Internal Limiting Peeling in Conjunction with Subretinal Injection of a Balanced Salt Solution in the Macular Region to Treat Refractory Diabetic Macular Edema.

Background: Diabetic macular edema (DME) is one of the primary causes of decreased visual acuity in patients with diabetic retinopathy (DR). Rapid, effective, and safe treatment of DME is important to ensure patients' vision. Objective: In this study, we observed the efficacy and safety of internal limiting membrane (ILM) peeling in conjunction with subretinal injection of balanced salt solution (BSS) in treating refractory DME. Methods: A prospective, non-case-control study. Patients diagnosed with refractory DME in our hospital between October 2021 and June 2022 were included. All patients received 23G PPV in conjunction with internal limiting membrane removal and subretinal injection of BSS. During and after surgery, intravitreal injections of an anti-VEGF drug were administered. We compared and analyzed the best-corrected visual acuities (BCVA), central macular thickness (CMT), recurrence rate, complications, and other observation indicators. Results: The investigation included 32 patients (32 eyes). The BCVA at each time point after surgery was significantly higher than it was before the surgery (P < .001). One month after the surgery, the BCVA was significantly higher than it was before surgery and one week after the surgery. Postoperative CMT was statistically significantly lower than before surgery, and the difference was statistically significant (P < .001). One month after surgery, CMT was significantly lower than before and one week after surgery, and the difference was statistically significant (P < .001). Still, there was no significant difference between three and six months after surgery. Three times of intravitreal injections of anti-VEGF drugs were administered. At the most recent follow-up, DME recurred in three eyes (9.4%). During the follow-up period, no complications such as vitreous hemorrhage, retinal detachment, macular epiretinal membrane, or macular hole were observed. Conclusion: Subretinal injection of BSS can be an effective treatment for refractory DME and is recommended for clinical use.

The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Background: Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Methods: Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. Results: We first identified specific non-coding variants in CTSB that drive the association with PD and are linked to changes in brain CTSB expression levels. Using iPSC-derived dopaminergic neurons we then find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. Moreover, in cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. Similarly, in midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition or knockout potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. Conclusions: The results of our genetic and functional studies indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

The use of a SOX10 reporter toward ameliorating oligodendrocyte lineage differentiation from human induced pluripotent stem cells.

Oligodendrocytes (OLs) are key players in the central nervous system, critical for the formation and maintenance of the myelin sheaths insulating axons, ensuring efficient neuronal communication. In the last decade, the use of human induced pluripotent stem cells (iPSCs) has become essential for recapitulating and understanding the differentiation and role of OLs in vitro. Current methods include overexpression of transcription factors for rapid OL generation, neglecting the complexity of OL lineage development. Alternatively, growth factor-based protocols offer physiological relevance but struggle with efficiency and cell heterogeneity. To address these issues, we created a novel SOX10-P2A-mOrange iPSC reporter line to track and purify oligodendrocyte precursor cells. Using this reporter cell line, we analyzed an existing differentiation protocol and shed light on the origin of glial cell heterogeneity. Additionally, we have modified the differentiation protocol, toward enhancing reproducibility, efficiency, and terminal maturity. Our approach not only advances OL biology but also holds promise to accelerate research and translational work with iPSC-derived OLs.

The effect of intraocular lens and lens eye on the treatment of macular splits in high myopia.

BACKGROUND: Macular retinoschisis in patients with high myopia is one of the main reasons for a decline in visual function and the perceived deformation of visual objects. OBJECTIVE: This study aimed to investigate the therapeutic effect of cataract phacoemulsification and foldable intraocular lens implantation (FILI) combined with internal limiting membrane stripping (ILMS) in the treatment of macular retinoschisis in patients with high myopia. METHODS: A total of 52 patients (55 eyes) who had been diagnosed with macular retinoschisis with high myopia between June 2019 and June 2020 were enrolled in the present study. Patients in the control group (25 eyes) received 23G vitreous surgery and macular ILMS and long-term inert gas (C3F8) filling of the vitreous cavity; patients in the research group (30 eyes) were additionally treated with cataract phacoemulsification and soft intraocular lens on the same treatment basis as the control group. RESULTS: The difference in average BCVA between the control and the research groups was not statistically significant before the surgery (P> 0.05) but was statistically significant 12 months after the procedure (P< 0.05). The minimum foveal thickness was significantly decreased in the two groups after the surgery compared with before the procedure (P< 0.05). CONCLUSION: Cataract phacoemulsification and FILI further improved the therapeutic effect of ILMS in the treatment of macular retinoschisis in patients with high myopia.

