Impairment of Gal-9 and Tim-3 crosstalk between Tregs and Th17 cells drives tobacco smoke-induced airway inflammation.

Overexpression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells has been observed in smokers. However, whether and how galectin-9 (Gal-9)/TIM-3 signal between T-regulatory cells (Tregs) and type 17 helper (Th17) cells contributes to tobacco smoke-induced airway inflammation remains unclear. Here, we aimed to explore the role of the Gal-9/TIM-3 signal between Tregs and Th17 cells during chronic tobacco smoke exposure. Tregs phenotype and the expression of TIM-3 on CD4+ T cells were detected in a mouse model of experimental emphysema. The role of TIM-3 in CD4+ T cells was explored in a HAVCR2-/- mouse model and in mice that received recombinant anti-TIM3. The crosstalk between Gal-9 and Tim-3 was evaluated by coculture Tregs with effector CD4+ T cells. We also invested the expression of Gal-9 in Tregs in patients with COPD. Our study revealed that chronic tobacco smoke exposure significantly reduces the frequency of Tregs in the lungs of mice and remarkably shapes the heterogeneity of Tregs by downregulating the expression of Gal-9. We observed a pro-inflammatory but restrained phenotypic transition of CD4+ T cells after tobacco smoke exposure, which was maintained by TIM-3. The restrained phenotype of CD4+ T cells was perturbed when TIM-3 was deleted or neutralised. Tregs from the lungs of mice with emphysema displayed a blunt ability to inhibit the differentiation and proliferation of Th17 cells. The inhibitory function of Tregs was partially restored by using recombinant Gal-9. The interaction between Gal-9 and TIM-3 inhibits the differentiation of Th17 cells and promotes apoptosis of CD4+ T cells, possibly by interfering with the expression of retinoic acid receptor-related orphan receptor gamma t. The expression of Gal-9 in Tregs was reduced in patients with COPD, which was associated with Th17 response and lung function. These findings present a new paradigm that impairment of Gal-9/Tim-3 crosstalk between Tregs and Th17 cells during chronic tobacco smoke exposure promotes tobacco smoke-induced airway/lung inflammation.

Management after cataract surgery for patients with diabetic retinopathy: a systematic review and meta-analysis.

PURPOSE: To evaluate the safety and effectiveness of various treatment modalities in patients with diabetic retinopathy (DR) who underwent cataract surgery. METHODS: A comprehensive search for randomized controlled trials (RCTs) was conducted using the PubMed, Embase, Cochrane Library, and CNKI databases up to December 22, 2021. The safety and efficacy of treatment modalities were assessed using the risk ratio (RR) to compare the progression of DR and the mean difference to evaluate the best corrected visual acuity (BCVA) and macular thickness (MT). RESULTS: The meta-analysis of the RCTs revealed that anti-VEGF (anti-vascular endothelial growth factor) drugs significantly reduced the progression of DR [RR: 0.37 (95%CI 0.19, 0.70), P = 0.002] and improved BCVA [mean difference = - 0.06 (- 0.12, - 0.01), P = 0.03] in patients with pre-existing DR who underwent cataract surgery. Steroid drugs also showed a significant reduction in macular thickness [mean difference = - 55.63 (- 90.73, - 20.53), I2 = 56%, P = 0.002] in DR patients two weeks after cataract surgery compared to the control group. The safety profiles of different management options did not differ significantly. CONCLUSION: The present meta-analysis suggests that anti-VEGF drugs can effectively slow down the progression of diabetic retinopathy, improve BCVA, and reduce MT in DR patients who underwent cataract surgery. Steroid drugs also show promise in reducing MT. However, further studies with larger sample sizes are required to compare the efficacy and safety of different management options in a multi-center clinical setting.

PATHOLOGIC STUDY OF UNTREATED INTRARETINAL GLIOSIS SURGICALLY EXCISED VIA PARS PLANA VITRECTOMY.

