diseases. Accordingly, glutamate excitotoxicity has been used as a model to study neuronal diseases. Immune proteins, such as major histocompatibility complex (MHC) class I molecules and their receptors, play important roles in many neuronal diseases, while T-cell receptors (TCR) are the primary receptors of MHCI. We previously showed that a critical component of TCR, CD3ζ, is expressed by mouse retinal ganglion cells (RGCs). The mutation of CD3ζ or MHCI molecules compromises the development of RGC structure and function. In this study, we investigated whether CD3ζ-mediated molecular signaling regulates RGC death in glutamate excitotoxicity. We show that mutation of CD3ζ significantly increased RGC survival in NMDA-induced excitotoxicity. In addition, we found that several downstream molecules of TCR, including Src (proto-oncogene tyrosine-protein kinase) family kinases (SFKs) and spleen tyrosine kinase (Syk), are expressed by RGCs. Selective inhibition of an SFK member, Hck, or Syk members, Syk or Zap70, significantly increased RGC survival in NMDA-induced excitotoxicity. These results provide direct evidence to reveal the underlying molecular mechanisms that control RGC death under disease conditions.

Abstract Introduction Plants are a source of natural ingredients with retinol-like properties that can deliver anti-aging benefits without the side effects typically associated with retinoid use. We hypothesized that by combining two such analogs, bakuchiol (BAK) and Vigna aconitifolia extract (VAE), with the potent retinoid retinal (RAL), the anti-photoaging potential of RAL could be enhanced without compromising its skin irritation profile. The purpose of this study was to demonstrate that BAK and VAE potentiate the anti-photoaging activity of RAL. Methods Gene expression profiling of full-thickness reconstructed skin was first used to examine the impact of BAK or VAE in combination with RAL on skin biology. Next, the irritative potential of this combination, and its capacity to reverse key signs of photoaging in an ex vivo model was assessed. Finally, a proof-of-concept open label clinical study was performed to evaluate the anti-photoaging capacity and skin compatibility of a cosmetic formulation (tri-retinoid complex; 3RC) containing this complex in combination with other well characterized anti-photoaging ingredients. Results In vitro profiling suggested that combining 0.1% RAL with BAK or VAE potentiates the effect of RAL on keratinocyte differentiation and skin barrier function without affecting its skin irritation profile. When formulated with other anti-photoaging ingredients, such as niacinamide and melatonin, 3RC reversed ultraviolet radiation-induced deficits in structural components of the dermal extracellular matrix, including hyaluronic acid and collagen. In vivo, it led to a reversal of clinical signs of age and photodamage, with statistically significant improvement to skin firmness (+5.6%), skin elasticity (+13.9%), wrinkle count (−43.2%), and skin tone homogeneity (+7.0%), observed within 28 days of once nightly use. Notably, the number of crow’s feet wrinkles was reduced in 100% of subjects. Furthermore, 3RC was very well tolerated. Conclusion These data suggest that 3RC is a highly effective and well-tolerated treatment for photoaging.

We have an example of a synergetic effect between neuroscience and connectome via artificial intelligence. The invention of Neocognitron, a machine learning algorithm, was inspired by the visual cortical circuitry for complex cells to be made by combinations of simple cells, which uses a hierarchical convolutional neural network (CNN). The CNN machine learning algorithm is powerful in classifying neuron borderlines on electron micrograph images for automatized connectomic analysis. CNN is also useful as a functional framework to analyze the neurocircuitry of the visual system. The visual system encodes visual patterns in the retina and decodes them in the corresponding cortical areas. The knowledge of evolutionarily chosen mechanisms in retinas may help the innovation of new algorithms. Since over a half-century ago, a classical style of serial section transmission electron microscopy has vastly contributed to cell biology. It is still useful to comprehensively analyze the small area of retinal neurocircuitry that is rich in natural intelligence of pattern recognition. I discuss the perspective of our study on the primary rod signal pathway in mouse and macaque retinas with special reference to electrical synapses. Photon detection under the scotopic condition needs absolute sensitivity but no intricate pattern recognition. This extreme case is regarded as the most simplified pattern recognition of the input with no autocorrelation. A comparative study of mouse and macaque retinas, where exists the 7-fold difference in linear size, may give us the underlying principle with quantitative verification of their adaptational designs of neurocircuitry. [ABSTRACT FROM AUTHOR]

