Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in TM dysfunction; however, whether the cellular effects of TM cells are involved in the pathogenesis of SIG remains unclear. Here, we found that the induction of cellular senescence was associated with TM dysfunction, causing SIG in cultured cells and mouse models. Especially, we established the transcriptome landscape in the TM tissue of SIG mice via microarray screening and identified ANRIL as the most differentially expressed long non-coding RNA, with a 5.4-fold change. The expression level of ANRIL was closely related to ocular manifestations (IOP elevation, cup/disc ratio, and retinal nerve fiber layer thickness). Furthermore, p15, the molecular target of ANRIL, was significantly upregulated in SIG and was correlated with ocular manifestations in an opposite direction to ANRIL. The reciprocal regulation between ANRIL and p15 was validated using luciferase reporter assay. Through depletion in cultured cells and a mouse model, ANRIL/p15 signaling was confirmed in cellular senescence via cyclin-dependent kinase activity and, subsequently, by phosphorylation of the retinoblastoma protein. ANRIL depletion imitated the SIG phenotype, most importantly IOP elevation. ANRIL depletion-induced IOP elevation in mice can be effectively suppressed by p15 depletion. Analyses of the single-cell atlas and transcriptome dynamics of human TM tissue showed that ANRIL/p15 expression is spatially enriched in human TM cells and is correlated with TM dysfunction. Moreover, ANRIL is colocalized with a GWAS risk variant (rs944800) of glaucoma, suggesting its potential role underlying genetic susceptibility of glaucoma. Together, our findings suggested that steroid treatment promoted cellular senescence, which caused TM dysfunction, IOP elevation, and irreversible vision loss. Molecular therapy targeting the ANRIL/p15 signal exerted a protective effect against steroid treatment and shed new light on glaucoma management.

Tissue-based functional genomics resources including molecular quantitative trait loci datasets lack diversity in ancestry and tissue types and thus are inadequate for comprehensively investigating gene regulation. Global efforts to increase the tissue diversity will help achieve more equitable medical care.

Congenital cataract (CC) is the primary cause of treatable childhood blindness worldwide. The establishment of reliable, epidemiological estimates is an essential first step towards management strategies. We undertook an initial systematic review and meta-analysis to estimate the prevalence and other epidemiological characteristics of CC. PubMed, Medline, Web of Science, Embase, and Cochrane Library were searched before January 2015. A meta-analysis with random-effects model based on a proportions approach was performed to determine the population-based prevalence of CC and to describe the data regarding the laterality, morphology, associated comorbidities and etiology. Heterogeneity was analyzed using the meta-regression method, and subgroup analyses were performed. 27 studies were selected from 2,610 references. The pooled prevalence estimate was 4.24 per 10,000 people, making it a rare disease based on WHO standards. Subgroup analyses revealed the highest CC prevalence in Asia, and an increasing prevalence trend through 2000. Other epidemiological characteristics showed CC tended to be bilateral, isolated, hereditary and in total/nuclear morphology. Huge heterogeneity was identified across most estimates (I(2) > 75%). Most of the variations could be explained by sample size, research period and age at diagnosis. The findings provide suggestions for etiology of CC, improvements in screening techniques and development of public health strategies.

Cryptophthalmos is a rare congenital disorder characterized by ocular dysplasia with eyelid malformation. Complete cryptophthalmos is characterized by the presence of continuous skin from the forehead over the eyes and onto the cheek, along with complete fusion of the eyelids. In the present study, we characterized the clinical manifestations of three patients with isolated bilateral cryptophthalmos. These patients shared the same c.6499C > T missense mutation in the FRAS1-related extracellular matrix protein 2 (FREM2) gene, while each individual presented an additional nonsense mutation in the same gene (Patient #1, c.2206C > T; Patient #2, c.5309G > A; and Patient #3, c.4063C > T). Then, we used CRISPR/Cas9 to generate mice carrying Frem2R725X/R2156W compound heterozygous mutations, and showed that these mice recapitulated the human isolated cryptophthalmos phenotype. We detected FREM2 expression in the outer plexiform layer of the retina for the first time in the cryptophthalmic eyes, and the levels were comparable to the wild-type mice. Moreover, a set of different expressed genes that may contribute secondarily to the phenotypes were identified by performing RNA sequencing (RNA-seq) of the fetal Frem2 mutant mice. Our findings extend the spectrum of FREM2 mutations, and provide insights into opportunities for the prenatal diagnosis of isolated cryptophthalmos. Furthermore, our work highlights the importance of the FREM2 protein during the development of eyelids and the anterior segment of the eyeballs, establishes a suitable animal model for studying epithelial reopening during eyelid development and serves as a valuable reference for further mechanistic studies of the pathogenesis of isolated cryptophthalmos.

