Background: Optic nerve injury (ONI) is a key cause of irreversible blindness and triggers retinal ganglion cells (RGCs) change and synapse loss. Microglia is the resistant immune cell in brain and retina and has been demonstrated to be highly related with neuron and synapse injury. However, the function of Sirtuin 1 (SIRT1), a neuroprotective molecule, in mediating microglial activation, retinal synapse loss and subsequent retinal ganglion cells death in optic nerve injury model as well as the regulatory mechanism remain unclear.Method: To this end, optic nerve crush (ONC) model was conducted to mimic optic nerve injury. Resveratrol and EX527, highly specific activator and inhibitor of SIRT1, respectively, were used to explore the function of SIRT1 in vivo and vitro. Cx3Cr1-Cre^ERT2/Raptor^F/Fmice were used to delete Raptor for inhibiting mammalian target of rapamycin complex 1 (mTORC1) activity in microglia. HEK293 and BV2 cells were transfected with plasmids to explore the regulatory mechanism of SIRT1.Results: We discovered that microglial activation and synapse loss in retinal inner plexiform layer (IPL) occurred after optic nerve crush, with later-development retinal ganglion cells death. SIRT1 activation induced by resveratrol inhibited microglial activation and attenuated synapse loss and retinal ganglion cells injury. After injury, microglial phagocytosed synapse and SIRT1 inhibited this process to protect synapse and retinal ganglion cells. Moreover, SIRT1 exhibited neuron protective effects via activating tuberous sclerosis complex 2 (TSC2) through deacetylation, and enhancing the inhibition effect of tuberous sclerosis complex 2 on mammalian target of rapamycin complex 1 activity.Conclusion: Our research provides novel insights into microglial SIRT1 in optic nerve injury and suggests a potential strategy for neuroprotective treatment of optic nerve injury disease.

Purpose: Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI. Methods: Cx3Cr1-Cre^ERT2/Raptor^F/F and Cx3Cr1-Cre^ERT2/Sirt1^F/F mice were used to delete Raptor and Sirt1 in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM). Results: Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of Raptor resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss. Conclusion: Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.

A high sensitivity analog front-end is presented for semi-passive HF RFID tag for implantable devices. The design is compatible with the ISO/IEC 14443 Type-A. A rectifier with high power conversion efficiency is presented to provide stable rectified voltage. Novel tag system architecture with wake-up circuit is proposed to improve the sensitivity. Other Key circuits are studied and designed to make the system work effectively. Simulation results show that the AFE has realized much longer recognition distance than passive tags. Its sensitivity is -5.7 dBm and can work properly when the magnetic field is 0.3A/m. The AFE was fabricated with HHNEC 0.13 μm 1P4M CMOS technology with an area of 416 μm×472 μm. The AFE is also measured with FPGA based digital baseband. Measurement results show that the proposed AFE can support the 100% ASK demodulation and a modulation depth of 16.4%. The AFE can also accommodate a data rates from 106 Kbps to 848 Kbps are supported. Its power consumption is as low as 129.6 μW. This chip meets the demands of a semi-passive HF RFID tag and has great potential for implantable devices.

Purpose: We aim to investigate the use of covalent organic framework (COF) nanoparticles in the local treatment of glaucoma, both as a means of protecting retinal ganglion cells (RGCs), and as a carrier for delayed release of the medication rapamycin following a single intravitreal injection. Methods: a water-dispersible COF, and a COF-based nanoplatform for rapamycin release (COF-Rapa) was constructed. C57BL/6J mice were randomly divided into four groups: intravitreal injection of 1.5 µL normal saline (NS), COF (0.67 ng/µL), rapamycin (300 µM) or COF-Rapa (0.67 ng/µL-300 µM), respectively. The ischemia–reperfusion (I/R) model was established to mimic high intraocular pressure (IOP)-induced retinal injury in glaucoma. Labeling of RGCs by Fluoro-Gold and retinal electroretinogram were used to evaluate retinal function. Immunohistochemistry and Western blotting analyses of retinas were performed. Results: COF nanoparticles were delivered in vitro and in vivo. Six weeks after the COF injection, the number of RGCs was unaffected. In addition, the number of RBPMS-positive RGCs, GFAP-positive astrocytes and Iba1-positive microglia did not differ from the normal control. COF could effectively reduce RGCs death, improve phototransduction function and alleviate the overactivation of microglia compared to NS control after retinal I/R injury. Within six weeks, the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in the retinas could be inhibited by a single intravitreal injection of COF-Rapa. Compared with single COF administration, COF-Rapa significantly reduced the inflammatory reaction after retinal I/R injury. Conclusions: COF may act as both an RGC protection agent and a carrier for prolonged rapamycin release. This research may lead to the development of novel RGC protection agents and drug delivery techniques, as well as the creation of multifunctional COF-based biomaterials for glaucoma retinopathy.

Glaucoma is the leading cause of irreversible vision loss worldwide. We aimed to uncover the molecular mechanisms and regulatory networks of hub genes in human glaucoma to identify promising targets for detection and treatment. We obtained GSE758, GSE2378, and GSE9944 datasets from the Gene Expression Omnibus database. The list of genes linked to regulated cell death (RCD) was obtained from a previous study. RCD-related differentially expressed genes (DEGs) were identified in patients with glaucoma and controls. Weighted Gene Co-Expression Network Analysis (WGCNA) and machine learning algorithms were used to identify hub genes. Gene set enrichment analysis (GSEA) was used to explore signaling pathways enriched by hub genes, and molecular docking analysis was performed to identify the gene-drug network of hub genes for potential treatment. Immunofluorescence was used to reveal the expression levels of hub genes in glaucomatous mice and controls. This study identified 358 RCD-related DEGs that distinguished healthy individuals from glaucoma patients and underscored the pivotal involvement of the immune response in human glaucoma pathogenesis. We systematically identified 33 hub genes, including PLEC, DLGAP4, Glycosylphosphatidylinositol (GPI), etc. that demonstrated significant diagnostic or treatment potential for glaucoma. The cytoskeletal regulator PLEC has emerged as a promising candidate gene associated with glaucomatous neurodegeneration with possible acting drugs. We constructed a machine-learning-driven analytical framework based on diverse RCD patterns to refine molecular subtypes and druggable genes. These findings may provide novel targets for glaucoma detection and treatment.