Water is usually indispensable for protein function. For ion-pumping rhodopsins, water molecules inside the proteins play an important role in ion transportation. In addition to amino acid residues, water molecules regulate the colors of retinal proteins. It was reported that a sodium-pumping rhodopsin, Krokinobacter eikastus rhodopsin 2 (KR2), showed a color change from red to purple upon dehydration under crystalline conditions. Here, we applied comprehensive visible and IR absorption spectroscopy and resonance Raman spectroscopy to KR2 in liposomes under hydration-controlled conditions. A large increase in the hydrogen-out-of-plane (HOOP) vibration at 947 (H–C11=C12–H Au mode) and moderate increases at 893 (C7–H and C10–H) and 808 (C14–H) cm−1 were observed under dehydrated conditions, which were assigned by using systematically deuterated retinal. Moreover, the Asn variant at Asp116, which functions as a counter ion for the protonated retinal Schiff base (PRSB), caused a large redshift in the absorption maximum and constitutive increase in the HOOP modes under hydrated and dehydrated conditions. The protonation of a counter ion at Asp116 clearly causes a redshift in the absorption maximum as the all-trans retinal chromophore twists upon dehydration. Namely, the results strongly suggested that water molecules are important for maintaining the hydrogen-bonding network at the PRSB and deprotonation state of Asp116 in KR2. [ABSTRACT FROM AUTHOR]

Introduction: Plants are a source of natural ingredients with retinol-like properties that can deliver anti-aging benefits without the side effects typically associated with retinoid use. We hypothesized that by combining two such analogs, bakuchiol (BAK) and Vigna aconitifolia extract (VAE), with the potent retinoid retinal (RAL), the anti-photoaging potential of RAL could be enhanced without compromising its skin irritation profile. The purpose of this study was to demonstrate that BAK and VAE potentiate the anti-photoaging activity of RAL. Methods: Gene expression profiling of full-thickness reconstructed skin was first used to examine the impact of BAK or VAE in combination with RAL on skin biology. Next, the irritative potential of this combination, and its capacity to reverse key signs of photoaging in an ex vivo model was assessed. Finally, a proof-of-concept open label clinical study was performed to evaluate the anti-photoaging capacity and skin compatibility of a cosmetic formulation (tri-retinoid complex; 3RC) containing this complex in combination with other well characterized anti-photoaging ingredients. Results: In vitro profiling suggested that combining 0.1% RAL with BAK or VAE potentiates the effect of RAL on keratinocyte differentiation and skin barrier function without affecting its skin irritation profile. When formulated with other anti-photoaging ingredients, such as niacinamide and melatonin, 3RC reversed ultraviolet radiation-induced deficits in structural components of the dermal extracellular matrix, including hyaluronic acid and collagen. In vivo, it led to a reversal of clinical signs of age and photodamage, with statistically significant improvement to skin firmness (+5.6%), skin elasticity (+13.9%), wrinkle count (−43.2%), and skin tone homogeneity (+7.0%), observed within 28 days of once nightly use. Notably, the number of crow's feet wrinkles was reduced in 100% of subjects. Furthermore, 3RC was very well tolerated. Conclusion: These data suggest that 3RC is a highly effective and well-tolerated treatment for photoaging. [ABSTRACT FROM AUTHOR]

