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Abstract Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied. Herein, we detected elevated FTO expression in vitreous fibrovascular membranes of patients with proliferative DR. FTO promoted cell cycle progression and tip cell formation of endothelial cells (ECs) to facilitate angiogenesis in vitro, in mice, and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC–microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO’s m6A demethylase activity, suppressed angiogenic phenotypes in vitro. To allow for systemic administration, we developed a nanoplatform encapsulating FB23-2 and confirmed its targeting and therapeutic efficiency in mice. Collectively, our study demonstrates that FTO is important for EC function and retinal homeostasis in DR, and warrants further investigation as a therapeutic target for DR patients.

Summary: Retinal pigment epithelium (RPE) dysfunction and choroidal neovascularization (CNV) are predominant features of age-related macular degeneration (AMD), with an unclear mechanism. Herein, we show that RNA demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) is up-regulated in AMD. In RPE cells, ALKBH5 overexpression associates with depolarization, oxidative stress, disturbed autophagy, irregular lipid homeostasis, and elevated VEGF-A secretion, which subsequently promotes proliferation, migration, and tube formation of vascular endothelial cells. Consistently, ALKBH5 overexpression in mice RPE correlates with various pathological phenotypes, including visual impairments, RPE anomalies, choroidal neovascularization (CNV), and interrupted retinal homeostasis. Mechanistically, ALKBH5 regulates retinal features through its demethylation activity. It targets PIK3C2B and regulates the AKT/mTOR signaling pathway with YTHDF2 as the N6-methyladenosine reader. IOX1, an ALKBH5 inhibitor, suppresses hypoxia-induced RPE dysfunction and CNV progression. Collectively, we demonstrate that ALKBH5 induces RPE dysfunction and CNV progression in AMD via PIK3C2B-mediated activation of the AKT/mTOR pathway. Pharmacological inhibitors of ALKBH5, like IOX1, are promising therapeutic options for AMD.

AIM: To identify the disease-causing mutation in a four-generation Chinese family diagnosed with Nance-Horan syndrome (NHS). METHODS: A Chinese family, including four affected patients and four healthy siblings, was recruited. All family members received ophthalmic examinations with medical histories provided. Targeted next-generation sequencing approach was conducted on the two affected males to screen for their disease-causing mutations. RESULTS: Two male family members diagnosed with NHS manifested bilateral congenital cataracts microcornea, strabismus and subtle facial and dental abnormalities, while female carriers presented posterior Y-sutural cataracts. A novel frameshift mutation (c.3916_3919del) in the NHS gene was identified. This deletion was predicted to alter the reading frame and generate a premature termination codon after a new reading frame. CONCLUSION: The study discovers a new frameshift mutation in a Chinese family with NHS. The findings broaden the spectrum of NHS mutations that can cause NHS in Chinese patients.

AIM: To observe the clinical effect of 25G vitrectomy combined with inner limiting membrane(ILM)peeling in the treatment of severe proliferative diabetic retinopathy(PDR)with macular displacement.METHODS: Clinical data of 36 cases(36 eyes), diagnosed as severe proliferative diabetic retinopathy with macular displacement in Jiangsu Province Hospital were collected. Eighteen cases admitted from January to December 2016 were included in the control group(18 eyes, treated by 25G vitrectomy), while 18 cases admitted from January to December 2017 were included in the combined group(18 eyes, treated by 25G vitrectomy with ILM peeling). Best corrected visual acuity(BCVA), intraocular pressure(IOP), complications, and the thickness of macular center area(CMT)were examined during follow-up at 7d, 1mo, 3mo and 6mo postoperative.RESULTS: BCVA showed a significant improvement at postoperative 6mo compared with baseline in both groups (PPP=1.000).CONCLUSION: In the treatment of severe PDR with macular displacement, 25G vitrectomy combined with ILM peeling can effectively and safely improve visual acuity and reduce the thickness of macular center area.

