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Abstract Background The gut microbiota plays a critical role in regulating brain function through the microbiome-gut-brain axis (MGBA). Dysbiosis of the gut microbiota is associated with neurological impairment in Traumatic brain injury (TBI) patients. Our previous study found that TBI results in a decrease in the abundance of Prevotella copri (P. copri). P. copri has been shown to have antioxidant effects in various diseases. Meanwhile, guanosine (GUO) is a metabolite of intestinal microbiota that can alleviate oxidative stress after TBI by activating the PI3K/Akt pathway. In this study, we investigated the effect of P. copri transplantation on TBI and its relationship with GUO-PI3K/Akt pathway. Methods In this study, a controlled cortical impact (CCI) model was used to induce TBI in adult male C57BL/6J mice. Subsequently, P. copri was transplanted by intragastric gavage for 7 consecutive days. To investigate the effect of the GUO-PI3K/Akt pathway in P. copri transplantation therapy, guanosine (GUO) was administered 2 h after TBI for 7 consecutive days, and PI3K inhibitor (LY294002) was administered 30 min before TBI. Various techniques were used to assess the effects of these interventions, including quantitative PCR, neurological behavior tests, metabolite analysis, ELISA, Western blot analysis, immunofluorescence, Evans blue assays, transmission electron microscopy, FITC-dextran permeability assay, gastrointestinal transit assessment, and 16 S rDNA sequencing. Results P. copri abundance was significantly reduced after TBI. P. copri transplantation alleviated motor and cognitive deficits tested by the NSS, Morris’s water maze and open field test. P. copri transplantation attenuated oxidative stress and blood-brain barrier damage and reduced neuronal apoptosis after TBI. In addition, P. copri transplantation resulted in the reshaping of the intestinal flora, improved gastrointestinal motility and intestinal permeability. Metabolomics and ELISA analysis revealed a significant increase in GUO levels in feces, serum and injured brain after P. copri transplantation. Furthermore, the expression of p-PI3K and p-Akt was found to be increased after P. copri transplantation and GUO treatment. Notably, PI3K inhibitor LY294002 treatment attenuated the observed improvements. Conclusions We demonstrate for the first time that P. copri transplantation can improve GI functions and alter gut microbiota dysbiosis after TBI. Additionally, P. copri transplantation can ameliorate neurological deficits, possibly via the GUO-PI3K/Akt signaling pathway after TBI.

Abstract Background White matter injury (WMI) is an important pathological process after traumatic brain injury (TBI). The correlation between white matter functions and the myeloid cells expressing triggering receptor‐2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism is crucial for early remyelination after demyelinating diseases. However, the potential roles of TREM2 expression and microglial sterol metabolism in WMI after TBI have not yet been explored. Methods Controlled cortical injury was induced in both wild‐type (WT) and TREM2 depletion (TREM2 KO) mice to simulate clinical TBI. COG1410 was used to upregulate TREM2, while PLX5622 and GSK2033 were used to deplete microglia and inhibit the liver X receptor (LXR), respectively. Immunofluorescence, Luxol fast blue staining, magnetic resonance imaging, transmission electron microscopy, and oil red O staining were employed to assess WMI after TBI. Neurological behaviour tests and electrophysiological recordings were utilized to evaluate cognitive functions following TBI. Microglial cell sorting and transcriptomic sequencing were utilized to identify alterations in microglial sterol metabolism‐related genes, while western blot was conducted to validate the findings. Results TREM2 expressed highest at 3 days post‐TBI and was predominantly localized to microglial cells within the white matter. Depletion of TREM2 worsened aberrant neurological behaviours, and this phenomenon was mediated by the exacerbation of WMI, reduced renewal of oligodendrocytes, and impaired phagocytosis ability of microglia after TBI. Subsequently, the upregulation of TREM2 alleviated WMI, promoted oligodendrocyte regeneration, and ultimately facilitated the recovery of neurological behaviours after TBI. Finally, the expression of DHCR24 increased in TREM2 KO mice after TBI. Interestingly, TREM2 inhibited DHCR24 and upregulated members of the LXR pathway. Moreover, LXR inhibition could partially reverse the effects of TREM2 upregulation on electrophysiological activities. Conclusions We demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia.

Abstract Objective To investigate the effects of the apolipoprotein E (APOE) gene on oxygen saturation and cerebral perfusion in the early stages of traumatic brain injury (TBI). Methods This study included 136 consecutive TBI patients and 51 healthy individuals. The APOE genotypes of all subjects were determined using quantitative fluorescence polymerase chain reaction (QF‐PCR). Regional cerebral oxygen saturation (rScO2) of patients with TBI and normal subjects was monitored using near‐infrared spectroscopy (NIRS). Computed tomography (CT) perfusion was used to obtain cerebral perfusion in patients with TBI and normal subjects. Results In the TBI group, the rScO2 of APOEε4 carriers (53.06 ± 6.87%) was significantly lower than that of non‐carriers (58.19 ± 5.83%, p 5.75 s, Marshall CT Class, and GCS were independent risk factors for early poor prognosis in patients with TBI. Conclusion Both cerebral perfusion and cerebral oxygen were significantly impaired after TBI, and low cerebral perfusion and hypoxia were related to poor prognosis of patients with TBI. Compared with APOE ε4 non‐carriers, APOE ε4 carriers not only had poorer cerebral perfusion and cerebral oxygen metabolism but also worse prognosis in the early stages of TBI. Furthermore, a negative correlation was observed between the rSCO2 and MTT levels. In addition, both CT perfusion scanning (CTP) and NIRS are reliable for monitoring the condition of patients with TBI in the neurological intensive care unit (NICU).

ObjectiveThis study compared 2 representative cases with ruptured aneurysms to explore the role of hemodynamic and morphological parameters in evaluating the rupture risk of intracranial aneurysms (IAs).MethodsCTA and 3-dimensional rotational angiography (3DRA) of 3 IAs in 2 patients were retrospectively analyzed in this study. Hemodynamics and morphological parameters were compared between a ruptured IA and an unruptured IA in case1, and between before and after aneurysm rupture in case 2.ResultsIn case 1, the ruptured aneurysm had larger morphological parameters including size ratio (SR), aspect ratio (AR), aneurysm vessel angle (θF), Aneurysm inclination angle (θA), Undulation index (UI), Ellipticity index (EI), and Non-sphericity Index (NSI) than the unruptured aneurysm. And oscillatory shear index (OSI) is also larger. Higher rupture resemblance score (RRS) was shown in the ruptured aneurysm. In case 2, the aneurysm had one daughter sac after 2 years. Partial morphological and hemodynamic parameters including SR, AR, θF, θA, UI, EI, NSI, OSI, and relative residence time (RRT) increased, and normalized wall shear stress (NWSS) was significantly reduced. RRS increased during this period.ConclusionSR and OSI may have predictive values for the risk of intracranial aneurysm rupture. It is possible that WSS Changes before and after IA rupture, yet the influence of high or low WSS on growth and rupture of IA remains unclear. RRS is promising to be used in the clinical assessment of the rupture risk of IAs and to guide the formulation of treatment plans.