Diabetic Retinopathy (DR) is a disorder of the eye caused by damage to blood vessels in the retina. Damage to the retinal blood vessels can be analyzed by segmenting the blood vessels on the image. This study proposes a combination of image enhancement and blood vessel segmentation in retinal images. Retinal image enhancement is carried out using the black hat transform method to obtain a detailed view of blood vessels in retinal images. Segmentation of blood vessels in retinal images is carried out using the U-Net architecture. The results of image enhancement are measured using MSE and PSNR. This study has an MSE value below 0.05 and a PSNR above 90dB. The MSE and PSNR values obtained show that the black hat transform method is very good at image enhancement. Segmentation has an accuracy value above 0.95 and a sensitivity value above 0.85. In addition, the specificity value and f1-score are above 0.8. This shows that the proposed stages of image enhancement and blood vessel segmentation are able to accurately recognize blood vessel features in retinal images. [ABSTRACT FROM AUTHOR]

The cell membrane of Halobacterium salinarum contains a retinal‐binding photoreceptor, sensory rhodopsin II (HsSRII), coupled with its cognate transducer (HsHtrII), allowing repellent phototaxis behavior for shorter wavelength light. Previous studies on SRII from Natronomonas pharaonis (NpSRII) pointed out the importance of the hydrogen bonding interaction between Thr204NpSRII and Tyr174NpSRII in signal transfer from SRII to HtrII. Here, we investigated the effect on phototactic function by replacing residues in HsSRII corresponding to Thr204NpSRII and Tyr174NpSRII. Whereas replacement of either residue altered the photocycle kinetics, introduction of any mutations at Ser201HsSRII and Tyr171HsSRII did not eliminate negative phototaxis function. These observations imply the possibility of the presence of an unidentified molecular mechanism for photophobic signal transduction differing from NpSRII–NpHtrII. [ABSTRACT FROM AUTHOR]

Schizorhodopsin (SzR) is a new family of light-driven inward proton-pumping rhodopsins discovered in the genomes of Asgard archaea. The genomic survey revealed the presence of SzR in a wide variety of environments including high-temperature waters. The X-ray crystallographic structure suggested that a convergent evolution occurred at the molecular level between SzR and xenorhodopsin, another inward proton-pumping rhodopsin. Interestingly, outward proton-pumping rhodopsin was converted to an inward proton pump by swapping only three residues in the retinal Schiff base region with corresponding ones of SzR, indicating the direction of proton transport is determined by this core region of rhodopsins. [ABSTRACT FROM AUTHOR]

Background: Retinal microvascular anomalies have been identified in patients with cardiovascular conditions such as arterial hypertension, diabetes mellitus, and carotid artery disease. We conducted a systematic review and meta-analysis (PROSPERO registration number CRD42024506589) to explore the potential of retinal vasculature as a biomarker for diagnosis and monitoring of patients with coronary artery disease (CAD) through optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). Methods: We systematically examined original articles in the Pubmed, Embase, and Web of Science databases from their inception up to November 2023, comparing retinal microvascular features between patients with CAD and control groups. Studies were included if they reported sample mean with standard deviation or median with range and/or interquartile range (which were computed into mean and standard deviation). Review Manager 5.4 (The Cochrane Collaboration, 2020) software was used to calculate the pooled effect size with weighted mean difference and 95% confidence intervals (CI) by random-effects inverse variance method. Results: Eleven studies meeting the inclusion criteria were incorporated into the meta-analysis. The findings indicated a significant decrease in the retinal nerve fiber layer (WMD −3.11 [−6.06, −0.16]), subfoveal choroid (WMD −58.79 [−64.65, −52.93]), and overall retinal thickness (WMD −4.61 [−7.05, −2.17]) among patients with CAD compared to controls (p < 0.05). Furthermore, vascular macular density was notably lower in CAD patients, particularly in the superficial capillary plexus (foveal vessel density WMD −2.19 [−3.02, −1.135], p < 0.0001). Additionally, the foveal avascular zone area was statistically larger in CAD patients compared to the control group (WMD 52.73 [8.79, 96.67], p = 0.02). Heterogeneity was significant (I2 > 50%) for most features except for subfoveal choroid thickness, retina thickness, and superficial foveal vessel density. Conclusion: The current meta-analysis suggests that retinal vascularization could function as a noninvasive biomarker, providing additional insights beyond standard routine examinations for assessing dysfunction in coronary arteries.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Proso millet (Panicum miliaceum) is neglected in human nutrition. Thanks to the composition of the grains, millet is suitable for people with celiac disease and it is also useful in the prevention of cardiovascular diseases. For screening the substances in all plant parts of millet via GC–MS, two varieties, Hanacká Mana and Unicum, were used. Substances from the group saccharides, amino acids, fatty acids, carboxylic acids, phytosterols and others were identified in the roots, leaves, stems, and seeds. The highest level of saccharides was found in the stems (83%); amino acids in the roots (6.9%); fatty acids in the seeds (24.6%); carboxylic acids in the roots (3%), phytosterols in the seeds (10.51%); other substances, such as tetramethyl-2-hexadecenol (1.84%) and tocopherols (2.15%), in the leaves; retinal in the roots (1.30%) and squalene in the seeds (1.29%). Saccharides were the dominant group in all plant parts of proso millet followed by fatty acids. The dominant saccharides in all parts of the millet plant were sucrose, fructose and psicose. On the contrary, turanose, trehalose, glucose and cellobiose belonged to the least represented sugars. Additionally, amyrin, miliacin, campesterol, stigmasterol, β-sitosterol, and others were identified. Varietal variability can be assumed, e.g., in retinal, miliacin or amyrin content. [ABSTRACT FROM AUTHOR]

