Superconductivity of thulium substituted clathrate hexahydrides at moderate pressure.

Due to the BCS theory, hydrogen, the lightest element, would be the prospect of room-temperature superconductor after metallization, but because of the difficulty of the hydrogen metallization, the theory about hydrogen pre-compression was proposed that the hydrogen-rich compounds could be a great option for the high Tc superconductors. The superior properties of TmH6, YbH6 and LuH6 indicated the magnificent potential of heavy rare earth elements for low-pressure stability. Here, we designed XTmH12 (X = Y, Yb, Lu, and La) to obtain higher Tc while maintaining low pressure stability. Most prominently, YbTmH12 can stabilize at a pressure of 60 GPa. Compared with binary TmH6 hydride, its Tc was increased to 48 K. The results provide an effective method for the rational design of moderate pressure stabilized hydride superconductors.

Open-Framework Vanadate as Efficient Ion Exchanger for Uranyl Removal.

The elimination of uranium from radioactive wastewater is crucial for the safe management and operation of environmental remediation. Here, we present a layered vanadate with high acid/base stability, [Me2NH2]V3O7, as an excellent ion exchanger capturing uranyl from highly complex aqueous solutions. The material possesses an indirect band gap, ferromagnetic characteristic and a flower-like morphology comprising parallel nanosheets. The layered structure of [Me2NH2]V3O7 is predominantly upheld by the H-bond interaction between anionic framework [V3O7]nn- and intercalated [Me2NH2]+. The [Me2NH2]+ within [Me2NH2]V3O7 can be readily exchanged with UO22+. [Me2NH2]V3O7 exhibits high exchange capacity (qm = 176.19 mg/g), fast kinetics (within 15 min), high removal efficiencies (>99%), and good selectivity against an excess of interfering ions. It also displays activity for UO22+ ion exchange over a wide pH range (2.00-7.12). More importantly, [Me2NH2]V3O7 has the capability to effectively remove low-concentration uranium, yielding a residual U concentration of 13 ppb, which falls below the EPA-defined acceptable limit of 30 ppb in typical drinking water. [Me2NH2]V3O7 can also efficiently separate UO22+ from Cs+ or Sr2+ achieving the highest separation factors (SFU/Cs of 589 and SFU/Sr of 227) to date. The BOMD and DFT calculations reveal that the driving force of ion exchange is dominated by the interaction between UO22+ and [V3O7]nn-, whereas the ion exchange rate is influenced by the mobility of UO22+ and [Me2NH2]+. Our experimental findings indicate that [Me2NH2]V3O7 can be considered as a promising uranium scavenger for environmental remediation. Additionally, the simulation results provide valuable mechanistic interpretations for ion exchange and serve as a reference for designing novel ion exchangers.

