眼科领域文献阅读汇编

Population-based genomic newborn screening identifying newborns at risk for early-onset cancers has not been evaluated. Here, within a Michigan birth cohort (1987-2020), we identify all children developing a solid or central nervous system malignancy by age 8 years (n = 1948). We perform targeted sequencing of 11 cancer predisposition genes using archived newborn dried blood spot DNA. We find pathogenic or likely-pathogenic germline variants (P/LP) in 6.8% of cases (n = 132): RB1 (n = 69), TP53 (n = 24), SMARCB1 (n = 8), WT1 (n = 7), RET (n = 6), SUFU (n = 6), PTCH1 (n = 4), DICER1 (n = 4), APC (n = 3) and PHOX2B (n = 1). We show approximately 1/27,000 newborns develop an early-onset malignancy with an associated pathogenic or likely-pathogenic variant. Germline variant prevalence is 100% in medullary thyroid carcinoma, 40% in retinoblastoma, and 11-30% across five additional diagnoses, with strong gene-tumor specificity (p < 0.001). P/LP variants are rare in comparison datasets from healthy newborns and gnomAD. Our data support newborn screening for selected cancer-risk genes.

Diabetic vascular complications are a major determinant of poor prognosis in diabetic patients, with their development closely linked to persistent low-grade inflammation. Macrophages, as key regulatory cells in the immune system, undergo significant metabolic reprogramming in the diabetic hyperglycemic microenvironment. This reprogramming involves a coordinated remodeling of key metabolic pathways, including carbohydrate metabolism, lipid metabolism, and amino acid metabolism. This review systematically discusses the classical theories of macrophage polarization and provides an in-depth analysis of how key molecules drive the M1/M2 imbalance. Additionally, it explores the intricate regulatory interactions between the three major metabolic pathways. The metabolic reprogramming-polarization axis is further examined in the context of four typical diabetic vascular complications-diabetic atherosclerosis, diabetic kidney disease, diabetic retinopathy, and diabetic cardiomyopathy-highlighting their specific pathological roles. This work aims to elucidate the theoretical value of this regulatory axis as a central mechanism in diabetic vascular complications and explores its clinical translational potential as a precise therapeutic target. It provides a systematic theoretical foundation and proposes new directions for future research.

Retinal neurodegenerative diseases, such as age-related macular degeneration, diabetic retinopathy, glaucoma, and inherited retinal dystrophies, are major causes of irreversible vision loss worldwide. Although they originate from different causes, these disorders increasingly appear to share a network of cellular stress pathways, including impaired mitochondrial function, oxidative stress, endoplasmic reticulum proteostasis collapse, chronic neuroinflammation, epigenetic dysregulation, and activation of regulated cell death pathways. The interactions among these processes create an integrated stress network that gradually disrupts retinal homeostasis and promotes neuronal degeneration, which explains the failure of therapies targeting single molecular pathways. Nutraceutical compounds found in food are gaining interest as potential agents to support retinal health because many exhibit pleiotropic biological activities that influence mitochondrial function, inflammatory signaling, antioxidant defenses, and transcriptional regulation. Herein, we consolidate knowledge of the molecular mechanisms underlying retinal neurodegeneration and how major classes of nutraceuticals (polyphenols, carotenoids, omega-3 fatty acids, and metabolic modulators) may interact with these pathways. We also discuss key translational challenges in developing therapies, including poor bioavailability and differences between human phenotypes and model systems. Additionally, we highlight emerging concepts such as microbiome-dependent metabolism of nutraceuticals, personalized nutrition strategies, and advanced ocular drug-delivery technologies. Collectively, these findings support a systems-level framework in which selected nutraceuticals may influence multiple nodes of retinal stress biology, although clinical validation remains limited.

