Insights into the Phase Purity and Storage Mechanism of Nonstoichiometric Na3.4 Fe2.4 (PO4 )1.4 P2 O7 Cathode for High-Mass-Loading and High-Power-Density Sodium-Ion Batteries.

Mixed-anion-group Fe-based phosphate materials, such as Na4 Fe3 (PO4 )2 P2 O7 , have emerged as promising cathode materials for sodium-ion batteries (SIBs). However, the synthesis of pure-phase material has remained a challenge, and the phase evolution during sodium (de)intercalation is debating as well. Herein, a solid-solution strategy is proposed to partition Na4 Fe3 (PO4 )2 P2 O7 into 2NaFePO4 ⋅ Na2 FeP2 O7 from the angle of molecular composition. Via regulating the starting ratio of NaFePO4 and Na2 FeP2 O7 during the synthesis process, the nonstoichiometric pure-phase material could be successfully synthesized within a narrow NaFePO4 content between 1.6 and 1.2. Furthermore, the proposed synthesis strategy demonstrates strong applicability that helps to address the impurity issue of Na4 Co3 (PO4 )2 P2 O7 and nonstoichiometric Na3.4 Co2.4 (PO4 )1.4 P2 O7 are evidenced to be the pure phase. The model Na3.4 Fe2.4 (PO4 )1.4 P2 O7 cathode (the content of NaFePO4 equals 1.4) demonstrates exceptional sodium storage performances, including ultrahigh rate capability under 100 C and ultralong cycle life over 14000 cycles. Furthermore, combined measurements of ex situ nuclear magnetic resonance, in situ synchrotron radiation diffraction and X-ray absorption spectroscopy clearly reveal a two-phase transition during Na+ extraction/insertion, which provides a new insight into the ionic storage process for such kind of mixed-anion-group Fe-based phosphate materials and pave the way for the development of high-power sodium-ion batteries.

Mapping of the novel powdery mildew resistance gene Pm2Mb from Aegilops biuncialis based on ph1b-induced homoeologous recombination.

KEY MESSAGE: A novel powdery mildew resistance gene Pm2Mb from Aegilops biuncialis was transferred into common wheat and mapped to chromosome 2MbL bin FL 0.49-0.66 by molecular cytogenetic analysis of 2Mb recombinants. Aegilops biuncialis, a wild relative of common wheat, is highly resistant to powdery mildew. Previous studies identified that chromosome 2Mb in Chinese Spring (CS)-Ae. biuncialis 2Mb disomic addition line TA7733 conferred high resistance to powdery mildew, and the resistance gene was temporarily designated as Pm2Mb. In this study, a total of 65 CS-Ae. biuncialis 2Mb recombinants were developed by ph1b-induced homoeologous recombination and they were grouped into 12 different types based on the presence of different markers of 2Mb-specificity. Segment sizes and breakpoints of each 2Mb recombinant type were further characterized using in situ hybridization and molecular marker analyses. Powdery mildew responses of each type were assessed by inoculation of each 2Mb recombinant-derived F2 progenies using the isolate E05. Combined analyses of in situ hybridization, molecular markers and powdery mildew resistance data of the 2Mb recombinants, the gene Pm2Mb was cytologically located to an interval of FL 0.49-0.66 in the long arm of 2Mb, where 19 2Mb-specific markers were located. Among the 65 2Mb recombinants, T-11 (T2DS.2DL-2MbL) and T-12 (Ti2DS.2DL-2MbL-2DL) contained a small 2MbL segment harboring Pm2Mb. Besides, a physical map of chromosome 2Mb was constructed with 70 2Mb-specific markers in 10 chromosomal bins and the map showed that submetacentric chromosome 2Mb of Ae. biuncialis was rearranged by a terminal intrachromosomal translocation. The newly developed 2Mb recombinants with powdery mildew resistance, the 2Mb-specific molecular markers and the physical map of chromosome 2Mb will benefit wheat disease breeding as well as fine mapping and cloning of Pm2Mb.

High-altitude exposure decreases bone mineral density and its relationship with gut microbiota: Results from the China multi-ethnic cohort (CMEC) study.