The cell death-related genes machine learning model for precise therapy and clinical drug selection in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the prevailing subtype of hepatocellular malignancy. While previous investigations have evidenced a robust link with programmed cell death (PCD) and tumorigenesis, a comprehensive inquiry targeting the relationship between multiple PCDs and HCC remains scant. Our aim was to develop a predictive model for different PCD patterns in order to investigate their impact on survival rates, prognosis and drug response rates in HCC patients. We performed functional annotation and pathway analysis on identified PCD-related genes (PCDRGs) using multiple bioinformatics tools. The prognostic value of these PCDRGs was verified through a dataset obtained from GEO. Consensus clustering analysis was utilized to elucidate the correlation between diverse PCD clusters and pertinent clinical characteristics. To comprehensively uncover the distinct PCD regulatory patterns, our analysis integrated gene expression profiling, immune cell infiltration and enrichment analysis. To predict survival differences in HCC patients, we established a PCD model. To enhance the clinical applicability for the model, we developed a highly accurate nomogram. To address the treatment of HCC, we identified several promising chemotherapeutic agents and novel targeted drugs. These drugs may be effective in treating HCC and could improve patient outcomes. To develop a cell death feature for HCC patients, we conducted an analysis of 12 different PCD mechanisms using eligible data obtained from public databases. Through this analysis, we were able to identify 1254 PCDRGs likely to contribute to cell death on HCC. Further analysis of 1254 PCDRGs identified 37 genes with prognostic value in HCC patients. These genes were then categorized into two PCD clusters A and B. The categorization was based on the expression patterns of the genes in the different clusters. Patients in PCD cluster B had better survival probabilities. This suggests that PCD mechanisms, as represented by the genes in cluster B, may have a protective effect against HCC progression. Furthermore, the expression of PCDRGs was significantly higher in PCD cluster A, indicating that this cluster may be more closely associated with PCD mechanisms. Furthermore, our observations indicate that patients exhibiting elevated tumour mutation burden (TMB) are at an augmented risk of mortality, in comparison to those displaying low TMB and low-risk statuses, who are more likely to experience prolonged survival. In addition, we have investigated the potential distinctions in the susceptibility of diverse risk cohorts towards emerging targeted therapies, designed for the treatment of HCC. Moreover, our investigation has shown that AZD2014, SB505124, LJI308 and OSI-207 show a greater efficacy in patients in the low-risk category. Conversely, for the high-risk group patients, PD173074, ZM447439 and CZC24832 exhibit a stronger response. Our findings suggest that the identification of risk groups and personalized treatment selection could lead to better clinical outcomes for patients with HCC. Furthermore, significant heterogeneity in clinical response to ICI therapy was observed among HCC patients with varying PCD expression patterns. This novel discovery underscores the prospective usefulness of these expression patterns as prognostic indicators for HCC patients and may aid in tailoring targeted treatment for those of distinct risk strata. Our investigation introduces a novel prognostic model for HCC that integrates diverse PCD expression patterns. This innovative model provides a novel approach for forecasting prognosis and assessing drug sensitivity in HCC patients, driving a more personalized and efficacious treatment paradigm, elevating clinical outcomes. Nonetheless, additional research endeavours are required to confirm the model's precision and assess its potential to inform clinical decision-making for HCC patients.

Functionalized sampling swabs array-based portable ATP bioluminescence sensor with on-site enrichment and high specificity for live Salmonella detection.

Live food-borne pathogens, featured with rapid proliferative capacity and high pathogenicity, pose an emerging food safety and public health crisis. The high-sensitivity detection of pathogens is particularly imperative yet remains challenging. This work developed a functionalized nylon swab array with enhanced affinity for Salmonella typhimurium (S.T.) for high-specificity ATP bioluminescence-based S.T. detection. In brief, the nylon swabs (NyS) were turned to N-methylation nylon (NyS-OH) by reacting with formaldehyde, and NyS-OH were further converted to NyS-CA by reacting with carboxylic groups of citric acid (CA) and EDC/NHS solution, for altering the NyS surface energy to favor biomodification. The antibody-immobilized nylon swab (MNyS-Ab) was ready for S.T.-specific adsorption. Three prepared MNyS-Ab were installed on a stirrer to form an MNyS-Ab array, allowing for on-site enrichment of S.T. through absorptive extraction. The enriched S.T. was quantified by measuring the bioluminescence of ATP released from cell lysis utilizing a portable ATP bioluminescence sensor. The bioassay demonstrated a detectable range of 102-107 CFU mL-1 with a detection limit (LOD) of 8 CFU/mL within 35 min. The signal of single MNyS-Ab swabs was 500 times stronger than the direct detection of 106 CFU/mL S.T. The MNyS-Ab array exhibited a 100-fold increase in extraction level compared to a single MNyS. This combination of a portable bioluminescent sensor and modified nylon swab array offers a novel strategy for point-of-care testing of live S.T. strains. It holds promise for high-sensitivity measurements of other pathogens and viruses.

Decoding the roles of heat shock proteins in liver cancer.

Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal malignancies, characterized by insidious onset and high propensity for metastasis and recurrence. Apart from surgical resection, there are no effective curative methods for HCC in recent years, due to resistance to radiotherapy and chemotherapy. Heat shock proteins (HSP) play a crucial role in maintaining cellular homeostasis and normal organism development as molecular chaperones for intracellular proteins. Both basic research and clinical data have shown that HSPs are crucial participants in the HCC microenvironment, as well as the occurrence, development, metastasis, and resistance to radiotherapy and chemotherapy in various malignancies, particularly liver cancer. This review aims to discuss the molecular mechanisms and potential clinical value of HSPs in HCC, which may provide new insights for HSP-based therapeutic interventions for HCC.

Association of Chinese visceral adiposity index with clinical outcome in patients after endovascular thrombectomy.

BACKGROUND AND PURPOSE: The Chinese Visceral Adiposity Index (CVAI) is a reliable indicator of visceral adiposity dysfunction in the Chinese population. We aimed to evaluate the association between CVAI and clinical outcome in Chinese ischemic stroke patients who received endovascular thrombectomy (EVT). METHODS: This study retrospectively included patients with large vessel occlusive stroke receiving EVT treatment in 2 China stroke centers. Baseline CVAI was calculated after admission. Patients with a modified Rankin scale score ≥ 3 at 3 months after ischemic stroke were defined as poor outcome. Binary multivariate logistic regression models were utilized to explore the association between CVAI and the risk of 90-day unfavorable outcome. RESULTS: A total of 453 patients (mean age, 70.4  ± 12.1 years; 280 male) were included. During the 90-day follow-up, 236 (52.1 %) patients experienced poor outcome. After multivariable adjustment for potential confounders, increasing CVAI was associated with an increased risk of 90-day poor outcome (odds ratios, per-standard deviation increase: 1.521; 95 % confidence interval, 1.127-2.052; P = 0.006). Similar significant results were observed when the CVAI was analyzed as a categorical variable. Furthermore, the multiple-adjusted spline regression model showed an inverted J-shape association between CVAI and risk of unfavorable outcome (P = 0.048 for non-linearity). CONCLUSIONS: This study demonstrated that CVAI is positively correlated with 90-day poor outcome in Chinese ischemic stroke patients after EVT.

Prediction of preoperative microvascular invasion by dynamic radiomic analysis based on contrast-enhanced computed tomography.

PURPOSE: Microvascular invasion (MVI) is a common complication of hepatocellular carcinoma (HCC) surgery, which is an important predictor of reduced surgical prognosis. This study aimed to develop a fully automated diagnostic model to predict pre-surgical MVI based on four-phase dynamic CT images. METHODS: A total of 140 patients with HCC from two centers were retrospectively included (training set, n = 98; testing set, n = 42). All CT phases were aligned to the portal venous phase, and were then used to train a deep-learning model for liver tumor segmentation. Radiomics features were extracted from the tumor areas of original CT phases and pairwise subtraction images, as well as peritumoral features. Lastly, linear discriminant analysis (LDA) models were trained based on clinical features, radiomics features, and hybrid features, respectively. Models were evaluated by area under curve (AUC), accuracy, sensitivity, specificity, positive and negative predictive values (PPV and NPV). RESULTS: Overall, 86 and 54 patients with MVI- (age, 55.92 ± 9.62 years; 68 men) and MVI+ (age, 53.59 ± 11.47 years; 43 men) were included. Average dice coefficients of liver tumor segmentation were 0.89 and 0.82 in training and testing sets, respectively. The model based on radiomics (AUC = 0.865, 95% CI: 0.725-0.951) showed slightly better performance than that based on clinical features (AUC = 0.841, 95% CI: 0.696-0.936). The classification model based on hybrid features achieved better performance in both training (AUC = 0.955, 95% CI: 0.893-0.987) and testing sets (AUC = 0.913, 95% CI: 0.785-0.978), compared with models based on clinical and radiomics features (p-value < 0.05). Moreover, the hybrid model also provided the best accuracy (0.857), sensitivity (0.875), and NPV (0.917). CONCLUSION: The classification model based on multimodal intra- and peri-tumoral radiomics features can well predict HCC patients with MVI.

Geochemical Characteristics and Productivity Evaluation of Water Produced from Coalbed Methane Wells in the Laochang Block, Eastern Yunnan.