The discovery of how a photon is converted into a chemical signal is one of the most important achievements in the field of vision. A key molecule in this process is the visual chromophore retinal. Several eye diseases are attributed to the abnormal metabolism of retinal in the retina and the retinal pigment epithelium. Also, the accumulation of two toxic retinal derivatives, N-retinylidene-N-retinylethanolamine and the retinal dimer, can damage the retina leading to blindness. RPE65 (Retinal pigment epithelium-specific 65 kDa protein) is one of the central enzymes that regulates the metabolism of retinal and the formation of its toxic metabolites. Its inhibition might decrease the rate of the retinas degeneration by limiting the amount of retinal and its toxic byproducts. Two RPE65 inhibitors, (R)-emixustat and (R)-MB001, were recently developed for this purpose.

Rhodopsin is a light receptor comprised of an opsin protein and a light-sensitive retinal chromophore. Despite more than a century of scrutiny, there is no evidence that opsins function in chemosensation. Here, we demonstrate that three Drosophila opsins, Rh1, Rh4, and Rh7, are needed in gustatory receptor neurons to sense a plant-derived bitter compound, aristolochic acid (ARI). The gustatory requirements for these opsins are light-independent and do not require retinal. The opsins enabled flies to detect lower concentrations of aristolochic acid by initiating an amplification cascade that includes a G-protein, phospholipase Cβ, and the TRP channel, TRPA1. In contrast, responses to higher levels of the bitter compound were mediated through direct activation of TRPA1. Our study reveals roles for opsins in chemosensation and raise questions concerning the original roles for these classical G-protein-coupled receptors.

Recent progress in extremophile biology, exploration of planetary bodies in the solar system, and the detection and characterization of extrasolar planets are leading to new insights in the field of astrobiology and possible distribution of life in the universe. Among the many extremophiles on Earth, the halophilic Archaea (Haloarchaea) are especially attractive models for astrobiology, being evolutionarily ancient and physiologically versatile, potentially surviving in a variety of planetary environments and with relevance for in situ life detection. Haloarchaea are polyextremophilic with tolerance of saturating salinity, anaerobic conditions, high levels of ultraviolet and ionizing radiation, subzero temperatures, desiccation, and toxic ions. Haloarchaea survive launches into Earth's stratosphere encountering conditions similar to those found on the surface of Mars. Studies of their unique proteins are revealing mechanisms permitting activity and function in high ionic strength, perchlorates, and subzero temperatures. Haloarchaea also produce spectacular blooms visible from space due to synthesis of red-orange isoprenoid carotenoids used for photoprotection and photorepair processes and purple retinal chromoproteins for phototrophy and phototaxis. Remote sensing using visible and infrared spectroscopy has shown that haloarchaeal pigments exhibit both a discernable peak of absorption and a reflective "green edge". Since the pigments produce remotely detectable features, they may influence the spectrum from an inhabited exoplanet imaged by a future large space-based telescope. In this review, we focus primarily on studies of two Haloarchaea, Halobacterium sp. NRC-1 and Halorubrum lacusprofundi.