The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

Transcriptional Dysregulation and Impaired Neuronal Activity in FMR1 Knock-Out and Fragile X Patients' iPSC-Derived Models.

Fragile X syndrome (FXS) is caused by a repression of the FMR1 gene that codes the Fragile X mental retardation protein (FMRP), an RNA binding protein involved in processes that are crucial for proper brain development. To better understand the consequences of the absence of FMRP, we analyzed gene expression profiles and activities of cortical neural progenitor cells (NPCs) and neurons obtained from FXS patients' induced pluripotent stem cells (IPSCs) and IPSC-derived cells from FMR1 knock-out engineered using CRISPR-CAS9 technology. Multielectrode array recordings revealed in FMR1 KO and FXS patient cells, decreased mean firing rates; activities blocked by tetrodotoxin application. Increased expression of presynaptic mRNA and transcription factors involved in the forebrain specification and decreased levels of mRNA coding AMPA and NMDA subunits were observed using RNA sequencing on FMR1 KO neurons and validated using quantitative PCR in both models. Intriguingly, 40% of the differentially expressed genes were commonly deregulated between NPCs and differentiating neurons with significant enrichments in FMRP targets and autism-related genes found amongst downregulated genes. Our findings suggest that the absence of FMRP affects transcriptional profiles since the NPC stage, and leads to impaired activity and neuronal differentiation over time, which illustrates the critical role of FMRP protein in neuronal development.

Identification of high-performing antibodies for Superoxide dismutase [Cu-Zn] 1 (SOD1) for use in Western blot, immunoprecipitation, and immunofluorescence.

Superoxide dismutase [Cu-Zn] 1 (SOD1), is an antioxidant enzyme encoded by the gene SOD1, responsible for regulating oxidative stress levels by sequestering free radicals. Identified as the first gene with mutations in Amyotrophic lateral sclerosis (ALS), SOD1 is a determinant for studying diseases of aging and neurodegeneration. With guidance on well-characterized anti-SOD1 antibodies, the reproducibility of SOD1 research would be enhanced. In this study, we characterized eleven SOD1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

Internal limiting membrane peeling combined with mouse nerve growth factor injection for idiopathic macular hole.