The water produced from coalbed methane (CBM) wells contains abundant hydrogeochemical information, which is of great significance for the productivity evaluation of CBM wells. Based on the analysis of the conventional ions, hydrogen and oxygen isotopes, and trace elements in the water produced from three CBM wells in the Laochang Block, eastern Yunnan, the geochemical characteristics of the water produced from three CBM wells and their impacts on productivity are analyzed. The results show that the conventional ions in the water produced from all the three CBM wells in the study area exhibit similar characteristics, with low concentrations of Ca2+, Mg2+, SO42-, and F-, medium concentrations of K+, and high concentrations of Na+, Cl-, and HCO3-. As the drainage time increased, the water produced from wells S-2 and S-3 changed from the Na-Cl-HCO3 type to the Na-HCO3 type, while the water produced from well S-1 remained the Na-Cl-HCO3 type. The concentrations of HCO3- and F- are roughly positively correlated with the gas production, with higher gas production at concentrations of approximately 2000 and 2 mg/L, respectively. The gas production from well S-1 is relatively low, and it is speculated that this situation is caused by reservoir damage. The gas production from well S-2 is the lowest among the three wells in the study area, and it is speculated that the cause of this phenomenon is roughly due to breakage of the sandstone at the top of the coal seam or collapse of the wellbore, which communicates with the aquifer. Based on the characteristics of the water production from well S-3 with a good gas production, a quantitative characterization range of trace element changes in the water production from CBM wells is proposed. σY values of around 1500 µg/L and σM values of 0.4-0.5 µg/L are beneficial for the long-term gas production.

Phase diagrams and superconductivity of ternary Ca-Al-H compounds under high pressure.

The search for high-temperature superconductors in hydrides under high pressure has always been a research hotspot. Hydrogen-based superconductors offer an avenue to achieve the long-sought goal of superconductivity at room temperature. Here we systematically explored the high-pressure phase diagram, electronic properties, lattice dynamics and superconductivity of the ternary Ca-Al-H system using ab initio methods. At 80 GPa, CaAlH5 transforms from Cmcm to P21/m phase. Both of Cmcm-CaAlH5 and Pnnm-CaAl2H8 are semiconductors. At 200 GPa, P4/mmm-CaAlH7 and a metastable compound Immm-Ca2AlH12 were found. Furthermore, P4/mmm-CaAlH7 shows obvious softening of the high frequency vibration modes, which improves the strength of electron-phonon coupling. Therefore, a superconducting transition temperature Tc of 71 K is generated in P4/mmm-CaAlH7 at 50 GPa. In addition, the thermodynamic metastable Immm-Ca2AlH12 exhibits a superconducting transition temperature of 118 K at 250 GPa. These results are very useful for the experimental searching of new high-Tc superconductors in ternary hydrides. Our work may provide an opportunity to search for high Tc superconductors at lower pressure.

Effects of concurrent aerobic and resistance training on vascular health in type 2 diabetes: a systematic review and meta-analysis.

Objective: To determine the impacts of concurrent aerobic and resistance training on vascular structure (IMT) and function (PWV, FMD, NMD) in type 2 diabetes (T2D). Methods: The electronic databases PubMed, Web of Science Core Collection, Cochrane Library, Embase, Scopus, CINAHL, and SPORTDiscus were systematically searched for articles on "type 2 diabetes" and "concurrent training" published from inception to August 2, 2022. We included randomized controlled trials that examined the effects of concurrent training versus passive controls on IMT, PWV, FMD and NMD in T2D. Results: Ten studies were eligible, including a total of 361 participants. For IMT, concurrent training showed a slight decrease by 0.05 mm (95% CI -0.11 to 0.01, p > 0.05). concurrent training induced an overall significant improvement in FMD by 1.47% (95% CI 0.15 to 2.79, p < 0.05) and PWV by 0.66 m/s (95% CI -0.89 to -0.43, p < 0.01) in type 2 diabetics. However, concurrent training seemed to exaggerate the impaired NMD (WMD = -2.30%, 95% CI -4.02 to -0.58, p < 0.05). Conclusions: Concurrent training is an effective method to improve endothelial function and artery stiffness in T2D. However, within 24 weeks concurrent training exacerbates vascular smooth muscle dysfunction. More research is needed to explore whether longer and/or higher-intensity concurrent training interventions could enhance the vascular structure and smooth muscle function in this population. Systematic review registration: www.crd.york.ac.uk/PROSPERO/, identifier CRD42022350604.

