Stable inhibition of choroidal neovascularization by adeno-associated virus 2/8-vectored bispecific molecules.

Neovascular age-related macular degeneration (nAMD) causes severe visual impairment. Pigment epithelium-derived factor (PEDF), soluble CD59 (sCD59), and soluble fms-like tyrosine kinase-1 (sFLT-1) are potential therapeutic agents for nAMD, which target angiogenesis and the complement system. Using the AAV2/8 vector, two bi-target gene therapy agents, AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59, were generated, and their therapeutic efficacy was investigated in laser-induced choroidal neovascularization (CNV) and Vldlr-/- mouse models. After a single injection, AAV2/8-mediated gene expression was maintained at high levels in the retina for two months. Both AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 significantly reduced CNV development for an extended period without side effects and provided efficacy similar to two injections of current anti-vascular endothelial growth factor monotherapy. Mechanistically, these agents suppressed the extracellular signal-regulated kinase and nuclear factor-κB pathways, resulting in anti-angiogenic activity. This study demonstrated the safety and long-lasting effects of AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 in CNV treatment, providing a promising therapeutic strategy for nAMD.

Recalled age of myopia onset may predict risk of high adult myopia in Chinese adults.

INTRODUCTION: This study aimed to investigate the relationship between age of myopia onset and high myopia and to explore if age of onset mediated the associations of high myopia with parental myopia and time spent on electronics. METHODS: This cross-sectional study enrolled 1118 myopic patients aged 18 to 40. Information was obtained via a detailed questionnaire. Multivariable logistic regression and linear regression models were utilized to assess age of onset in relation to high myopia and spherical equivalent refractive error, respectively. Structural equation models examined the mediated effect of onset age on the association between parental myopia, time spent on electronics and high myopia. RESULTS: An early age at myopia onset was negatively correlated with spherical equivalent refractive power. Subjects who developed myopia before the age of 12 were more likely to suffer from high myopia than those who developed myopia after the age of 15. Age of myopia onset was the strongest predictor of high myopia, with an area under the curve (AUC) in Receiver Operator Characteristic (ROC) analysis of 0.80. Additionally, age of myopia onset served as a mediator in the relationships between parental myopia, electronic device usage duration, and the onset of high myopia in adulthood. CONCLUSIONS: Age of myopia onset might be the single best predictor for high myopia, and age at onset appeared to mediate the associations of high myopia with parental myopia and time spent on electronics.

Specialized Retinal Endothelial Cells Modulate Blood-Retina Barrier in Diabetic Retinopathy.

Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing. Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in diabetic retina; sphingolipid metabolism is a prominent aspect correlated with changes in retinal function. Among sphingolipid-related genes, alkaline ceramidase 2 (ACER2) showed the most significant increase. Plasma samples of patients with nonproliferative diabetic retinopathy (NPDR) with diabetic macular edema (DME) or without DME (NDME) and active proliferative DR (PDR) were collected for mass spectrometry analysis. Metabolomic profiling revealed that the ceramide levels were significantly elevated in NPDR-NDME/DME and further increased in active PDR compared with control patients. In vitro analyses showed that ACER2 overexpression retarded endothelial barrier breakdown induced by ceramide, while silencing of ACER2 further disrupted the injury. Moreover, intravitreal injection of the recombinant ACER2 adeno-associated virus rescued diabetes-induced vessel leakiness, inflammatory response, and neurovascular disease in diabetic mouse models. Together, this study revealed a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression. These findings provide insights into cell-type targeted interventions for diabetic retinopathy.

Chimpanzee adenovirus-mediated multiple gene therapy for age-related macular degeneration.