BACKGROUND: The study was intended to confirm whether Pars Plana Vitrectomy (PPV) with Internal Limiting Membrane (ILM) peeling and intravitreal injection mouse Nerve Growth Factor(mNGF) was effective for the treatment of Idiopathic Macular Hole(IMH) by Optical Coherence Tomography Angiography(OCTA) and microperimetry. METHODS: A retrospective study was performed in adults' patients. A total of 44 eyes (March 2021-October 2021) with IMH who received surgical treatment in the Affiliated Eye Hospital of Nanchang University in Nanchang City, Jiangxi Province were selected. The subjects were treated using PPV combined with ILM peeling and intravitreal mNGF (combined group) or PPV combined with ILM peeling (placebo group). The Best Corrected Visual Acuity (BCVA), Optical Coherence Tomography Angiography (OCTA) and MP-3 microperimetry were carried out and observed at baseline, 1 week(1W), 1,3 and 6 months (1 M,3 M,6 M) postoperatively. RESULTS: The minimum diameter of MH were (568.650 ± 215.862)µm and (533.348 ± 228.836)µm in the Placebo and Combine group pre-operative. During the observation, the macular hole closure rate in the placebo group and combined group were 90% and 95.8% respectively and the difference was not statistically significant(p = 0.583). Compared to pre-surgery, the perimeter and circularity of Foveal Avascular Zone (FAZ) in the placebo group decreased at 1,3,6 M (p = 0.001, < 0.001, < 0.001) and 1W,1,6 M (p = 0.045,0.010, < 0.001) post-surgery respectively. And the perimeter and circularity of FAZ showed significant reduction in the combined group at 1,3,6 M (p = 0.005,0.004, < 0.001) and at each follow-up time point (all values of p < 0.001). The vascular density of SCP increased at 1W(p = 0.031) and 6 M(p = 0.007), the perfusion density of SCP was significantly improved at each follow-up time point (p = 0.028, 0.011, 0.046, 0.004) in the combined group. The BCVA in the combined group was more obvious than that in the placebo group at 1 M, 3 M and 6 M after operation (t1 = 2.248, p1 = 0.030; t3 = 3.546, p3 = 0.001; t6 = 3.054, p6 = 0.004). The changes of BCVA in the combined group was more conspicuous than that in the placebo group at each follow-up time point, and the difference was statistically significant (t1 = 2.206,p1 = 0.033;t2 = 2.54,p2 = 0.015;t3 = 3.546,p3 = 0.001;t6 = 3.124,p6 = 0.003).At 1 M, 3 M and 6 M, the MRS of 2° and 4° in the combined group was better than that in the placebo group(t = -2.429,-2.650,-3.510,-2.134,-2.820,-3.099 p = 0.020,0.011,0.001,0.039,0.007,0.004). During various time points, the MRS of 12°in the combined group was better than that in the placebo group, the difference was statistically significant (t = -3.151, -3.912, -4.521, -4.948, p1 = 0.003, < 0.001, < 0.001 < 0.001). The integrity of External Limiting Membrane (ELM) in combination group was better than that in placebo group at 6 M postoperative(p = 0.022) and that of Ellipsoid Zone(EZ) was preferable in the combined group at 3 M and 6 M after surgery(p = 0.012,0.004). Correlation analysis showed that the integrity of EZ was correlated with 12°MRS at 1 M, 3 M and 6 M after surgery(r = -0.318, -0.343,-0.322;p = 0.023,0.033, < 0.001). There was no correlation between postoperative ELM integrity and postoperative BCVA and 12°MRS(p > 0.05). CONCLUSIONS: Our results manifested that PPV combined with ILM peeling and intravitreal injection mNGF might be more effective for initial IMH. This method increased the blood flow, MRS and promoted the recovery of ELM and EZ in the macular and might improve the visual function of patients postoperatively.

NCBP1 Improves Cognitive Function in Mice by Reducing Oxidative Stress, Neuronal Loss, and Glial Activation After Status Epilepticus.

Status epilepticus (SE) is a severe manifestation of epilepsy which can cause neurologic injury and death. This study aimed to identify key proteins involved in the pathogenesis of epilepsy and find a potential drug target for SE treatment. Tandem mass tag (TMT)-based quantitative proteomic analysis was applied to screen differentially expressed proteins (DEPs) in epilepsy. The adeno-associated virus was employed to overexpress candidate DEP in mice, and kainic acid (KA) was used to generate a mouse model of epilepsy. Then histopathological examination of the hippocampal tissue was performed, and the inflammatory factors levels in serum and hippocampus were measured. The IP-MS analysis was carried out to identify the interacting protein of nuclear cap-binding protein 1 (NCBP1). The results were that NCBP1 was downregulated in the epileptic hippocampus. NCBP1 overexpression alleviated KA-induced cognitive impairment in mice and reduced the apoptosis and damage of hippocampal neurons. Additionally, overexpressed NCBP1 increased the expression of NeuN and reduced the expression of GFAP and IBA-1 in the hippocampus of the mice. Further study indicated that NCBP1 overexpression inhibited the expression of IL-6, IL-1ß, and IFN-γ in serum and hippocampus as well as MDA and LDH in the hippocampus, whereas it increased the SOD levels, suggesting that overexpression of NCBP1 could diminish KA-induced inflammatory responses and oxidative stress. The IP-MS analysis identified that ELAVL4 was the NCBP1-interacting protein. In conclusion, this finding suggests that NCBP1 may potentially serve as a drug target for the treatment of epilepsy.

