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Background Microglia are important for secreting chemical mediators of inflammatory responses in the central nervous system. Interleukin (IL)-10 and IL-1β secreted by glial cells support neuronal functions, but the related mechanisms remain vague. Our goal was to demonstrate the efficacy of IL-10 in suppressing IL-1β and in inflammasome activation in mice with epileptic seizure based on an epileptic-seizure mouse model. Methods In this study, mice in which epileptic seizures were induced by administering picrotoxin (PTX) were used as a case group, and mice injected with saline were employed as the control group. The expression of nucleic acids, cytokines, or signaling pathways was detected by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), flow cytometry, and Western blotting. Results Our results demonstrated that IL-10 inhibits IL-1β production through two distinct mechanisms: (1) Treatment with lipopolysaccharides (LPS) results in IL-10 overexpression in microglia and reduced NLRP3 inflammasome activity, thus inhibiting caspase-1-related IL-1β maturation; (2) next, autocrine IL-10 was found to subsequently promote signal transducer and activator of transcription-3 (STAT-3), reducing amounts of pro-IL-1β. Conclusions Our results indicate that IL-10 is potentially effective in the treatment of inflammation encephalopathy, and suggest the potential usefulness of IL-10 for treating autoimmune or inflammatory ailments.

When lithium-ion batteries experience thermal runaway, a large amount of heat rapidly accumulates inside, causing the internal pressure to rise sharply. Once the pressure exceeds the battery’s safety valve design capacity, the valve activates and releases flammable gas. If ignited in a high-temperature environment, the escaping gas can cause a jet fire containing high-temperature substances. Effectively controlling the internal temperature of the jet fire, especially rapidly cooling the core area of the flame during the jet process, is important to prevent the spread of lithium-ion battery fires. Therefore, this work proposes a strategy of a synergistic effect using microcapsule fire extinguishing agents and fine water mist to achieve an external barrier and an internal attack. The microcapsule fire extinguishing agents are prepared by using melamine–urea–formaldehyde resin as the shell and 1,1,1,2,2,3,3,4,4-nonafluoro-4-methoxybutane (C5H3F9O) and 1,1,2,2,3,3,4-heptafluorocyclopentane (C5H3F7) as the composite core. During the process of lithium-ion battery thermal runaway, the microcapsule fire extinguishing agents can enter the inner area of the jet fire under the protection of the fine water mist. The microcapsule shell ruptures at 100 °C, releasing the highly effective composite fire suppressant core inside the jet fire. The fine water mist significantly blocks the transfer of thermal radiation, inhibiting the spread of the fire. Compared to the suppression with fine water mist only, the time required to reduce the battery temperature from the peak value to a low temperature is reduced by 66 s and the peak temperature of the high-temperature substances above the battery is reduced by 228.2 °C. The propagation of the thermal runaway is suppressed, and no thermal runaway of other batteries around the faulty unit will occur. This synergistic suppression strategy of fine water mist and microcapsule fire extinguishing agent (FWM@M) effectively reduces the adverse effects of jet fires on the propagation of thermal runaway (TR) of lithium-ion batteries, providing a new solution for efficiently extinguishing lithium-ion battery fires.