Long non-coding RNAs (lncRNAs) are increasingly recognized as cis- and trans-acting regulators of protein-coding genes in plants, particularly in response to abiotic stressors. Among these stressors, high soil salinity poses a significant challenge to crop productivity. Radish (Raphanus sativus L.) is a prominent root vegetable crop that exhibits moderate susceptibility to salt stress, particularly during the seedling stage. Nevertheless, the precise regulatory mechanisms through which lncRNAs contribute to salt response in radish remain largely unexplored. In this study, we performed genome-wide identification of lncRNAs using strand-specific RNA sequencing on radish fleshy root samples subjected to varying time points of salinity treatment. A total of 7,709 novel lncRNAs were identified, with 363 of them displaying significant differential expression in response to salt application. Furthermore, through target gene prediction, 5,006 cis- and 5,983 trans-target genes were obtained for the differentially expressed lncRNAs. The predicted target genes of these salt-responsive lncRNAs exhibited strong associations with various plant defense mechanisms, including signal perception and transduction, transcription regulation, ion homeostasis, osmoregulation, reactive oxygen species scavenging, photosynthesis, phytohormone regulation, and kinase activity. Notably, this study represents the first comprehensive genome-wide analysis of salt-responsive lncRNAs in radish, to the best of our knowledge. These findings provide a basis for future functional analysis of lncRNAs implicated in the defense response of radish against high salinity, which will aid in further understanding the regulatory mechanisms underlying radish response to salt stress.

Highlights 1. Neuroblasts migrated along the activated astrocytic tunnel, directed by BDNF gradient between SVZ and injured cortex after TBI. CCL2 might be a key regulator in the above endogenous neuroblasts migration. 2. Exogenous CCL2 promoted neuroblasts migration and reactive astrocytes-derived BDNF expression not only in normal mice but also in mice on day 28 after CCI. 3. Notably, these neuroblasts also possessed the potential to differentiate into mature neurons.

Abstract Background Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model. Methods Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study. Results The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-α, IL-1β, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion. Conclusions Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI. Graphical Abstract

Abstract Background Nontuberculous mycobacteria (NTM) usually invades vulnerable hosts. Disseminated NTM (dNTM) infection can affect nearly all organs and be easily misdiagnosed as metastatic carcinoma or other systemic diseases, especially in seemingly immunocompetent hosts. Identification of underlying immunodeficiency is critical for the diagnosis and treatment of dNTM. Adult-onset immunodeficiency (AOID) with anti-IFN-γ autoantibodies has recently been recognized as a crucial but frequently neglected risk factor for dNTM infection. Frequent relapses of infection are common in AOID patients despite appropriate anti-infective treatment and B-cell-depleting therapy has shown some promising results. Herein, we report a case of dNTM infection mimicking malignancy in an AOID patient who was successfully treated with rituximab. Case presentation A middle-aged male presented with fever, productive cough, multifocal skin abscesses and multiple osteolytic lesions with pathological fractures. Chest CT revealed consolidation of the lingula while bronchoscopy showed a mass completely blocking the airway opening of the inferior lingual segment. Metagenomic next-generation sequencing and mycobacterial culture of skin pus and bronchoalveolar lavage fluid reported Mycobacterium Colombiense, confirming the diagnosis of dNTM infection. However, anti-NTM antibiotics alone failed to prevent disease relapse and progression. Further evaluation indicated undetectable serum IFN-γ concentration and high-titer autoantibodies against IFN-γ, suggesting that AOID was the underlying reason for dNTM. Rituximab was added to treatment and successfully controlled the infection without relapse at one-year follow-up. Conclusion We reported a rare case of disseminated Mycobacterium Colombiense infection manifested with pulmonary mass, pathological fracture and dermapostasis in a host with AOID. Our case demonstrated that AOID should be screened when patients get the episode of disseminated NTM infection particularly when other risk factors are excluded. Besides prolonged anti-NTM therapy, AOID-associated NTM infection should be treated with B-cell-depleting therapy to prevent recurrence.

Abstract. Meningiomas are the most common primary intracranial neoplasm with diverse pathological types and complicated clinical manifestations. The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), published in 2021, introduces major changes that advance the role of molecular diagnostics in meningiomas. To follow the revision of WHO CNS5, this expert consensus statement was formed jointly by the Group of Neuro-Oncology, Society of Neurosurgery, Chinese Medical Association together with neuropathologists and evidence-based experts. The consensus provides reference points to integrate key biomarkers into stratification and clinical decision making for meningioma patients. Registration:. Practice guideline REgistration for transPAREncy (PREPARE), IPGRP-2022CN234

Abstract This study aimed to investigate the role of tanshinone IIA (TSO IIA) in astrocytic swelling caused by ischemia–reperfusion-like injury in an in vitro model and the molecular mechanisms underlying this effect. Primary brain astrocytes were cultured under conditions of glucose and oxygen deprivation and reoxygenation (OGD/R). The study explored the effects of TSO IIA treatment on cell swelling and injury and the protein levels of aquaporin 4 (AQP4) in the plasma membrane. It then examined the involvement of the high-mobility group box protein 1 (HMGB1)/receptors for advanced-glycation end products (RAGE)/nuclear factor-kappa B (NF-κB)/interleukin-6 (IL-6) pro-inflammatory axis in TSO IIA-mediated protection. The treatment with TSO IIA alleviated OGD/R-induced astrocytic swelling and the overclustering of AQP4 protein in the plasma membrane. In addition, TSO IIA significantly reduced the overexpression of HMGB1 and the high levels of the NF-κB protein in the nucleus and of the IL-6 protein in the cytoplasm and extracellular media induced by OGD/R. The combination of TSO IIA and recombinant HMGB1 reversed these effects. The inhibition of the RAGE, the receptor of HMGB1, induced results similar to those of TSO IIA. In addition, exogenous IL-6 reversed TSO IIA-mediated effect on AQP4 overclustering and cell swelling. TSO IIA significantly reduced astrocyte swelling after OGD/R injury in vitro, via blocking the activation of the HMGB1/RAGE/NF-κB/IL-6 pro-inflammatory axis and thereby decreasing the expression of AQP4 in the plasma membrane.

Abstract Background Traumatic brain injury (TBI) provokes secondary pathological damage, such as damage to the blood–brain barrier (BBB), ischaemia and inflammation. Major facilitator superfamily domain-containing 2a (Mfsd2a) has been demonstrated to be critical in limiting the increase in BBB vesicle transcytosis following brain injury. Recent studies suggest that a novel and selective modulator of the sphingosine-1-phosphate receptor 1 (S1P1), CYM-5442, maintains the integrity of the BBB by restricting vesicle transcytosis during acute ischaemic stroke. In the current study, we investigated whether CYM-5442, evaluated in a short-term study, could protect the brains of mice with acute-stage TBI by reversing the increase in vesicle transport due to reduced Mfsd2a expression after TBI. Methods We used the well-characterized model of TBI caused by controlled cortical impact. CYM-5442 (0.3, 1, 3 mg/kg) was intraperitoneally injected 30 min after surgery for 7 consecutive days. To investigate the effect of CYM-5442 on vesicle transcytosis, we downregulated and upregulated Mfsd2a expression using a specific AAV prior to evaluation of the TBI model. MRI scanning, cerebral blood flow, circulating blood counts, ELISA, TEM, WB, and immunostaining evaluations were performed after brain injury. Results CYM-5442 significantly attenuated neurological deficits and reduced brain oedema in TBI mice. CYM-5442 transiently suppressed lymphocyte trafficking but did not induce persistent lymphocytopenia. After TBI, the levels of Mfsd2a were decreased significantly, while the levels of CAV-1 and albumin were increased. In addition, Mfsd2a deficiency caused inadequate sphingosine-1-phosphate (S1P) transport in the brain parenchyma, and the regulation of BBB permeability by Mfsd2a after TBI was shown to be related to changes in vesicle transcytosis. Downregulation of Mfsd2a in mice markedly increased the BBB permeability, neurological deficit scores, and brain water contents after TBI. Intervention with CYM-5442 after TBI protected the BBB by significantly reducing the vesicle transcytosis of cerebrovascular endothelial cells. Conclusion In addition to transiently suppressing lymphocytes, CYM-5442 alleviated the neurological deficits, cerebral edema and protective BBB permeability in TBI mice by reducing the vesicle transcytosis of cerebrovascular endothelial cells.