PURPOSE: To evaluate the pathologic process of intraretinal glioses by investigating mass tissues resected from untreated eyes with intraretinal glioses. METHODS: Five patients with intraretinal gliosis without previous conservative treatment were included. All patients underwent pars plana vitrectomy. The mass tissues were excised and processed for the pathologic study. RESULTS: During surgery, it was observed that the intraretinal gliosis mainly affected the neuroretina and the retinal pigment epithelium was not affected. Pathologic examination revealed that all intraretinal glioses consisted of different proportions of hyaline vessels and hyperplastic spindle-shaped glial cells. In one case, the intraretinal gliosis was mainly composed of hyaline vascular components. In another case, the intraretinal gliosis showed a predominance of glial cells. The intraretinal glioses in the other three cases had vascular and glial components. The proliferated vessels showed different amounts of collagen deposits against different backgrounds. Vascularized epiretinal membrane was found in some intraretinal glioses. CONCLUSION: Intraretinal glioses affected the inner retinal layer. Hyaline vessels were the most characteristic pathologic changes; the proportion of proliferative glial cells varied in different intraretinal glioses. The natural course of intraretinal gliosis may involve the proliferation of abnormal vessels in the early stage, which then gradually become scarred and are replaced by glial cells.

The association between circulating neutrophil extracellular trap related biomarkers and retinal vein occlusion incidence: A case-control pilot study.

Retinal vein occlusion (RVO) is the second most common retinal vascular disorders and causes visual damage in a large population. Neutrophil extracellular traps (NETs) formation (NETosis) is an important cause of vascular diseases, however, the association between NETs related biomarkers and RVO development remained unclear. In this pilot study, a total of 77 RVO cases and 48 controls were included between Jan 2020 and July 2020. Besides, the circulating levels of three NETs related markers, cell-free DNA (cfDNA), myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit), were detected in all the participants and thus the association between NETosis and RVO incidence was analyzed. Advanced assays were conducted to investigate the inflammation and thrombosis related biomarkers in RVO cases with higher or lower NETs biomarkers. When the results were considered, it was found that NETs biomarkers, including cfDNA, MPO-DNA and H3Cit, were increased in the RVO cases comparing with the controls (P < 0.05). Through the receiver operating characteristic (ROC) analyses, we found that circulating NETs related biomarkers demonstrated potential diagnostic effects for RVO and the AUCs of plasma cfDNA, MPO-DNA and H3Cit were 0.859, 0.871 and 0.928, respectively (P < 0.001). Through analyzing the correlations between circulating NETs markers and RVO stages and durations, inflammatory markers as well as thrombotic indexes, it was found that NETs were related with the RVO subtypes, inflammatory status and thrombus formation. In conclusion, the plasma NETs remnants are significantly increased in RVO cases. Besides, advanced studies demonstrate that inflammation as well as thrombus formation might be involved in this association.

Porcine circovirus type 2 upregulates endothelial-derived IL-8 production in porcine iliac artery endothelial cells via the RIG-I/MDA-5/MAVS/JNK signaling pathway.

BACKGROUND: Dysfunction of endothelial cells and vascular system is one of the most important pathological changes of porcine circovirus disease (PCVD) caused by porcine circovirus type 2 (PCV2). PCV2-infected endothelial cells can upregulate the production of endothelial-derived IL-8, which can inhibit the maturation of dendritic cells. Endothelial-derived IL-8 has different structural and biological characteristics compared with monocyte-derived IL-8. However, the mechanism of endothelial-derived IL-8 production is still unclear. RESULTS: Key molecules of RIG-I-like signaling pathway RIG-I, MDA-5, MAVS and a key molecule of JNK signaling pathway c-Jun in PCV2-infected porcine iliac artery endothelial cells (PIECs) were upregulated significantly detected with quantitative PCR, Western blot and fluorescence confocal microscopy, while no significant changes were found in NF-κB signaling pathway. Meanwhile, the expression of endothelial-derived IL-8 was downregulated after RIG-I, MDA-5, or MAVS genes in PIECs were knocked down and PIECs were treated by JNK inhibitor. CONCLUSIONS: PCV2 can activate RIG-I/MDA-5/MAVS/JNK signaling pathway to induce the production of endothelial-derived IL-8 in PIECs, which provides an insight into the further study of endothelial dysfunction and vascular system disorder caused by PCV2.