Exploring the Effect of the Gut Microbiome on the Risk of Age-Related Macular Degeneration From the Perspective of Causality.

Purpose: To explore the mechanisms relating the gut microbiome (GM) to age-related macular degeneration (AMD), as they remain unclear. GM taxa that appear to act within the gut-retina axis may affect the risk of AMD. Methods: Single-nucleotide polymorphisms (SNPs) of 196 GM taxa were obtained from the MiBioGen consortium, and a Mendelian randomization (MR) study was carried out to estimate the causality between GM taxa and AMD (defined as an endpoint based on ICD-9 and ICD-10). Using the data from the FinnGen consortium (6157 patients and 288,237 controls), we explored the GM taxa for causality and verified the results at the replication stage based on the MRC-IEU consortium (3553 cases and 147,089 controls). Inverse variance weighting (IVW) was the main method used to analyze causality, and the MR results were verified using heterogeneity tests and pleiotropy tests. Results: According to the MR results, order Rhodospirillales (P = 3.38 × 10-2), family Victivallaceae (P = 3.14 × 10-2), family Rikenellaceae (P = 3.58 × 10-2), genus Slackia (P = 3.15 × 10-2), genus Faecalibacterium (P = 3.01 × 10-2), genus Bilophila (P = 1.11 × 10-2), and genus Candidatus Soleaferrea (P = 2.45 × 10-2) were suggestively associated with AMD. In the replication stage, only order Rhodospirillales (P = 0.03) passed validation. The heterogeneity (P > 0.05) and pleiotropy (P > 0.05) tests in two stages confirmed the robustness of the MR results. Conclusions: We confirmed that order Rhodospirillales influenced the risk of AMD based on the gut-retina axis, providing new impetus for the development of the GM as an intervention to prevent the occurrence and development of AMD.

The identification of high-performing antibodies for RNA-binding protein FUS for use in Western Blot, immunoprecipitation, and immunofluorescence.

RNA-binding protein Fused-in Sarcoma (FUS) plays an essential role in various cellular processes. Mutations in the C-terminal domain region, where the nuclear localization signal (NLS) is located, causes the redistribution of FUS from the nucleus to the cytoplasm. In neurons, neurotoxic aggregates are formed as a result, contributing to neurogenerative diseases. Well-characterized anti-FUS antibodies would enable the reproducibility of FUS research, thereby benefiting the scientific community.  In this study, we characterized ten FUS commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

Combined transcriptomics and proteomics forecast analysis for potential biomarker in the acute phase of temporal lobe epilepsy.

Background: Temporal lobe epilepsy (TLE) is a common chronic episodic illness of the nervous system. However, the precise mechanisms of dysfunction and diagnostic biomarkers in the acute phase of TLE are uncertain and hard to diagnose. Thus, we intended to qualify potential biomarkers in the acute phase of TLE for clinical diagnostics and therapeutic purposes. Methods: An intra-hippocampal injection of kainic acid was used to induce an epileptic model in mice. First, with a TMT/iTRAQ quantitative labeling proteomics approach, we screened for differentially expressed proteins (DEPs) in the acute phase of TLE. Then, differentially expressed genes (DEGs) in the acute phase of TLE were identified by linear modeling on microarray data (limma) and weighted gene co-expression network analysis (WGCNA) using the publicly available microarray dataset GSE88992. Co-expressed genes (proteins) in the acute phase of TLE were identified by overlap analysis of DEPs and DEGs. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) algorithms were used to screen Hub genes in the acute phase of TLE, and logistic regression algorithms were applied to develop a novel diagnostic model for the acute phase of TLE, and the sensitivity of the diagnostic model was validated using receiver operating characteristic (ROC) curves. Results: We screened a total of 10 co-expressed genes (proteins) from TLE-associated DEGs and DEPs utilizing proteomic and transcriptome analysis. LASSO and SVM-RFE algorithms for machine learning were applied to identify three Hub genes: Ctla2a, Hapln2, and Pecam1. A logistic regression algorithm was applied to establish and validate a novel diagnostic model for the acute phase of TLE based on three Hub genes in the publicly accessible datasets GSE88992, GSE49030, and GSE79129. Conclusion: Our study establishes a reliable model for screening and diagnosing the acute phase of TLE that provides a theoretical basis for adding diagnostic biomarkers for TLE acute phase genes.