Pathological choroidal neovascularization underlies vision loss in neovascular age-related macular degeneration (nAMD), yet the molecular regulators coordinating vascular and immune components remain incompletely defined. Here, we investigated the role of the endolysosomal cation channel, two-pore channel 2 (TPC2) in choroidal angiogenesis. Loss of TPC2 in mice markedly reduced ex vivo choroidal sprouting, while pharmacological activation enhanced vascular growth. Mechanistically, Tpc2-deficiency led to downregulation of multiple microglia-derived pro-angiogenic factors and impaired the ability of the microglial secretome to stimulate neovascularization. In choroidal vascular cells, TPC2 loss attenuated NF-κB/MAPK signaling pathways. Tpc2-deficiency is also associated with lysosomal secretion of cathepsins, especially CTSD, resulting in decreased extracellular proteolytic activity and impaired paracrine regulation of angiogenesis. Extending these findings to human cells, TPC2 knockout in iPSC-derived endothelial cells impaired migration, tube formation, and CTSD activity in the secretome, mirroring the murine phenotype. Together, these results establish TPC2 as one of the regulators of lysosome-mediated choroidal angiogenesis, highlighting its potential as a therapeutic target in nAMD.

Lactate was once regarded merely as a byproduct of glycolysis, but is now recognized as a multifunctional metabolite that coordinates energy redistribution, intercellular communication, receptor-mediated signaling, and epigenetic regulation. In the retina, these functions are especially consequential because visual processing depends on a highly specialized and energetically demanding tissue, characterized by steep oxygen gradients, a dual vascular supply, and tightly integrated metabolic crosstalk among photoreceptors (PCs), Müller glia, the retinal pigment epithelium, vascular cells, and retinal ganglion cells. In this review, we synthesize current advances in lactate signaling and lactylation in the retina, and examine how their dysregulation contributes to neovascularization, inflammation, and neurodegeneration in disorders including diabetic retinopathy, age-related macular degeneration, autoimmune uveitis and glaucoma. Drawing from these metabolic insights, therapeutic interventions targeting lactate signaling and lactylation are discussed as potential approaches to mitigate retinal abnormalities. Collectively, this review highlights the central importance of lactate signaling and lactylation in retinal physiology and pathology, and provides a conceptual framework for developing metabolic interventions aimed at restoring retinal lactate homeostasis.

Vision sensors are central to machine vision and intelligence. However, conventional planar devices rely on multielement optics and external processors to correct optical aberrations. This approach constrains miniaturization, reduces power efficiency and generally limits the field of view. Curved sensors can provide compact, aberration-corrected imaging, but their resolution has been below practicable levels. Here we present a bioinspired bionic eye system based on a hemispherical tandem artificial retina. This high curvature image sensor achieves a pixel density of 1,905 ppi with 367,500 total pixels, providing full-colour imaging across 300-800 nm and an aberration-corrected field of view exceeding 160°. Furthermore, the tandem design enables in-sensor, event-driven motion detection. Compared with frame-based imaging, this approach reduces the demand for bandwidth by over 99.95% and achieves a motion recognition accuracy of 98.6%. This work addresses the resolution bottleneck of hemispherical sensors and highlights their promise as compact, multifunctional vision applications.

The human retina contains photoreceptor cells that detect light and enable vision. The development of these cells involves a tightly regulated cascade of structural and molecular events, and their dysfunction leads to irreversible blindness in many retinal diseases. Human retinal organoids derived from stem cells have become powerful tools to model retinal development and disease, but they often remain immature and lack key features required for full function. Light is not only the sensory target of photoreceptors but also an important developmental signal in vivo. However, light has rarely been used as a deliberate stimulus during in vitro differentiation. Here we show that exposing retinal organoids to rhythmic light flickering at a specific frequency enhances photoreceptor maturation across multiple levels. This stimulation improves formation of presumptive outer segments, promotes transcriptional shifts from precursor toward more mature photoreceptor states, and is associated with enhanced responsiveness of downstream retinal neurons. These findings identify patterned light as a potent and physiologically relevant signal for driving retinal differentiation in vitro. This approach represents a non-invasive and easily scalable method for improving the quality of retinal organoids, with implications for disease modelling, drug discovery and the preparation of photoreceptors for cell-based therapies.