ObjectivesBoth burdens of tuberculosis (TB) and systemic lupus erythematosus (SLE) in China are ranked as top three in the world. SLE patients are at high risk for TB, but so far, there are no guidelines for TB prevention and management targeting this population in China. This study aims to investigate the incidence of active tuberculosis (ATB) and to explore the risk factors for developing ATB in SLE patients, and to provide evidence for TB prevention and management for SLE patients in China.MethodsA multi-center prospective cohort study was conducted. SLE patients were enrolled from clinics and wards of 13 tertiary hospitals in Eastern, Middle, and Western China from September 2014 to March 2016. Baseline demographic features, TB infection status, clinical information, and laboratory data were collected. ATB development was examined during follow-up visits. Kaplan-Meier method was applied to plot survival curves, and Log-rank test was used to evaluate differences. Cox proportional-hazards model was used to explore the risk factors for ATB development.ResultsWith a median follow-up time of 58 months [interquartile range (IQR): 55-62], 16 out of 1361 SLE patients developed ATB. The 1-year incidence of ATB was 368 [95% confidence interval (CI): 46-691] per 100,000. Over a 5-year period, the cumulative incidence of ATB was 1141 [95% CI: 564-1718] per 100,000, and the incidence density was 245 per 100,000 person-years. Cox regression models were constructed with maximum daily dose of glucocorticoids (GCs) as a continuous variable and a categorical variable, respectively. In model 1, maximum daily dose of GCs (pills per day) [adjusted hazard ratio (aHR)=1.16, 95%CI: 1.04-1.30, p=0.010] and TB infection (aHR=8.52, 95%CI: 3.17-22.92, p

The current database has no information on the infiltration of glioma samples. Here, we assessed the glioma samples’ infiltration in The Cancer Gene Atlas (TCGA) through the single-sample Gene Set Enrichment Analysis (ssGSEA) with migration and invasion gene sets. The Weighted Gene Co-expression Network Analysis (WGCNA) and the differentially expressed genes (DEGs) were used to identify the genes most associated with infiltration. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the major biological processes and pathways. Protein–protein interaction (PPI) network analysis and the least absolute shrinkage and selection operator (LASSO) were used to screen the key genes. Furthermore, the nomograms and receiver operating characteristic (ROC) curve were used to evaluate the prognostic and predictive accuracy of this clinical model in patients in TCGA and the Chinese Glioma Genome Atlas (CGGA). The results showed that turquoise was selected as the hub module, and with the intersection of DEGs, we screened 104 common genes. Through LASSO regression, TIMP1, EMP3, IGFBP2, and the other nine genes were screened mostly in correlation with infiltration and prognosis. EMP3 was selected to be verified in vitro. These findings could help researchers better understand the infiltration of gliomas and provide novel therapeutic targets for the treatment of gliomas.

Subarachnoid hemorrhage refers to an uncommon but severe subtype of stroke leading to high mortality and disability rates. Electroacupuncture, a traditional Chinese medical therapy combined with modern technology, shows evident curative effects on cerebral vascular diseases. This study attempts to investigate the possible treatment effects and mechanisms of EA on early brain injury after SAH. Data were gathered among sham group, SAH-induced group, and EA-treated group of male SD rats, concerning mortality rates, weight loss, rotarod latencies, cerebral blood flow, cell apoptosis, pro-inflammatory cytokines releasing, apoptotic protein level, microglia activation and related signal pathway. All results were collected 24–72 h after SAH induction. EA treatment demonstrated significant improvement on motor function 24 h after SAH without significant changes in mortality rate, weight loss, and cerebral blood flow. Another important finding was that EA regulated Bax and Bcl-2 imbalance and reduced cleaved casepase-3 caused by SAH. Additionally, levels of TNF-α, IL-1β, IL-6 were suppressed. The neuron apoptosis was suppressed by EA. The M1 polarization of activated microglia decreased while M2 polarized phenotype increased after EA treatment. Furthermore, pSTAT3-NOX2 signal axis, the M1 phenotype related activation pathway, was depressed after EA treatment. These findings suggested that EA improved motor deficits and ameliorated early brain injury after SAH probably via decreasing neuron apoptosis and anti-inflammation, which may involve modulation of microglia polarization. Taken together, EA may be a potential therapy for SAH treatment.

BackgroundCurrent studies indicate a contradictory relationship between decreased mortality risks of spontaneous intracerebral hemorrhage (sICH) and elevated low-density lipoprotein cholesterol (LDL-C) levels. Thus, this meta-analysis was designed to examine the involvement of high LDL-C levels in a lower mortality risk of sICH patients.MethodsPubMed, Cochrane, and Embase databases were searched up to the date of August 3rd, 2022. Pooled odds ratio (OR) with a 95% confidence interval (CI) was estimated for the higher vs. lower serum LDL-C level groups. Subgroup and sensitivity analyses were also carried out. Egger's test was applied to detect any potential publication bias.ResultsOf 629 citations reviewed, 8 eligible cohort studies involving 83,013 patients were enrolled in this meta-analysis. Compared with lower serum LDL-C levels containing patients, higher serum LDL-C patients exhibited significantly decreased risks of 3-month mortality (OR: 0.51; 95%CI: 0.33–0.78; I2 = 47.8%); however, the LDL-C level change wasn't significantly associated with in-hospital mortality risks (OR: 0.92; 95%CI: 0.63–1.33; I2 = 91.4%) among sICH subjects. All studies included were classified as high-quality investigations.ConclusionsThis meta-analysis suggests a higher LDL-C level may decrease the mortality risk in sICH patients. LDL-C level increase is inversely associated with the 3-month mortality risks in these patients but not significantly correlated with the in-hospital mortality risks. Further well-designed prospective studies with extended follow-up periods are needed to confirm these findings and explore underlying cross-talks.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022318318, identifier: PROSPERO 2022 CRD42022318318.

In early brain injury (EBI) after subarachnoid hemorrhage (SAH), white matter (WM) axonal injury plays a key role in the prognosis of the disease. The purpose of this study was to investigate the effects of phosphatase and tensin homolog deleted on chromosome ten (PTEN) on axonal injury and neuronal apoptosis post-SAH in rats and to find its underlying mechanism. Adeno-associated virus was injected into the lateral ventricle to suppress or promote PTEN. Neural function post-SAH in animals was determined by the modified Garcia score, beam balance, and Rotarod test, and the blood–brain barrier disruption was assessed by the brain water content. Axonal injury post-SAH was observed by TEM and determined by IF, and neuron apoptosis was measured by TUNEL staining. The mechanism was analyzed by Western blot to detect p-PTEN/PTEN, p-AKT/AKT, p-GSK-3β/GSK-3β, p-CRMP-2/CRMP-2, axonal injury marker β-APP and pro- and anti-apoptosis proteins, including Bax and Bcl-2, expression. We found 1. After knocking down PTEN, neuronal apoptosis and axonal injury were alleviated, and nerve function and blood–brain barrier were protected; accordingly, after overexpression of PTEN, neuronal apoptosis and axon damage were aggravated, and nerve function damage and blood–brain barrier damage were increased. 2. PTEN and AKT/GSK-3β/CRMP-2 pathway were jointly involved in regulating neuronal apoptosis and WM axon injury after SAH. According to our research, PTEN was a negative factor of EBI, and together with the AKT/GSK-3β/CRMP-2 signaling pathway aggravates neuronal apoptosis and WM axon damage after SAH. Inhibition of PTEN expression may become a new target for SAH treatment.

