Potential biomarkers for evaluating the BCG vaccination response based on humoral immunity.

Background: The current prophylactic tuberculosis vaccine Bacille Calmette-Guérin (BCG), was derived in the 1920s, but the humoral immune responses induced by BCG vaccination have not been fully elucidated to date. In this study, our aim was to reveal the profiles of antibody responses induced by BCG vaccination in adults and identify the potential biomarkers for evaluating the BCG vaccination response. Methods: Proteome microarrays were performed to reveal the serum profiles of antibody responses induced by BCG vaccination in adults. ELISA was used to validate the potential biomarkers in validation cohort (79 healthy controls and 58 BCG-vaccinated subjects). Then combined panel was established by logistic regression analysis based on OD values of potential biomarkers. Results: Multiple antigens elicited stronger serum IgG or IgM antibody responses in BCG vaccinated subjects than healthy subjects at 12 weeks post BCG vaccination; among the antigens, Rv0060, Rv2026c and Rv3379c were further verified using 137 serum samples and presented the moderate performance in assessment of the BCG vaccination response by receiver operating characteristic analysis. Furthermore, a combined panel exhibited an improved AUC of 0.923, and the sensitivity and specificity were 77.59 % and 91.14 %, respectively. In addition, the antibody response against Rv0060, Rv2026c and Rv3379c was related to the clinical background to a certain extent. Conclusions: The novel antigens identified in our study could offer better knowledge towards developing a more efficacious vaccine based on humoral immune responses, and they could be potential biomarkers in assessments of BCG vaccination responses.

Multifunctional Nanoparticle-Loaded Injectable Alginate Hydrogels with Deep Tumor Penetration for Enhanced Chemo-Immunotherapy of Cancer.

Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor vaccines in vivo severely restricts the antitumor effect of chemo-immunotherapy. In this work, an injectable sodium alginate platform is reported to promote penetration of the chemotherapeutic doxorubicin (DOX) and delivery of personalized tumor vaccines. The injectable multifunctional sodium alginate platform cross-links rapidly in the presence of physiological concentrations of Ca2+, forming a hydrogel that acts as a drug depot and releases loaded hyaluronidase (HAase), DOX, and micelles (IP-NPs) slowly and sustainedly. By degrading hyaluronic acid (HA) overexpressed in tumor tissue, HAase can make tumor tissue "loose" and favor other components to penetrate deeply. DOX induces potent immunogenic cell death (ICD) and produces tumor-associated antigens (TAAs), which could be effectively captured by polyethylenimine (PEI) coated IP-NPs micelles and form personalized tumor vaccines. The vaccines efficaciously facilitate the maturation of dendritic cells (DCs) and activation of T lymphocytes, thus producing long-term immune memory. Imiquimod (IMQ) loaded in the core could further activate the immune system and trigger a more robust antitumor immune effect. Hence, the research proposes a multifunctional drug delivery platform for the effective treatment of colorectal cancer.

Edaravone dexborneol attenuates oxidative stress in experimental subarachnoid hemorrhage via Keap1/Nrf2 signaling pathway.