A structurally homogeneous keratan sulfate (KS) was purified from bovine cornea using an optimized method integrating enzymatic digestion and ion-exchange chromatography. Comprehensive structural analyses, including 1D/2D NMR, FT-IR, and disaccharide profiling, demonstrated a highly sulfated, linear polymer composed of repeating [-3Galβ1-4GlcNAcβ1-] units, with predominant 6-O-sulfation on both galactose and N-acetylglucosamine residues, comprising nearly equal proportions of disulfated (Gal6S-GlcNAc6S, 48.63%) and monosulfated (GlcNAc6S, 51.11%) disaccharides, with only trace amounts of non-sulfated units (<0.3%). HPGPC confirmed a narrow molecular weight distribution centered at approximately 43 kDa. Fluorescence quenching spectroscopy demonstrated that KS interacts with collagen with moderate affinity, a 1:1 stoichiometric ratio, and an enthalpy-driven mechanism. Circular dichroism analysis further suggested that KS association induces partial destabilization of the collagen triple-helical structure. At the single-molecule level, fluorescence correlation spectroscopy confirmed the formation of the KS-collagen complex, with further mechanistic insights provided by molecular docking and molecular dynamics simulations. Functionally, KS attenuated LPS-induced pro-inflammatory cytokine expression in RAW 264.7 macrophages, with network pharmacology implicating multi-target regulation of the TLR4/NF-κB pathway. This study establishes a direct link between the fine structure of corneal KS and its biological functions, providing a quantitative framework for understanding stromal matrix organization and guiding KS-based biomaterial design.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that affects cardiovascular, musculoskeletal, and ocular tissues, with premature death often resulting from dissection of the thoracic aorta. MFS results from pathogenic variants in FBN1, which encodes fibrillin-1, a glycoprotein that promotes elastic fibre organization and stability and contributes to smooth muscle cell mechano-sensing of extracellular matrix. It has been 35 years since the discovery that FBN1 variants cause MFS, yet understanding links between a variant and thoracic aortic disease remains incomplete, and definitive treatments remain wanting. We review advances in understanding disease progression in the aorta in MFS from perspectives of genetics, histology, mechanobiology, and biomechanics, with a focus on mouse models that include further genetic modifications to assess factors contributing to disease progression as well as effects of pharmacological treatments. This monogenic disease results in hundreds of differentially expressed genes in the aorta, many cell specific, that should be delineated as protective compensations, pathologic consequences, or neutral changes, and therapies should promote beneficial compensations and prevent detrimental consequences. Given the complexity of aortic disease in MFS, data-informed and data-driven computational models promise to help integrate multimodal data and increase understanding of molecular and cellular changes that drive disease progression, with a goal of improved therapies that prevent disease progression.

Sensitization to birch pollen is a major contributor to allergic rhinitis in Europe, with sensitization rates in many countries from 10% to 20% of the general population. Growing evidence suggests that air pollution enhances the allergenicity of pollen; however, the clinical consequences of this co-exposure remain poorly understood. This study investigated whether air pollution intensifies birch pollen allergenicity and assessed its effects on symptom severity and basophil activation in allergic and non-allergic individuals. Fifty birch-allergic patients and twenty-five non-atopic controls were examined over two consecutive pollen seasons (2023-2024). Daily nasal, ocular, and asthma symptoms were recorded using a mobile application. Ambient air pollutants (PM2.5, PM10, and O3) and birch pollen concentrations were continuously monitored in Kraków. Basophil activation tests (BAT) were performed using commercial birch pollen extracts, Bet v1 allergen, and natural pollen collected from highly and less polluted areas. Basophil activation was quantified by CD63 expression using flow cytometry. Asthmatic symptoms showed significant positive correlations with both birch pollen and PM concentrations (p < 0.05), especially in 2023. Pollen collected from polluted sites induced significantly stronger basophil activation compared with pollen from less polluted areas (p < 0.0001). The magnitude of basophil activation correlated with serum IgE levels to birch and Bet v 1, as well as with clinical symptom scores. Air pollution enhances the allergenic potency of birch pollen, resulting in heightened basophil activation and more severe allergic symptoms. These findings highlight the importance of integrating air pollution monitoring alongside pollen surveillance when assessing allergic disease burden and evaluating the effectiveness of allergen immunotherapy.