Emerging evidence shows immune-related long noncoding RNAs (ir-lncRNAs) perform critical roles in tumor progression and prognosis assessment. However, the identification of ir-lncRNAs and their clinical significance in human glioblastoma multiforme (GBM) remain largely unexplored. Here, a designed computational frame based on immune score was used to identify differentially expressed ir-lncRNAs (DEir-lncRNAs) from The Cancer Genome Atlas (TCGA) GBM program. The immune-related lncRNA signature (IRLncSig) composed of prognosis-related DEir-lncRNAs selected by Cox regression analysis and its clinical predictive values were verified, which was further validated by another dataset from the Gene Expression Omnibus database (GEO). Subsequently, the association between IRLncSig and immune cell infiltration, immune checkpoint inhibitor (ICI) biomarkers, O6-methylguanine-DNA methyltransferase (MGMT) gene expression, and biological function were also analyzed. After calculation, five prognosis-related ir-lncRNAs were included in the establishment of IRLncSig. The risk assessment based on IRLncSig indicated that the high-IRLncSig-score group was significantly associated with poor prognosis (p < 0.001), significant aggregation of macrophages (p < 0.05), higher ICI biomarker expression, and MGMT gene expression (p < 0.05). Signature-related lncRNAs may be involved in immune activities in the tumorigenesis and progression of GBM. In summary, the novel IRLncSig shows a promising clinical value in predicting the prognosis and immune landscape of GBM.

Aquaporins (AQPs) constitute a highly diverse family of channel proteins that transport water and neutral solutes. AQPs play crucial roles in plant development and stress responses. However, the characterization and biological functions of RsAQPs in radish (Raphanus sativus L.) remain elusive. In this study, 61 non-redundant members of AQP-encoding genes were identified from the radish genome database and located on nine chromosomes. Radish AQPs (RsAQPs) were divided into four subfamilies, including 21 plasma membrane intrinsic proteins (PIPs), 19 tonoplast intrinsic proteins (TIPs), 16 NOD-like intrinsic proteins (NIPs), and 5 small basic intrinsic proteins (SIPs), through phylogenetic analysis. All RsAQPs contained highly conserved motifs (motifs 1 and 4) and transmembrane regions, indicating the potential transmembrane transport function of RsAQPs. Tissue- and stage-specific expression patterns of AQP gene analysis based on RNA-seq data revealed that the expression levels of PIPs were generally higher than TIPs, NIPs, and SIPs in radish. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) revealed that seven selected RsPIPs, according to our previous transcriptome data (e.g., RsPIP1-3, 1-6, 2-1, 2-6, 2-10, 2-13, and 2-14), exhibited significant upregulation in roots of salt-tolerant radish genotype. In particular, the transcriptional levels of RsPIP2-6 dramatically increased after 6 h of 150 mM NaCl treatment during the taproot thickening stage. Additionally, overexpression of RsPIP2-6 could enhance salt tolerance by Agrobacterium rhizogenes-mediated transgenic radish hairy roots, which exhibited the mitigatory effects of plant growth reduction, leaf relative water content (RWC) reduction and alleviation of O2– in cells, as shown by nitro blue tetrazolium (NBT) staining, under salt stress. These findings are helpful for deeply dissecting the biological function of RsAQPs on the salt stress response, facilitating practical application and genetic improvement of abiotic stress resistance in radish.

During the deployment of practical applications, reservoir computing (RC) is highly susceptible to radiation effects, temperature changes, and other factors. Normal reservoirs are difficult to vouch for. To solve this problem, this paper proposed a random adaptive fault tolerance mechanism for an echo state network, i.e., RAFT-ESN, to handle the crash or Byzantine faults of reservoir neurons. In our consideration, the faulty neurons were automatically detected and located based on the abnormalities of reservoir state output. The synapses connected to them were adaptively disconnected and withdrawn from the current computational task. On the widely used time series with different sources and features, the experimental results show that our proposal can achieve an effective performance recovery in the case of reservoir neuron faults, including prediction accuracy and short-term memory capacity (MC). Additionally, its utility was validated by statistical distributions.

In recent years, with the frequency of marine disasters, water quality has become an important environmental problem for researchers, and much effort has been put into the prediction of marine water quality. The temporal and spatial correlation of marine water quality parameters directly determines whether the marine time-series data prediction task can be completed efficiently. However, existing research has only focused on the correlation analysis of marine data in a certain area and has ignored the temporal and spatial characteristics of marine data in complex and changeable marine environments. Therefore, we constructed a spatio-temporal dynamic analysis model of marine water quality based on a cross-recurrence plot (CRP) and cross-recurrence quantitative analysis (CRQA). The time-series data of marine water quality were first mapped to high-dimensional space through phase space reconstruction, and then the dynamic relationship among various factors affecting water quality was visually displayed through CRP. Finally, their correlation was quantitatively explained by CRQA. The experimental results showed that our scheme demonstrated well the dynamic correlation of various factors affecting water quality in different locations, providing important data support for the spatio-temporal prediction of marine water quality.

Our previous studies shown that syndecan-1 (SDC1) may be a novel class of biomarkers for the diagnosis and treatment of glioma, but its specific roles and the in-depth molecular mechanism remain elusive. Here, we used Estimation of STromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithms and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms to evaluate the immune score of tumor samples and quantify the relative infiltration of immune cells in the tumor microenvironment (TME), respectively, in different data sets obtained from the Chinese Glioma Genome Atlas and The Cancer Gene Atlas. Next, we calculate the correlation of the immune score and immune cells with SDC1, respectively. To identify the specific process regulated by SDC1, the differentially expressed genes (DEGs) analysis between the high and low expression of SDC1 of glioma samples were used to discover the hub genes through Weighted Gene Coexpression Network Analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed cardinal biological processes and pathways involved in genes and tumor grade correlation and survival analysis verified its significance in glioma. The results show that SDC1 is associated with the immune infiltration of glioma in the TME, especially activated CD4+T cells and CD8+T cells. The three data sets filter 8,887 DEGs, the genes in the blue modules were selected as hub genes in WGCNA. GO and KEGG analysis found eight genes in the blue modules involved in antigen processing and presentation in T cells in glioma. Kaplan–Meier estimator and log-rank test statistic determined that the introduced genes are associated with poor prognosis in glioma. Protein–protein network interaction analysis showed that SDC1 may regulate antigen processing and presentation through CTSL or CD4 in glioma. Finally, this study provided insights and clues for the next research direction of SDC1 and identified the key pathways and genes that might participate in the immune escape of glioma. These results might provide a new insight on the study of immune infiltration of glioma in the future.

The main purpose of the study was to explore a reliable way to automatically handle emergency cases, such as intracerebral hemorrhage (ICH). Therefore, an artificial intelligence (AI) system, named, H-system, was designed to automatically recognize medical text data of ICH patients and output the treatment plan. Furthermore, the efficiency and reliability of the H-system were tested and analyzed. The H-system, which is mainly based on a pretrained language model Bidirectional Encoder Representations from Transformers (BERT) and an expert module for logical judgment of extracted entities, was designed and founded by the neurosurgeon and AI experts together. All emergency medical text data were from the neurosurgery emergency electronic medical record database (N-eEMRD) of the First Affiliated Hospital of Chongqing Medical University, Chongqing Emergency Medical Center, and Chongqing First People’s Hospital, and the treatment plans of these ICH cases were divided into two types. A total of 1,000 simulated ICH cases were randomly selected as training and validation sets. After training and validating on simulated cases, real cases from three medical centers were provided to test the efficiency of the H-system. Doctors with 1 and 5 years of working experience in neurosurgery (Doctor-1Y and Doctor-5Y) were included to compare with H-system. Furthermore, the data of the H-system, for instance, sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver operating characteristics curve (AUC), were calculated and compared with Doctor-1Y and Doctor-5Y. In the testing set, the time H-system spent on ICH cases was significantly shorter than that of doctors with Doctor-1Y and Doctor-5Y. In the testing set, the accuracy of the H-system’s treatment plan was 88.55 (88.16–88.94)%, the specificity was 85.71 (84.99–86.43)%, and the sensitivity was 91.83 (91.01–92.65)%. The AUC value of the H-system in the testing set was 0.887 (0.884–0.891). Furthermore, the time H-system spent on ICH cases was significantly shorter than that of doctors with Doctor-1Y and Doctor-5Y. The accuracy and AUC of the H-system were significantly higher than that of Doctor-1Y. In addition, the accuracy of the H-system was more closed to that of Doctor-5Y. The H-system designed in the study can automatically recognize and analyze medical text data of patients with ICH and rapidly output accurate treatment plans with high efficiency. It may provide a reliable and novel way to automatically and rapidly handle emergency cases, such as ICH.