Background: Subarachnoid hemorrhage (SAH) serves as a disease characterized by high incidence rate, which is exceedingly prevalent and severe. Presently, there is no unambiguous or efficacious intervention for the neurological impairment following SAH. Administering multi-targeted neuroprotective agents to reduce oxidative stress (OS) and neuroinflammation caused by early brain injury (EBI) has been demonstrated to improve neurological function and prognosis following SAH. Edaravone dexborneol (EDB), a novel multi targeted neuroprotective medication, combines four parts edaravone (EDA) with 1 part (+)-borneol in proportion. Clinical trials conducted in China have revealed during 2 days of acute ischemic stroke (AIS), early administration of EDB leads to improved therapeutic outcomes compared to treatment in EDA monotherapy. Currently, there is no clear evidence that EDB can effectively treat SAH, therefore, our study aims to investigate its potential therapeutic effects and mechanisms on EBI after SAH. Method: We used the intravascular threading method to establish a mouse model of SAH to explore whether EDA and EDB could produce anti-OS and anti-apoptosis effects. Behavioral assessment of mice was conducted using the balance beam experiment and the modified Garcia scoring system. Neuronal damage due to OS and Keap1/Nrf2 signaling pathway were detected through techniques of immunofluorescence, Western blotting, spectrophotometry. The group of EDA and EDB were injected intraperitoneally for 72 h after SAH. Results: The experiment results indicated that EDB lead to remarkably positive results by significantly enhancing neurological function, reducing blood-brain barrier (BBB) injury, and effectively inhibiting neuronal apoptosis after SAH. Further examination indicated EDB significantly reduced the expression of Keap1 and increased the expression of Nrf2, and it inhibited MDA, and enhanced SOD activity after SAH. These outcomes surpassed the effectiveness observed in EDA monotherapy. However, the application of ML385 reversed the anti-OS effects of EDB and EDA. Conclusion: Our experimental findings indicated that EDB could activate Keap1/Nrf2 signaling pathway to reduce OS damage, thereby protecting neurological function and enhancing behavioral abilities after SAH. These outcomes could facilitate the creation of new approaches for the clinical management of SAH.

Fe doping enhanced Cr(VI) adsorption efficiency of cerium-based adsorbents: Adsorption behaviors and inner removal mechanisms.

Cerium-based adsorbents possessed unique advantages of valence variability and abundant oxygen vacancies in hexavalent chromium (Cr(VI)) adsorption, but high cost and unstable properties restricted their application in Cr(VI) contained wastewater treatment. Herein, a series of bimetallic adsorbents with different cerium/iron ratios (CeFe@C) were prepared by adding inexpensive Fe into Ce-based adsorbents (Ce@C), and the effect of Fe doping on adsorption properties of Ce@C for Cr(VI) was investigated thoroughly. Compared with pristine Ce@C, CeFe@C exhibited excellent removal performance for Cr(VI), and the improved maximum adsorption capacity reached 75.11 mg/g at 25℃. Benefiting from Fe doping, CeFe@C had good regeneration property, with only 25 % decrease after five adsorption-desorption cycles. Contents of trivalent cerium (Ce(III)) and oxygen vacancies (Ov) in bimetallic adsorbents were positively correlated with divalent iron (Fe(II)) doping, indicating that the formation of Ce(III) and surface defects on Ce@C could be effectively regulated by Fe doping. Density functional theory (DFT) calculation results further proved that the doped Fe enhanced the electron transfer effectively and lowered the energy barriers of Cr(VI) adsorption onto Ce@C surface, strengthening the reduction and complexation to Cr(VI). This study provides new insights for improving the Cr(VI) removal performance by modified Ce-based adsorbents, and further promotes the utilization potentiality of low-cost and low-toxicity Ce-based adsorbents in Cr(VI)-containing wastewater treatment.

The changes of intestinal microbiota and metabolomics during the inhibition of bladder cancer by liquiritigenin.

Liquiritigenin is a natural medicine. However, its inhibitory effect and its potential mechanism on bladder cancer (BCa) remain to be explored. It was found that it could be visualized that the transplanted tumours in the low-dose liquiritigenin -treated group and the high-dose liquiritigenin -treated group were smaller than those in the model group. Liquiritigenin treatment led to alterations in Lachnoclostridium, Escherichia-Shigella, Alistipes and Akkermansia. Non-targeted metabolomics analysis showed that a total of multiple differential metabolites were identified between the model group and the high-dose liquiritigenin-treated group. This provides a new direction and rationale for the antitumour effects of liquiritigenin.

Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides.

Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

Identification of key genes and immune infiltration in peripheral blood biomarker analysis of delayed cerebral ischemia: Valproic acid as a potential therapeutic drug.

