Angiogenic and Fibrogenic Dual-effect of Gremlin1 on Proliferative Diabetic Retinopathy.

Ocular angiogenic diseases, such as proliferative diabetic retinopathy (PDR), are often characterized by pathological new vessels and fibrosis formation. Anti-vascular endothelial growth factor (VEGF) therapy, despite of its efficiency to inhibit new vessels, has limitations, including drug resistance and retinal fibrosis. Here, we identified that Gremlin1, a novel angiogenesis and fibrosis inducer, was secreted from Müller glial cells, and its expression increased in the vitreous fluid from patients with PDR. Mechanistically, Gremlin1 triggered angiogenesis by promoting endothelial-mesenchymal transition via the EGFR/RhoA/ROCK pathway. In addition, Gremlin1 activated microglia to present profibrotic and fibrogenic properties. Further, anti-Gremlin1 antibody inhibited ocular angiogenesis and microglia fibrosis in mouse models. Collectively, Gremlin1 could be a potential therapeutic target in the treatment of ocular angiogenic diseases.

Clinical effect of cold and heat ablation on patients with advanced lung cancer and its influence on immune function.

OBJECTIVE: This study was designed to explore the clinical effect of cold and heat ablation on patients with advanced lung cancer (LC) and its influence on immune function. METHODS: Data of 104 cases of advanced LC treated between July 2015 and April 2017 in the First Affiliated Hospital of Hunan University of Chinese Medicine were retrospectively analyzed. Among them, 49 patients receiving argon helium cryoablation (AHC) were regarded as group A, and 55 patients receiving radiofrequency ablation (RFA) were regarded as group B. The short-term postoperative efficacy and local tumour control rate were compared between the two groups. The changes in immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM) were compared between the two groups before and after treatment. After treatment, the changes in carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) were compared between the two groups. During the treatment, the complications and incidence of adverse reactions were compared between the two groups. Cox regression analysis was applied to analyze the factors influencing the prognosis of patients. RESULTS: There was no statistical difference in IgA, IgG and IgM between the two groups after treatment (P>0.05). There was no statistical difference in CEA and CYFRA21-1 between the two groups after treatment (P>0.05). There was no notable difference in disease control rate and response rate between the two groups at 3 and 6 months after operation (P>0.05). The incidence of pleural effusion in group A was obviously lower than that in group B (P<0.05). The incidence of intraoperative pain in group A was obviously higher than that in group B (P<0.05). Age, clinical stage, CEA and CYFRA21-1 were found to be independent prognostic factors impacting overall survival (P<0.05). CONCLUSION: AHC and RFA are minimally invasive procedures that lead to few complications in the treatment of advanced LC. Cold and heat ablation is a relatively safe and effective minimally invasive technique for tumour treatment, which is worthy of application and promotion in the clinical treatment of LC.

A novel model of subretinal edema induced by DL-alpha aminoadipic acid.

In this study we described a new model of subretinal edema induced by single intraocular injection of DL-alpha-aminoadipic acid (DLAAA) that can be employed to study the mechanism of retinal edema and test the efficacy or potential toxicity of treatments. The progression of subretinal edema was evaluated by fundus photography, fluorescein angiography and optical coherence tomography for up to 4 weeks following DLAAA injection. The VEGF, IL-6, TNF-α, Occludin, ZO-1, AQP4, Kir4.1, GFAP and GS levels were examined in DLAAA models by immunostaining, immumohistochemical staining and Western blot. Additionally, bulk RNA-seq was used to detect the mechanism involved in DLAAA-induced retinal Müller cellular injuries. In vivo and vitro assays were further conducted to confirm the sequencing results. Subretinal edema was successfully induced by DLAAA in New Zealand White rabbits (1.29 mg/eye) and C57BL/6 mice (50 or 100 µg/eye). Our results demonstrated that the disruption of blood-retinal-barrier, including vascular hyperpermeability, inflammation, and Müller cell dysfunction of fluid clearance, was involved in subretinal edema formation in the model. Bulk RNA-seq and in vitro studies indicated the activation of p38 MAPK signaling pathway in DLAAA models. This DLAAA-induced subretinal edema model can be used for mechanistic studies or drug screening.

Industrial digitization and synergy between pollution and carbon emissions control: new empirical evidence from China.