Abstract The level of microRNA-9-5p (miRNA-9-5p) in brain tissues is significantly changed in the chronic phase after traumatic brain injury (TBI). However, the effect of miRNA-9-5p on brain function after TBI has not been elucidated. In this study, we used a controlled cortical impact (CCI) model to induce TBI in Sprague–Dawley rats. Brain microvascular endothelial cells (BMECs), astrocytes, and neurons were extracted from immature Sprague–Dawley rats and cocultured to reconstruct the neurovascular unit (NVU) in vitro. The results showed that downregulation of miRNA-9-5p in the chronic phase contributed to neurological function recovery by promoting astrocyte proliferation and increasing the release of astrocyte-derived neurotrophic factors around injured brain tissues after TBI. A dual-luciferase reporter assay validated that miRNA-9-5p was a post-transcriptional modulator of thrombospondin 2 (Thbs-2), and downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes. Furthermore, we verified that Thbs-2 can promote Notch pathway activation by directly binding to Jagged and Notch. Through in vitro experiments, we found that the expression of synaptic proteins and the number of synaptic bodies were increased in neurons in the NVU, which was constructed using astrocytes pretreated with miRNA-9-5p inhibitor. Moreover, we also found that downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes, which activated the Notch/cylindromatosis/transforming growth factor-β-activated kinase 1 pathway in neurons and promoted the expression of synaptic proteins, including post-synaptic density protein 95 and synaptotagmin. Based on these results, miRNA-9-5p may be a new promising prognostic marker and treatment target for TBI.

Abstract Background The members of the sucrose non-fermenting 1-related protein kinase 2 (SnRK2) family are specific serine/threonine protein kinases in plants that play important roles in stress signal transduction and adaptation. Because of their positive regulatory roles in response to adverse conditions, the genes encoding thes proteins are considered potential candidates for breeding of plants for disease resistance and genetic improvement. However, there is far less information about this kinase family, and the function of these genes has not been explored in Rosaceae. Results A genome-wide survey and analysis of the genes encoding members of the SnRK2 family were performed in pear (Pyrus bretschneideri) and seven other Rosaceae species. A total of 71 SnRK2 genes were identified from the eight Rosaceae species and classified into three subgroups based on phylogenetic analysis and structural characteristics. Purifying selection played a crucial role in the evolution of SnRK2 genes, and whole-genome duplication and dispersed duplication were the primary forces underlying the characteristics of the SnRK2 gene family in Rosaceae. Transcriptome data and qRT-PCR assay results revealed that the distribution of PbrSnRK2s was very extensive, including across the roots, leaves, pollen, styles, and flowers, although most of them were mainly expressed in leaves. In addition, under stress conditions, the transcript levels of some of the genes were upregulated in leaves in response to ABA treatment. Conclusions This study provides useful information and a theoretical introduction for the study of the evolution, expression, and functions of the SnRK2 gene family in plants.

In this study, four representative finite element (FE) based modelling techniques and an analytical solution for the prediction of 2D woven fabrics’ deformation during forming are compared back-to-back. Ordered from high to low fidelity they are: 1/a Multi-Filament (MF) method that sits between micro- and meso-scale that uses multiple beam element chains to represent each fibre yarn; 2/a meso-scale 3D representation (3D-Shell method) that uses 2D structural shell elements to model each fibre yarn; 3/a 2D continuum element approach that uses coincident membrane and shell elements with user defined material properties to capture the deformation response of textiles in an homogenised sense at the macro-scale; 4/pin-jointed net (PJN) models where the reinforcement directions are represented by extendable 1D elements, pin-jointed at the elements’ crossover points. These modelling approaches are systematically compared for identical forming processes with identical process and material parameters such as boundary conditions, weave architecture and tooling geometries. For completeness and to highlight the importance of considering inter-yarn and preform-to-tool interactions, a kinematic drape algorithm (based on geometrical mapping) is also considered. An attempt is made to visualise the overall modelling performance and computational cost of all representative modelling approaches by simplified metrics.

Traumatic brain injury (TBI) is the major cause of high mortality and disability rates worldwide. Pioglitazone is an activator of peroxisome proliferator-activated receptor-gamma (PPARγ) that can reduce inflammation following TBI. Clinically, neuroinflammation after TBI lacks effective treatment. Although there are many studies on PPARγ in TBI animals, only few could be converted into clinical, since TBI mechanisms in humans and animals are not completely consistent. The present study, provided a potential theoretical basis and therapeutic target for neuroinflammation treatment after TBI. First, we detected interleukin-6 (IL-6), nitric oxide (NO) and Caspase-3 in TBI clinical specimens, confirming a presence of a high expression of inflammatory factors. Western blot (WB), quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were used to detect PPARγ, IL-6, and p-NF-κB to identify the mechanisms of neuroinflammation. Then, in the rat TBI model, neurobehavioral and cerebral edema levels were investigated after intervention with pioglitazone (PPARγ activator) or T0070907 (PPARγ inhibitor), and PPARγ, IL-6 and p-NF-κB were detected again by qRT-PCR, WB and immunofluorescence (IF). The obtained results revealed that: 1) increased expression of IL-6, NO and Caspase-3 in serum and cerebrospinal fluid in patients after TBI, and decreased PPARγ in brain tissue; 2) pioglitazone could improve neurobehavioral and reduce brain edema in rats after TBI; 3) the protective effect of pioglitazone was achieved by activating PPARγ and reducing NF-κB and IL-6. The neuroprotective effect of pioglitazone on TBI was mediated through the PPARγ/NF-κB/IL-6 pathway. Keywords: Traumatic brain injury, IL-6, Pioglitazone, PPARγ, p-NF-κB

Deep learning has become a mainstream method in marine data processing field. However, the raw marine data, characterized by fluctuations, outliers and noise, is a serious obstacle to its performance improvement. To address this problem, a hybrid deep computing model is developed for marine sensor data prediction, combining smoothing and deep belief echo state network (DBEN). The proposed structure adopts a two-stage data processing mode to deal with the complex characteristics of marine time series. In the preprocessing stage, four smoothing methods are considered for fluctuation reduction and outlier handling, so that purer data conducive to achieving a higher prediction accuracy can be gained. In the prediction stage, DBEN equipped with efficient feature learning serves as a nonlinear approximator. The effectiveness of the constructed hybrid model is tested on real-world marine time series of different sources and traits, and its superiority in prediction accuracy is demonstrated by readout comparisons and statistical measures.

Seawater quality prediction has a tremendous potential of enabling future smart ocean. However, this time-sensitive application puts forward a strict delay requirement, thus easily leading to overwhelmed networks. Edge computing is emerging as an effective means of solving network overload, due to its edge-based distributed processing. Therefore, we develop a hybrid multivariate prediction model for seawater quality assessment in an edge computing environment, considering the combination of principal component analysis (PCA) and relevance vector machine (RVM). The PCA method is employed for dimension reduction of ten seawater quality factors in advance. Six principal components are extracted from multiple features, used as input variables of the subsequent predictor. Finally, a RVM is developed to predict the future trends of dissolved oxygen and pH, measuring seawater quality. Experimental results on the real-world ocean sensor data show that our PCA-RVM based multivariate prediction model outperforms single RVM, SVM and its extended version in prediction accuracy and efficiency, meanwhile statistical testings confirm this finding.