The role of aldosterone in the pathogenesis of diabetic retinopathy.

Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR.

Evaluation of retinal microcirculation alterations using OCTA in hyperopic ametropic amblyopia patients before and after treatment.

PURPOSE: We aimed to compare retinal microcirculation in hyperopic ametropic amblyopia patients before and after treatment and in healthy children using optical coherence tomography angiography (OCTA), and to explore the pathogenesis of hyperopic ametropic amblyopia. METHODS: Eighteen patients with hyperopic ametropic amblyopia aged 4-8 years were selected as the patient group, and 18 age-matched healthy children were randomly selected as controls. The foveal avascular zone (FAZ) area, perimeter and circularity, vessel density (VD) and perfusion density (PD) of macular superficial retinal capillary plexus, macular thickness, peripapillary retinal nerve fiber layer thickness, and ganglion cell-inner plexiform layer thickness were compared between both groups. After 6 months of amblyopia treatment, the same parameters were measured again. RESULTS: The VD and PD in the central, inner, inner nasal, and inner inferior regions in hyperopic ametropic amblyopia were lower than in the control group after adjustment for axial length. After 6 months of treatment, the VD increased significantly, except in the outer nasal and outer inferior regions. The PD in the central (p < 0.001), inner superior (p = 0.001), inner inferior (p = 0.011) and inner temporal (p = 0.026) regions increased. The FAZ perimeter and circularity significantly differed between the groups. After 6 months of treatment, the FAZ area and perimeter decreased, but circularity increased. CONCLUSION: Hyperopic ametropic amblyopia eyes showed a significant decrease in vessel and perfusion densities. After amblyopia treatment, the vessel and perfusion densities of patients with hyperopic ametropic amblyopia increased, suggesting that abnormalities in the microvascular system are a pathogenic factor of amblyopia.

Evaluation of retinal microcirculation alterations using optical coherence tomography angiography in patients with hyperopia ametropic amblyopia: A case-control study.

Given that there are controversial findings regarding vessel density in amblyopia, we quantified retinal microcirculation using optical coherence tomography angiography and compared it between hyperopic ametropic amblyopia eyes and age-matched control eyes. This case-control study was conducted from March 2021 to March 2022 at the Affiliated Eye Hospital of Nanchang University, Nanchang, China. Both groups included 72 eyes. Foveal avascular zone area, circularity and perimeter, perfusion density and vessel density of macular superficial retinal capillary plexus, macular thickness, macular volume, peripapillary retinal nerve fiber layer thickness, and ganglion cell-inner plexiform layer thickness were compared between hyperopia ametropic amblyopia eyes and age-matched control eyes. Additionally, best-corrected visual acuity, maximum corneal curvature, minimum corneal curvature, and anterior chamber depth were measured. In the hyperopia ametropic amblyopia eyes and control eyes, vessel density was 7.51 ± 2.13 and 9.91 ± 2.71 mm-1 in the central, 17.20 ± 1.38 and 18.25 ± 1.37 mm-1 in the inner, and 17.90 ± 0.88 and 18.43 ± 0.97 mm-1 in the full regions, respectively. The perfusion densities were 0.17 ± 0.06 and 0.23 ± 0.07 in the central, 0.41 ± 0.05 and 0.44 ± 0.03 in the inner, and 0.44 ± 0.03 and 0.46 ± 0.02 in the full regions, respectively. The central macular thicknesses of hyperopia ametropic amblyopia and control eyes were 240.04 ± 20.11 and 235.08 ± 24.41 µm, respectively. Foveal avascular zone perimeter and circularity (P < .043 and P = .001) significantly differed between the 2 groups. Hyperopia ametropic amblyopia eyes showed lower appreciably in vessel and perfusion densities, which could be one of the major pathophysiological mechanisms of hyperopia ametropic amblyopia and provide a new direction for the diagnosis and treatment of amblyopia.