Neovascular age-related macular degeneration AMD (nAMD) is characterized by choroidal neovascularization (CNV) and could lead to irreversible blindness. However, anti-vascular endothelial growth factor (VEGF) therapy has limited efficacy. Therefore, we generated a chimpanzee adenoviral vector (AdC68-PFC) containing three genes, pigment endothelial-derived factor (PEDF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble forms of CD59 (sCD59), to treat nAMD. The results showed that AdC68-PFC mediated a strong onset of PEDF, sFlt-1, and sCD59 expression both in vivo and in vitro. AdC68-PFC showed preventive and therapeutic effects following intravitreal (IVT) injection in the laser-induced CNV model and very low-density lipoprotein receptor-deficient (Vldlr-/-) mouse model. In vitro assessment indicated that AdC68-PFC had a strong inhibitory effect on endothelial cells. Importantly, the safety test showed no evidence of in vivo toxicity of adenovirus in murine eyes. Our findings suggest that AdC68-PFC may be a long-acting and safe gene therapy vector for future nAMD treatments.

Exercise alleviates neovascular age-related macular degeneration by inhibiting AIM2 inflammasome in myeloid cells.

The neovascular form of age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Vascular endothelial growth factor (VEGF) plays a crucial role in choroidal neovascularization (CNV), and anti-VEGF therapy is recommended as first-line therapy for nvAMD. However, many patients do not radically benefit from this therapy. Epidemiological data suggest that physical exercise is beneficial for many human diseases, including nvAMD. Yet, its protective mechanism and therapeutic potential remain unknown. Here, using clinical samples and mouse models, we found that exercise reduced CNV and enhanced anti-angiogenic therapy efficacy by inhibiting AIM2 inflammasome activation. Furthermore, transfusion of serum from exercised mice transferred the protective effects to sedentary mice. Proteomic data revealed that exercise promoted the release of adiponectin, an anti-inflammatory adipokine from adipose tissue into the circulation, which reduced ROS-mediated DNA damage and suppressed AIM2 inflammasome activation in myeloid cells of CNV eyes through AMPK-p47phox pathway. Simultaneous targeting AIM2 inflammasome product IL-1ß and VEGF produced a synergistic effect for treating choroidal neovascularization. Collectively, this study highlights the therapeutic potential of an exercise-AMD axis and uncovers the AIM2 inflammasome and its product IL-1ß as potential targets for treating nvAMD patients and enhancing the efficacy of anti-VEGF monotherapy.

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High intensity grazing is considered as an important cause of grassland degradation. Numerous studies have explored effects of grazing activities on grassland ecosystems. Nevertheless, the research regarding grazing activity itself, especially the quantification methods and gradient division of grazing pressure, is relatively insufficient. Based on a total of 141 Chinese and English papers containing keywords such as 'grazing pressure', 'grazing intensity', and giving specific quantification methods and classification standards, we sorted out the definition, quantification methods, and grading standards of grazing pressure. The results showed that the definition of grazing pressure in current studies could be classified into two categories: considering the number of livestock carried in the current grassland ecosystem only from the perspective of the amount of grazing livestock; or considering the impacts or consequences on grassland ecosystems. Small-scale manipulative experiments mainly quantified and divided gra-zing pressure by controlling the number of livestock, grazing duration, grazing area, etc. Ecosystem responses to grazing activities were also converted by the above indicators, while the large-scale data spatialization method only considered number of livestock per unit area. The method of remote sensing inversion focused on ecosystem responses, that is, the impacts of grazing activities on grasslands, and it was difficult to separate the role of climatic factors. The quantitative standards of grazing pressure in different grassland types were quite different, even in the same grassland type, and such difference was directly related to grassland productivity.

Association of Physical Activity with Retinal Thickness and Vascular Structure in Elderly Chinese Population.