Smurf2-Mediated Ubiquitination of FOXO4 Regulates Oxygen-glucose Deprivation/Reperfusion-induced Pyroptosis of Cortical Neurons.

BACKGROUND: Smad ubiquitination regulatory factor 2 (Smurf2) has been observed to alleviate ischemia-reperfusion injury. This study sought to explore the molecular mechanism of Smurf2-mediated forkhead box O4 (FOXO4) ubiquitination in oxygen-glucose deprivation/ reperfusion (OGD/R)-induced pyroptosis of cortical neurons. METHODS: Human cortical neurons (HCN-2) were subjected to OGD/R to establish a cell model of cerebral stroke. Smurf2, FOXO4, and doublecortin domain containing 2 (DCDC2) expressions were determined by RT-qPCR and Western blot. LDH release, pyroptosis-related proteins NLRP3, GSDMD-N, and cleaved-caspase-3, as well as inflammatory factors IL-1ß and IL-18, were assessed by LDH assay kit, Western blot, and ELISA. The ubiquitination level of FOXO4 was determined by ubiquitination assay. The bindings of Smurf2 to FOXO4 and FOXO4 to DCDC2 were testified by Co-IP, ChIP, and dual-luciferase assays. Rescue experiments were designed to validate the role of FOXO4/DCDC2 in the pyroptosis of HCN-2 cells. RESULTS: Smurf2 was weakly expressed, while FOXO4 and DCDC2 were prominently expressed in OGD/R-treated HCN-2 cells. Smurf2 overexpression promoted LDH release, reduced NLRP3, GSDMD-N, and cleaved-caspase-3 proteins, and decreased IL-1ß and IL-18 concentrations. Sumrf2 improved the ubiquitination level of FOXO4 to downregulate its protein level. FOXO4 is bound to the DCDC2 promoter to facilitate its transcription. Overexpression of FOXO4 or DCDC2 reversed the inhibition of Smurf2 overexpression on pyroptosis of OGD/Rtreated HCN-2 cells. CONCLUSION: Smurf2 overexpression facilitated the ubiquitination of FOXO4 to reduce its protein level, thereby suppressing DCDC2 transcription and restricting OGD/R-induced pyroptosis of cortical neurons.

LETMD1, a target of KLF4, hinders endothelial inflammation and pyroptosis: A protective mechanism in the pathogenesis of atherosclerosis.

Atherosclerosis (AS), a metabolic disorder, is usually caused by chronic inflammation. LETM1 Domain-Containing Protein 1 (LETMD1) is a mitochondrial outer membrane protein required for mitochondrial structure. This study aims to evaluate the functional role of LETMD1 in endothelial pathogenesis of AS. Oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) and high-fat diet apolipoprotein E-deficient (ApoE-/-) mice were used to establish in vitro and in vivo models, respectively. Recombinant adenovirus vectors were constructed to investigate the role of LETMD1 in AS. mRNA sequencing was used to explore the effect of LETMD1 overexpression on gene expression in ox-LDL-induced HUVECs. A dual-luciferase reporting assay and chromatin immunoprecipitation (ChIP)-PCR were further conducted to verify the relationship between KLF4 and LETMD1. Results showed that LETMD1 was highly expressed in the aortas of atherosclerotic animals. LETMD1 overexpression reduced the expression of inflammatory factors, pyroptosis, ROS production, and NF-κB activation in ox-LDL-induced HUVECs, whereas LETMD1 knockdown had the opposite impact. LETMD1 overexpression was involved in regulating gene expression in ox-LDL-induced HUVECs. Overexpression of LETMD1 in mice reduced serum lipid levels as well as atherosclerotic lesions in the aortic roots. Furthermore, LETMD1 overexpression suppressed inflammatory reactions, cell pyroptosis, nuclear p65 protein level, cell apoptosis, and ROS generation in the aortas of AS mice. KLF4 (Krüppel-like factor 4) was found to be the transcriptional regulator of LETMD1. In conclusion, LETMD1, a target of KLF4, hinders endothelial inflammation and pyroptosis, which is a mechanism inhibiting the development of atherosclerosis.

