The activation of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers pyroptosis proinflammatory cell death in experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanisms of the inflammatory processes of microglia in EAE remain unclear. Our previous studies suggested that interleukin-1 receptor-associated kinase (IRAK)-M down-regulates the toll-like receptor 4/interleukin-1 receptor signaling pathway. Here, we used IRAK-M knockout (IRAK-M−/−) mice and their microglia to dissect the role of IRAK-M in EAE. We found that deletion of IRAK-M increased the incidence rate and exacerbated the clinical symptoms in EAE mice. We then found that IRAK-M deficiency promoted the activation of microglia, activated NLRP3 inflammasomes, and enhanced GSDMD-mediated pyroptosis in the microglia of EAE. In contrast, over-expression of IRAK-M exerted inhibitory effects on neuroinflammation, NLRP3 activation, and pyroptosis. Moreover, IRAK-M deficiency enhanced the phosphorylation of IRAK1, while IRAK-M over-expression downregulated the level of phosphorylated IRAK1. Finally, we found upregulated binding of IRAK1 and TNF receptor-associated factor 6 (TRAF6) in IRAK-M−/− EAE mice compared to WT mice, which was blocked in AAVIRAK-M EAE mice. Our study reveals a complex signaling network of IRAK-M, which negatively regulates microglial NLRP3 inflammasomes and pyroptosis by inhibiting IRAK1 phosphorylation during EAE. These findings suggest a potential target for the novel therapeutic approaches of multiple sclerosis (MS)/EAE and NLRP3-related inflammatory diseases.

For large ground-based telescopes, static and dynamic disturbances would greatly degrade the optical performance. This is especially true for wide field survey telescopes with prime focus optics. The estimation of disturbance effects on large telescopes is becoming increasingly important during the design phase. Therefore, a wide field survey telescope with 2.5 m aperture and 3.5 deg field of view is studied in this research. This telescope is under construction now, and its first light is expected at the beginning of 2023. The estimation method for the optical performance under static and dynamic disturbances in the temporal domain and the active compensation method to improve the optical alignment, are investigated, which is a supplement for the simulation in the frequency domain. First, based on the mechanical model, the optical misalignment is established, where the deviation of the primary mirror is obtained from the length gauges and the deviation of the corrector is computed using the fitting method. Second, a method for compensating the static and dynamic disturbances is proposed, improving the optical performance. This method uses the disturbed primary mirror as the reference, and the corrector is actively controlled to align with it. Finally, a series of experimental tests and numerical simulations is conducted. The results show that the mechanical modeling error is within 10% and the maximum optical misalignment is reduced from 12 ′ ′ / 0.27 to 0.2 ′ ′ / 0.006 m m for static disturbance and from 1.3 ′ ′ / 0.03 to 0.4 ′ ′ / 0.01 m m for dynamic disturbance. Through active compensation, the telescope optical property is greatly improved. The modeling method and the simulation process mentioned in this research can also be used in the other relevant fields.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare neurological inflammatory disorder, characterized by recurrent myelitis and optic neuritis, which can lead to severe paralysis and blindness.It is reported that more than 75% of NMOSD patients are seropositive for aquaporin-4 immunoglobulin G (AQP4-IgG) [1].

Anti-N-methyl-D-aspartate receptor (NMDA) receptor encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Ectopic expression of NMDA receptors associated with ovarian teratoma is thought to mediate the initial autoimmune response against NMDA receptor encephalitis. Due to the lack of suitable animal models, the underlying mechanism of the disease remains unclear. This study described a new mice model of active immunization against the NMDA receptor with amino-terminal domain (ATD) peptides. After 12 weeks of immunization, mice were showed significant behavioral disorders and memory loss. Antibodies from CSF of immunized mice decreased surface NMDAR cluster density on hippocampus neurons. It also impaired the LTP induced at the Schaffer collateral to CA1 synapse and reduced NMDA receptors-induced calcium influx. The new model may help further research into the pathogenesis of the disease and the development of potential new therapies.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease with variable clinical manifestations caused by NMDAR autoantibody. The underlying molecular underpinnings of this disease are rarely characterized on a genomic scale. Anti-NMDAR encephalitis mainly affects the hippocampus, however, its effect on gene expression in hippocampal neurons is unclear at present. Here, we construct the active and passive immunization mouse models of anti-NMDAR encephalitis, and use single-nucleus RNA sequencing to investigate the diverse expression profile of neuronal populations isolated from different hippocampal regions. Dramatic changes in cell proportions and differentially expressed genes were observed in excitatory neurons of the dentate gyrus (DG) subregion. In addition, we found that ATP metabolism and biosynthetic regulators related genes in excitatory neurons of DG subregion were significantly affected. Kcnq1ot1 in inhibitory neurons and Meg3 in interneurons also changed. Notably, the latter two molecules exhibited opposite changes in different models. Therefore, the above genes were used as potential targets for further research on the pathological process of anti-NMDAR encephalitis. These data involve various hippocampal neurons, which delineate a framework for understanding the hippocampal neuronal circuit and the potential molecular mechanisms of anti-NMDAR encephalitis. K E Y W O R D Santi-N-methyl-D-aspartate receptor encephalitis, hippocampus, neuronal types, single-nucleus RNA sequencing Yunmeng Bai, Zhuhe Liu, and Tinglin Qian contributed equally to this study.