INTRODUCTION: We aimed to assess the association of physical activity (PA) with retinal thickness and vascular structure in an elderly Chinese population. METHODS: This study enrolled 220 retirees aged 50 years and above from Tianjin University of Sport, China. PA data gathered through the International Physical Activity Questionnaires were computed for metabolic equivalent of task-minutes per week. All participants underwent full ophthalmic examination including optical coherence tomography angiography (OCTA). Multiple linear regression analyses were used to evaluate the association of PA with retinal thickness and vascular structure. RESULTS: A high amount of total PA was associated with smaller size of foveal avascular zone (FAZ) (high vs. low: area, ß=-0.04; circumference ß=-0.14) and greater central vessel (VD) (ß=1.04) and perfusion densities (PD) (ß=0.02). For domain-specific PA, participants with high and moderate recreational PA levels were found to have greater central VDs and PDs. Non-leisure activities demonstrated negative relationship with FAZ perimeter ratio (moderate vs. low: ß=-0.08; high vs. low: ß=-0.13) and, counter-intuitively, negative relation with VDs measured at the inner (high vs. low: ß=-0.98) and outer retinal layers (high vs. low: ß=-0.38). Additionally, higher levels of total PA were related to increased macular fovea thickness and average thickness of retinal nerve fiber layer. CONCLUSIONS: High PA level, particularly recreational PA, was associated with smaller FAZ and greater VD and PD in senior adults. Non-leisure time PA might not confer the same health benefits as leisure time PA. Our data supports a possible protective role of recreational PA in the retina against microvascular changes.

Spatiotemporal Variation in Rainfall Erosivity and Correlation with the ENSO on the Tibetan Plateau since 1971.

Soil erosion is a serious ecological problem in the fragile ecological environment of the Tibetan Plateau (TP). Rainfall erosivity is one of the most important factors controlling soil erosion and is associated with the El Niño southern oscillation (ENSO). However, there is a lack of studies related to the spatial distribution and temporal trends of rainfall erosivity on the TP as a whole. Additionally, the understanding of the general influence of ENSO on rainfall erosivity across the TP remains to be developed. In this study, long-term (1971-2020) daily precipitation data from 91 meteorological stations were selected to calculate rainfall erosivity. The analysis combines co-kriging interpolation, Sen's slope estimator, and the Mann-Kendall trend test to investigate the spatiotemporal patten of rainfall erosivity across the TP. The Oceanic Niño Index (ONI) and multivariate ENSO Index (MEI) were chosen as ENSO phenomenon characterization indices, and the relationship between ENSO and rainfall erosivity was explored by employing a continuous wavelet transform. The results showed that an increasing trend in annual rainfall erosivity was detected on the TP from 1971 to 2020. The seasonal and monthly rainfall erosivity was highly uneven, with the summer erosivity accounting for 60.36%. The heterogeneous spatial distribution of rainfall erosivity was observed with an increasing trend from southeast to northwest. At the regional level, rainfall erosivity in the southeastern TP was mainly featured by a slow increase, while in the northwest was more destabilizing and mostly showed no significant trend. The rainfall erosivity on the whole TP was relatively high during non-ENSO periods and relatively low during El Niño/La Niña periods. It is worth noting that rainfall erosivity in the northwest TP appears to be more serious during the La Niña event. Furthermore, there were obvious resonance cycles between the rainfall erosivity and ENSO in different regions of the plateau, but the cycles had pronounced discrepancies in the occurrence time, direction of action and intensity. These findings contribute to providing references for soil erosion control on the TP and the formulation of future soil conservation strategies.

Epidemiology of Sports-Related Eye Injuries Among Athletes in Tianjin, China.

Purpose: To investigate the incidence, characteristics, and risk factors of sports-related eye injuries among athletes in Tianjin, China. Methods: A cross-sectional study was carried out from March 2018 to October 2018. In this study, the athletes from Tianjin University of Sports, Tianjin Vocational College of Sports, and Tianjin provincial sports teams were selected for general investigation. In total, 1,673 athletes were invited and 1,413 participated in the study (response rate of 84.5%). Results: In total, 1,413 athletes were enrolled; 151 had suffered from sports-related eye injuries, with an incidence of 10.7% (95% CI: 9.1-12.0%). Handball (38.5%) was the sport with the highest incidence of eye injuries, followed by water polo (36.4%) and diving (26.7%). Overall, 42.4% of the athletes were injured by ball and 22.5% of injuries came from teammates. The eye injuries usually occurred during training (64.2%) and competitions (14.6%). Adnexa wound (51.7%) was the most common type of injury. About 11.9% of the athletes with eye injuries had the impaired vision; 66.7% failed to see doctors on time. The athletes <18 years of age had a higher risk of eye injuries (odds ratio [OR] =1.60, 95% CI: 1.06-2.40). The athletes with lower family income (<1,000 RMB) were at risk population for sports-related eye injuries (OR = 3.91, 95% CI: 2.24-6.82). Training >4 h a day increased the risk of eye injuries (OR = 2.21, 95% CI: 1.42-3.43). Conclusion: The incidence of sports-related eye injuries among athletes was 10.7% in Tianjin, China. Handball, water polo, and diving were the most common activities of injury. Age, family income, and training time were the risk factors for sports-related eye injuries.