BACKGROUND: Delayed cerebral ischemia (DCI) is a common and serious complication of subarachnoid hemorrhage (SAH). Its pathogenesis is not fully understood. Here, we developed a predictive model based on peripheral blood biomarkers and validated the model using several bioinformatic multi-analysis methods. METHODS: Six datasets were obtained from the GEO database. Characteristic genes were screened using weighted correlation network analysis (WGCNA) and differentially expressed genes. Three machine learning algorithms, elastic networks-LASSO, support vector machines (SVM-RFE) and random forests (RF), were also used to construct diagnostic prediction models for key genes. To further evaluate the performance and predictive value of the diagnostic models, nomogram model were constructed, and the clinical value of the models was assessed using Decision Curve Analysis (DCA), Area Under the Check Curve (AUC), Clinical Impact Curve (CIC), and validated in the mouse single-cell RNA-seq dataset. Mendelian randomization(MR) analysis explored the causal relationship between SAH and stroke, and the intermediate influencing factors. We validated this by retrospectively analyzing the qPCR levels of the most relevant genes in SAH and SAH-DCI patients. This experiment demonstrated a statistically significant difference between SAH and SAH-DCI and normal group controls. Finally, potential small molecule compounds interacting with the selected features were screened from the Comparative Toxicogenomics Database (CTD). RESULTS: The fGSEA results showed that activation of Toll-like receptor signaling and leukocyte transendothelial cell migration pathways were positively correlated with the DCI phenotype, whereas cytokine signaling pathways and natural killer cell-mediated cytotoxicity were negatively correlated. Consensus feature selection of DEG genes using WGCNA and three machine learning algorithms resulted in the identification of six genes (SPOCK2, TRRAP, CIB1, BCL11B, PDZD8 and LAT), which were used to predict DCI diagnosis with high accuracy. Three external datasets and the mouse single-cell dataset showed high accuracy of the diagnostic model, in addition to high performance and predictive value of the diagnostic model in DCA and CIC. MR analysis looked at stroke after SAH independent of SAH, but associated with multiple intermediate factors including Hypertensive diseases, Total triglycerides levels in medium HDL and Platelet count. qPCR confirmed that significant differences in DCI signature genes were observed between the SAH and SAH-DCI groups. Finally, valproic acid became a potential therapeutic agent for DCI based on the results of target prediction and molecular docking of the characterized genes. CONCLUSION: This diagnostic model can identify SAH patients at high risk for DCI and may provide potential mechanisms and therapeutic targets for DCI. Valproic acid may be an important future drug for the treatment of DCI.

Enhanced degradation of emerging contaminants by Far-UVC photolysis of peracetic acid: Synergistic effect and mechanisms.

Krypton chloride (KrCl*) excimer lamps (222 nm) are used as a promising irradiation source to drive ultraviolet-based advanced oxidation processes (UV-AOPs) in water treatment. In this study, the UV222/peracetic acid (PAA) process is implemented as a novel UV-AOPs for the degradation of emerging contaminants (ECs) in water. The results demonstrate that UV222/PAA process exhibits excellent degradation performance for carbamazepine (CBZ), with a removal rate of 90.8 % within 45 min. Notably, the degradation of CBZ in the UV222/PAA process (90.8 %) was significantly higher than that in the UV254/PAA process (15.1 %) at the same UV dose. The UV222/PAA process exhibits superior electrical energy per order (EE/O) performance while reducing resource consumption associated with the high-energy UV254/PAA process. Quenching experiments and electron paramagnetic resonance (EPR) detection confirm that HO• play a dominant role in the reaction. The contributions of direct photolysis, HO•, and other active species (RO• and 1O2) are estimated to be 5 %, 88 %, and 7 %, respectively. In addition, the effects of Cl-, HCO3-, and humic acid (HA) on the degradation of CBZ are evaluated. The presence of relatively low concentrations of Cl-, HCO3-, and HA can inhibit CBZ degradation. The UV222/PAA oxidation process could also effectively degrade several other ECs (i.e., iohexol, sulfamethoxazole, acetochlor, ibuprofen), indicating the potential application of this process in pollutant removal. These findings will propel the development of the UV222/PAA process and provide valuable insights for its application in water treatment.

TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity.

Energy status is linked to the production of reactive oxygen species (ROS) in macrophages, which is elevated in obesity. However, it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity. Here, we show that the Rab-GTPase activating protein (RabGAP) TBC1D1, a substrate of the energy sensor AMP-activated protein kinase (AMPK), is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development. TBC1D1 deletion decreases, whereas an energy overload-mimetic non-phosphorylatable TBC1D1S231A mutation increases, ROS production and M1-like polarization in macrophages. Mechanistically, TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation. Transplantation of TBC1D1S231A bone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable TtSOD for removal of ROS selectively in macrophages alleviates both TBC1D1S231A mutation- and diet-induced obesity. Our findings therefore have implications for drug discovery to combat obesity.

Molecular ferroelectric with low-magnetic-field magnetoelectricity at room temperature.

Magnetoelectric materials, which encompass coupled magnetic and electric polarizabilities within a single phase, hold great promises for magnetic controlled electronic components or electric-field controlled spintronics. However, the realization of ideal magnetoelectric materials remains tough due to the inborn competion between ferroelectricity and magnetism in both levels of symmetry and electronic structure. Herein, we introduce a methodology for constructing single phase paramagnetic ferroelectric molecule [TMCM][FeCl4], which shows low-magnetic-field magnetoelectricity at room temperature. By applying a low magnetic field (≤1 kOe), the halogen Cl‧‧‧Cl distance and the volume of [FeCl4]- anions could be manipulated. This structural change causes a characteristic magnetostriction hysteresis, resulting in a substantial deformation of ~10-4 along the a-axis under an in-plane magnetic field of 2 kOe. The magnetostrictive effect is further qualitatively simulated by density functional theory calculations. Furthermore, this mechanical deformation significantly dampens the ferroelectric polarization by directly influencing the overall dipole configuration. As a result, it induces a remarkable α31 component (~89 mV Oe-1 cm-1) of the magnetoelectric tensor. And the magnetoelectric coupling, characterized by the change of polarization, reaches ~12% under 40 kOe magnetic field. Our results exemplify a design methodology that enables the creation of room-temperature magnetoelectrics by leveraging the potent effects of magnetostriction.

PPIA dictates NRF2 stability to promote lung cancer progression.

Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability. Ablation of PPIA promotes NRF2 protein degradation and blocks NRF2-driven growth in NSCLC cells. Mechanistically, PPIA physically binds to NRF2 and blocks the access of ubiquitin/Kelch Like ECH Associated Protein 1 (KEAP1) to NRF2, thus preventing ubiquitin-mediated degradation. Our X-ray co-crystal structure reveals that PPIA directly interacts with a NRF2 interdomain linker via a trans-proline 174-harboring hydrophobic sequence. We further demonstrate that an FDA-approved drug, cyclosporin A (CsA), impairs the interaction of NRF2 with PPIA, inducing NRF2 ubiquitination and degradation. Interestingly, CsA interrupts glutamine metabolism mediated by the NRF2/KLF5/SLC1A5 pathway, consequently suppressing the growth of NRF2-hyperactivated NSCLC cells. CsA and a glutaminase inhibitor combination therapy significantly retard tumor progression in NSCLC patient-derived xenograft (PDX) models with NRF2 hyperactivation. Our study demonstrates that targeting NRF2 protein stability is an actionable therapeutic approach to treat NRF2-hyperactivated NSCLC.

Perioperative Outcomes and Survival after Neoadjuvant Immunochemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.