BACKGROUND: Geographic altitude is a potent environmental factor for human microbiota and bone mineral density. However, little evidence exists in population-based studies with altitude diversity ranges across more than 3000 m. This study assessed the associations between a wide range of altitudes and bone mineral density, as well as the potential mediating role of microbiota in this relationship. METHODS: A total of 99,556 participants from the China Multi-Ethnic Cohort (CMEC) study were enrolled. The altitude of each participant was extracted from global Shuttle Radar Topography Mission (SRTM) 4 data. Bone mineral density was measured by calcaneus quantitative ultrasound index (QUI). Stool samples were collected for 16S rRNA gene sequencing (n = 1384). The metabolites of gut microbiota, seven kinds of short-chain fatty acids (SCFAs), were detected by gas chromatography-mass spectrometry (GC-MS, n = 128). After screening, 73,974 participants were selected for the "altitude-QUI" analysis and they were placed into the low-altitude (LA) and high-altitude (HA) groups. Additionally, a subgroup (n = 1384) was further selected for the "altitude-microbiota-QUI" analysis. Multivariate linear regression models and mediation analyses were conducted among participants. RESULTS: A significant negative association between high-altitude and QUI was obtained (mean difference = -0.373 standard deviation [SD], 95% confidence interval [CI]: -0.389, -0.358, n = 73,974). The same negative association was also observed in the population with microbiota data (mean difference = -0.185 SD, 95%CI: -0.360, -0.010, n = 1384), and a significant mediating effect of Catenibacteriumon on the association between altitude and QUI (proportion mediated = 25.2%, P = 0.038) was also noticed. Additionally, the acetic acid, butyric acid, and total amount of seven SCFAs of the low-altitude group were significantly higher than that of the high-altitude group (P < 0.05). CONCLUSION: High-altitude exposure may decrease bone mineral density in adults, thus increasing the risk of osteoporosis. The modulation of gut microbiota may be a potential strategy for alleviating the decrease of bone mineral density.

BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. METHODS: Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). RESULTS: BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. CONCLUSIONS: BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

[Respiratory Tract Infection Pathogen Spectrum Study of 376 Pneumoconiosis Inpatients in Chengdu].

OBJECTIVE: To investigate the status of infections caused by respiratory pathogens and the patterns of infections caused by pathogens in different seasons, age groups and stages of pneumoconiosis so as to explore the pathogen spectrum of respiratory tract infections in pneumoconiosis patients. METHODS: The sputum samples of 376 pneumoconiosis patients admitted to an occupational disease hospital in Chengdu between January, 2017 and October, 2019 were collected. Clinical information of the patients was collected and lab tests were conducted to check for 23 kinds of common respiratory viruses, bacteria and fungi in the sputum. The relationship between seasons, ages, and different stages of pneumoconiosis and the pathogen detection rate was analyzed. RESULTS: In the 376 sputum samples, the detection rates of pathogens, viruses, bacteria and fungi were 42.29% (159/376), 32.98% (124/376), 9.57% (36/376) and 6.12% (23/376), respectively. The six pathogens with the highest detection rates were parainfluenza virus, rhinovirus, influenza virus, Candida albicans, Klebsiella pneumoniae and Candida krousei. The severity of respiratory tract infection did not show significant difference in different seasons, age groups, and pneumoconiosis stages. CONCLUSION: The pathogen spectrum of respiratory tract infections in patients with pneumoconiosis is complicated and the proportion of viral infection is high. However, the severity of the infection is not associated with age, seasonal, or pneumoconiosis staging differences.

Sign change of magnetoresistance in Gd-doped amorphous carbon granular films.

Gd/C granular films with 11% Gd were fabricated by facing-target magnetron sputtering at room temperature and then annealed at 300-650 °C for 1.5 h. A magnetoresistance of -82% was obtained in the Gd/C films annealed at 650 °C at 3 K under a magnetic field of 50 kOe. A sign change of the magnetoresistance from negative to positive and then back to negative was observed in all samples as the temperature decreases. Grain boundary scattering effects, wave-function-shrinkage, cotunneling and Gd-Gd interactions account for the mechanisms of the magnetoresistance effects in different temperature regions. The sign of the magnetoresistance also varies as the magnetic field increases. At the transition temperature of 25 K, the wave-function-shrinkage effect competes with cotunneling and Gd-Gd interactions at different magnetic fields. The competition between the wave-function-shrinkage effect and the grain boundary scattering effect is approximately at the transition temperature of 100 K. The temperature range of positive magnetoresistance expands and transition temperatures are changed as the annealing temperature increases. It is related to the expansion of the temperature region for the wave-function-shrinkage effect which occurs in the Mott variable range hopping conduction mechanism.