Broadband electromagnetic (EM) wave absorbers are persistently desired in the past decades due to their extensive applications in different fields. In this paper, we proposed and demonstrated a metamaterial absorber (MA) based on a hybrid structure of stereo and planar resistive metamaterial elements. In principle, this hybrid MA is a combination of the Dällenbach layer absorber and circuit analog (CA) absorber. By adjusting its dispersion feature, the stereo metamaterial based on standing resistive patch can work as a broadband artificial Dällenbach layer absorber for C, X and Ku bands. Such stereo metamaterial was also utilized as a dispersive dielectric spacer and a metasurface consisting of resistive circle rings was deployed on the top of it to implement an improved CA absorber for S and C bands. By combing them together, the proposed hybrid MA can achieve absorption over 90% in an ultra-broad bandwidth from S to Ku band (2.59–16.80 GHz). Since our design takes full advantage of the physical space, the hybrid MA achieves an actual thickness as only 1.075 times of the ultimate thickness corresponding to its absorption performance. Furthermore, the hybrid MA has comprehensive advantages in terms of stability against oblique incidence, easy processing and light-weight. The MA prototype was fabricated assisted by the silk screen printing process and its ultra-broadband absorption performance was experimentally validated by the measured results. The new concept of hybrid MA and specific design scheme proposed here provide a promising approach for broadband, low-profile and light weight EM absorber.

Microvascular dysfunction (MVD) has long plagued the medical field despite improvements in its prevention, diagnosis, and intervention. Microvascular lesions from MVD increase with age and further lead to impaired microcirculation, target organ dysfunction, and a mass of microvascular complications, thus contributing to a heavy medical burden and rising disability rates. An up-to-date understanding of molecular mechanisms underlying MVD will facilitate discoveries of more effective therapeutic strategies. Recent advances in epigenetics have revealed that RNA methylation, an epigenetic modification, has a pivotal role in vascular events. The N6-methylation of adenosine (m6A) modification is the most prevalent internal RNA modification in eukaryotic cells, which regulates vascular transcripts through splicing, degradation, translation, as well as translocation, thus maintaining microvascular homeostasis. Conversely, the disruption of the m6A regulatory network will lead to MVD. Herein, we provide a review discussing how m6A methylation interacts with MVD. We also focus on alterations of the m6A regulatory network under pathological conditions. Finally, we highlight the value of m6A regulators as prognostic biomarkers and novel therapeutic targets, which might be a promising addition to clinical medicine.

"AIM: To introduce a new method for suprachoroidal fluid drainage before 23-gauge pars plana vitrectomy. METHODS: A 15º side-port blade was firstly used to create a sclerotomy into the suprachoroidal space for initial drainage. A 30-guage needle was then applied to inject balanced saline solution through the existing sclerotomy for further drainage. After most of the suprachoroidal fluid was drained, standard 3-port 23-guage pars plana vitrectomy was performed. RESULTS: We have succeeded in using this technique to treat five patients with retinal detachment and kissing choroidal detachment (KCD). The choroidal detachment was visibly recessed in all cases after drainage with no intraoperative complications. After removal of silicon oil at 3mo follow-up, all patients obtained a reattached retina. No postoperative complications such as hypotony and endophthalmitis occurred. CONCLUSION: The new technique is efficient and safe for suprachoroidal fluid drainage for patients with rhegmatogenous retinal detachment. In future, further larger series are needed to attest to its safety and efficacy."

AIM: To observe and analyze the safety and clinical efficacy of full-thickness scleral incision and in situ paracentesis in the treatment of patients with coexisting rhegmatogenous retinal detachment and choroidal detachment using minimally invasive vitrectomy. METHODS: From April 2015 to April 2017, 20 patients(20 eyes)with coexisting rhegmatogenous retinal detachment and choroidal detachment who were treated in Department of Ophthalmology, Jiangsu Province Hospital were enrolled in this retrospective analysis. All patients received modified scleral puncture drainage combined with 23G minimally invasive vitrectomy. This study analyzed and compared intraoperative paracentesis success rate, the incidence of intraoperative, postoperative visual acuity, intraocular pressure, and postoperative retinal reattachment rate. RESULTS: Suprachoroidal fluid from all patients were drainaged successfully. Compared with preoperative conditions, the postoperative visual acuity was significantly improved(PPCONCLUSION: The modified scleral puncture surgery in the treatment of patients with coexisting rhegmatogenous retinal detachment and choroidal detachment in 23G vitrectomy has great clinical effects. It not only simplifies the procedure of operation, but also reduces the difficulty and complication of operation.

Letter to the editor