OBJECTIVE: This study aimed to compare the difference in perioperative outcomes and prognosis between neoadjuvant immunochemotherapy (nICT) and neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESCC). METHODS: The LA-ESCC patients receiving nICT or nCRT were identified from a prospectively maintained database at Zhongshan Hospital of Fudan University between Jan 2018 and March 2022. Propensity score matching (PSM) was performed to balance the two groups. RESULTS: A total of 124 patient pairs were enrolled in the final analysis. The complete pathological response rate (20.2% vs. 29.0%, p=0.140) was similar in the two groups while the lower major pathological response rate (44.4% vs. 61.3%, p=0.011) was observed in the nICT group. nICT was associated with a lower rate of adverse events (42.7% vs. 55.6%, p=0.047) without additional postoperative complications (38.7% vs. 35.5%, p=0.693). The nICT group had lower distant metastasis (6.5% vs. 16.1%, p=0.027) and overall recurrence (11.3% vs. 23.4%, p=0.019) in the postoperative 1 year. Also, nICT was associated with better progression-free survival (HR=0.50; 95% CI: 0.32-0.77; p=0.002). Cox proportional hazard analysis showed that nICT (univariable: HR=0.55; 95% CI: 0.37-0.82; p=0.003; multivariable: HR=0.44; 95% CI: 0.29-0.65; p<0.001) was one of the independent prognostic factors for progression-free survival. The two groups had similar overall survival (HR=0.62; 95%CI: 0.36-1.09; p=0.094) at the latest follow-up. CONCLUSION: This retrospective study showed that nICT was safe and effective for LA-ESCC patients. Further verification is needed in the randomized controlled trials.

A Mendelian randomization study of the effect of mental disorders on cardiovascular disease.

Objective: The effect of mental disorders (MD) on cardiovascular disease (CVD) remains controversial, and this study aims to analyze the causal relationship between eight MD and CVD by Mendelian randomization (MR). Methods: Single nucleotide polymorphisms of attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), depression, obsessive-compulsive disorder (OCD), schizophrenia (SCZ), and CVD were obtained from UK Biobank and FinnGen. Exposure-outcome causality was tested using inverse variance weighted (IVW), MR-Egger, and weighted median. Horizontal pleiotropy and heterogeneity were assessed by MR-Egger intercept and Cochran's Q, respectively, while stability of results was assessed by leave-one-out sensitivity analysis. Results: MR analysis showed that ANX (IVW [odds ratio (OR) 1.11, 95% confidence intervals (CI) 1.07-1.15, p < 0.001]; MR-Egger [OR 1.03, 95% CI 0.92-1.14, p = 0.652]; weighted median [OR 1.09, 95% CI 1.03-1.14, p = 0.001]), ASD (IVW [OR 1.05, 95% CI 1.00-1.09, p = 0.039]; MR-Egger [OR 0.95, 95% CI 0.84-1.07, p = 0.411]; weighted median [OR 1.01, 95% CI 0.96-1.06, p = 0.805]), depression (IVW [OR 1.15, 95% CI 1.10-1.19, p < 0.001]; MR-Egger [OR 1.10, 95% CI 0.96-1.26, p = 0.169]; weighted median [OR 1.13, 95% CI 1.08-1.19, p < 0.001]) were significantly associated with increased risk of CVD, whereas ADHD, AN, BD, OCD, and SCZ were not significantly associated with CVD (p > 0.05). Intercept analysis showed no horizontal pleiotropy (p > 0.05). Cochran's Q showed no heterogeneity except for BD (p = 0.035). Sensitivity analysis suggested that these results were robust. Conclusions: ANX, ASD, and depression are associated with an increased risk of CVD, whereas AN, ADHD, BD, OCD, and SCZ are not causally associated with CVD. Active prevention and treatment of ANX, ASD, and depression may help reduce the risk of CVD.

Model for end-stage liver disease-dependent prognostic capacity of platelet-to-lymphocyte ratio following liver transplantation for hepatocellular carcinoma.