Proteomic evidence that ABCA4 is vital for traumatic proliferative vitreoretinopathy formation and development.

Proliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment failure. The mechanism of PVR development is complex and still not completely elucidated. There are no proven methods for early prevention or clinical treatment. Retinal proteins are abnormally expressed during the entire PVR disease process. Due to the limitations of research methods and techniques, we do not fully understand the retinal protein changes in PVR. This proteomics study systemically analyzed and identified differential protein expression between retinas of PVR and non-PVR (normal) eyes. Retinal samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) coupled with mass spectrometry. Raw data were processed and analyzed by Maxquant software and then searched against the human UniProKB (201510) protein database. Differentially expressed proteins were selected and further validated in a human retinal pigment epithelial (RPE) cell line. The effects of dysregulated proteins on cell proliferation, apoptosis, and migration were studied. Systemic proteomics analysis identified several PVR-enriched proteins. The differentially expressed proteins were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation to find abnormal pathways involved in PVR. Retinal-specific ATP-binding cassette transporter (ABCA4) expression was one of the most increased proteins in PVR tissue. ABCA4 knockdown significantly reduced proliferation and affected the cell cycle in the human RPE cell line. ABCA4 knockdown also induced apoptosis and inhibited retinal cell migration. In conclusion, systemic proteomics analysis identified differentially expressed proteins in traumatic PVR, with ABCA4 being highly expressed. Disruption of ABCA4 expression induced apoptosis and inhibited cell proliferation and migration in a human RPE cell line.

Endothelial IL-8 induced by porcine circovirus type 2 affects dendritic cell maturation and antigen-presenting function.

BACKGROUND: Porcine circovirus (PCV) disease caused by PCV type 2 (PCV2) is mainly attributed to immunosuppression and immune damage. PCV2 can infect vascular endothelial cells and induce high expression of endothelial IL-8. Dendritic cells (DCs), as professional antigen-presenting cells, can not only present antigens but also activate naïve T-cells, causing an immune response. METHODS: To demonstrate whether endothelial IL-8 is the main factor inhibiting the maturation and related functions of dendritic cells during PCV2 infection, monocyte-derived DCs (MoDCs) and porcine iliac artery endothelial cells (PIECs) processed by different methods were co-cultured in two ways. Flow cytometry, molecular probe labeling, fluorescence quantitative PCR, and the MTS assay were used to detect the changes in related functions and molecules of MoDCs. RESULTS: Compared to those in the PIEC-DC group, the endothelial IL-8 upregulation co-culture group showed significantly lower double-positive rates for CD80/86 and MHC-II of MoDCs and significantly increased endocytosis of MoDCs. Meanwhile, the adhesion rate and average fluorescence intensity of MoDCs were significantly downregulated in migration and adhesion experiments. Furthermore, the MHC-I and LAMP7 mRNA levels in MoDCs and the proliferation of MoDC-stimulated T-cells were markedly reduced. However, the changes in MoDCs of the endothelial IL-8 downregulation co-culture group were the opposite. CONCLUSIONS: PCV2-induced endothelial IL-8 reduces the adhesion and migration ability of MoDCs, resulting in a decreased maturation rate of MoDCs, and further inhibits antigen presentation by DCs. These results may explain the immunosuppressive mechanism of PCV2 from the perspective of the interaction between endothelial cells and DCs in vitro.

LncRNA HOTAIR/miR-613/c-met axis modulated epithelial-mesenchymal transition of retinoblastoma cells.