Risk Factors for Band Keratopathy in Aphakic Eyes With Silicone Oil Tamponade for Open-Globe Injuries: A Multicenter Case-Control Study.

Band keratopathy (BK) is a common complication in aphakic eyes with silicone oil tamponade for open-globe injury (OGI), characterized by the grayish-white opacities in the cornea, resulting in a significantly decreased vision when extending to the visual axis. To identify the risk factors for BK in aphakic eyes following vitreoretinal surgical treatment with silicone oil tamponade for OGIs, we performed a multicenter case-control study. The incidence of BK was 28% (28/100 eyes). The multivariate binary logistic regression revealed the silicone oil retention time (SORT) ≥6 months and zone III injury were significant risk factors for BK. From the hierarchical interaction, SORT ≥6 months had a significant risk for BK in eyes with rupture, aniridia, and zone III injury, while zone III injury had a significant risk for BK in eyes with rupture, incomplete/complete iris, and SORT ≥6 months. By using restricted cubic splines with three knots at the 25th, 50th, and 75th centiles to model the association of SORT with BK, we also found a marked increase in the risk for BK at ≥10 months and a slow increase after 6 months, but almost stable within 4-6 months.

Association of cigarette smoking with retinal thickness and vascular structure in an elderly Chinese population.

BACKGROUND: To explore the association of cigarette smoking with retinal thickness and vascular structure in an elderly Chinese population. METHODS: This cross-sectional study enrolled employees and retirees aged over 50 years at Tianjin University of Sport from October 2020 to December 2020. Information on smoking status and lifestyle was obtained using a detailed questionnaire. All participants underwent full ophthalmic examination. OCTA image was acquired. Vascular and the thickness parameters in central fovea and peripapillary parameters were automatically calculated. Multiple linear regression analyses were utilized to assess the association of smoking with retinal thickness and vascular structure after controlling potential confounders. RESULTS: Compared with non-smoking adults, current smokers (ß=-36.78; P = 0.01) and ever smokers (ß=-35.45; P = 0.00) tended to have thinner macular fovea. Cigarettes daily, pack-years of smoking and CSI were negatively related to macular thickness (cigarettes daily: ß=-1.43; pack-years: ß=-14.73; CSI: ß=-14.70), while they were positively associated with the circumference (cigarettes daily: ß=0.03; pack-years: ß=0.30; CSI: ß=0.31) and the area of FAZ (cigarettes daily: ß=0.01; pack-years: ß=0.07). CONCLUSIONS: Cigarette smoking seems associated with decreased macular fovea thickness and elevated circumference and area of the FAZ compared to non-smokers. Our data add to evidence of smoking on retinal thickness and the microvascular system in the macular area.

Clinical efficacy of intravitreal corticoid as an adjunctive therapy to anti-VEGF treatment of neovascular age-related macular degeneration: a Meta-analysis.