BACKGROUND: To improve liver organ allocation, the model for end-stage liver disease (MELD) score was adopted in candidates reflecting the severity of liver disease and the physical condition of patients. Inflammatory markers are prognostic factors for various cancers and play prognostic roles in patients after liver transplantation (LT) for hepatocellular carcinoma (HCC). Researchers focused more on pre-LT inflammatory markers, while the role of dynamic change of these inflammatory markers is still unknown. The purpose of this study was to estimate the prognostic value of pre-LT and post-LT inflammatory markers. MATERIAL AND METHODS: We collected the pre-LT complete blood count and the post-LT result with highest count of white blood cells within 48 h. Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio and systemic immune-inflammation index were calculated, and their prognostic roles were analyzed for their MELD scores. RESULTS: This retrospective two-center cohort study enrolled 290 patients after LT for HCC. Multivariate analysis identified pre-LT PLR as independent risk factor for recurrence-free survival (RFS) [HR (95%CI): 1.002 (1.000-1.003), p = 0.023]. A high pre-LT PLR or post-LT PLR were associated with poorer RFS (p < 0.001 and p = 0.004, respectively). Based on the MELD scores, the pre-LT PLR value was able to predict the RFS in high MELD group (p < 0.001) but had no predictive power in low MELD group (p = 0.076). On the contrary, the post-LT PLR value was better to predict the overall RFS value in low MELD group (p = 0.007) but could not predict the overall RFS value in high MELD group (p = 0.136). CONCLUSIONS: Both pre-LT PLR and post-LT PLR demonstrated prognostic value in patients following LT for HCC. Monitoring PLR values based on the MELD score can improve the predictive prognosis and more effectively guide the individual decisions for the postoperative intervention.

TSFAN: tensorized spatial-frequency attention network with domain adaptation for cross-session EEG-based biometric recognition.

Objective.Electroencephalogram (EEG) signals are promising biometrics owning to their invisibility, adapting to the application scenarios with high-security requirements. However, It is challenging to explore EEG identity features without the interference of device and state differences of the subject across sessions. Existing methods treat training sessions as a single domain, affected by the different data distribution among sessions. Although most multi-source unsupervised domain adaptation (MUDA) methods bridge the domain gap between multiple source and target domains individually, relationships among the domain-invariant features of each distribution alignment are neglected.Approach.In this paper, we propose a MUDA method, Tensorized Spatial-Frequency Attention Network (TSFAN), to assist the performance of the target domain for EEG-based biometric recognition. Specifically, significant relationships of domain-invariant features are modeled via a tensorized attention mechanism. It jointly incorporates appropriate common spatial-frequency representations of pairwise source and target but also cross-source domains, without the effect of distribution discrepancy among source domains. Additionally, considering the curse of dimensionality, our TSFAN is approximately represented in Tucker format. Benefiting the low-rank Tucker Network, the TSFAN can scale linearly in the number of domains, providing us the great flexibility to extend TSFAN to the case associated with an arbitrary number of sessions.Main results.Extensive experiments on the representative benchmarks demonstrate the effectiveness of TSFAN in EEG-based biometric recognition, outperforming state-of-the-art approaches, as verified by cross-session validation.Significance.The proposed TSFAN aims to investigate the presence of consistent EEG identity features across sessions. It is achieved by utilizing a novel tensorized attention mechanism that collaborates intra-source transferable information with inter-source interactions, while remaining unaffected by domain shifts in multiple source domains. Furthermore, the electrode selection shows that EEG-based identity features across sessions are distributed across brain regions, and 20 electrodes based on 10-20 standard system are able to extract stable identity information.

The safety and clinical outcomes of endovascular treatment versus microsurgical clipping of ruptured anterior communicating artery aneurysms: a 2-year follow-up, multicenter, observational study.

