With the aggravation of environmental bacterial pollution, an efficient and useful sterilization technology is urgently needed. In this paper, a new type of Ag/CuS/carbon cloth bactericidal material was prepared using hydrothermal and photo-reduction method. The bactericidal effects of Ag/CuS/carbon cloth on Bacillus subtilis in photocatalysis, electrocatalysis, and photoelectric synergy technologies were experimentally determined. The effects of different input voltages, concentrations, light intensities, catalysts, solutions, and other operating conditions on the bactericidal effect were studied. The results showed that compared with photocatalysis and electrocatalysis, under the input voltage of 2 V, the photoelectrocatalysis sterilization achieved 99.99% bactericidal removal effect in 22.5 min. Bacillus subtilis can be effectively removed through the bactericidal action of Ag and Cu combined with the photo catalysis and electric field bactericidal action. Photoelectrocatalysis syntheses have a good sterilization prospects and development potential.

Intraventricular hemorrhage (IVH) commonly occurs as an extension of intracerebral hemorrhage (ICH) into the brain ventricular system, leading to worse outcomes without effective management. Using a mouse model of IVH, we found that impaired neurogenesis is evident in the subventricular zone (SVZ), along with persistent microglia activation, leukocyte infiltration and cell death. Pharmacological depletion of microglia using PLX3397, an inhibitor of colony stimulating factor 1 receptor (CSF1R), promotes neurogenesis, and alleviated delayed functional impairments in IVH mice. Meanwhile, an elevated level of microglia-derived CC chemokine ligand 20 (CCL20) is observed in the SVZ following IVH, which can induce the upregulation of pro-inflammatory factors in microglia and impair the proliferation and survival of neural stem cells (NSCs) in vitro. Blocking CCL20 in microglia leads to downregulation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/the nuclear factor-κB (NF-κB) signaling pathway, which may contribute to CCL20-dependent pro-inflammatory responses and neural injury. These findings demonstrate a detrimental role of microglia in the neurogenesis and neurorepair after IVH in which CCL20 likely plays a role.

Methods In this prospective, multicentre cohort study, we recruited patients with suspected MG to evaluate the diagnostic accuracy of cell-based assay (CBA), radioimmunoprecipitation assay (RIPA) and enzyme-linked immunosorbent assay (ELISA) in detecting AChR and MuSK autoantibodies. This study is registered with www. clinicaltrials.gov, number NCT05219097. Findings 2272 eligible participants were recruited, including 2043 MG, 229 non-MG subjects. AChR antibodies were detected in 1478, 1310, and 1280 out of a total of 2043 MG patients by CBA, RIPA, and ELISA, respectively; sensitivity, 72.3% (95% CI, 70.3-74.3), 64.1% (95% CI, 62.0-66.2), 62.7% (95% CI, 60.5-64.8); specificity, 97.8% (95% CI, 95.0-99.3), 97.8% (95% CI, 95.0-99.3), 94.8% (95% CI, 91.9-97.7). MuSK antibodies were found in 59, 50, and 54 from 2043 MG patients by CBA, RIPA and ELISA, respectively; sensitivity, 2.9% (95% CI, 2.2-3.7), 2.4% (95% CI, 1.8-3.2), 2.6% (95% CI, 2.0-3.4); specificity, 100% (95% CI, 98.4-100), 100% (95% CI, 98.4-100), and 99.1% (95% CI, 96.9-99.9). The area under the curve of AChR antibodies tested by CBA was 0.858, and there were statistical differences with RIPA (0.843; p = 0.03) and ELISA (0.809; p < 0.0001). Interpretation CBA has a higher diagnostic accuracy compared to RIPA or ELISA in detecting AChR and MuSK autoantibodies for MG diagnosis. Funding New Terrain Biotechnology, Inc., Tianjin, China. Copyright <(c)> 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION:Intracerebral hemorrhage (ICH) accounts for 10%-15% of all strokes and culminates in high mortality and disability. After ICH, brain injury is initiated by the mass effect of hematoma, followed by secondary cytotoxic injury from dying brain cells, hematoma disintegration, and cascading brain immune response. However, the molecular mechanism of secondary cytotoxic brain injury in ICH is not completely understood. The sensitive purinergic receptor, P2X4 receptor (P2X4R), was known to recognize extracellular free ATP released by dying cells during tissue injury.AIMS:In this study, we aim to understand the role of P2X4R in acute brain injury triggered by ICH.RESULTS:In this study, we found that the sensitive purinergic receptor, P2X4R, was upregulated in the brain of patients with ICH as well as in a mouse model of ICH induced by collagenase injection. P2X4R blockage with the specific inhibitor 5-BDBD attenuated brain injury in ICH mice by significantly reducing brain edema, blood-brain barrier leakage, neural death, and ultimately acute neurodeficits. Further study indicated that the protective effect of P2X4R inhibition is related to decreased pro-inflammatory activity of microglia and recruitment of peripheral immune cells into the hemorrhagic brain.CONCLUSIONS:These results suggest that the P2X4 receptor is activated by ICH stimuli which worsen brain injury following ICH.