Comparison of anterior sclera thickness in emmetropes and myopes.

BACKGROUND: This study aimed to compare anterior scleral thicknesses (ASTs) in people with emmetropia and myopia to explore the effect of myopia on AST. METHODS: In this cross-sectional study, 93 participants (i.e., 93 eyes) with emmetropia and myopia underwent ocular imaging via anterior segment optical coherence tomography. We acquired raw B-scan OCT images along each of the four meridians (superior, inferior, nasal, and temporal), The AST was estimated from the limbus to a distance of 6 mm. The participants were aged between 20 and 50 years (mean age: 30.2 ± 8.8 years). The axial length (AL) was 22.50 ~ 33.04 mm (mean AL: 26.51 ± 2.65 mm), and the spherical equivalent (SE) was + 0.50 ~ 27.5 D (mean SE: -7.20 ± 6.5 D). The selected sample comprised 37 males and 56 females who were categorized as emmetropes, mild-moderate myopes, or high myopes. The four meridians of AST, AL, and refractive error were observed. RESULTS: The AL was significantly negatively correlated with the four meridians of AST (the r value ranged between - 0.511 and - 0.228, P < 0.05). There was no significant correlation between age and inferior diameter (r = 0.113, P = 0.314), but age was positively correlated with the average AST of the superior, temporal, and nasal diameters (the r value ranged between 0.452 and 0.552, P < 0.05). There was no significant correlation between sex and AST (the T value ranged between - 1.816 and - 0.130, P > 0.05). Except for the inferior diameters of 1 mm, 5 mm, and 6 mm and the temporal diameter of 1 mm, the four diameters in the emmetropia group and the high myopia group were statistically significant at a distance of 0 ~ 6 mm from the limbus (P < 0.05). CONCLUSION: The AST is negatively correlated with AL and positively correlated with age. Compared with emmetropic eyes, the AST is thinner in highly myopic eyes. Myopia affects AST, which may be useful for monitoring progression in cases of myopia.

Loss of C9orf72 perturbs the Ran-GTPase gradient and nucleocytoplasmic transport, generating compositionally diverse Importin ß-1 granules.

A hexanucleotide (GGGGCC)n repeat expansion in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), eliciting toxic effects through generation of RNA foci, dipeptide repeat proteins, and/or loss of C9orf72 protein. Defects in nucleocytoplasmic transport (NCT) have been implicated as a pathogenic mechanism underlying repeat expansion toxicity. Here, we show that loss of C9orf72 disrupts the Ran-GTPase gradient and NCT in vitro and in vivo. NCT disruption in vivo is enhanced by the presence of compositionally different types of cytoplasmic Importin ß-1 granule that exhibit neuronal subtype-specific properties. We show that the abundance of Importin ß-1 granules is increased in the context of C9orf72 deficiency, disrupting interactions with nuclear pore complex proteins. These granules appear to associate with the nuclear envelope and are co-immunoreactive for G3BP1 and K63-ubiquitin. These findings link loss of C9orf72 protein to gain-of-function mechanisms and defects in NCT.

TFEB attenuates hyperglycemia-induced retinal capillary endothelial cells injury via autophagy regulation.

Diabetic retinopathy is a common microvascular complication of diabetes mellitus. The maintenance of retinal capillary endothelial cell homeostasis requires a complete and unobtrusive flow of autophagy because it may help combat the inflammatory response, apoptosis, and oxidative stress damage of cells in diabetes mellitus. The transcription factor EB is a master regulator of autophagy and lysosomal biogenesis, but its role in diabetic retinopathy remains unknown. This study aimed to confirm the involvement of transcription factor EB in diabetic retinopathy and explore the role of transcription factor EB in hyperglycemia-linked endothelial injury in vitro. First, the expression levels, including the nuclear location of transcription factor EB and autophagy, were reduced in diabetic retinal tissues and high glucose-treated human retinal capillary endothelial cells. Subsequently, autophagy was mediated by transcription factor EB in vitro. Moreover, transcription factor EB overexpression reversed high glucose-induced autophagy inhibition and lysosomal dysfunction and protected human retinal capillary endothelial cells from inflammation, apoptosis, and oxidative stress damage caused by high glucose treatment. Additionally, under high-glucose stimulation, the autophagy inhibitor chloroquine attenuated transcription factor EB overexpression-mediated protection, and the autophagy agonist Torin1 rescued transcription factor EB knockdown-induced damage effects. Taken together, these results suggest that transcription factor EB is involved in the development of diabetic retinopathy. In addition, transcription factor EB protects human retinal capillary endothelial cells from high glucose-induced endothelial damage via autophagy.