Since lncRNAs could modulate neoplastic development by modulating downstream miRNAs and genes, this study was carried out to figure out the synthetic contribution of HOTAIR, miR-613 and c-met to viability, apoptosis and proliferation of retinoblastoma cells. Totally 276 retinoblastoma tissues and tumour-adjacent tissues were collected, and human retinoblastoma cell lines (ie, Y79, HXO-Rb44, SO-Rb50 and WERI-RB1) were also gathered. Moreover, transfections of pcDNA3.1-HOTAIR, si-HOTAIR, miR-613 mimic, miR-613 inhibitor, pcDNA3.1/c-met were performed to evaluate the influence of HOTAIR, miR-613 and c-met on viability, apoptosis and epithelial-mesenchymal transition (EMT) of retinoblastoma cells. Dual-luciferase reporter gene assay was also arranged to confirm the targeted relationship between HOTAIR and miR-613, as well as between miR-613 and c-met. Consequently, up-regulated HOTAIR and down-regulated miR-613 expressions displayed associations with poor survival status of retinoblastoma patients (P < 0.05). Besides, inhibited HOTAIR and promoted miR-613 elevated E-cadherin expression, yet decreased Snail and Vimentin expressions (P < 0.05). Simultaneously, cell proliferation and cell viability were also less-motivated (P < 0.05). Nonetheless, c-met prohibited the functioning of miR-613, resulting in promoted cell proliferation and viability, along with inhibited cell apoptosis (P < 0.05). Finally, HOTAIR was verified to directly target miR-613, and c-met was the direct target gene of miR-613 (P < 0.05). In conclusion, the role of lncRNA HOTAIR/miR-613/c-met signalling axis in modulating retinoblastoma cells' viability, apoptosis and expressions of EMT-specific proteins might provide evidences for developing appropriate diagnostic and treatment strategies for retinoblastoma.

The interactive effects of genetic polymorphisms within LFA-1/ICAM-1/GSK-3ß pathway and environmental hazards on the development of Graves' opthalmopathy.

The purpose of this investigation was to explore the combined effects of single nucleotide polymorphisms (SNPs) within LFA-1/ICAM-1/GSK-3ß pathway and environmental hazards on susceptibility to Graves' opthalmopathy (GO) among a Chinese Han population. Altogether 305 GO patients and 283 Graves' disease (GD) subjects were recruited. Information relevant to the participants' age, gender, body mass index (BMI), regular physical activity, smoking history, alcohol intake, stressful work environment, stress at work, family history of thyroid disease and 131I treatment were summarized, and the participants' related SNPs of LFA-1/ICAM-1/GSK-3ß were also detected. Then the gene-gene and gene-environment interactions were evaluated by logistic regression model and multi-factor dimensionality reduction (MDR) modeling. The results exhibited that age, BMI, smoking history, stressful work, stress at home, family history of thyroid disease and 131I treatment appeared as potential indicators regulating GO risk, when either univariate or multivariate regression analysis was performed (all P < 0.05). Moreover, rs12716977 (T > C) and rs2230433 (G > C) of LFA-1, rs1799969 (G > A) and rs5498 (A > G) of ICAM-1, as well as rs6438552 (T > C) and rs334558 (T > C) of GSK-3ß were significantly associated with altered susceptibility to GO under the allelic models (all P < 0.05). Also haplotype TGAATC acted as a protective factor against GO risk (P < 0.05), whereas haplotype CGAACC largely elevated risk of GO (P < 0.05). Besides, logistic regression analysis demonstrated that rs12716927, rs5498 and rs6438552 all would affect the influences exerted by age, BMI, smoking history, stressful work, stress at home, family history of thyroid disease or 131I treatment on GO susceptibility (all P < 0.05). MDR modeling implied that the combined model of rs12716977, rs2230433 and rs1799969 was the supreme interactive model when BMI was co-assessed, and the interactive model of rs12716977, rs334558 and rs5491 was the most desirable among the smoking population. In conclusion, gene-gene and gene-environment interactions served as a crucial manner in affecting susceptibility to GO, providing solid evidences for screening effective GO-susceptible biomarkers and exploring potential GO treatment strategies.

Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration.

BACKGROUND/AIMS: Age-related macular degeneration (AMD) is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. METHODS: We examined the CD4+ T cell compartments and their functions in AMD patients. RESULTS: AMD patients presented significantly higher frequencies of interferon (IFN)-γ-expressing and interleukin (IL)-17-expressing CD4+ T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4+ T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3+ and CCR4+CCR6+ expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE)-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. CONCLUSIONS: This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ- and IL-17-dependent fashion, and could potentially serve as therapeutic targets.

Experiment of vitreous liquefaction induced by C3F8.