Background and Purpose: Primary brain swelling occurs in aneurysmal subarachnoid hemorrhage (aSAH) patients. The absence of a dynamic quantitative method restricts further study of primary brain swelling. This study compared differences in the change rate of brain volume (CRBV) between patients with and without primary brain swelling in the early stage of aSAH. Moreover, the relationship between CRBV and clinical outcomes was evaluated.Methods: Patients hospitalized within 24 h after aSAH were included in this retrospective study. Utilizing a qualitative standard established before the study to recognize primary brain swelling through brain CT after aSAH, clinical outcomes after 3 months of SAH were evaluated with a modified Rankin scale (mRS). The brain volume (BV) of each patient was calculated with a semiautomatic threshold algorithm of 3D-slicer, and the change in brain volume (CIBV) was obtained by subtracting the two extreme values (CIBV = BVmax – BVmin). The CRBV was obtained by CIBV/BVmin × 100%. The CRBV values that predicted unfavorable prognoses were estimated.Results: In total, 130 subjects were enrolled in the study. The mean CRBV in the non-swelling group and swelling group were 4.37% (±4.77) and 11.87% (±6.84), respectively (p < 0.05). CRBV was positively correlated with the length of hospital stay, blood in the ambient cistern, blood in the lateral ventricle, and lateral ventricular volume (Spearman ρ = 0.334; p < 0.001; Pearson ρ = 0.269, p = 0.002; Pearson ρ = 0.278, p = 0.001; Pearson ρ = 0.233, p = 0.008, respectively). Analysis of variance showed significant differences in CIBV, CRBV, blood in the ambient cistern, blood in the lateral ventricle, and lateral ventricular volume among varying modified Fisher scale (mFisher), with higher admission mFisher scale, indicating larger values of these variables. After adjusting for risk factors, the model showed that for every 1% increase in the CRBV, the probability of poor clinical prognosis increased by a factor of 1.236 (95% CI = 1.056–1.446). In the stratified analysis, the odds of worse clinical outcomes increased with increases in the CRBV. Receiver operating characteristic curve analysis showed that HH grade, mFisher scale, and score of CRBV (SCRBV) had diagnostic performance for predicting unfavorable clinical outcomes.Conclusion: Primary brain swelling increases brain volume after aSAH. The CRBV quantified by 3D-Slicer can be used as a volumetric representation of the degree of brain swelling. A larger CRBV in the early stage of aSAH is associated with poor prognosis. The CRBV can be used as a neuroimaging biomarker of early brain injury after bleeding and may be an effective predictor of patients' clinical prognoses.

An echo state network (ESN) is an efficient recurrent neural network (RNN) that is widely used in time series prediction tasks due to its simplicity and low training cost. However, the “black-box” nature of reservoirs hinders the development of ESN. Although a large number of studies have concentrated on reservoir interpretability, the perspective of reservoir modeling is relatively single, and the relationship between reservoir richness and reservoir projection capacity has not been effectively established. To tackle this problem, a novel reservoir interpretability framework based on permutation entropy (PE) theory is proposed in this paper. In structure, this framework consists of reservoir state extraction, PE modeling, and PE analysis. Based on these, the instantaneous reservoir states and neuronal time-varying states are extracted, which are followed by phase space reconstruction, sorting, and entropy calculation. Firstly, the obtained instantaneous state entropy (ISE) and global state entropy (GSE) can measure reservoir richness for interpreting good reservoir projection capacity. On the other hand, the multiscale complexity–entropy analysis of global and neuron-level reservoir states is performed to reveal more detailed dynamics. Finally, the relationships between ESN performance and reservoir dynamic are investigated via Pearson correlation, considering different prediction steps and time scales. Experimental evaluations on several benchmarks and real-world datasets demonstrate the effectiveness and superiority of the proposed reservoir interpretability framework.

Objective: The coiling and clipping of unruptured cerebral aneurysms (UCAs) in older patients has increased rapidly, and aneurysm size was a significant factor for decision-making in the treatment of UCAs. The purpose of the study was to investigate the impact of age on the functional outcomes of patients between the small versus large UCAs.Methods: We conducted a retrospective study for consecutive cases of UCAs admitted from May 2011 to December 2020. According to the maximum diameter of UCA, patients were divided into small UCAs (≤ 5 mm) group and large UCAs (>5 mm) group. Baseline characteristics, clinical complications, and outcomes of patients between the two groups were analyzed.Results: A total of 564 UCA patients received preventive treatment, including 165 small UCAs and 399 large UCAs. Compared with the small UCA group, the incidence of ischemia event in the large UCA group was significantly higher (7.3 vs. 2.4%; p = 0.029). Multivariable analysis demonstrating age (p = 0.006) and treatment modality (p < 0.001) were independent risk factors associated with poor outcome for patients with large UCAs.Conclusions: Preventive treatment of small UCAs is safe and effective, but older patients with large UCAs are at high risk of poor outcome, and the operations should be more cautious.

Feature learning has been introduced in the modeling of echo state networks (ESNs). However, the procedure of feature learning is generally accompanied by certain information loss. In this regard, this paper proposes a hybrid neural network model from the information compensation view, named echo-state restricted Boltzmann machine (ERBM). It is deemed as a unified and coherent architecture with the successive functionalities of feature learning, information compensation, input superposition, and supervised nonlinear approximation. This is the first systematic model seeking to improve the ESN representative by that a direct weighted compensation channel is built to enhance feature learning. On the widely used benchmarks, we demonstrate that ERBM is fully competent to handle the nonlinear approximation tasks and superior to the state of the art in nonlinear approximation, robustness, and memory capacity.

Marine data prediction plays an increasingly important role in marine environmental monitoring. The support vector machine (SVM) is viewed as a useful machine learning tool in marine data processing, whereas it is not completely suitable for the abruptly fluctuating, multi-noise, non-stationary, and abnormal data. To address this issue, this paper proposes a novel machine learning framework for marine sensor data prediction, i.e., a support vector regression architecture with smoothness priority. This is a united and consistent system with functions of data acquisition, smoothness, and nonlinear approximation. Here, the smoothness is used to process the outliers and noises of the acquired marine sensor data. Whereafter, a nonlinear approximator based on the SVM is constructed for marine time series prediction. This architecture is the first attempt to consider the collective efficacy of smoother and SVM in marine data processing tasks. The experimental results show that our model significantly surpasses the single SVM in the real-world marine data prediction. Besides, standard statistical evaluation methods, such as QQPlot, PDF, CDF, and BoxPlot, are utilized to verify its superior nonlinear approximation capacity.

As a frequent natural disaster, red tide has attracted more and more attentions. In fact, red tide results from the joint actions of multiple complex marine environmental factors. Unfortunately, there is no work on the interaction analysis between these factors. To inaugurate a systematic research of this area, a novel machine learning based framework is developed for marine environmental series analysis. It combines cross recurrence plot (CRP), cross recurrence quantification analysis (CRQA) and statistical analysis. This framework provides a general way to transform two marine series into a high-dimensional space. CRP is used to visualize internal dynamics, while the influence of factors is quantitatively analyzed through CRQA. Finally, the representative factors in each field are statistically determined by boxplot. This is the first analysis framework attempting to reveal the similarity in intrinsic dynamics of marine factors. Experimental results show that the framework is competent to perform the visualization of marine time series. Besides, the results also demonstrate the degree of similarity between different marine factors through quantitative analysis.