Construction of a cuproptosis-associated lncRNA prognostic signature for bladder cancer and experimental validation of cuproptosis-related lncRNA UBE2Q1-AS1.

Introduction: Bladder cancer (BLCA) is the ninth most common malignancy worldwide and the fourth most common cancer in men. Copper levels are significantly altered in patients with thyroid, breast, lung, cervical, ovarian, pancreatic, oral, gastric, bladder, and prostate cancers. Outcomes can be predicted by constructing signatures using lncRNA-related genes associated with outcomes. Methods: We identified lncRNAs related to outcomes, those differentially expressed in bladder cancer, and cuproptosis-related lncRNAs from TCGA. We identified the intersection to obtain 12 genes and established a prognostic risk signature consisting of eight genes using LASSO-penalized multivariate Cox analysis. We constructed a training set, performed survival analysis on the high-and low-risk groups, and performed validation in the test and full sets. There existed a substantial contrast in the likelihood of survival among the cohorts of high and low risk. An in-depth analysis of the gene mutations associated with tumors was conducted to evaluate the risk of developing cancer. We also performed gene analysis on neoadjuvant chemotherapy. We conducted experimental validation on the key gene UBE2Q1-AS1 in our prognostic signature. Results: The risk signature we constructed shows significant differences between the high-risk group and the low-risk group. Univariate survival analysis of the eight genes in our signature showed that each gene distinguished between high- and low-risk groups. Sub-group analysis revealed that our risk score differed significantly in tumor stage, age, and gender. The analysis results of the tumor mutation burden (TMB) showed a significant difference in the TMB between the low- and high-risk groups, which had a direct impact on the outcomes. These findings highlight the importance of TMB as a potential prognostic marker in cancer detection and prevention. We analyzed the immune microenvironment and found significant differences in immune function, validation responses, immunotherapy-related positive markers, and critical steps in the tumor immunity cycle between the high- and low-risk groups. We found that the effect of anti-CTLA4 and PD-1 was higher in the high-risk group than in the low-risk group.Gene analysis of neoadjuvant chemotherapy revealed that the treatment effect in the high-risk group was better than in the low-risk group. The key gene UBE2Q1-AS1 in our prognostic signature can significantly influence the cell viability, migration, and proliferation of cancer cells. Discussion: We established a signature consisting of eight genes constructed from cuproptosis-related lncRNAs that have potential clinical applications for outcomes prediction, diagnosis, and treatment.

KPNA2 Silencing, Regulated by E3 Ubiquitin Ligase FBXW7, Alleviates Endothelial Dysfunction and Inflammation Through Inhibiting the Nuclear Translocation of p65 and IRF3: A Possible Therapeutic Approach for Atherosclerosis.

Atherosclerosis (AS), characterized by a maladaptive inflammatory response, is one of the most common causes of death among the elderly. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, has been reported to play a pro-inflammatory role in various pathological processes by regulating the nuclear translocation of pro-inflammatory transcription factors. However, the function of KPNA2 in AS remains unknown. ApoE-/- mice were fed high-fat diets for 12 weeks to establish an AS mice model. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish an AS cell model. We found that KPNA2 was upregulated in the aortic roots of atherosclerotic mice and LPS-stimulated cells. KPNA2 knockdown inhibited LPS-induced secretion of pro-inflammatory factors and monocyte-endothelial adhesion in HUVECs, whereas KPNA2 overexpression exerted the opposite effects. p65 and interferon regulatory factor 3 (IRF3), the transcription factors known to regulate the transcription of pro-inflammatory genes, interacted with KPNA2, and their nuclear translocations were blocked following KPNA2 silencing. Furthermore, we found that KPNA2 protein level was decreased by E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7), which was downregulated in the atherosclerotic mice. FBXW7 overexpression induced ubiquitination with subsequent proteasomal degradation of KPNA2. Meanwhile, the effects of KPNA2 deficiency on atherosclerotic lesions were further confirmed by in vivo experiments. Taken together, our study indicates that KPNA2 downregulation, regulated by FBXW7, may alleviate endothelial dysfunction and related inflammation in the progression of AS by suppressing the nuclear translocation of p65 and IRF3.