Background: Neuromyelitis optica (NMO), multiple sclerosis (MS) and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy are idiopathic inflammatory demyelinating diseases (IIDDs) that mainly present as encephalomyelitis. Heparan sulfate (HS) and hyaluronic acid (HA) are two components of glycocalyx, a carbohydrate-rich layer on the surface of blood vessels that mediates interaction with blood. Degradation of glycocalyx in IIDDs is poorly understood. Purpose: To detect the serum and cerebrospinal fluid (CSF) levels of shed HS and HA and to correlate these levels with disease severity to determine their diagnostic value. Methods: We obtained serum and CSF samples from 24 NMO patients, 15 MS patients, 10 autoimmune GFAP astrocytopathy patients, and 18 controls without non-inflammatory neurological diseases. Soluble HS and HA, and IFNγ, IL17A, and matrix metalloproteinase (MMP) 1 were detected via ELISA. Results: Serum and CSF levels of HS, HA and related cytokines but not of plasma MMP1 were significantly elevated in these diseases. Notably, HS and HA levels were positively correlated with Expanded Disability Status Scale scores. Conclusions: Our results indicate glycocalyx degradation and inflammation in NMO, MS and autoimmune GFAP astrocytopathy. Moreover, increased shedding of HS or HA may indicate a worse clinical situation. Furthermore, therapeutic strategies that protect glycocalyx may be effective in these diseases.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. However, the underlying mechanisms of this disease remain unclear, in part because of a lack of suitable animal models. This study describes a novel mouse model of anti-NMDAR encephalitis that was induced by active immunization against NMDARs using amino-terminal domain peptides. After 12 weeks of immunization, the mice showed significant behavioral disorders and memory loss. Furthermore, antibodies from the cerebrospinal fluid of immunized mice lowered the surface NMDAR cluster density in hippocampal neurons. Immunization also impaired long-term potentiation at Schaffer collateral–CA1 synapses and reduced NMDAR-induced calcium influx. This novel mouse model may allow further research into the pathogenesis of anti-NMDAR encephalitis and aid in the development of new therapies for this disease.

Background Neuromyelitis optica (NMO), multiple sclerosis (MS) and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy belong to autoimmune diseases incentral nervous system mainly manifestate encephalomyelitis. The glycocalyx (GLX), consists of several membrane-bound macromolecules, is located on the luminal side of the endothelium and mediates the blood and the vessel interaction. Until now, there is still lacking a holistic understanding of the GLX degradation in autoimmune encephalomyelitis. Aim This study aimed to detect the shedding levels of GLX components, heparan sulfate (HS) and hyaluronic acid (HA) in serum and cerebrospinal fluid (CSF), correlate them with the severity and assess the diagnostic value of them, and evaluate their correlations with pro-inflammatory cytokines. Methods Serum and CSF samples were obtained from 24 NMO patients, 15 MS patients, 10 autoimmune GFAP astrocytopathy patients, and 18 controls without non-inflammatory neurological diseases. Soluble HS, HA and IFN-γ, IL-17A, matrix metalloproteinase (MMP)-1 were detected by enzyme linked immunosorbent assay ELISA. Results Besides levels of serum and CSF levels of HS, HA and related cytokines were significantly elevated in these diseases. Notably, HS, HA in NMO, MS patients, and autoimmune GFAP astrocytopathy diseases were widely correlated with EDSS scores. Importantly, the ROC curve analysis suggested a potential diagnostic role of HS or HA . Conclusions The results here suggested the GLX degradation and inflammation in NMO, MS and autoimmune GFAP astrocytopathy. Moreover, increased shedding of HS or HA may indicate worse clinical situation. Importantly, CSF HS and HA may be informative diagnostic biomarkers for telling autoimmune encephalomyelitis from the non-inflammatory neurological controls. Furthermore, therapeutic strategy for protecting GLX may be effective to these diseases.