Directional thermal emission and display using pixelated non-imaging micro-optics.

Thermal radiation is intrinsically broadband, incoherent and non-directional. The ability to beam thermal energy preferentially in one direction is not only of fundamental importance, but it will enable high radiative efficiency critical for many thermal sensing, imaging, and energy devices. Over the years, different photonic materials and structures have been designed utilizing resonant and propagating modes to generate directional thermal emission. However, such thermal emission is narrowband and polarised, leading to limited thermal transfer efficiency. Here we experimentally demonstrate ultrabroadband polarisation-independent directional control of thermal radiation with a pixelated directional micro-emitter. Our compact pixelated directional micro-emitter facilitates tunable angular control of thermal radiation through non-imaging optical principles, producing a large emissivity contrast at different view angles. Using this platform, we further create a pixelated infrared display, where information is only observable at certain directions. Our pixelated non-imaging micro-optics approach can enable efficient radiative cooling, infrared spectroscopy, thermophotovoltaics, and thermal camouflaging.

Adaptive Memory Broad Learning System for Unsupervised Time Series Anomaly Detection.

Time series anomaly detection is the process of identifying anomalies within time series data. The primary challenge of this task lies in the necessity for the model to comprehend the characteristics of time-independent and abnormal data patterns. In this study, a novel algorithm called adaptive memory broad learning system (AdaMemBLS) is proposed for time series anomaly detection. This algorithm leverages the rapid inference capabilities of the broad learning algorithm and the memory bank's capacity to differentiate between normal and abnormal data. Furthermore, an incremental algorithm based on multiple data augmentation techniques is introduced and applied to multiple ensemble learners, thereby enhancing the model's effectiveness in learning the characteristics of time series data. To bolster the model's anomaly detection capabilities, a more diverse ensemble approach and a discriminative anomaly score are recommended. Extensive experiments conducted on various real-world datasets demonstrate that the proposed method exhibits superior inference speed and more accurate anomaly detection compared to the existing competitors. A detailed experimental investigation is presented to elucidate the effectiveness of the proposed method and the underlying reasons for its efficacy.

Comparative study of two models predicting the risk of deep vein thrombosis progression in spinal trauma patients after operation.

OBJECTIVE: Patients with preoperative deep vein thrombosis (DVT) exhibit a notable incidence of postoperative deep vein thrombosis progression (DVTp), which bears a potential for silent, severe consequences. Consequently, the development of a predictive model for the risk of postoperative DVTp among spinal trauma patients is important. METHODS: Data of 161 spinal traumatic patients with preoperative DVT, who underwent spine surgery after admission, were collected from our hospital between January 2016 and December 2022. The least absolute shrinkage and selection operator (LASSO) combined with multivariable logistic regression analysis was applied to select variables for the development of the predictive logistic regression models. One logistic regression model was formulated simply with the Caprini risk score (Model A), while the other model incorporated not only the previously screened variables but also the age variable (Model B). The model's capability was evaluated using sensitivity, specificity, positive predictive value, negative predictive value, accuracy, F1 score, and receiver operating characteristic (ROC) curve. Nomograms simplified and visually presented Model B for the clinicians and patients to understand the predictive model. The decision curve was used to analyze the clinical value of Model B. RESULTS: A total of 161 DVT patients were enrolled in this study. Postoperative DVTp occurred in 48 spinal trauma patients, accounting for 29.81% of the total patient enrolled. Model A inadequately predicted postoperative DVTp in spinal trauma patients, with ROC AUC values of 0.595 for the training dataset and 0.593 for the test dataset. Through the application of LASSO regression and multivariable logistic regression, a screening process was conducted for seven risk factors: D-dimer, blood platelet, hyperlipidemia, blood group, preoperative anticoagulant, spinal cord injury, lower extremity varicosities. Model B demonstrated superior and consistent predictive performance, with ROC AUC values of 0.809 for the training dataset and 0.773 for the test dataset. According to the calibration curves and decision curve analysis, Model B could accurately predict the probability of postoperative DVTp after spine surgery. The nomograms enhanced the interpretability of Model B in charts and graphs. CONCLUSIONS: In summary, we established a logistic regression model for the accurate predicting of postoperative deep vein thrombosis progression in spinal trauma patients, utilizing D-dimer, blood platelet, hyperlipidemia, blood group, preoperative anticoagulant, spinal cord injury, lower extremity varicosities, and age as predictive factors. The proposed model outperformed a logistic regression model based simply on CRS. The proposed model has the potential to aid frontline clinicians and patients in identifying and intervening in postoperative DVTp among traumatic patients undergoing spinal surgery.