Background Trio-based whole-exome sequencing (trio-WES) enables identification of pathogenic variants, including copy-number variants (CNVs), in children with unexplained neurodevelopmental delay (NDD) and neurodevelopmental comorbidities (NDCs), including autism spectrum disorder (ASD), epilepsy, and attention deficit hyperactivity disorder. Further phenotypic and genetic analysis on trio-WES-tested NDD-NDCs cases may help to identify key phenotypic factors related to higher diagnostic yield of using trio-WES and novel risk genes associated with NDCs in clinical settings. Methods In this study, we retrospectively performed phenotypic analysis on 163 trio-WES-tested NDD-NDCs children to determine the phenotypic differences between genetically diagnosed and non-genetically diagnosed groups. Additionally, we conducted genetic analysis of ASD genes with the help of Simons Foundation for Autism Research Institute (SFARI) Gene database to identify novel possible ASD-risk genes underlying genetic NDD conditions. Results Among these 163 patients, pathogenic variants were identified in 82 cases (82/163, 50.3%), including 20 cases with CNVs. By comparing phenotypic variables between genetically diagnosed group (82 cases) and non-genetically diagnosed group (81 cases) with multivariate binary logistic regression analysis, we revealed that NDD-NDCs cases presenting with severe-profound NDD [53/82 vs 17/81, adjusted-OR (95%CI): 4.865 (2.213 – 10.694), adjusted- P < 0.001] or having multiple NDCs [26/82 vs 8/81, adjusted-OR (95%CI): 3.731 (1.399 – 9.950), adjusted- P = 0.009] or accompanying ASD [64/82 vs 35/81, adjusted-OR (95%CI): 3.256 (1.479 – 7.168), adjusted- P = 0.003] and head circumference abnormality [33/82 vs 11/81, adjusted-OR (95%CI): 2.788 (1.148 – 6.774), adjusted- P = 0.024] were more likely to have a genetic diagnosis using trio-WES. Moreover, 37 genes with monogenetic variants were identified in 48 patients genetically diagnosed with NDD-ASD, and 15 dosage-sensitive genes were identified in 16 individuals with NDD-ASD carrying CNVs. Most of those genes had been proven to be ASD-related genes. However, some of them (9 genes) were not proven sufficiently to correlate with ASD. By literature review and constructing protein-protein interaction networks among these 9 candidate ASD-risk genes and 102 established ASD genes obtained from the SFARI Gene database, we identified CUL4B , KCNH1 , and PLA2G6 as novel possible ASD-risk genes underlying genetic NDD conditions. Conclusions Trio-WES testing is recommended for patients with unexplained NDD-NDCs that have severe-profound NDD or multiple NDCs, particularly those with accompanying ASD and head circumference abnormality, as these independent factors may increase the likelihood of genetic diagnosis using trio-WES. Moreover, NDD patients with pathogenic variants in CUL4B , KCNH1 and PLA2G6 should be aware of potential risks of developing ASD during their disease courses.

Background Nonerythrocytic spectrin beta 1 (SPTBN1) is an important cytoskeletal protein that involves in normal cell growth and development via regulating TGFβ/Smad signaling pathway, and is aberrantly expressed in various cancer types. But, the exact role of SPTBN1 in pan-cancer is still unclear. This report aimed to display expression patterns and prognostic landscapes of SPTBN1 in human cancers, and further assess its prognostic/therapeutic value and immunological role in kidney renal carcinoma (KIRC) and uveal melanoma (UVM). Methods We firstly analyzed expression patterns and prognostic landscapes of SPTBN1 in human cancers using various databases and web-based tools. The relationships between SPTBN1 expression and survival/tumor immunity in KIRC and UVM were further investigated via R packages and TIMER 2.0 platform. The therapeutic roles of SPTBN1 in KIRC and UVM were also explored via R software. Following this, the prognostic value and cancer immunological role of SPTBN1 in KIRC and UVM were validated in our cancer patients and GEO database. Results Overall, cancer tissue had a lower expression level of SPTBN1 frequently in pan-cancer, compared with those in adjacent nontumor one. SPTBN1 expression often showed a different effect on survival in pan-cancer; upregulation of SPTBN1 was protective to the survival of KIRC individuals, which was contrary from what was found in UVM patients. In KIRC, there were significant negative associations between SPTBN1 expression and pro-tumor immune cell infiltration, including Treg cell, Th2 cell, monocyte and M2-macrophage, and expression of immune modulator genes, such as tumor necrosis factor superfamily member 9 (TNFSF9); while, in UVM, these correlations exhibited opposite patterns. The following survival and expression correlation analysis in our cancer cohorts and GEO database confirmed these previous findings. Moreover, we also found that SPTBN1 was potentially involved in the resistance of immunotherapy in KIRC, and the enhance of anti-cancer targeted treatment in UVM. Conclusions The current study presented compelling evidence that SPTBN1 might be a novel prognostic and therapy-related biomarker in KIRC and UVM, shedding new light on anti-cancer strategy.