Mendelian randomization analysis reveals causal relationships between gut microbiome and optic neuritis.

BACKGROUND: It is unclear whether gut microbiota (GM) affects the risk of optic neuritis (ON) through the "gut-brain" axis and the "gut-retina" axis. To examine the causal relationship between GM and ON, we conducted Mendelian randomization (MR) study. METHODS: Up to 18,340 samples of 24 population-based cohorts were included in genome-wide association study (GWAS) of 196 GM taxa. ON outcomes were selected from the FinnGen GWAS (951 ON cases and 307,092 controls). In addition, the GWAS based on UK Biobank (UKB) (105 ON cases and 456,243 controls) was used for further exploration. Inverse variance weighted (IVW) was carried out to estimate their effects on ON risk and the MR assumptions were evaluated in sensitivity analyses. RESULTS: Among the 196 GM taxa, the IVW results confirmed that Family -Peptococcaceae (P = 2.17 × 10-3), Genus- Hungatella (P = 4.57 × 10-3) and genus-Eubacterium_rectale_group (P = 0.02) were correlated with the risk of ON based on Finngen GWAS. Based on data from UKB, Genus- Eubacterium_hallii_group (P = 1.50 × 10-3) and Genus- Ruminococcaceae_UCG_002 (P = 0.02) were correlated with the risk of ON. At the phylum, class and order levels, no GM taxa were causally related to ON (P > 0.05). Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analysis confirmed the robustness of the MR results. CONCLUSION: Our MR findings support the causal effect of specific GM taxa on ON. GM may affect the risk of ON through the "gut-brain" axis and the "gut-retina" axis. However, further research is needed to confirm the relevant mechanism of the relationship between GM and ON.

Integrative analyses of a mitophagy-related gene signature for predicting prognosis in patients with uveal melanoma.

We aimed to create a mitophagy-related risk model via data mining of gene expression profiles to predict prognosis in uveal melanoma (UM) and develop a novel method for improving the prediction of clinical outcomes. Together with clinical information, RNA-seq and microarray data were gathered from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. ConsensusClusterPlus was used to detect mitophagy-related subgroups. The genes involved with mitophagy, and the UM prognosis were discovered using univariate Cox regression analysis. In an outside population, a mitophagy risk sign was constructed and verified using least absolute shrinkage and selection operator (LASSO) regression. Data from both survival studies and receiver operating characteristic (ROC) curve analyses were used to evaluate model performance, a bootstrap method was used test the model. Functional enrichment and immune infiltration were examined. A risk model was developed using six mitophagy-related genes (ATG12, CSNK2B, MTERF3, TOMM5, TOMM40, and TOMM70), and patients with UM were divided into low- and high-risk subgroups. Patients in the high-risk group had a lower chance of living longer than those in the low-risk group (p < 0.001). The ROC test indicated the accuracy of the signature. Moreover, prognostic nomograms and calibration plots, which included mitophagy signals, were produced with high predictive performance, and the risk model was strongly associated with the control of immune infiltration. Furthermore, functional enrichment analysis demonstrated that several mitophagy subtypes may be implicated in cancer, mitochondrial metabolism, and immunological control signaling pathways. The mitophagy-related risk model we developed may be used to anticipate the clinical outcomes of UM and highlight the involvement of mitophagy-related genes as prospective therapeutic options in UM. Furthermore, our study emphasizes the essential role of mitophagy in UM.