Tryptanthrin promotes pressure ulcers healing in mice by inhibiting macrophage-mediated inflammation via cGAS/STING pathways.

BACKGROUND: Pressure ulcers (PUs) is ischemic necrosis caused by long-term local tissue pressure, directly affecting postoperative functional recovery. There is evidence that inflammation has an adverse impact on the development of PUs and contributes to unfavorable outcomes, suggesting that blocking the inflammatory response may be a promising therapeutic strategy for PUs. Tryptanthrin (Tryp), a natural product isolated from indigenous plants, has an anti-inflammatory biological function. However, the efficacy of Tryp in PUs remains unclear. METHODS: Efficacy of Tryp suppressed inflammation was assessed using magnets-induced PUs model in mice. Hematoxylin-Eosin staining, masson staining and immunohistochemistry were used to evaluate the histologic changes after the formation of PUs. The expression of inflammatory cytokines was detected by qRT-PCR. And we detected the expression of protein by Western blotting. RESULTS: Tryp could promote wound healing, such as epidermal thickening, revascularization, and nerve regeneration. Then the treatment of Tryp was able to promote fibroblast migration and collagen deposition. Moreover, Tryp attenuated inflammation through inducing macrophage polarization to M2 phenotype by suppressing the activation of cGAS-STING pathway. CONCLUSION: Tryp could reduce the release of inflammatory cytokines, and induce RAW 264.7 polarization to M2 phenotype by targeting cGAS/STING/TBK1 pathways. In summary, Tryp may be a novel medicine for the treatment of PUs in the future.

Optimizing prediction accuracy for early recurrent lumbar disc herniation with a directional mutation-guided SVM model.

Percutaneous endoscopic lumbar discectomy (PELD) is one of the main means of minimally invasive spinal surgery, and is an effective means of treating lumbar disc herniation, but its early recurrence is still difficult to predict. With the development of machine learning technology, the auxiliary model based on the prediction of early recurrent lumbar disc herniation (rLDH) and the identification of causative risk factors have become urgent problems in current research. However, the screening ability of current models for key factors affecting the prediction of rLDH, as well as their predictive ability, needs to be improved. Therefore, this paper presents a classification model that utilizes wrapper feature selection, developed through the integration of an enhanced bat algorithm (BDGBA) and support vector machine (SVM). Among them, BDGBA increases the population diversity and improves the population quality by introducing directional mutation strategy and guidance-based strategy, which in turn allows the model to secure better subsets of features. Furthermore, SVM serves as the classifier for the wrapper feature selection method, with its classification prediction results acting as a fitness function for the feature subset. In the proposed prediction method, BDGBA is used as an optimizer for feature subset filtering and as an objective function for feature subset evaluation based on the classification results of the support vector machine, which improves the interpretability and prediction accuracy of the model. In order to verify the performance of the proposed method, this paper proves the performance of the model through global optimization experiments and prediction experiments on real data sets. The accuracy of the proposed rLDH prediction model is 93.49% and sensitivity is 88.33%. The experimental results show that Level of herniated disk, Modic change, Disk height, Disk length, and Disk width are the key factors for predicting rLDH, and the proposed method is an effective auxiliary diagnosis method.

Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury.

ABSTRACT: The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury. Regulation of shifting microglia polarization from M1 (neurotoxic and proinflammatory type) to M2 (neuroprotective and anti-inflammatory type) after spinal cord injury appears to be crucial. Tryptanthrin possesses an anti-inflammatory biological function. However, its roles and the underlying molecular mechanisms in spinal cord injury remain unknown. In this study, we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro. Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway. Additionally, we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury, inhibited neuronal loss, and promoted tissue repair and functional recovery in a mouse model of spinal cord injury. Finally, using a conditional co-culture system, we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis. Taken together, these results suggest that by targeting the cGAS/STING/NF-κB axis, tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Tenacissoside H repressed the progression of glioblastoma by inhibiting the PI3K/Akt/mTOR signaling pathway.