Industrial digital transformation is a key engine to help developing countries reduce pollution and carbon emissions. We used the composite system synergy model (CSSM) and modified entropy weight method to measure the degree of synergy between pollution and carbon emissions control (SPCEC) and the level of industrial digitization in each province and city based on the Chinese inter-provincial panel data from 2011 to 2020. We then used the two-way fixed effects and panel quantile regression models to test the heterogeneous influence of industrial digitization on the SPCEC. We found that: (1) industrial digitization had a positive contribution to the SPCEC. (2) Digitization of industry contributes more to the SPCEC level than the digitization of agriculture and services. (3) The promotion of SPCEC by industrial digitization is significant in the western region, but not in the eastern, central and northeastern regions. (4) In provinces and municipalities with lower level of SPCEC, the contribution of industrial digitization to the SPCEC is higher. This paper reveals the impact of industrial digitization on the SPCEC and can provide a policy reference for the realization of the SPCEC from the perspective of the integration of industry and digitization.

JP1, a polypeptide specifically targeting integrin αVß3, ameliorates choroidal neovascularization and diabetic retinopathy in mice.

Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVß3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 µg) or ranibizumab (RBZ, 10 µg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 µg JP1; a combined IVT injection of JP1 (20 µg) and RBZ (5 µg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 µg) or RBZ (10 µg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVß3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.

Do carbon emission trading scheme policies induce green technology innovation? New evidence from provincial green patents in China.

Carbon emission trading scheme (ETS) policy is a quota-based market-motivated environmental regulation policy that by transforming environmental responsibility of enterprises into self-consciousness behavior induces green innovation behavior in enterprises and influences the level of regional green innovation. Based on panel data on green patents in 30 Chinese provinces from 2010 to 2019, the paper uses six Chinese pilot provinces for ETS as the treatment group to investigate the induced effects of Chinese ETS policy on the quantity and quality of green technology innovation using difference in difference model and analyzes the effects of Chinese ETS policy on green technology innovation in different pilot regions using a synthetic control method. The findings indicate that (1) compared with non-pilot areas, the carbon emission trading policies in pilot areas can induce green technology innovation activities. (2) In all pilot regions, ETS policies significantly promoted the quantity and quality of green technology innovation, but the quantity promotion effect was significantly better than the quality promotion effect, and the low-quality promotion effect was better than the high-quality promotion effect. (3) In terms of individual pilot region, ETS policies in Guangdong, Hubei and Tianjin significantly promoted the quantity of green technology innovation and low-quality green technology innovation, but significantly inhibited or suppressed high-quality green technology innovation in a short term. This paper not only enriches the research on environmental equity trading policies and green technology innovation theoretically, but also provides empirical evidence for the effectiveness of carbon emission trading schemes pilots program in China.

Somatostatin signalling promotes the differentiation of rod photoreceptors in human pluripotent stem cell-derived retinal organoid.

OBJECTIVES: Stem cell-derived photoreceptor replacement therapy is a promising strategy for the treatment of retinal degenerative disease. The development of 3D retinal organoids has permitted the production of photoreceptors. However, there is no strategy to enrich a specific photoreceptor subtype due to inadequate knowledge of the molecular mechanism underlying the photoreceptor fate determination. Hence, our aim is to explore the uncharacterized function of somatostatin signalling in human pluripotent stem cell-derived photoreceptor differentiation. MATERIALS AND METHODS: 3D retinal organoids were achieved from human embryonic stem cell. The published single-cell RNA-sequencing datasets of human retinal development were utilized to further investigate the transcriptional regulation of photoreceptor differentiation. The assays of immunofluorescence staining, lentivirus transfection, real-time quantitative polymerase chain reaction and western blotting were performed. RESULTS: We identified that the somatostatin receptor 2 (SSTR2)-mediated signalling was essential for rod photoreceptor differentiation at the precursor stage. The addition of the cognate ligand somatostatin in human 3D retinal organoids promoted rod photoreceptor differentiation and inhibited cone photoreceptor production. Furthermore, we found that the genesis of rod photoreceptors was modulated by endogenous somatostatin specifically secreted by developing retinal ganglion cells. CONCLUSIONS: Our study identified SSTR2 signalling as a novel extrinsic regulator for rod photoreceptor fate determination in photoreceptor precursors, which expands the repertoire of functional signalling pathways in photoreceptor development and sheds light on the optimization of the photoreceptor enrichment strategy.