Long-lived proteins provide a uniquely informative substrate for studying the molecular chemistry of human ageing, and the eye offers one of the most accessible and spatially resolved systems for examining this process. The lens remains the principal model: its central crystallins are synthesized during embryonic and early postnatal life and are retained throughout the lifespan, thereby preserving a cumulative record of irreversible chemical damage. We then extend this framework to other ocular compartments that contain long-lived or slowly turned-over proteins, including Bruch's membrane, the lens capsule and membrane proteome, the trabecular meshwork, and the corneal stroma, where cumulative chemical damage to structural proteins and extracellular matrices may likewise shape tissue ageing and disease susceptibility. With age, these proteins acquire extensive post-translational modifications, including deamidation, isoaspartate formation, racemization, truncation, oxidation, disulfide rearrangement, glycation, carbamylation, and photochemical adducts, which progressively reshape their conformational landscape. This review, we propose that the progressive, cumulative effect of these modifications constitutes a process defined as conformational drift: a chemically encoded displacement of protein ensembles away from their native conformational states toward heterogeneous, destabilized, poorly soluble, and aggregation-prone forms. For instance, in the lens, this process disrupts crystallin packing, depletes the chaperone reserve of α-crystallin, promotes phase separation and light scattering, and contributes to age-related stiffening of the lens nucleus. Finally, we critically evaluate current analytical strategies for mapping these molecular events and argue that the human eye offers an underused model for mechanistic geroscience beyond ophthalmology.

Congenital nasolacrimal duct obstruction (CNLDO) is a common condition in infants. While observation and surgical probing are commonly used in clinical practice, evidence to guide the choice between these approaches is lacking, and the efficacy of lacrimal sac massage remains controversial. To assess whether lacrimal sac massage is noninferior to lacrimal duct probing for treating CNLDO in infants. This noninferiority randomized clinical trial took place at an outpatient clinic in Guangzhou, China, from April to September 2025 and included 160 infants younger than 1 year with CNLDO, presenting with epiphora or discharge in 1 or both eyes since birth. Children with bilateral eye disease were only analyzed for the right eye. Patients were excluded if they had previously undergone surgery for CNLDO or had another systemic disease or ocular infection. Patients were randomly assigned to receive lacrimal duct probing in the consultation room (n = 80) or standardized, regular lacrimal sac massage performed by parents (n = 80). The primary outcome was the resolution rate at 3 months, defined as complete or substantial resolution of epiphora, alongside the complete resolution of purulent discharge. The prespecified noninferiority margin was -10 percentage points. The mean (SD) age of the participants was 6.2 (2.5) months, and 98 (61.3%) were male. Resolution occurred in 69 of 80 participants (86.2%) in the massage group compared with 67 of 80 (83.7%) in the probe group (difference, 2.5 percentage points; 95% CI, -8.78 to 13.76). No serious complications occurred. The mean (SD) symptom resolution time was 1.1 (0.5) weeks in the probe group and 3.8 (2.8) weeks in the massage group (difference, 2.7 weeks; 95% CI, 1.96 to 3.38; P < .001). For infants younger than 1 year with CNLDO, lacrimal sac massage for 3 months was noninferior to lacrimal duct probing in efficacy, with no serious complications in either group. These findings support lacrimal sac massage as an alternative to surgical probing for CNLDO in infants younger than 1 year similar to those enrolled in this trial. ClinicalTrials.gov Identifier: NCT06924723.

The retinoblastoma protein (Rb) is a tumour suppressor best known for repressing E2F transcription factors and halting cell cycle progression1. In hormone receptor-positive (HR+) breast cancer, CDK4/6 inhibitors activate Rb by preventing its phosphorylation, forming a key component of current endocrine therapy regimens2. How pharmacologically activated Rb remodels chromatin and influences transcription beyond cell cycle arrest remains poorly understood. Here we show that CDK4/6 inhibition induces redistribution of hypophosphorylated Rb to promoters and enhancers. Although Rb predictably binds to cell cycle gene promoters to repress transcription, at other sites, it unexpectedly promotes expression of oestrogen-responsive genes by integrating into oestrogen receptor (ER)-rich transcriptional hubs. CDK4/6 inhibition enhances ER target gene expression in breast cancer cells, patient-derived xenografts and clinical HR+ breast cancer samples in an Rb-dependent manner. This reprogramming is mediated in part by KDM5A, whose interaction with Rb contributes to gene regulation at these loci. Critically, components of this Rb-driven ER transcriptional program are pro-proliferative. In endocrine-sensitive tumours, this effect can be neutralized with anti-oestrogen therapy, explaining therapeutic synergy. In endocrine-resistant settings such as ESR1-mutant breast cancer, the program persists, limiting the therapeutic efficacy of CDK4/6 inhibition. These findings reframe Rb as a dual-function transcriptional regulator that, although enforcing cell cycle arrest, can also activate programs that counteract its tumour suppressor function.