Background and objective: Current data on the optimal treatment modality for ruptured anterior communicating artery (AComA) aneurysms are limited. We conducted this multicenter retrospective study to evaluate the safety and clinical outcomes of endovascular treatment (EVT) and microsurgical clipping (MC) for the treatment of ruptured AComA patients. Methods: Patients with ruptured AComA aneurysms were screened from the Chinese Multicenter Cerebral Aneurysm Database. Propensity score matching (PSM) was used to adjust for baseline characteristic imbalances between the EVT and MC groups. The safety outcomes included total procedural complications, procedure-related morbidity/death and remedial procedure for complication. The primary clinical outcome was 2-year functional independence measured by the modified Rankin scale (mRS) score. Results: The analysis included 893 patients with ruptured AComA aneurysms (EVT: 549; MC: 346). PSM yielded 275 pairs of patients in the EVT and MC cohorts for comparison. Decompressive craniectomy being more prevalent in the MC group (19.3% vs. 1.5%, p < 0.001). Safety data revealed a lower rate of total procedural complications (odds ratio [OR] = 0.62, 95% CI 0.39-0.99; p = 0.044) in the EVT group and similar rates of procedure-related morbidity/death (OR = 0.91, 95% CI 0.48-1.73; p = 0.880) and remedial procedure for complication (OR = 1.35, 95% CI 0.51-3.69, p = 0.657) between the groups. Compared with that of MC patients, EVT patients had a greater likelihood of functional independence (mRS score 0-2) at discharge (OR = 1.68, 95% CI 1.14-2.50; p = 0.008) and at 2 years (OR = 1.89, 95% CI 1.20-3.00; p = 0.005), a lower incidence of 2-year all-cause mortality (OR = 0.54, 95% CI 0.31-0.93; p = 0.023) and a similar rate of retreatment (OR = 1.00, 95% CI 0.23-4.40; p = 1.000). Conclusion: Clinical outcomes after treatment for ruptured AComA aneurysms appear to be superior to those after treatment with MC, with fewer overall procedure-related complications and no increase in the retreatment rate. Additional studies in other countries are needed to verify these findings.

Causal effects of 731 immune cell phenotypes on autism spectrum disorder: a Mendelian randomization study.

Objective: The role of different immune cells in autism spectrum disorders (ASD) is still controversial. The purpose of this study was to evaluate the causal effects of different immune cell phenotypes on ASD via Mendelian randomization (MR). Methods: Datasets of immune cell phenotypes were obtained from the European Bioinformatics Institute, and datasets of ASD were obtained from the IEU Open GWAS project. Single nucleotide polymorphisms were selected based on the assumptions of association, independence, and exclusivity. Inverse variance weighted was utilized as the main method for MR analysis. MR-Egger was employed to assess the horizontal pleiotropy of the results. Cochran's Q and leave-one-out method were used for heterogeneity analysis and sensitivity analysis of the results, respectively. Results: MR analysis showed that TD CD8br AC [odds ratio (OR), 1.137; 95% confidence interval (CI), 1.031-1.254; p = 0.010], CD8br %leukocyte (OR, 1.142; 95% CI, 1.067-1.223; p < 0.001), CD8br and CD8dim %leukocyte (OR, 1.117; 95% CI, 1.032-1.210; p = 0.006), naive CD8br %T cell (OR, 1.052; 95% CI, 1.004-1.104; p = 0.035), CD28- CD8dim %T cell (OR, 1.097; 95% CI, 1.038-1.158; p < 0.001), CD127- CD8br AC (OR, 1.086; 95% CI, 1.006-1.171; p = 0.034), CD45 on CD8br (OR, 1.059; 95% CI, 1.021-1.099; p = 0.002), CD3 on HLA DR+ CD8br (OR, 1.098; 95% CI, 1.041-1.158; p < 0.001), CD4 on activated Treg (OR, 1.048; 95% CI, 1.001-1.096; p = 0.046), CD3 on CD39+ resting Treg (OR, 1.070; 95% CI, 1.012-1.131; p = 0.018), IgD+ CD38- %lymphocyte (OR, 1.103; 95% CI, 1.023-1.190; p = 0.011), CD62L- plasmacytoid DC %DC (OR, 1.046; 95% CI, 1.001-1.093; p = 0.046), and FSC-A on plasmacytoid DC (OR, 1.075; 95% CI, 1.003-1.153; p = 0.042) were associated with increased genetic susceptibility to ASD. MR-Egger displayed no horizontal pleiotropy (p ≥ 0.05). Cochran's Q revealed no heterogeneity of results (p ≥ 0.05). Sensitivity analysis indicated that the results were robust. Conclusion: This MR analysis revealed 13 immune cell phenotypes associated with increased genetic susceptibility to ASD and emphasized the importance of CD8 T cells and Tregs, which provides new directions for the pathogenesis and drug research of ASD.