AIM: To evaluate the efficacy and safety of intravitreal corticoid as an adjunctive therapy to anti-vascular endothelial growth factor (VEGF) treatment of neovascular age-related macular degeneration (nvAMD). METHODS: Four databases including PubMed, Embase, Cochrane Library, and the clinicaltrials.gov were comprehensively searched for studies comparing intravitreal corticoid plus anti-VEGF (IVC/IVA) vs anti-VEGF monotherapy (IVA) in patients with nvAMD. GRADE profiler was used to assess the quality of outcomes. Best-corrected visual acuity (BCVA), central macular thickness (CMT) and adverse events including the occurrence of severe elevation of intraocular pressure (IOP) and the progress of cataract were extracted from the eligible studies. Review Manager (RevMan) 5.3 was used to analyze the data. RESULTS: There was no statistic difference of mean change in BCVA at 6 and 12mo between IVC/IVA and IVA group [95% confidence interval (CI): -2.28 to 4.24, P=0.55; 95%CI: -3.01 to 8.70, P=0.34]. No statistic difference was found in the change of CMT between two groups at 6mo time point (95%CI: -17.98 to 16.42, P=0.93) while the CMT reduction in IVC/IVA group was significantly more obvious than IVA group at 12mo time point [mean difference (MD)=-44.08, 95%CI: -80.52 to -7.63, P=0.02]. The risk of occurrence of severe elevation of IOP in the IVC/IVA group was higher than that in the IVA group (95%CI: 1.92 to 9.48; P=0.0004). Cataract progression risk was calculated no statistic difference between two groups (95%CI: 0.74 to 4.66; P=0.18). CONCLUSION: No visual or anatomical benefits are observed in IVC/IVA group at 6mo. At 12mo, the CMT of the IVC/IVA group is significantly lower than that of the IVA group. Risk of severe elevation of IOP is significantly higher when treated by IVC/IVA.

Source apportionment of nitrogen and phosphorus from non-point source pollution in Nansi Lake Basin, China.

Nitrogen (N) and phosphorus (P) from non-point source (NPS) pollution in Nansi Lake Basin greatly influenced the water quality of Nansi Lake, which is the determinant factor for the success of East Route of South-North Water Transfer Project in China. This research improved Johnes export coefficient model (ECM) by developing a method to determine the export coefficients of different land use types based on the hydrological and water quality data. Taking NPS total nitrogen (TN) and total phosphorus (TP) as the study objects, this study estimated the contributions of different pollution sources and analyzed their spatial distributions based on the improved ECM. The results underlined that the method for obtaining output coefficients of land use types using hydrology and water quality data is feasible and accurate, and is suitable for the study of NPS pollution at large-scale basins. The average output structure of NPS TN from land use, rural breeding and rural life is 33.6, 25.9, and 40.5%, and the NPS TP is 31.6, 43.7, and 24.7%, respectively. Especially, dry land was the main land use source for both NPS TN and TP pollution, with the contributed proportions of 81.3 and 81.8% respectively. The counties of Zaozhuang, Tengzhou, Caoxian, Yuncheng, and Shanxian had higher contribution rates and the counties of Dingtao, Juancheng, and Caoxian had the higher load intensities for both NPS TN and TP pollution. The results of this study allowed for an improvement in the understanding of the pollution source contribution and enabled researchers and planners to focus on the most important sources and regions of NPS pollution.

Simulation of the spatial stresses due to territorial land development on Yellow River Delta Nature Reserve using a GIS-based assessment model.

This study aimed at assessing the stresses from land development in or around Yellow River Delta Nature Reserve (YRDNR) and identifying the impacted areas. Major land development types (reservoirs, pond, aquafarm, salt pan, road, residential land, industry land, farming land, and fishing land) in or around the YRDNR from 1995 to 2014 were identified using spatial data sets derived from remote sensing imageries. The spatial stresses were simulated by considering disturbance due to land development activities and accessibility of disturbance using a geographic information system based model. The stresses were then used to identify the impacted area by land development (IALD). The results indicated that main increasing land development types in the study area from 1995 to 2014 were salt pan and construction land. The 98.2% of expanded land development area and 93.7% of increased pump number showed a good control of reserve function zone on land development spread. The spatial stress values and percentages of IALD increased from 1995 to 2014, and IALD percentage exceeded 50% for both parts of YRDNR in 2014. The results of this study also provided the information that detailed planning of the YRDNR (2014-2020) could decrease the spatial stress and IALD percentage of the whole YRDNR on the condition that the area of land development activities increased by 24.4 km2 from 2014 to 2020. Effective measures should be taken to protect such areas from being further disturbed in order to achieve the goal of a more effective conservation of the YRDNR, and attention should be paid to the disordered land development activities in or around the natural reserves.