To investigate the effect and safety of vitreous liquefaction induced by C3F8 (an inert gas) injected into vitreous cavit of rabbit eyes. 24 rabbits (48 eyes) were randomly divided into four groups, named group A, group B, group C and group D, with 6 rabbits in each group. The right eye in each rabbit was taken as the experimental eye while the left as the control eye. The experimental eyes in group A were injected with 0.1mL disinfectant air; the experimental eyes in group B, group C and group D were all injected with C3F8 0.1mL, 0.2mL and 0.3mL respectively after receiving anterior chamber penetration; and the controlled eyes in all group were injected with 0.1mL balanced salt solution (BSS). During the first 7 d after injection, all the rabitts' eyes were examined by slit lamp, ophthalmoscope, intraocular pressure (IOP) and dark-adapted retina Electroretinography (ERG) each day. After that, the examination of IOG and ERP were reviewed weekly. Besides, B ultrasound should be examined to observe the situation of posterior vitreous detachment (PVD) in the 4th and 8th weeks. The rabbits were killed in the end of the 8th week, with their specimens examined by the light microscope, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Except group A, all the experimental eyes were produced with vitreous liquefaction. In group C and group D, in addition to the produced vitreous liquefaction, posterior vitreous detachment (PVD), even complete PVD, were induced in different extent. But in group B, the vitreous body was returned to the gel state at 2 weeks after gas absorption. In group C and group D, the vitreous body was not found to recover its original state at 8 weeks. In group D, there was a little increase of intraocular pressure, a mild delay of wave a and wave b after ERG in the 4th day after the gas injection. While there was no such situation in other groups. After the examination of B ultrasound in the 8th week, the complete PVD occurred in group C (with 2 experimental eyes occurred) and group D (with 4 experimental eyes occurred). Light microscope and transmission electron microscope examination showed no obvious abnormality. Smooth inner limiting membrane could be seen in the eye with PVD occurred when scanning electron microscope used. The injection of C3F8 into rabbit eyes can improve the vitreous liquefaction of the vitreous body and a certain volume of C3F8 can successfully and safely induce the PVD, and a larger volume of C3F8 was also effective but with a transient high IOP in rabbit eyes.

Association Between IL-10 Gene Polymorphism and Diabetic Retinopathy.

BACKGROUND: Genetic and environmental factors both play important roles in the occurrence and progression of diabetic retinopathy (DR). IL-10 592 gene polymorphism is associated with diabetes pathogenesis. This study analyzed the relationship between IL-10 gene promoter-592 loci polymorphism (SNP) in a diabetic model rats with DR. MATERIAL AND METHODS: Streptozotocin (STZ) was injected through the tail vein to establish a diabetic rat model. The rats were randomly divided into 2 groups for 3 months' feeding, including 100 rats in the diabetes-positive control group and 100 rats only injected with citric acid buffer as the blank control group. Fundus fluorescein angiography (FFA) was used to observe retinal vascular changes. Polymerase chain reaction-restriction fragment polymorphisms assay (PCR-RFLP) was used to detect IL-10 gene promoter-592 loci polymorphism in DNA samples. Enzyme-linked immunosorbent assay (ELISA) was performed to test serum IL-10 concentration. RESULTS: Serum IL-10 level in DR rats was 33.18±5.0 pg/mL and in the control rats it was 53.33±4.16 pg/mL in (P<0.01). Diabetes susceptibility with IL-10-592 genotype frequency and gene frequency analysis showed that IL-10-592 genotype frequency and allele frequency were significantly different in the DR group compared with the control group (P<0.01). CONCLUSIONS: IL-10 592 polymorphism was associated with DR susceptibility, suggesting that the gene polymorphism might be a risk factor for DR.

Causal role of immune cells in uveitis: Mendelian randomization study.