自然杀伤(NK)细胞是一类独特的天然免疫淋巴细胞,在机体的感染、肿瘤、生殖和组织损伤等方面具有重要的免疫调控作用.NK细胞的主要免疫功能包括自然杀伤作用和免疫因子分泌功能.研究表明,NK细胞的表型和功能具有器官特异性,在人体不同的组织器官内,NK细胞的分布、表型和功能存在差异.近年来研究表明,在中枢神经系统(CNS)特定疾病微环境下如神经免疫病、脑血管病、神经退行性疾病和脑衰老疾病中,NK细胞是疾病病理演变的重要参与者和潜在的治疗靶点.本文将对NK细胞在CNS疾病中的研究进展进行回顾和总结,并对NK细胞在CNS疾病中的研究和应用方向进行展望.

Acute brain insults elicit pronounced inflammation that amplifies brain damage in intracerebral hemorrhage (ICH). We profiled perihematomal tissue from patients with ICH, generating a molecular landscape of the injured brain, and identified formyl peptide receptor 1 (FPR1) as the most abundantly increased damage-associated molecular pattern (DAMP) receptor, predominantly expressed by microglia. Circulating mitochondrial N-formyl peptides, endogenous ligands of FPR1, were augmented and correlated with the magnitude of brain edema in patients with ICH. Interactions of formyl peptides with FPR1 activated microglia, boosted neutrophil recruitment, and aggravated neurological deficits in two mouse models of ICH. We created an FPR1 antagonist T-0080 that can penetrate the brain and bind both human and murine FPR1. T-0080 attenuated brain edema and improved neurological outcomes in ICH models. Thus, FPR1 orchestrates brain inflammation after ICH and could be targeted to improve clinical outcome in patients.

Perihematomal edema (PHE) occurs within hours after intracerebral hemorrhage (ICH), leading to secondary injury manifested by impaired blood-brain barrier (BBB) integrity and destruction of adjacent tissue. To dissect the mechanisms underlying PHE formation, we profiled human and mouse perihematomal tissues and identified natural killer (NK) cells as the predominant immune cell subset that outnumbers other infiltrating immune cell types during early stages of ICH. Unbiased clustering of single-cell transcriptional profiles revealed two major NK cell subsets that respectively possess high cytotoxicity or robust chemokine production features in the brain after ICH, distinguishing them from NK cells of the periphery. NK cells exacerbate BBB disruption and brain edema after ICH via cytotoxicity toward cerebral endothelial cells and recruitment of neutrophils that augment focal inflammation. Thus, brain-bound NK cells acquire new features that contribute to PHE formation and neurological deterioration following ICH.

OBJECTIVETo identify differentially expressed serum proteins that could serve as sensitive biomarkers of heterotopic ossification in patients with traumatic brain injury.METHODSFrom August 2014 to December 2015, 18 patients with traumatic brain injury were enrolled in the study, and blood samples were collected. Patients with traumatic brain injury were divided based on the presence (n=9 patients, heterotopic ossification group) or absence (n=9 patients, traumatic brain injury group or control group) of heterotopic ossification. Protein expression profiles were compared using 2-dimensional electrophoresis. Differentially expressed proteins were examined using matrix-assisted laser desorption/ionization and time-of-flight tandem mass spectrometry (MALDI-TOF/TOF). The differentially expressed proteins identified were further confirmed by Western blotting.RESULTSSeven protein spots were differentially expressed between heterotopic ossification and traumatic brain injury groups in 2-dimensional electrophoresis analysis. Vitamin D binding protein (Gc protein), retinol binding protein 4 (RBP4) and haptoglobin expression decreased significantly in the heterotopic ossification group compared with the control group (p < 0.05), and this was further confirmed by Western blotting.CONCLUSIONLower levels of expression of Gc protein, RBP4 and haptoglobin may be closely related to heterotopic ossification after traumatic brain injury. These proteins may be potential biomarkers of heterotopic ossification secondary to traumatic brain injury.