Glaucoma is a multifactorial optic neuropathy in which intraocular pressure is the principal modifiable risk factor but not the whole of the disease. Three recurring observations in the epidemiology and pharmacology of open-angle glaucoma, each of which has several possible explanations, together motivate a mechanistic question: open-angle glaucoma incidence rises steeply across the presbyopic decades, glaucoma risk is increased in myopia, and the intraocular pressure of some normal-tension eyes falls in response to muscarinic agonists. This review develops, and then critically grades, the hypothesis that these observations are connected by the mechanical role that accommodation may play in the regulation of aqueous dynamics. The proposal, termed accommodative aqueous regulation (AAR), is that the cyclic ciliary-muscle engagement delivered to the anterior segment during ordinary accommodation contributes to the regulation of aqueous humour, principally by conditioning conventional (trabecular) outflow, the accommodative outflow mechanism (AOM), and that its progressive loss at presbyopia is one contributory, refractive-state-dependent factor in the outflow deterioration that predisposes susceptible eyes to glaucoma. The claim is deliberately limited. The mechanism is offered as a threshold-lowering modifier acting in susceptible eyes within a multifactorial disease, not as a necessary or sufficient cause, and the mapping of refractive state onto glaucoma subtype, associating emmetropia with high-tension open-angle disease, hyperopia with angle-closure, and high myopia with the normal-tension phenotype, is presented as a probabilistic tendency rather than a rule that any individual eye must obey. Established physiology is separated from hypothesis at every step. The mechanical coupling of the ciliary muscle to a mechanosensitive outflow apparatus is supported; the central claim, that ordinary accommodative cycling conditions outflow across a lifetime and that its loss contributes to glaucoma, remains untested and is graded as such. We conclude by specifying the experiments that would confirm or refute it.

To investigate the efficacy and safety of a novel dual-sided composite defocus (DSCD) lens for pediatric myopia control. Prospective, randomized, double-masked, three-arm, parallel-controlled clinical trial with 1-year follow-up. A total of 225 children aged 6-14 years with myopia ranging from -0.50 D to -6.00 D were randomized 1:1:1 to DSCD, single-surface defocus (SSD), or single-vision spectacle (SVS) lenses. Overall, 194 participants (86.2%) completed the 1-year follow-up. Participants were randomly assigned to the DSCD, SSD, or SVS lens group. The DSCD lens incorporated a front-surface microlens array and a posterior freeform aspheric design intended to generate an asymmetric peripheral myopic defocus profile. Outcomes were measured at baseline and during the 12-month follow-up. Statistical analyses included analysis of covariance, Pearson correlation, and exploratory subgroup analyses. The primary outcomes were 12-month changes in axial length (AL) and spherical equivalent refraction (SER). At 12 months, the DSCD group exhibited significantly less SER progression than the SVS group (-0.22 ± 0.37 D vs -0.83 ± 0.47 D; P < 0.001) and the SSD group (-0.22 ± 0.37 D vs -0.45 ± 0.43 D; P = 0.005). Axial elongation was also significantly slower with DSCD than with SVS lenses (0.19 ± 0.14 mm vs 0.42 ± 0.18 mm; P < 0.001). No statistically significant difference in axial elongation was observed between the DSCD and SSD groups. The DSCD lens reduced SER progression by 73.6% and AL elongation by 55.2% relative to SVS lenses. Exploratory subgroup analyses suggested less progression in children aged 8-12 years, those with baseline AL of 24-25 mm, and those with low myopia. No lens-related adverse events were observed, and all groups demonstrated high compliance and good adaptation. Over 12 months, DSCD lenses resulted in significantly less SER progression and axial elongation than SVS lenses. Compared with the SSD lenses tested in this study, DSCD lenses showed significantly less SER progression, whereas the difference in axial elongation was not statistically significant. DSCD lenses were generally well tolerated and may represent a spectacle-based option for pediatric myopia control.