Abstract Background Scalp arteriovenous fistula (sAVF) is a rare vascular disease; so far, the standard guidelines for the treatment of sAVF are still unclear. Since its complex vascular anatomical structure, surgical management of sAVF remains an enormous challenge. Methods Between March 2016 and October 2017, three patients with sAVF admitted to the First Affiliated Hospital of Chongqing Medical University were reviewed, and clinical characteristics, imaging features, and surgical outcomes were analyzed. Results Three consecutive patients with sAVF were admitted to our hospital during the study period. Two patients received intravascular embolization and one patient received surgical resection. No procedure-related complications occurred after successfully treatment. During the long-term follow-up period, three patients recovered well and had no recurrence of lesion. Conclusions Either intravascular embolization or surgical resection is an effective therapy method for sAVF. Careful identification of angioarchitecture features contributes to successful treatment for the complex sAVF; therefore, it is recommended that neurosurgeons make the best treatment plan based on the location and number of the fistulas, feeding the artery, and draining the vein.

Background and TargetFollowing brain trauma, blood–brain barrier (BBB) disruption and inflammatory response are critical pathological steps contributing to secondary injury, leading to high mortality and morbidity. Both pathologies are closely associated with endothelial remodeling. In the present study, we concentrated on annexin A1 (ANXA1) as a novel regulator of endothelial function after traumatic brain injury.MethodsAfter establishing controlled cortical impact (CCI) model in male mice, human recombinant ANXA1 (rANXA1) was administered intravenously, followed by assessments of BBB integrity, brain edema, inflammatory response, and neurological deficits.ResultAnimals treated with rANXA1 (1 μg/kg) at 1 h after CCI exhibited optimal BBB protection including alleviated BBB disruption and brain edema, as well as endothelial junction proteins loss. The infiltrated neutrophils and inflammatory cytokines were suppressed by rANXA1, consistent with decreased adhesive and transmigrating molecules from isolated microvessels. Moreover, rANXA1 attenuated the neurological deficits induced by CCI. We further found that the Ras homolog gene family member A (RhoA) inhibition has similar effect as rANXA1 in ameliorating brain injuries after CCI, whereas rANXA1 suppressed CCI-induced RhoA activation.ConclusionOur findings suggest that the endothelial remodeling by exogenous rANXA1 corrects BBB disruption and inflammatory response through RhoA inhibition, hence improving functional outcomes in CCI mice.

Background and Purpose: Stent-assisted coiling (SAC) of intracranial aneurysms is usually treated with antiplatelet therapy to reduce the risk of postoperative ischemic events. However, using the same antiplatelet therapy for all patients may increase the risk of bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH). Thromboelastography-platelet mapping (TEG-PM) measures platelet function, which reflects the effect of antiplatelet drugs. This study aimed to evaluate the benefits of individualized antiplatelet regimens based on TEG-PM parameters for patients with aSAH who underwent SAC.Methods: We retrospectively included patients with aSAH who treated with SAC during the period from June 2012 to December 2019. Patients were divided into two groups: patients whose antiplatelet therapy adjusted by TEG-PM parameters after surgery (adjustment group) and patients who were treated with standard dual antiplatelet therapy without TEG-PM test (control group). The occurrence of major/minor bleeding events, major/minor thromboembolic events, and favorable outcome (modified Rankin scale

Objective: To investigate the effects of the apolipoprotein E gene (APOE) on the cerebral oxygen saturation of patients after traumatic brain injury (TBI).Methods: Clinical data of 114 patients with TBI and 54 normal people were collected. The APOE genotypes of all subjects were determined by quantitative fluorescent polymerase chain reaction (QF-PCR). The regional cerebral oxygen saturation (rScO2) of TBI patients and normal people were monitored by near-infrared spectroscopy (NIRS).Results: The mean rScO2 of patients was (55.06 ± 7.60)% in the early stage of TBI, which was significantly lower than that of normal people (67.21 ± 7.80)% (P < 0.05). Single-factor and multifactor logistic regression analyses showed APOEε4 was an independent risk factor that caused the early decline of rScO2 in TBI patients. Furthermore, in the TBI group, the rScO2 of APOEε4 carriers (52.23 ± 8.02)% was significantly lower than that of non-ε4 carriers (60.33 ± 7.12)% (P < 0.05). But in the normal group, no significant differences in rScO2 were found between APOEε4 carriers and non-carriers.Conclusion: The rScO2 may be significantly decreased after TBI, and APOEε4 may be a risk factor for decreased rScO2 in the early stage of TBI.

Abstract Aim To investigate the effect of estrogen on axon regeneration and neurological recovery after subcortical axon injury, and further explore its underlying molecular mechanisms. Method Subcortical axonal fiber injury model was used in this study. Morris water maze was conducted to detect the learning and memory ability of the rats; modified neurological severity score (mNSS) and beam walking test were performed to evaluate the behavioral; and diffusion tensor imaging (DTI) was used for the determination of recovery after subcortical axonal injury, while Western blotting was performed to detect the expression of p‐Akt, CDK5, p‐Ser262, p‐Ser404, and p‐Thr205. Results Compared with the Sham group, the injury of subcortical axonal fiber resulted in higher mNSS, higher beam walking scores, longer time of escape latency, less number, time and shorter distance of crossing the quadrant, and less FA values. After ovariectomy, the mNSS, beam walking scores, and escape latency reached the peak; inversely, the others reached a minimum. High estrogen treatment reduced the mNSS, beam walking score, and escape latency; improved the number, time, and distance of crossing the quadrant; and increased the FA value. Western blotting results showed that estrogen increased the expression of p‐Akt and decreased the expression of CDK5, p‐Ser262, p‐Ser404, and p‐Thr205. All the changes were counteracted to some extent by Akt inhibitor LY294002. Conclusion After subcortical axonal injury, estrogen could improve the regeneration of axons and improve their functions via regulating the PI3K/Akt/CDK5/Tau pathway.

Background: Small ruptured cerebral aneurysms (≤5 mm) account for the majority of aneurysmal subarachnoid hemorrhages, and its clinical management remains a challenge. The aim of this study was to identify the effect of age-related complications on the outcome of patients with small ruptured aneurysm.Methods: A retrospective review was performed in patients with small ruptured aneurysms who underwent microsurgical clipping or endovascular coiling from September 2012 to December 2018. According to their ages, the patients were divided into the elderly group and the non-elderly group. Baseline characteristics, clinical complications, and outcome of patients were analyzed between the two groups. A multivariate logistic regression analysis was used to determine the risk factors associated with the poor outcome of the elderly patients.Results: In the elderly group, 83 patients were treated with clipping and 50 were treated with coiling. In the non-elderly group, 188 patients were treated with clipping and 117 were treated with coiling. The incidence of neurological complications with neurologic deficit in the elderly group was significantly higher compared with that in the non-elderly group (P = 0.006). The elderly patients had a longer hospital stay (P = 0.032) and a poorer outcome (P = 0.001) compared with the non-elderly patients. A multivariate analysis showed that irregular aneurysms (P = 0.045) and ischemic events (P < 0.001) were independent risk factors associated with poor outcome in the elderly.Conclusions: Neurological complications with neurologic deficit, especially ischemic complications, were clearly more common in the elderly patients. Irregular small aneurysms or postoperative ischemic events should be paid attention as the higher risk of poor outcome in the elderly.

Traumatic brain injury (TBI) causes a high rate of mortality and disability worldwide, and there exists almost none effective drugs to protect against TBI. Neurotoxicity occurring after TBI can be derived from microglia and astrocytes, and causes neuronal death and synapse loss. Bexarotene has been demonstrated to protect neurons in CNS diseases. In the present study, we aimed to investigate the potential role of bexarotene in protecting against neurotoxicity after TBI, as well as the underlying mechanism. The controlled cortical impact (CCI) model was established on adult C57BL/6 mice, followed by intraperitoneal administration of bexarotene for 14 consecutive days. We found that bexarotene improved sensorimotor function and cognitive recovery in CCI mice. In addition, bexarotene decreased neuronal death and synapse loss, as well as inhibited apoptotic cascade. Moreover, bexarotene treatment reduced M1 microglia polarization, microglia-derived pro-inflammatory cytokines, and the number of A1 astrocytes after CCI. These effects of bexarotene were partially abolished by T0070907, an antagonist of peroxisome proliferator–activated receptor gamma (PPARγ). Additionally, bexarotene enhanced nuclear translocation and transcriptional activity of PPARγ. These findings show that bexarotene inhibits neurotoxicity in mice after TBI, at least in part through a PPARγ-dependent mechanism.