Lens opacity seriously affects the visual development of infants. Slit-illumination images play an irreplaceable role in lens opacity detection; however, these images exhibited varied phenotypes with severe heterogeneity and complexity, particularly among pediatric cataracts. Therefore, it is urgently needed to explore an effective computer-aided method to automatically diagnose heterogeneous lens opacity and to provide appropriate treatment recommendations in a timely manner.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.

Alleles that cause advantageous phenotypes with positive selection contribute to adaptive evolution. Investigations of positive selection in protein-coding genes rely on the accuracy of orthology, models, the quality of assemblies, and alignment. Here, based on the latest genome assemblies and gene annotations, we present a comparative analysis on positive selection in four great ape species and identify 211 high-confidence positively selected genes (PSGs). Even the differences in population size among these closely related great apes have resulted in differences in their ability to remove deleterious alleles and to adapt to changing environments, we found that they experienced comparable numbers of positive selection. We also uncovered that more than half of multigene families exhibited signals of positive selection, suggesting that imbalanced positive selection resulted in the functional divergence of duplicates. Moreover, at the expression level, although positive selection led to a more non-uniform pattern across tissues, the correlation between positive selection and expression patterns is diverse. Overall, this updated list of PSGs is of great significance for the further study of the phenotypic evolution in great apes.

To investigate the characteristics of young adult cataract (YAC) patients over a 10-year period.

Capsular outcomes of anterior/posterior capsulorhexis opening (ACO/PCO) are essential for performing a secondary in-the-bag intraocular lens implantation. To compare the capsular outcomes with different primary capsulorhexis sizes, Thirty-eight eligible patients (45 eyes) were randomly assigned to three groups by anterior capsulorhexis diameter (Group A: 3.0-3.9, Group B: 4.0-5.0, and Group C: 5.1-6.0 mm). The areas of ACO/PCO and posterior capsule opening opacity (PCOO) as primary outcomes, while, the incidence of visual axis opacity (VAO) as secondary outcome were measured at follow-up visits. Among the thirty eyes included in the final analysis, the mean area of the ACO decreased significantly, whereas the PCO enlarged with time. Group A had the highest anterior capsule constriction and percentage reduction, which increased with time. There were significant differences in the percentage reductions at 6 months and 1 year compared to 1 month in Group A and B. Group C had the highest posterior capsule enlargement. The percentage of PCOO to PCO area and the incidence of VAO was highest in Group A and lowest in Group C. Thus, Capsulorhexis diameter of 4.0-5.0 mm may yield better capsular outcomes, considering moderate contraction of ACO, moderate enlargement of PCO, and lower percentage of PCOO and VAO.

Ischemia-reperfusion (I/R) is a common pathology when the blood supply to an organ was disrupted and then restored. During the reperfusion process, inflammation and tissue injury were triggered, which were mediated by immunocytes and cytokines. However, the mechanisms initiating I/R-induced inflammation and driving immunocytes activation remained largely unknown. In this study, we identified long non-coding RNA (lncRNA)-H19 as the key onset of I/R-induced inflammation. We found that I/R increased lncRNA-H19 expression to significantly promote NLRP3/6 inflammasome imbalance and resulted in microglial pyroptosis, cytokines overproduction, and neuronal death. These damages were effectively inhibited by lncRNA-H19 knockout. Specifically, lncRNA-H19 functioned via sponging miR-21 to facilitate PDCD4 expression and formed a competing endogenous RNA network (ceRNET) in ischemic cascade. LncRNA H19/miR-21/PDCD4 ceRNET can directly regulate I/R-induced sterile inflammation and neuronal lesion in vivo. We thus propose that lncRNA-H19 is a previously unknown danger signals in the molecular and immunological pathways of I/R injury, and pharmacological approaches to inhibit H19 seem likely to become treatment modalities for patients in the near future based on these mechanistic findings.