Background Pathogenic heterozygous variants in the gene encoding proline-rich transmembrane protein 2 ( PRRT2 ) have been recently identified as the major cause of familial infantile convulsion and choreoathetosis syndrome (OMIM#602,066), a spectrum of autosomal dominant paroxysmal neurological disorders, including self-limited infantile epilepsy (SeLIE) and infantile convulsion that can be isolated (IC) or associated with paroxysmal kinesigenic dyskinesia (PKD/IC). Incomplete penetrance of PRRT2 variants and variable phenotypes without developmental impairment have been widely reported in previous studies of this syndrome, but no studies to date have documented global development delay (GDD) with growth retardation (GR) occurred in a family with multiple phenotypes of this syndrome. Case presentation Here, using family-based whole-exome sequencing, we identified a pathogenic heterozygous PRRT2 variant (NM_145239.3: c.718C > T, p.Arg240*) in a 3-generation Chinese family of infantile convulsion and choreoathetosis syndrome. The variant was detected in five family members, of which two ( pedigree III.1 and III.3) were diagnosed with PKD/IC, one ( pedigree III.2) presented uncontrolled generalized/focal seizures with GDD and GR; the GR of this patient was aggravated with the progression of the epileptic condition; she was then diagnosed with IC and developmental impairment, one ( pedigree II.2) was diagnosed with SeLIE, and one ( pedigree II.3) was phenotypically unaffected and recognized as an obligate carrier. Conclusions In conclusion, we reported a PRRT2 -related syndrome family harboring multiple phenotypic features, including uncontrolled seizures with developmental impairment, which may potentially expand PRRT2 -related clinical spectrum. Moreover, our findings suggest that children with PRRT2 -related seizures/convulsions, especially those who suffer from uncontrolled multiple seizure types, should be aware of potential risks of having developmental impairment aggravation and need timely and effective antiepileptic medications.

The mitochondria-associated ER membrane (MAM) plays a critical role in cellular energetics and calcium homeostasis; however, how MAM is affected under diabetic condition remains elusive. This study presented a comprehensive proteome profiling of isolated brain MAM from long-term type 2 diabetic mice vs. non-diabetic controls. MAM protein was extracted efficiently by a surfactant-aided precipitation/on-pellet digestion (SOD) method, and MAM proteome was quantified by an ion-current-based MS1 method combined with nanoLC-MS/MS. A total of 1,313 non-redundant proteins of MAM were identified, among which 144 proteins were found significantly altered by diabetes. In-depth IPA analysis identified multiple disease-relevant signaling pathways associated with the MAM proteome changes in diabetes, most significantly the unfolded protein response (UPR), p53, hypoxia-related transcription factors, and methyl CpG binding protein 2. Using immunofluorescence labeling we confirmed the activation of three UPR branches and increased ERp29 and calreticulin in diabetic retinas. Moreover, we found GRP75, a key MAM tethering protein, was drastically reduced by long-term diabetes. In vitro , acute high glucose treatment reduces ER-mitochondrial contact in retinal endothelial cells. This study provides first insight into the significant alterations in MAM proteome associated with activation of the UPR in diabetes, which may serve as novel benchmarks for the future studies of diabetic complications.

ANKRD17 has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chromosomal microarray analysis (CMA), we identified two unrelated cases with novel de novo heterozygous ANKRD17 variants. Case 1 describes a fetus with multiple congenital anomalies, where genetic analysis revealed a microdeletion at 4q13.3 truncating the ANKRD17 gene. Case 2 involves a 12-year-old male presenting with mild ID and progressive social impairments, associated with a NM_032217.5: c.1252 C > T (p.Arg418*) variation in ANKRD17 . Our study highlighted in mouse models an association between Ankrd17 haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety. Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown. These results expand the genetic and phenotypic spectrum of ANKRD17 -related disorders, underscore the critical role of mitochondrial dysfunction in the pathophysiology of ANKRD17 -related ID and ASD.

