Identification of systemic biomarkers and potential drug targets for age-related macular degeneration.

Purpose: Since age-related macular degeneration (AMD) is tightly associated with aging and cellular senescence, objective of this study was to investigate the association between plasma levels of senescence-related proteins (SRPs) and risk of AMD. Design: The whole study was based on two-sample Mendelian randomization (MR) analysis. Methods: For MR analysis, the primary approach for MR analysis was the inverse-variance weighted (IVW) method and the heterogeneity and pleiotropy of results were tested. The instrumental single-nucleotide polymorphisms (SNPs) associated with 110 SRPs were filtered and selected from a large genome-wide association study (GWAS) for plasma proteome involving 35,559 participants. The GWAS data of AMD was obtained from FinnGen consortium (6,157 AMD cases and 288,237 controls) and further validated by using data from UK Biobank consortium (3,553 AMD cases and 147,089 controls). Results: The MR results at both discovery and validation stages supported the causality (IVW-P < 0.00045) between plasma levels of 4 SRPs (C3b, CTNNB1, CCL1, and CCL3L1) and the risk of AMD and supported potential causality (IVW-P < 0.05) between other 10 SRPs and risk of AMD. No heterogeneity or pleiotropy in these results was detected. Conclusion: Our findings supported that high plasma levels of C3b, CTNNB1, CCL1, and CCL3L1 were associated with increased risk of AMD, thereby highlighting the role of systemic inflammation in AMD pathogenesis and providing the rationale for developing new preventative and therapeutic strategies.

Multiomics analysis reveals the molecular mechanisms underlying virulence in Rhizoctonia and jasmonic acid-mediated resistance in Tartary buckwheat (Fagopyrum tataricum).

Rhizoctonia solani is a devastating soil-borne pathogen that seriously threatens the cultivation of economically important crops. Multiple strains with a very broad host range have been identified, but only 1 (AG1-IA, which causes rice sheath blight disease) has been examined in detail. Here, we analyzed AG4-HGI 3 originally isolated from Tartary buckwheat (Fagopyrum tataricum), but with a host range comparable to AG1-IA. Genome comparison reveals abundant pathogenicity genes in this strain. We used multiomic approaches to improve the efficiency of screening for disease resistance genes. Transcriptomes of the plant-fungi interaction identified differentially expressed genes associated with virulence in Rhizoctonia and resistance in Tartary buckwheat. Integration with jasmonate-mediated transcriptome and metabolome changes revealed a negative regulator of jasmonate signaling, cytochrome P450 (FtCYP94C1), as increasing disease resistance probably via accumulation of resistance-related flavonoids. The integration of resistance data for 320 Tartary buckwheat accessions identified a gene homolog to aspartic proteinase (FtASP), with peak expression following R. solani inoculation. FtASP exhibits no proteinase activity but functions as an antibacterial peptide that slows fungal growth. This work reveals a potential mechanism behind pathogen virulence and host resistance, which should accelerate the molecular breeding of resistant varieties in economically essential crops.

Single-cell sequencing reveals an important role of SPP1 and microglial activation in age-related macular degeneration.

Purpose: To investigate the role of senescence-related cytokines (SRCs) in the pathophysiology of age-related macular degeneration (AMD). Design: The whole study is based on single-cell and bulk tissue transcriptomic analysis of the human neuroretinas with or without AMD. The transcriptomic data of human neuroretinas was obtained from Gene-Expression Omnibus (GEO) database. Methods: For single-cell transcriptomic analysis, the gene expression matrix goes through quality control (QC) filtering, being normalized, scaled and integrated for downstream analysis. The further analyses were performed using Seurat R package and CellChat R package. After cell type annotation, the expression of phenotype and functional markers of microglia was investigated and cell-cell communication analysis was performed. For bulk tissue transcriptomic analysis, GSE29801 dataset contains the transcriptomic data of human macular neuroretina (n = 118) from control group and AMD patients. The expression of SPP1 in control and AMD subtypes were compared by Student's t-test. In addition, the AMD macular neuroretina were classified into SPP1-low and SPP1-high groups according to the expression level of SPP1. The differentially expressed genes between these two groups were subsequently identified and the pathway enrichment analysis for these genes was further conducted. Results: Secreted phosphoprotein 1, as an SRC, was revealed to be highly expressed in microglia of AMD neuroretina and the SPP1-receptor signaling was highly activated in AMD neuroretina. In addition, SPP1 signaling was associated with the pro-inflammatory phenotype and phagocytic state of microglia. SPP1 expression was elevated in macular neuroretina with late dry and wet AMD and the inflammatory pathways were found to be activated in SPP1-high AMD macular neuroretina. Conclusion: Our findings indicated that SPP1 and microglial activation might play an important role in the pathophysiology of AMD. Therefore, SPP1 might serve as a potential therapeutic target for AMD. More in vitro and in vivo studies are required to confirm the results and the therapeutic effect of SPP1-targeting strategy.

Risk prediction of dysthyroid optic neuropathy based on CT imaging features combined the bony orbit with the soft tissue structures.

Purpose: To analyze computed tomographic (CT) imaging features of patients with dysthyroid optic neuropathy (DON) retrospectively and deduce a more appropriate predictive model. Methods: The CT scans and medical records of 60 patients with clinically proven Graves' ophthalmopathy (GO) with (26 women and 10 men) and without DON (16 women and 8 men) were retrospectively reviewed, and 20 age- and sex-matched control participants (12 women and 8 men) were enrolled consecutively. The bony orbit [orbital rim angle (ORA), medial and lateral orbital wall angles (MWA and LWA), orbital apex angle (OAA), and length of the lateral orbital wall (LWL)], and the soft tissue structures [maximum extraocular muscle diameters (Max EOMD), muscle diameter index (MDI), medial and lateral rectus bulk from inter-zygomatic line (MRIZL and LRIZL), proptosis, intraorbital optic nerve stretching length (IONSL), superior ophthalmic vein diameter (SOVD), apical crowding, and presence of intracranial fat prolapse] were assessed on a clinical workstation. The CT features among groups were compared, and a multivariate logistic regression analysis was performed to evaluate the predictive features of DON. Results: All bony orbital angle indicators, except ORA (p = 0.461), were statistically different among the three groups (all p < 0.05). The values of MWA, LWA, OAA, and LWL were larger in the orbits with the DON group than in the orbits without the DON group (all p < 0.05). The MDI, MRIZL, proptosis, IONSL, and SOVD were statistically significantly different among the three groups (all p < 0.05), in which the orbits with the DON group were significantly higher than the orbits without the DON group and control group. The apical crowding was more severe in the orbits with the DON group than in the orbits without the DON group (p = 0.000). There were no significant differences in the LRIZL and the presence of intracranial fat prolapse (all p > 0.05). The multivariate regression analysis showed that the MWA, MDI, and SOVD were the independent factors predictive of DON. The sensitivity and specificity for the presence of DON by combining these three indicators were 89 and 83%, respectively. Conclusion: Bone and soft tissue CT features are useful in the risk prediction of DON, especially the MWA, MDI, and SOVD were the independent factors predictive of DON.