In the retina, retinoids involved in vision are under constant threat of oxidation, and their oxidation products exhibit deleterious properties. Using pulse radiolysis, this study determined that the bimolecular rate constants of scavenging cation radicals of retinoids by taurine are smaller than 2 × 107 M−1s−1 whereas lutein scavenges cation radicals of all three retinoids with the bimolecular rate constants approach the diffusion-controlled limits, while zeaxanthin is only 1.4–1.6-fold less effective. Despite that lutein exhibits greater scavenging rate constants of retinoid cation radicals than other antioxidants, the greater concentrations of ascorbate in the retina suggest that ascorbate may be the main protectant of all visual cycle retinoids from oxidative degradation, while α-tocopherol may play a substantial role in the protection of retinaldehyde but is relatively inefficient in the protection of retinol or retinyl palmitate. While the protection of retinoids by lutein and zeaxanthin appears inefficient in the retinal periphery, it can be quite substantial in the macula. Although the determined rate constants of scavenging the cation radicals of retinol and retinaldehyde by dopa-melanin are relatively small, the high concentration of melanin in the RPE melanosomes suggests they can be scavenged if they are in proximity to melanin-containing pigment granules.

Inherited retinal dystrophies (IRDs) are a global problem that is largely unaddressed, especially in Africa. Black indigenous Africans are rarely represented in research that develops genetic tests and genetic therapies for IRDs, yet their genomes are more diverse. The aim of this literature review is to synthesize information on the IRD genetic research conducted among indigenous black Africans to identify challenges and opportunities for progress. PubMed was searched to identify empirical publications reporting the genetic analysis of IRDs among indigenous Africans. A total of 11 articles were selected for the review. Based on the information in the articles, the main genetic testing methods in use include next-generation, whole exome, and Sanger sequencing. The main IRDs characterized by the genetic tests include retinitis pigmentosa, Leber Congenital Amaurosis, Stagardt disease, and cone dystrophy. Examples of implicated genes include MERTK, GUCY2D, ABCA4, and KCNV2 for the four IRDs, respectively. Research activities on the genetics of IRDs are generally scanty in Africa. Even in South Africa and North Africa where some research activities were noted, only a few indigenous black Africans were included in the study cohorts. There is an urgent need for genetic research on IRDs, especially in East, Central, and West Africa. [ABSTRACT FROM AUTHOR]

The retinal blood vessels in humans are major components with different shapes and sizes. The extraction of the blood vessels from the retina is an important step to identify the type or nature of the pattern of the diseases in the retina. Furthermore, the retinal blood vessel was also used for diagnosis, detection, and classification. The most recent solution in this topic is to enable retinal image improvement or enhancement by a convolution filter and Sauvola threshold. In image enhancement, gamma correction is applied before filtering the retinal fundus. After that, the image should be transformed to a gray channel to enhance pictorial clarity using contrast-limited histogram equalization. For filter, this paper combines two convolution filters, namely sharpen and smooth filters. The Sauvola threshold, the morphology, and the medium filter are applied to extract blood vessels from the retinal image. This paper uses DRIVE and STARE datasets. The accuracies of the proposed method are 95.37% for DRIVE with a runtime of 1.77 s and 95.17% for STARE with 2.05 s runtime. Based on the result, it concludes that the proposed method is good enough to achieve average calculation parameters of a low time quality, quick, and significant. [ABSTRACT FROM AUTHOR]