CC-Cruiser is an artificial intelligence (AI) platform developed for diagnosing childhood cataracts and providing risk stratification and treatment recommendations. The high accuracy of CC-Cruiser was previously validated using specific datasets. The objective of this study was to compare the diagnostic efficacy and treatment decision-making capacity between CC-Cruiser and ophthalmologists in real-world clinical settings.

Glaucoma is the leading cause of irreversible vision loss, affecting more than 70 million individuals worldwide. Circulatory disturbances of aqueous humor (AH) have long been central pathological contributors to glaucomatous lesions. Thus, targeting the AH outflow is a promising approach to treat glaucoma. However, the epigenetic mechanisms initiating AH outflow disorders and the targeted treatments remain to be developed. Studying glaucoma patients, we identified GDF7 (growth differentiation factor 7) hypomethylation as a crucial event in the onset of AH outflow disorders. Regarding the underlying mechanism, the hypomethylated GDF7 promoter was responsible for the increased GDF7 production and secretion in primary open-angle glaucoma (POAG). Excessive GDF7 protein promoted trabecular meshwork (TM) fibrosis through bone morphogenetic protein receptor type 2 (BMPR2)/Smad signaling and upregulated pro-fibrotic genes, α-smooth muscle actin (α-SMA) and fibronectin (FN). GDF7 protein expression formed a positive feedback loop in glaucomatous TM (GTM). This positive feedback loop was dependent on the activated TET (ten-eleven translocation) enzyme, which kept the GDF7 promoter region hypomethylated. The phenotypic transition in TM fortified the AH outflow resistance, thus elevating the intraocular pressure (IOP) and attenuating the nerve fiber layer. This methylation-dependent mechanism is also confirmed by a machine-learning model in silico with a specificity of 84.38% and a sensitivity of 89.38%. In rhesus monkeys, we developed GDF7 neutralization therapy to inhibit TM fibrosis and consequent AH outflow resistance that contributes to glaucoma. The neutralization therapy achieved high-efficiency control of the IOP (from 21.3 ± 0.3 to 17.6 ± 0.2 mmHg), a three-fold improvement in the outflow facility (from 0.1 to 0.3 μL/min · mmHg), and protection of nerve fibers. This study provides new insights into the epigenetic mechanism of glaucoma and proposes an innovative GDF7 neutralization therapy as a promising intervention.

Depression and depressive symptoms are common mental disorders that have a considerable effect on patients' health-related quality of life and satisfaction with medical care, but the prevalence of these conditions varies substantially between published studies. The aim of this study is to conduct a systematic review and meta-analysis to provide a precise estimate of the prevalence of depression or depressive symptoms among outpatients in different clinical specialties.

Schistosomiasis japonicum remains a considerable economic and public health concern in China, the Philippines and Indonesia. Currently available measures to control the unique intermediate host Oncomelania hupensis are frequently associated with severe side effects. Previous studies have demonstrated that linalool-rich extracts from various plants exhibited promising biological activities including cytotoxic, anti-microbial and anti-parasitic properties.

The aim of the present study was to identify the proteomic differences among human lenses in different physiopathological states and to screen for susceptibility genes/proteins via proteogenomic characterization.

To establish and validate a universal artificial intelligence (AI) platform for collaborative management of cataracts involving multilevel clinical scenarios and explored an AI-based medical referral pattern to improve collaborative efficiency and resource coverage.

Color vision is the ability to detect, distinguish, and analyze the wavelength distributions of light independent of the total intensity. It mediates the interaction between an organism and its environment from multiple important aspects. However, the physicochemical basis of color coding has not been explored completely, and how color perception is integrated with other sensory input, typically odor, is unclear.

The prevalence of myopia, or nearsightedness, has skyrocketed in the past few decades, creating a public health crisis that is commonly attributed to lifestyle changes. Here we report an overall increase in the frequencies of myopia-associated mutant alleles over 25 years among participants of the UK Biobank. Although myopia itself appears to be selected against, many of the mutant alleles are associated with reproductive benefits, suggesting that reproduction-related selection inadvertently contributes to the myopia epidemic. We estimate that, in the UK alone, natural selection adds more than 100 000 myopia cases per generation, and argue that antagonistic pleiotropy be broadly considered in explaining the spreads of apparently disadvantageous phenotypes in humans and beyond.

We aimed to evaluate the impacts of metabolomic body mass index (metBMI) phenotypes on the risks of cardiovascular and ocular diseases outcomes.