Background: Uveitis, characterized by inflammation of the iris, ciliary body, and choroid, presents a significant global clinical challenge, contributing substantially to visual impairment. Risk factors include autoimmune diseases and immune cell dysfunctions, yet many remain unidentified. Immune cells, notably T cells, B cells, and monocytes, play pivotal roles in uveitis pathogenesis. While biologic agents show promise, comprehensive studies on immune cell types in ocular diseases are lacking. Genome-wide association studies (GWAS) and Mendelian randomization (MR) present promising avenues to elucidate genetic susceptibilities and causal relationships between immune cell traits and uveitis risk. Methods: Two-sample MR analysis was used to evaluate the causal relationship between 731 immune cells and uveitis, and genome-wide significance analysis was performed for genetic variation in 731 immune cells traits (P < 5 × 10-8). Immune characteristics include median fluorescence intensity (MFI), relative cell counts (RC), absolute cell counts (AC), and morphological parameters (MP), which were determined by published GWAS, and public data from the IEU Open GWAS database. The main analysis method of MR is inverse variance weighting (IVW). Heterogeneity and horizontal pleiotropy were also assessed. Results: 5 immunophenotypes, including CD62L-DC %DC, IgD+ CD38dim %B cell, CD3 on CM CD4+T cell, CD3 on CD45RA-CD4 +T cell, and CD3 on CD39+ CD4+ Treg may increase the risk of uveitis. 5 immunophenotypes, including CD11b on CD33dim HLA DR-Myeloid cell, HLA DR on CD33dim HLA DR+ CD11b-myeloid cell, CD14-CD16 + %monocyte, HLA DR on CD14-CD16 + monocyte and PDL-1 on CD14-CD16 + monocyte was negatively associated with the risk of uveitis. Among them, HLA DR on CD14-CD16 + monocyte (OR=0.921, 95%CI =0.875-0.970, P=0.001) and HLA DR on CD33dim HLA DR+ CD11b- (OR=0.879, 95%CI = 0.833-0.927, P=0.00) were negatively associated with the risk of uveitis in bi-direction. Conclusion: These results indicate that 10 immune cells traits are significantly associated with the risk of developing uveitis and 2 of them were strongly associated with uveitis bi-directionally, after excluding the effects of confounding factors such as some immune diseases, which provided new ideas and therapeutic targets for the study of immune mechanism of uveitis.

Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome.

Congenital acorea is a rare disease with the absence of a pupil in the eye. To date, only one family and two isolated cases with congenital acorea have been reported. The gene associated with acorea has not been identified. In this study, we recruited a Chinese family acorea-microphthalmia-cataract syndrome. By analyzing the whole-exome sequencing (WES) data of this Chinese family, we revealed the association of a novel heterozygous variant, NM_005267.5:c.137G>A (p.G46E) in the gap junction protein alpha 8 (GJA8) gene encoding connexin 50 or CX50, with familial acorea-microphthalmia-cataract syndrome. Additionally, another variant, NM_005267.5:c.151G>A (p.D51N) in GJA8, was identified to co-segregate with this syndrome in an unrelated Japanese family. Ectopic expression of p.G46E and p.D51N mutant GJA8 genes in cultured cells caused protein mislocalization, suggesting that the p.G46E and p.D51N mutations in GJA8 impaired the function of the gap junction channels. These results established GJA8 as the first gene associated with familial acorea-microphthalmia-cataract syndrome.

Intravitreal Dexamethasone Implant (Ozurdex) for Ocular Toxocariasis.

This study aimed to evaluate the efficacy and safety of intravitreal dexamethasone implants in the treatment of ocular toxocariasis (OT). A retrospective analysis was performed on 6 cases in which laboratory tests diagnosed OT. All patients were administered with intravitreal dexamethasone implants with or without vitrectomy. The average follow-up time was 19.7 months. All operated eyes achieved anatomic success, and all patients' visual acuity was improved. Five of these six had a visual acuity of 20/100, and three had final acuity of 20/40 or even better. Intravitreal dexamethasone implants can be used to treat different types of OT, which not only effectively control inflammation and improve the patient's vision but also reduce the use of systemic glucocorticoids.

Knockdown H19 Accelerated iPSCs Reprogramming through Epigenetic Modifications and Mesenchymal-to-Epithelial Transition.