Glioblastoma (GBM) is one of the most common intracranial primary malignancies with the highest mortality rate, and there is a lack of effective treatments. In this study, we examined the anti-GBM activity of Tenacissoside H (TH), an active component isolated from the traditional Chinese medicine Marsdenia tenacissima (Roxb.) Wight & Arn (MT), and investigated the potential mechanism. Firstly, we found that TH decreased the viability of GBM cells by inducing cell cycle arrest and apoptosis, and inhibited the migration of GBM cells. Furthermore, combined with the Gene Expression Omnibus database (GEO) and network pharmacology as well as molecular docking, TH was shown to inhibit GBM progression by directly regulating the PI3K/Akt/mTOR pathway, which was further validated in vitro. In addition, the selective PI3K agonist 740 y-p partially restored the inhibitory effects of TH on GBM cells. Finally, TH inhibited GBM progression in an orthotopic transplantation model by inactivating the PI3K/Akt/mTOR pathway in vivo. Conclusively, our results suggest that TH represses GBM progression by inhibiting the PI3K/Akt/mTOR signaling pathway in vitro and in vivo, and provides new insight for the treatment of GBM patients.

Assessing Risk of Health Outcomes From Brain Activity in Sleep: A Retrospective Cohort Study.

Background and Objectives: Patterns of electrical activity in the brain (EEG) during sleep are sensitive to various health conditions even at subclinical stages. The objective of this study was to estimate sleep EEG-predicted incidence of future neurologic, cardiovascular, psychiatric, and mortality outcomes. Methods: This is a retrospective cohort study with 2 data sets. The Massachusetts General Hospital (MGH) sleep data set is a clinic-based cohort, used for model development. The Sleep Heart Health Study (SHHS) is a community-based cohort, used as the external validation cohort. Exposure is good, average, or poor sleep defined by quartiles of sleep EEG-predicted risk. The outcomes include ischemic stroke, intracranial hemorrhage, mild cognitive impairment, dementia, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality. Diagnoses were based on diagnosis codes, brain imaging reports, medications, cognitive scores, and hospital records. We used the Cox survival model with death as the competing risk. Results: There were 8673 participants from MGH and 5650 from SHHS. For all outcomes, the model-predicted 10-year risk was within the 95% confidence interval of the ground truth, indicating good prediction performance. When comparing participants with poor, average, and good sleep, except for atrial fibrillation, all other 10-year risk ratios were significant. The model-predicted 10-year risk ratio closely matched the observed event rate in the external validation cohort. Discussion: The incidence of health outcomes can be predicted by brain activity during sleep. The findings strengthen the concept of sleep as an accessible biological window into unfavorable brain and general health outcomes.

Dual targeting agent Thiotert inhibits the progression of glioblastoma by inducing ER stress-dependent autophagy.

Glioblastoma (GBM) is the most aggressive and lethal type of tumor in the central nervous system, characterized by a high incidence and poor prognosis. Thiotert, as a novel dual targeting agent, has potential inhibitory effects on various tumors. Here, we found that Thiotert effectively inhibited the proliferation of GBM cells by inducing G2/M cell cycle arrest and suppressed the migratory ability in vitro. Furthermore, Thiotert disrupted the thioredoxin (Trx) system while causing cellular DNA damage, which in turn caused endoplasmic reticulum (ER) stress-dependent autophagy. Knockdown of ER stress-related protein ATF4 in U251 cells inhibited ER stress-dependent autophagy caused by Thiotert to some extent. Orthotopic transplantation experiments further showed that Thiotert had the same anti-GBM activity and mechanism as in vitro. Conclusively, these results suggest that Thiotert induces ER stress-dependent autophagy in GBM cells by disrupting redox homeostasis and causing DNA damage, which provides new insight for the treatment of GBM.

Columbianadin suppresses glioblastoma progression by inhibiting the PI3K-Akt signaling pathway.