Although emerging animal- or cell-based evidence supports the relationship between casein kinase 2 alpha protein 1 (CSNK2A1) and cancers, no pan-cancer analysis is available. Thus, this report aimed to display the prognostic landscape of CSNK2A1 in pan-cancer and investigate the relationship between CSNK2A1 and tumor immunity. In the current study, we investigated the expression pattern, genetic alterations and survival analysis of CSNK2A1 in pan-cancer across multiple datasets and online platforms. The correlations between CSNK2A1 expression and tumor immunity were explored and visualized via R language software. Following this, immunohistochemical (IHC) staining and Kaplan-Meier survival analysis were conducted in clinical patients for proving the bioinformatic findings. Analysis of protein-protein interaction and gene functional enrichment was conducted using GeneMANIA platform and gene set enrichment analysis (GSEA), respectively. In TCGA, tumor tissue had a higher expression level of CSNK2A1 compared with that in corresponding normal tissue. An increased expression level of CSNK2A1 was related to poor clinical prognosis in most types of cancer such as LIHC. The following expression and survival analysis in clinical liver hepatocellular carcinoma (LIHC) patients confirmed these TCGA findings. CSNK2A1 expression had significant positive correlations with pro-tumor-infiltrating immune cells (TIICs) like M1-macrophages and fibroblasts, and significant negative correlations with anti-tumor-TIICs like activated CD8+ T cells and NK cells, suggesting specific interactions between CSNK2A1 and certain TIICs subtypes. Furthermore, CSNK2A1 expression had the most significant positive correlations with common markers of immune checkpoint including programmed death ligand-1 (PDL1) in LIHC. These findings were validated by an IHC analysis. GSEA analysis demonstrated that high expression of CSNK2A1 was related to cell signaling pathways and immunity-related activities. These findings suggested that CSNK2A1 was not only related to poor clinical prognosis in cancer like LIHC but also a novel immunotherapy-related biomarker in cancers, especially in LIHC, shedding new light on anti-tumor strategy.

MOG-IgG-associated encephalomyelitis (MOG-EM), a of common type of autoimmune encephalomyelitis (AE), is an autoimmune disease (AID) of the central nervous system that predominantly affects the brain and spinal cord. Rituximab (RTX) - a chimeric anti-CD20 monoclonal antibody - has been increasingly used as an effective immunotherapeutic agent in the treatment of AE. However, interstitial lung disease (ILD) is an exceedingly rare but potentially fatal complication of RTX treatment. Case report and review of the literature: Herein, we describe the first case of RTX-induced ILD (R-ILD) in a teenager with MOG-EM. In addition, we systematically review the literature on R-ILD cases in patients with AID and discuss the clinical characteristics of R-ILD in individuals with differential diagnosis of AID. R-ILD should be suspected in patients with AE undergoing RTX treatment who present with dyspnea and/or cough without any signs or symptoms of infection. Meanwhile, by reviewing the literature systematically, we suggest that regardless of the dosage, RTX therapy for AID should be very cautious and well-monitored especially in young individuals including age groups of children, adolescents, and young adults due to the possibility of relatively higher mortality caused by R-ILD.

Purpose Metal green parts fabricated by indirect selective laser sintering (SLS) have lower mechanical properties, and thus, they cannot satisfy practical application. To enhance their performance, two polymer resins were compounded as a modified material to infiltrate into the metal parts by SLS. Design/methodology/approach The viscosity and glass-transition temperature were tested by a viscometer and differential scanning calorimetry, respectively. The microstructure and morphology of the interface of parts by polymer resin infiltrated were observed to be using scanning electron microscopy. The tensile strength of sample parts was tested, too. The temperature tolerances of two mass ratio polymer materials were tested and compared by thermo-gravimetric analysis (TGA). Findings Compared to those without being polymer material infiltrated, the results of test showed that the tensile strength of the metallic parts is enhanced obviously, about four times. In addition, the analysis of TGA showed that the resin of mass ratio of 2:1 can be endured up to 200° and can be used as infiltrating materials for metal parts. Originality/value Therefore, plastic injection mold and function part can be manufactured by this method.