H19 is an essential imprinted gene that is expressed to govern normal embryonic development. During reprogramming, the parental pronuclei have asymmetric reprogramming capacities and the critical reprogramming factors predominantly reside in the male pronucleus. After inhibiting the expression of H19 and Gtl2, androgenetic haploid ESCs (AG-haESCs) can efficiently and stably support the generation of healthy SC pups at a rate of ~20%, and double-knockout parthenogenetic haESCs can also produce efficiently. Induced pluripotent stem (iPS) cell reprogramming is thought to have a characteristic epigenetic pattern that is the reverse of its developmental potential; however, it is unclear how H19 participates in iPS cell reprogramming. Here, we showed that the expression of H19 was transiently increased during iPSC reprogramming. H19 knockdown resulted in greater reprogramming efficiency. The genes associated with pluripotency showed enhanced expression during the early reprogramming process, and the Oct4 promoter was demethylated by bisulfite genomic sequencing analysis. Moreover, expression analysis revealed that the mesenchymal master regulators associated with epithelial-to-mesenchymal transition (EMT) were downregulated during reprogramming in H19 knockdown. These findings provide functional insight into the role of H19 as a barrier to the early reprogramming process.

Efficacy and Safety of Biosimilar QL1207 vs. the Reference Aflibercept for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Phase 3 Trial.

INTRODUCTION: This trial aimed to compare the efficacy and safety between biosimilar QL1207 and the reference aflibercept for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: This randomized, double-blind, phase 3 trial was conducted at 35 centers in China. Patients aged ≥ 50 years old with untreated subfoveal choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) letter score of 73-34 were eligible. Patients were randomly assigned to receive intravitreous injections of QL1207 or aflibercept 2 mg (0.05 ml) in the study eye every 4 weeks for the first 3 months, followed by 2 mg every 8 weeks until week 48, stratified by baseline BCVA ≥ or < 45 letters. The primary endpoint was BCVA change from baseline at week 12. The equivalence margin was ± 5 letters. The safety, immunogenicity, pharmacokinetics (PK), and plasma vascular endothelial growth factor (VEGF) concentration were also evaluated. RESULTS: A total of 366 patients were enrolled (QL1207 group, n = 185; aflibercept group, n = 181) from Aug 2019 to Jan 2022 with comparable baseline characteristics. The least-squares mean difference in BCVA changes was - 1.1 letters (95% confidence interval - 3.0 to 0.7; P = 0.2275) between the two groups, within the equivalence margin. The incidences of treatment-emergent adverse events (TEAE; QL1207: 71.4% [132/185] vs. aflibercept: 71.8% [130/181]) and serious TEAE (QL1207: 14.1% [26] vs. aflibercept: 12.7% [23]) appeared comparable between treatment groups, and no new safety signal was found. Anti-drug antibody, PK profiles, and VEGF concentration were similar between the two groups. CONCLUSIONS: QL1207 has equivalent efficacy to aflibercept for nAMD with similar safety profiles. It could be used as an alternative anti-VEGF agent for clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05345236 (retrospectively registered on April 25, 2022); National Medical Products Administration of China: CTR20190937 (May 20, 2019).

Cytotoxicity and Antimicrobial Resistance of Salmonella enterica Subspecies Isolated from Raised Reptiles in Beijing, China.

BACKGROUND: Reptiles are asymptomatic carriers of Salmonella spp. Reptile-associated Salmonella infections have been noticed as a significant contributor to overall human salmonellosis. However, it remains unclear regarding the prevalence of reptile-associated Salmonella in China. METHODS: Fecal and gastrointestinal mucosal samples were taken from 104 snakes, 21 lizards, and 52 chelonians and cultured on selective medium. The positive clones were validated and annotated by biochemical screening and multiplex PCR verification. In addition, the antibiotic resistance of identified Salmonella isolates was detected and followed by cytotoxic activity detection on human colon cells via co-culturation. RESULTS: The overall prevalence of Salmonella in reptiles was 25.99%, with rates of 30.77%, 47.62%, and 7.69% in snakes, lizards, and chelonians, respectively. Further, all isolates showed variable drug-resistant activity to 18 antibiotics, of which 14 strains (30.43%) were resistant to more than eight kinds of antibiotics. More than half of isolated Salmonella strains were more toxic to host cells than the standard strain, SL1344. Whole genome sequencing (WGS) results showed that all lizard-associated strains belong to 4 serovar types, and 7 of them fall into the highly pathogenic serovars "Carmel" and "Pomona." CONCLUSIONS: Our results highlight the potential threat of zoonotic salmonellosis from captive reptiles in the Beijing area of China.