Glioblastoma (GBM) is the most common malignant glioma among brain tumors with low survival rate and high recurrence rate. Columbianadin (CBN) has pharmacological properties such as anti-inflammatory, analgesic, thrombogenesis-inhibiting and anti-tumor effects. However, it remains unknown that the effect of CBN on GBM cells and its underlying molecular mechanisms. In the present study, we found that CBN inhibited the growth and proliferation of GBM cells in a dose-dependent manner. Subsequently, we found that CBN arrested the cell cycle in G0/G1 phase and induced the apoptosis of GBM cells. In addition, CBN also inhibited the migration and invasion of GBM cells. Mechanistically, we chose network pharmacology approach by screening intersecting genes through targets of CBN in anti-GBM, performing PPI network construction followed by GO analysis and KEGG analysis to screen potential candidate signaling pathway, and found that phosphatidylinositol 3-kinase/Protein Kinase-B (PI3K/Akt) signaling pathway was a potential target signaling pathway of CBN in anti-GBM. As expected, CBN treatment indeed inhibited the PI3K/Akt signaling pathway in GBM cells. Furthermore, YS-49, an agonist of PI3K/Akt signaling, partially restored the anti-GBM effect of CBN. Finally, we found that CBN inhibited GBM growth in an orthotopic mouse model of GBM through inhibiting PI3K/Akt signaling pathway. Together, these results suggest that CBN has an anti-GBM effect by suppressing PI3K/Akt signaling pathway, and is a promising drug for treating GBM effectively.

Development of a Dynamic Nomogram for Predicting the Probability of Satisfactory Recovery after 6 Months for Cervical Traumatic Spinal Cord Injury.

OBJECTIVE: Cervical traumatic spinal cord injury (CTSCI) is a seriously disabling disease that severely affects the physical and mental health of patients and imposes a huge economic burden on patients and their families. Accurate identification of the prognosis of CTSCI patients helps clinicians to design individualized treatment plans for patients. For this purpose, a dynamic nomogram was developed to predict the recovery of CTSCI patients after 6 months. METHODS: We retrospectively included 475 patients with CTSCI in our institution between March 2013 and January 2022. The outcome variable of the current study was a satisfactory recovery of patients with CTSCI at 6 months. Univariate analyses and univariate logistic regression analyses were used to assess the factors affecting the prognosis of patients with CTSCI. Subsequently, variables (P < 0.05) were included in the multivariate logistic regression analysis to evaluate these factors further. Eventually, a nomogram model was constructed according to these independent risk factors. The concordance index (C-index) and the calibration curve were utilized to assess the model's predictive ability. The discriminating capacity of the prediction model was measured by the receiver operating characteristic (ROC) area under the curve (AUC). One hundred nine patients were randomly selected from 475 patients to serve as the center's internal validation test cohort. RESULTS: The multivariate logistic regression model further screened out six independent factors that impact the recovery of patients with CTSCI. Including admission to the American Spinal Injury Association Impairment Scale (AIS) grade, the length of high signal in the spinal cord, maximum spinal cord compression (MSCC), spinal segment fractured, admission time, and hormonal therapy within 8 h after injury. A nomogram prediction model was developed based on the six independent factors above. In the training cohort, the AUC of the nomogram that included these predictors was 0.879, while in the test cohort, it was 0.824. The nomogram C-index incorporating these predictors was 0.872 in the training cohort and 0.813 in the test cohort, while the calibration curves for both cohorts also indicated good consistency. Furthermore, this nomogram was converted into a Web-based calculator, which provided individual probabilities of recovery to be generated for individuals with CTSCI after 6 months and displayed in a graphical format. CONCLUSION: The nomogram, including ASIA grade, the length of high signal in the spinal cord, MSCC, spinal segment fractured, admission time, and hormonal therapy within 8 h after injury, is a promising model to predict the probability of content recovery in patients with CTSCI. This nomogram assists clinicians in stratifying patients with CTSCI, enhancing evidence-based decision-making, and individualizing the most appropriate treatment.

Comprehensive analysis of different types of ginsenosides in the different parts of American ginseng by targeted and nontargeted MS/MS scanning.