AIMS:Intracerebral hemorrhage (ICH) is a devastating type of stroke without specific treatment. Activator protein 1 (AP-1), as a gene regulator, initiates cytokine expression in response to environmental stimuli. In this study, we investigated the relationship between AP-1 and neuroinflammation-associated brain injury triggered by ICH.METHODS:Intracerebral hemorrhage mice were developed by autologous blood or collagenase infusion. We measured the dynamics of AP-1 in mouse brain tissues during neuroinflammation formation after ICH. The effects of the AP-1 inhibitor SR11302 on brain injury and neuroinflammation as well as the underlying mechanisms were investigated in vivo and in vitro.RESULTS:AP-1 was significantly upregulated in mouse brain tissue as early as 6 hours after ICH, accompanied by elevations in proinflammatory factors, including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. Inhibition of AP-1 using SR11302 reduced neurodeficits and brain edema at day 3 after ICH. SR11302 ablated microglial IL-6 and TNF-α production and brain-infiltrating leukocytes in ICH mice. In addition, SR11302 treatment diminished thrombin-induced production of IL-6 and TNF-α in cultured microglia.CONCLUSIONS:Inhibition of AP-1 curbs neuroinflammation and reduces brain injury following ICH.

Astrocyte loss induced by neuromyelitis optica (NMO)-IgG and complement-dependent cytotoxicity (CDC) is the hallmark of NMO pathology. The survival of astrocytes is thought to reflect astrocyte exposure to environmental factors in the CNS and the response of astrocytes to these factors. However, still unclear are how astrocytes respond to NMO-IgG and CDC, and what CNS environmental factors may impact the survival of astrocytes. In a murine model of NMO induced by intracerebral injection of NMO-IgG and human complement, we found dramatic upregulation of IL-15 in astrocytes. To study the role of astrocytic IL-15 in NMO, we generated a transgenic mouse line with targeted expression of IL-15 in astrocytes (IL-15tg), in which the expression of IL-15 is controlled by a glial fibrillary acidic protein promoter. We showed that astrocyte-targeted expression of IL-15 attenuates astrocyte injury and the loss of aquaporin-4 in the brain. Reduced blood–brain barrier leakage and immune cell infiltration are also found in the lesion of IL-15tg mice subjected to NMO induction. IL-15tg astrocytes are less susceptible to NMO-IgG-mediated CDC than their wild-type counterparts. The enhanced resistance of IL-15tg astrocytes to cytotoxicity and cell death involves NF-κB signaling pathway. Our findings suggest that IL-15 reduces astrocyte loss and NMO pathology.

INTRODUCTION:Agrin is essential for the formation and maintenance of neuromuscular junctions (NMJs). NT-1654 is a C-terminal fragment of mouse neural agrin. In this study, we determined the effects of NT-1654 on the severity of experimental autoimmune myasthenia gravis (EAMG).METHODS:EAMG was induced in female Lewis rats by immunization with the Torpedo acetylcholine receptor (tAChR) and complete Freund's adjuvant (CFA). NT-1654 was dissolved in phosphate-buffered saline (PBS) and injected daily subcutaneously into tAChR immunized rats during the first 10 days after immunization, and then every other day for the following 20 days.RESULTS:We showed that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats.DISCUSSION:We demonstrated that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats. Muscle Nerve 57: 814-820, 2018.

Brain ischemia elicits microglial activation and microglia survival depend on signaling through colony-stimulating factor 1 receptor (CSF1R). Although depletion of microglia has been linked to worse stroke outcomes, it remains unclear to what extent and by what mechanisms activated microglia influence ischemia-induced inflammation and injury in the brain. Using a mouse model of transient focal cerebral ischemia and reperfusion, we demonstrated that depletion of microglia via administration of the dual CSF1R/c-Kit inhibitor PLX3397 exacerbates neurodeficits and brain infarction. Depletion of microglia augmented the production of inflammatory mediators, leukocyte infiltration, and cell death during brain ischemia. Of note, microglial depletion-induced exacerbation of stroke severity did not solely depend on lymphocytes and monocytes. Importantly, depletion of microglia dramatically augmented the production of inflammatory mediators by astrocytes after brain ischemia . In vitro studies reveal that microglia restricted ischemia-induced astrocyte response and provided neuroprotective effects. Our findings suggest that neuroprotective effects of microglia may result, in part, from its inhibitory action on astrocyte response after ischemia.

Recent studies have demonstrated that lymphocytes play a key role in ischemic brain injury. However, there is still a lack of viable approaches to non-invasively track infiltrating lymphocytes and reveal their key spatiotemporal events in the inflamed central nervous system (CNS). Here we describe an in vivo imaging approach for sequential monitoring of brain-infiltrating CD4(+) T cells in experimental ischemic stroke. We show that magnetic resonance imaging (MRI) or Xenogen imaging combined with labeling of SPIO-Molday ION Rhodamine-B (MIRB) can be used to monitor the dynamics of CD4(+) T cells in a passive transfer model. MIRB-labeled CD4(+) T cells can be longitudinally visualized in the mouse brain and peripheral organs such as the spleen and liver after cerebral ischemia. Immunostaining of tissue sections showed similar kinetics of MIRB-labeled CD4(+) T cells when compared with in vivo observations. Our results demonstrated the use of MIRB coupled with in vivo imaging as a valid method to track CD4(+) T cells in ischemic brain injury. This approach will facilitate future investigations to identify the dynamics and key spatiotemporal events for brain-infiltrating lymphocytes in CNS inflammatory diseases.

Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood–brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

Background and Purpose: Astrocytes play a pivotal role in post-ischemic brain inflammation, but the relevant astrocyte-derived mediators of ischemic brain injury remain to be defined. This study aims to investigate the impact of astrocyte-derived factors such as IL-15 on ischemic brain injury. Methods and Results: We show that IL-15 is a prominent factor relased by astrocytes after brain ischemia in a mouse model of transient focal brain ischemia. To further eluciate the biological functions of astrcoyte-derived IL-15 in ischemic stroke, we generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15-expressing transgenic mouse line (GFAP-IL-15 tg ). We demonstrate that astrocyte-specific overproduction of IL-15 leads to larger brain infarcts, worse neurodeficits and enhanced lymphocyte infiltration. In GFAP-IL-15 tg mice, we found increased accumulation and activation of CD8 + T and natural killer (NK) cells after cerebral ischemia. Importantly, depletion of either CD8 + T or NK cells in GFAP-IL-15 tg mice prior to cerebral ischemia attenuates the accelerated brain infarction and neurodeficits. Of note, CD8 + T and NK cells are within the proximity of astrocytes in the post-ischemic brain and either knockdown of IL-15 receptor α or blockade of cell-to-cell contact diminishes the activation and effector function of CD8 + T and NK cells caused by astrocytic overproduction of IL-15, suggesting that astrocytic IL-15 is delivered in trans to target cells. Additionally, CD8 + T and NK cells are seen closely adjacent to IL-15-producing astrocytes in acute ischemic lesions of postmortem human brain tissues, implying that astrocytic IL-15-mediated brain injury may be relevant to human stroke. Conclusion: These findings indicate that astrocytic IL-15 contributes to post-ischemic brain damage.

Significance Ischemic stroke is a leading cause of death and disability worldwide. Evidence indicates the detrimental effects of lymphocyte infiltration into the ischemic brain. However, a knowledge gap exists relating to the brain-specific cellular constituents and environmental factors that dictate the phenotype and function of infiltrating lymphocytes. Astrocytes bridge interactions between ischemic neurons and lymphocytes. We show that brain ischemia induces robust up-regulation of astrocytic interleukin-15 (IL-15). The present study was directed toward understanding the role of astrocyte-derived factors such as IL-15 in stroke. We discovered that astrocytic IL-15 is necessary and sufficient to amplify cell-mediated immune responses that promote ischemic brain injury. These results provide definitive evidence on the role of astrocyte-derived IL-15 in ischemic brain injury.

Background: Severe brain injury significantly influences immune responses. However, the levels at which such influence occur and the involvement of neurogenic pathways are not well defined. Methods: 39 eligible patients with supratentorial ICH within 24 hours of onset and 20 matched healthy controls were enrolled. Hematoma sizes at admission were calculated via computed tomography (CT). Perihematomal edema (PHE) and spleen volume at day 3 and 14 were measured via T2-weighted magnetic resonance imaging (MRI), respectively. Tissue diffusion and capillary perfusion of spleen were quantified by Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) with 9 b values. Peripheral lymphocyte subsets were quantified by flow cytometry. Neurotransmitters and stress hormone were detected by enzyme-linked immunosorbent assay (ELISA). Association of splenic and cellular alterations with progression of PHE and the outcomes of ICH patients were analyzed. Mechanisms governing the spleen and lymphocyte alterations after ICH were investigated in mouse models of ICH. Results: Average spleen shrinkage of 37ml accompanied by splenic capillary perfusion increase occurred in ICH patients at day 3 after disease onset. The magnitude of spleen shrinkage was associated with hematoma size upon admission. Concurrently, patients with severe spleen shrinkage (> 37ml) had less progression of PHE. Lymphopenia was observed in ICH patients after ictus and persisted up to 14 day, which was not parallel with spleen alteration. Patients with infections exhibited poorer functional outcome and significant T and NK cell deficiency. In ICH models, signals derived from adrenergic and hypothalamus-pituitary-adrenal (HPA) axis activation contributed to loss of white blood cells in the white pulp. Conclusions: Spleen shrinkage and lymphopenia reflect the impact of ICH on the immune system at the organ and cellular levels, such impacts are derived from coordinated action of sympathetic innervation and HPA axis. The magnitude of spleen shrinkage might be associative with the progression of PHE and clinical outcome of ICH patients. Additionally specific cellular immunity deficiency was associated with increased infection risk in patients.