A Study on Mobile Resources for Language Education of Preschool Children Based on Wireless Network Technology in Artificial Intelligence Context.

Preschool language education is a requirement of basic education reform as well as a requirement for children's growth in all aspects of body and mind. It is extremely important and valuable in encouraging the entire growth of preschool education as well as children's general harmonious development. The degree of informatization is changing day by day, and many information technology concepts and tools have entered the preschool education field. The Internet, electronic school bags, ECE whiteboards, terminal devices, and rich digital resources and tools have been introduced into kindergarten classrooms. The continuous advancement and application of information technology have provided the feasibility of building a smart learning environment for kindergartens. To this end, this paper starts from the core concepts and theoretical foundations of preschool education and sorts out the concepts of learning resources, smart learning, and smart learning environments. Learning theory, teaching theory, and activity theory provide the theoretical foundation for the creation of language learning tools in preschool education. The technologies of campus network, Internet of Things, artificial intelligence, and rich media are examined under the role and inspiration of smart learning environment to provide theoretical support for scientific design of smart language learning environment in preschool education.

A retrospective analysis on comparison of optical coherence tomography manifestations among AMD, CEC, PM and ICN and its relationship with vision.

Background: Both macular choroidal neovascularization (MCN) and visual changes can occur in age-related macular degeneration (AMD), central exudative chorioretinopathy (CEC), pathological myopia (PM) and idiopathic choroidal neovascularization (ICN), but whether the optical coherence tomography (OCT) manifestations of the four diseases are different and their relationships with vision are not clear. This study clarifies this problem and can guide clinicians to prevent vision changes of patients according to OCT performance. Methods: 76 patients with MCN, included 25 AMD, 21 CEC, 18 PM and 12 ICN [refer to Chinese Ophthalmology (3rd Edition)], detected by OCT instrument, were enrolled in this study from June 2020 to June 2022. The OCT manifestations and indexes were observed. A comprehensive refractometer was used for detection of best corrected visual acuity (BCVA) and axial length (AL). Pearson chi squared and 1 way analysis of variance were used for enumeration data and continuous data test, and Pearson correlation coefficient was used for relationship analysis. Results: (I) Macular edema proportions in the MCN eyes among AMD, CEC, PM and ICN groups were 96.00% and 94.12%, 14.29% and 14.29%, 44.44% and 32.00%, 33.33% and 28.57%, with statistical differences (both P<0.001). (II) Patients with macular edema had a significantly higher loose and thickened tissue reflex of the neuroepithelial layer (100.00% vs. 4.26%) and limited non-reflective dark area (100.00% vs. 4.26%) (both P<0.001). (III) PM had the lowest width, height and central fovea thickness (CFT) [(1,403.43±114.41), (210.74±21.22) and (250.70±41.36) µm], and the highest distance to the fovea, BCVA and AL [(234.44±288.69) µm, (0.30±0.08) Log minimal angle of resolution (MAR), (28.48±5.72) mm] (all P<0.001). (IV) The width and height of patients with macular edema were lower than those of patients without macular edema [(1,738.43±348.71) vs. (2,493.95±771.53) µm, P<0.001; (305.71±81.22) vs. (367.29±107.91) µm, P=0.002] (P<0.05). (V) The width and height, CFT were negatively correlated to BCVA (r=-0.635, -0.712, -0.724, all P<0.001), and height, CFT were negatively correlated to AL (r=-0.244, -0.275, P=0.018, 0.007). The distance to the fovea was positively correlated to BCVA and AL (r=0.241, P=0.019; r=0.267, P=0.007). Conclusions: Most of the OCT indexes were related to the BCVA and AL in MCN patients, and MCN patients with OCT changes should be reminded to protect their vision.