B7-H4 reduces the infiltration of CD8+T cells and induces their anti-tumor dysfunction in gliomas.

B7-H4 is a promising immune checkpoint molecule in tumor immunotherapy. Our previous study showed that high B7-H4 expression was strongly correlated with deficiency in tumor infiltrated lymphocytes (TILs) in glioma patients. On this basis, we investigated the impact of B7-H4 on CD8+TILs in gliomas and the associated molecular mechanism here. B7-H4-positive tumor samples (n=129) from our glioma cohort were used to assess B7-H4 expression and CD8+TIL quantification by immunohistochemistry. CD8+TILs from five glioma patients cultured with B7-H4 protein were used to evaluate anti-tumor dysfunction by flow cytometry and ELISpot. An orthotopic murine glioma model was used to investigate the role of B7-H4 in glioma CD8+TILs by immunohisto- chemistry and flow cytometry. CD8+TILs from glioma patients cultured with B7-H4 protein were used to explore the potential molecular mechanism by RNA sequencing and western blot. Our results showed that glioma CD8+TIL density was negatively correlated with B7-H4 expression both in glioma patient cohort (P < 0.05) and orthotopic glioma murine model (P < 0.01). B7-H4 also lowered the expression of CD137 and CD103 (P < 0.05 for both) in glioma CD8+TILs and reduced their secretion of the anti-tumor cytokines IFN-γ and TNF-α (P < 0.01 for both) in a dose-dependent manner. Furthermore, B7-H4 was found to induce early dysfunction of glioma CD8+TILs by downregulating the phosphorylation of AKT and eNOS (P < 0.05 for both). In conclusion, B7-H4 reduced the infiltration of glioma CD8+TILs and induced an anti-tumor dysfunction phenotype. B7-H4 may also impair the anti-tumor function of glioma CD8+TILs via the AKT-eNOS pathway. These results indicated that B7-H4 may serve as a potential target in future glioma immunotherapy.

Strong and Tough MXene Bridging-induced Conductive Nacre.

Nacre is a classic model, providing an inspiration for fabricating high-performance bulk nanocomposites with the two-dimensional platelets. However, the "brick" of nacre, aragonite platelet, is an ideal building block for making high-performance bulk nanocomposites. Herein, we demonstrated a strong and tough conductive nacre through reassembling aragonite platelets with bridged by MXene nanosheets and hydrogen bonding, not only providing high mechanical properties but also excellent electrical conductivity. The flexural strength and fracture toughness of the obtained conductive nacre reach ~282 MPa and ~6.3 MPa m1/2, which is 1.6 and 1.6 times higher than that of natural nacre, respectively. These properties are attributed to densification and high orientation degree of the conductive nacre, which is effectively induced by the combined interactions of hydrogen bonding and MXene nanosheets bridging. The crack propagations in conductive nacre are effectively inhibited through crack deflection with hydrogen bonding, and MXene nanosheets bridging between aragonite platelets. In addition, our conductive nacre also provides a self-monitoring function for structural damage and offers exceptional electromagnetic interference shielding performance. Our strategy of reassembling the aragonite platelets exfoliated from waste nacre into high-performance artificial nacre, provides an avenue for fabricating high-performance bulk nanocomposites through the sustainable reutilization of shell resources.

Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts.

Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.