Abstract Backgrounds Whole-body bone scintigraphy (WBBS) and MRI are widely used in assessment of patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. However, the value of F-18 fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) in SAPHO syndrome was unclear. The aim of this study was to characterize the manifestation of SAPHO syndrome on 18F-FDG PET/CT and explore its relationship with clinical symptoms and WBBS. Methods Twenty-six patients who suffered from SAPHO syndrome and had undergone whole-body 18F-FDG PET/CT were recruited in Peking Union Medical College Hospital from 2004 to 2016. Clinical manifestations and laboratory findings were recorded for all patients. Imaging data on 18F-FDG PET/CT and WBBS were collected and analyzed retrospectively. Results All the 26 patients (20 females and 6 males) exhibited skeletal abnormalities on 18F-FDG PET/CT. Multiple skeletal lesions affecting the anterior chest wall or spine with low to moderate 18F-FDG uptake and coexistence of osteolysis and osteosclerosis presented as the typical features of SAPHO syndrome. Sixteen (61.5%) patients had abnormal 18F-FDG uptake outside the osteoarticular system. PET scan had moderate to substantial agreement with CT and WBBS in revealing lesions in the anterior chest wall and axial skeleton. Nonetheless, the correlation between increased 18F-FDG uptake and clinical symptoms was weak. Conclusions SAPHO syndrome exhibits characteristic features on 18F-FDG PET/CT. It showed comparable capacity in revealing skeletal lesions with bone scintigraphy.

A correction to this paper has been published: https://doi.org/10.1038/s41419-021-03429-w

Abstract Apolipoprotein E (ApoE), encoded by the ApoE gene (APOE), influences the outcomes of traumatic brain injury (TBI), but the mechanism remains unclear. The present study aimed to investigate the effects of different ApoEs on the outcome of TBI and to explore the possible mechanisms. Controlled cortical impact (CCI) was performed on APOEε3 (E3) and APOEε4 (E4) transgenic mice, APOE-KO (KO) mice, and wild type (WT) mice to construct an in vivo TBI model. Neurological deficits, blood brain barrier (BBB) permeability and brain edema were detected at days 1, 3, and 7 after TBI. The results revealed no significant differences among the four groups at day 1 or day 3 after injury, but more severe deficits were found in E4 and KO mice than in E3 and WT mice. Furthermore, a significant loss of tight junction proteins was observed in E4 and KO mice compared with E3 and WT mice at day 7. Additionally, more expression and activation of NF-κB and MMP-9 were found in E4 mice compared with E3 mice. Different ApoEs had distinct effects on neuro-function and BBB integrity after TBI. ApoE3, but not E4, might inhibit the NF-κB/MMP-9 pathway to alleviate BBB disruption and improve TBI outcomes.

Abstract Background Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms. Methods A total of 299 male Sprague–Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood–brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI. Results We found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices. Conclusions These results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.

Vascular smooth muscle cells (VSMCs) play an important role after a subarachnoid hemorrhage (SAH). The changes in VSMCs following bexarotene treatment after SAH are unknown. In the present study, neurological impairment, decreased cerebral cortical blood flow and transformation of cerebral VSMCs from a contractile to a synthetic phenotype were observed after SAH. Bexarotene reduced neurological impairment, improved cerebral cortical blood flow, inhibited VSMC phenotypic transformation and suppressed the expression of 5-lipoxygenase-activating protein (FLAP) and leukotriene B4 (LTB 4 ), which was partly reversed by GW9662, an inhibitor of peroxisome proliferator-activated receptor gamma (PPARγ). Mechanistically, sh-PPARγ-mediated phenotypic transformation of VSMCs was partially suppressed by MK886, an antagonist of FLAP. Therefore, we conclude that bexarotene reduced neurological impairment, improved cerebral cortical blood flow and inhibited the VSMC phenotypic transformation after SAH, which was achieved by activating PPARγ-mediated inhibition of FLAP/LTB 4 in VSMCs

The aldo-keto reductase (AKR) superfamily plays a major role in oxidation-reduction in plants. D-galacturonic acid reductase (GalUR), an ascorbic acid (AsA) biosynthetic enzyme, belongs to this superfamily. However, the phylogenetic relationship and evolutionary history of the AKR gene family in plants has not yet been clarified. In this study, a total of 1268 AKR genes identified in 36 plant species were used to determine this phylogenetic relationship. The retention, structural characteristics, and expression patterns of AKR homologous genes in Brassica rapa and Arabidopsis thaliana were analyzed to further explore their evolutionary history. We found that the AKRs originated in algae and could be divided into A and B groups according to the bootstrap value; GalURs belonged to group A. Group A AKR genes expanded significantly before the origin of angiosperms. Two groups of AKR genes demonstrated functional divergence due to environmental adaptability, while group A genes were more conservative than those in group B. All 12 candidate GalUR genes were cloned, and their expression patterns under stress were analyzed, in Pak-choi. These genes showed an obvious expression divergence under multiple stresses, and BrcAKR22 exhibited a positive correlation between its expression trend and AsA content. Our findings provide new insights into the evolution of the AKR superfamily and help build a foundation for further investigations of GalUR’s functional characteristics.

COG1410, a mimetic peptide derived from the apolipoprotein E (apoE) receptor binding region, exerts positive effect on neurological deficits in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). Currently the neuroprotective effect of COG1410 includes inhibiting BBB disruption, reducing neuronal apoptosis, and neuroinflammation. However, the effect and mechanism of COG1410 to subcellular organelles disorder have not been fully investigated. As the main pathway for recycling long-lived proteins and damaged organelles, neuronal autophagy is activated in SAH and exhibits neuroprotective effects by reducing the insults of EBI. Pharmacologically elevated autophagy usually contributes to alleviated brain injury, while few of the agents achieved clinical transformation. In this study, we explored the activation of autophagy during EBI by measuring the Beclin-1 and LC3B-II protein levels. Administration of COG1410 notably elevated the autophagic markers expression in neurons, simultaneously reversed the neurological deficits. Furthermore, the up-regulated autophagy by COG1410 was further promoted by p-GSK-3β agonist, whereas decreased by p-GSK-3β inhibitor. Taken together, these data suggest that the COG1410 might be a promising therapeutic strategy for EBI via promoting autophagy in SAH.

To understand the molecular mechanism underlying salt stress response in radish, iTRAQ-based proteomic analysis was conducted to investigate the differences in protein species abundance under different salt treatments. In total, 851, 706, and 685 differential abundance protein species (DAPS) were identified between CK vs. Na100, CK vs. Na200, and Na100 vs. Na200, respectively. Functional annotation analysis revealed that salt stress elicited complex proteomic alterations in radish roots involved in carbohydrate and energy metabolism, protein metabolism, signal transduction, transcription regulation, stress and defense and transport. Additionally, the expression levels of nine genes encoding DAPS were further verified using RT-qPCR. The integrative analysis of transcriptomic and proteomic data in conjunction with miRNAs was further performed to strengthen the understanding of radish response to salinity. The genes responsible for signal transduction, ROS scavenging and transport activities as well as several key miRNAs including miR171, miR395, and miR398 played crucial roles in salt stress response in radish. Based on these findings, a schematic genetic regulatory network of salt stress response was proposed. This study provided valuable insights into the molecular mechanism underlying salt stress response in radish roots and would facilitate developing effective strategies toward genetically engineered salt-tolerant radish and other root vegetable crops.