Pseudomonas aeruginosa (P. aeruginosa) keratitis can progress rapidly to vision-threatening disease, even with intensive therapy. Virulence-associated genes are key determinants of ocular-surface pathogenesis. We therefore sought to develop a composite wbp-exo genotyping framework for risk stratification and to guide wbp-dependent, LPS-directed, levofloxacin-polymyxin B (LVX-POL) combination therapy for high-risk corneal infections. A well-characterised clinical P. aeruginosa keratitis cohort was integrated with whole-genome sequencing. Based on comprehensive virulence-gene identification and annotation, the relationship between strain-level genetic features and clinical prognosis was analysed. The differences between WBP1 strains and WBP2 strains in adhesion, invasion, and biofilm formation in corneal epithelial cells were further evaluated. To establish biological plausibility, wbp genotypes were correlated with LPS O-antigen electrophoretic profiles and in vivo corneal inflammatory phenotypes in murine infection, including the observation of leucocyte recruitment and cytokine responses. To further confirm the key role of wbp gene status and LPS O-antigen in pathogenicity, wbpL knockout and reconstitution strains were constructed. Their appearances in vitro and in vivo were evaluated. Finally, a mechanistic rationale for an LPS-directed LVX-POL regimen was tested in a high-risk WBP1 P. aeruginosa murine keratitis. Whole-genome sequencing was performed on 46 clinical P. aeruginosa isolates and identified an average of 332 virulence- and fitness-associated genes per strain. The exo and wbp gene families were significantly associated with patient prognosis. A fusion model (AUC = 0.86) outperformed single-gene-family models (EXO: 0.66; WBP: 0.72) for predicting clinical outcomes. Intact wbp cassettes were enriched in poor-outcome isolates, and electrophoretic LPS profiles indicated that WBP1 strains produce highly polymerised O-antigen associated with sustained neutrophil recruitment and cytokine production. Murine experiments further implicated wbp genes in clinical pathogenesis, showing stronger immune responses and higher expression of TLR4, MyD88, TRAF6, p65, p-p65, IL-6, TNF-α, and IL-1β throughout the inflammatory course. After knocking out wbpL gene, the WBP1 strain got stronger in biofilm formation and adhesion but weaker in inflammation and ocular surface survival. In the high-risk WBP1 P. aeruginosa keratitis model, LVX-POL combinations achieved complete ulcer resolution and markedly improved stromal infiltration and hypopyon, outperforming LVX monotherapy. The wbp gene family was identified as a key genetic factor that contributes to the LPS O-antigen structure, inflammatory intensity, bacterial ocular surface survival and poor prognosis in P. aeruginosa keratitis. A WBP1-targeted, LPS-directed LVX-POL regimen was proposed as a mechanistically informed option for high-risk strains. This research was supported by Beijing Public Health High-level Talent Training Program (Phase III-03-14), Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project (2026ZD01909300) and Beijing Natural Science Foundation "QiYan" Undergraduate Research Fund (QY26496).

Amacrine cells (ACs) comprise a heterogeneous class of inhibitory neurons in the vertebrate retina, exhibiting morphological and functional complexity rivaling that of cortical interneurons. Here, we integrate single-cell and single-nucleus transcriptomic atlases from 24 vertebrate species to reconstruct the evolutionary origins of this extreme diversity. We identify 42 orthologous AC types, most of which exhibit a one-to-one correspondence across amniotes and, in many cases, across vertebrates. While core molecular identities are conserved, AC types vary in abundance and gene expression across species, likely reflecting adaptations to distinct visual ecologies. AC diversity scales with that of retinal ganglion cells (RGCs), indicative of coevolution. Last, we suggest that ACs arose from an AC-RGC hybrid precursor, with glycinergic ACs diverging early in vertebrate evolution, followed by a bifurcation between RGCs and GABAergic ACs. Together, these findings establish a unified evolutionary framework for understanding the diversity, development, and function of a class of inhibitory neurons across vertebrates.