To comprehensively study the ginsenosides distribution in the various tissues of American ginseng, the qualitative and quantitative-targeted and nontargeted mass spectroscopic methods were established using the high-performance liquid chromatography coupled with Qtrap triple quadrupole mass spectrometry (HPLC-QtrapQQQ-MS). The total ginsenosides of the root, stem, and leaf of American ginseng were determined by a colorimetric method, and the contents showed the order from high to low root, stem, and leaf. Eighty-two kinds of ginsenosides were detected in the different parts of American ginseng by enhanced mass scan-information-dependent data acquisition (IDA)-enhanced product ion (EPI) scan mode, including 69 from the root, 62 from the stem, and 48 from the leaf. An HPLC-multiple reaction monitoring (MRM) method was established, and 28 representative ginsenosides were further quantified in the three parts. Nearly all ginsenosides had the highest contents in the root and the lowest content in the leaf. Three types of ginsenosides (protopanaxadiol [PPD]-, protopanaxatiol [PPT]-, and oleanolic acid [OA]-types) were analyzed by precursor ion-IDA-EPI and MRM-IDA-EPI scan modes. Root had the most abundant ginsenosides in PPD- and PPT-type ginsenosides. Meanwhile, the OA-type ginsenosides are significantly enriched in the stem and leaf of American ginseng. The results provided a supplement to the quality assessment of American ginseng. PRACTICAL APPLICATION: The distribution profile of ginsenosides in the parts of American ginseng is different. Except for the root, the stem, and leaf of American ginseng have the most abundant ginsenosides in oleanolic acid type. The results reported herein can help the manufacturers choose appropriate materials to extract the ginsenosides.

Inhibition of TANK-binding kinase1 attenuates the astrocyte-mediated neuroinflammatory response through YAP signaling after spinal cord injury.

AIMS: TANK-binding kinase 1 (TBK1) is involved in regulating the pathological process of a variety of inflammatory diseases in the central nervous system. However, its role and underlying molecular mechanisms in spinal cord injury (SCI) remain largely unknown. METHODS: We employed the TBK1 inhibitor amlexanox (ALX) to address this question. An in vivo clip-compressive SCI model and in vitro lipopolysaccharide (LPS)-induced astrocyte inflammation model were established to examine the effects of TBK1 inhibition on the expression of proinflammatory cytokines. RESULTS: In this study, we found that TBK1 and TBK1-medicated innate immune pathways, such as TBK1/IRF3 and noncanonical NF-κB signaling, were activated in astrocytes and neurons after SCI. Furthermore, inhibition of TBK1 by ALX alleviated neuroinflammation response, reduced the loss of motor neurons, and improved the functional recovery after SCI. Mechanistically, inhibition of TBK1 activity promoted the activation of the noncanonical NF-κB signaling pathway and inhibited p-IRF3 activity in LPS-induced astrocytes, and the TBK1 activity was required for astrocytic activation through yes-associated protein (YAP) signaling after SCI and in LPS-induced astrocytes inflammation model. CONCLUSION: TBK1-medicated innate immune pathway in astrocytes through YAP signaling plays an important role in the pathogenesis of SCI and inhibition of TBK1 may be a potential therapeutic drug for SCI.

Automated detection of immune effector cell-associated neurotoxicity syndrome via quantitative EEG.

OBJECTIVE: To develop an automated, physiologic metric of immune effector cell-associated neurotoxicity syndrome among patients undergoing chimeric antigen receptor-T cell therapy. METHODS: We conducted a retrospective observational cohort study from 2016 to 2020 at two tertiary care centers among patients receiving chimeric antigen receptor-T cell therapy with a CD19 or B-cell maturation antigen ligand. We determined the daily neurotoxicity grade for each patient during EEG monitoring via chart review and extracted clinical variables and outcomes from the electronic health records. Using quantitative EEG features, we developed a machine learning model to detect the presence and severity of neurotoxicity, known as the EEG immune effector cell-associated neurotoxicity syndrome score. RESULTS: The EEG immune effector cell-associated neurotoxicity syndrome score significantly correlated with the grade of neurotoxicity with a median Spearman's R2 of 0.69 (95% CI of 0.59-0.77). The mean area under receiving operator curve was greater than 0.85 for each binary discrimination level. The score also showed significant correlations with maximum ferritin (R2 0.24, p = 0.008), minimum platelets (R2 -0.29, p = 0.001), and dexamethasone usage (R2 0.42, p < 0.0001). The score significantly correlated with duration of neurotoxicity (R2 0.31, p < 0.0001). INTERPRETATION: The EEG immune effector cell-associated neurotoxicity syndrome score possesses high criterion, construct, and predictive validity, which substantiates its use as a physiologic method to detect the presence and severity of neurotoxicity among patients undergoing chimeric antigen receptor T-cell therapy.