Higher Serum E-Selectin Levels Associated with Malignant Brain Edema after Endovascular Thrombectomy for Ischemic Stroke: A Pilot Study.

Background and Purpose: Little is known about the effect of soluble adhesion molecules on malignant brain edema (MBE) after endovascular thrombectomy (EVT). This study aimed to explore the association between serum concentrations of E-selectin and the risk of MBE in patients who received EVT. Methods: Patients with a large vessel occlusion stroke in the anterior circulation who underwent EVT were prospectively recruited. Serum soluble E-selectin concentrations were measured after admission for all patients. MBE was defined as a midline shift of ≥5 mm on follow-up imaging within 72 h after surgery. Multivariate logistic regression analyses were performed to determine the association between E-selectin levels and the risk of MBE. Results: Among the 261 included patients (mean age, 69.7 ± 12.3 years; 166 males), 59 (22.6%) developed MBE. Increasing circulating E-selectin levels were associated with an increased risk of MBE after multivariable adjustment (odds ratios [OR], highest vs. lowest quartile: 3.593; 95% confidence interval [CI], 1.178-10.956; p = 0.025). We further observed a significantly positive association between E-selectin and MBE (per 1-standard deviation increase; OR, 1.988; 95% CI, 1.379-2.866, p = 0.001) when the E-selectin levels were analyzed as a continuous variable. Furthermore, the restricted cubic spline demonstrated a linear correlation between serum E-selectin levels and the risk of MBE (p < 0.001 for linearity). Conclusions: In this prospective study, circulating levels of E-selectin were associated with an increased risk of MBE after EVT. Further mechanistic studies are warranted to elucidate the pathophysiology underlying this association.

Association Between Inflammatory Burden Index and Unfavorable Prognosis After Endovascular Thrombectomy in Acute Ischemic Stroke.

Background: Inflammatory burden index (IBI) is a systemic inflammation indicator that reflects the inflammatory status. We aimed to investigate the prognostic value of IBI after endovascular thrombectomy (EVT) in patients with acute ischemic stroke. Methods: We enrolled patients treated with EVT from a multicenter cohort between June 2020 and December 2021. The IBI was calculated as C-reaction protein × neutrophil / lymphocyte count. The primary outcome was the unfavorable functional outcome (90-day modified Rankin scale score 3-6). C-statistics and net reclassification indexes were used to assess the predictive accuracy. Multivariable logistic regression models were used to investigate the association between IBI and unfavorable outcome. Results: A total of 295 patients (mean age, 64.0 ± 12.8 years; male, 63.7%) were enrolled in this study. In multivariable models, higher IBI levels were associated with an increased risk of 90-day unfavorable outcome after EVT (per 1-SD: odds ratio, 1.754; 95% confidence interval, 1.241-2.587; P = 0.002). Restricted cubic spline curve displayed a linear relationship between the IBI level and 90-day unfavorable outcome (P for nonlinearity = 0.410). Besides, IBI was a more accurate biomarker for predicting unfavorable outcomes with the highest predictive accuracy and reclassification indexes. Conclusion: This study demonstrated that higher IBI was associated with an increased risk of 90-day unfavorable outcome in acute ischemic stroke treated with EVT.

Sodium Tanshinone IIA Sulfonate Ameliorates Oxygen-glucose Deprivation/Reoxygenation-induced Neuronal Injury via Protection of Mitochondria and Promotion of Autophagy.

Sodium tanshinone IIA sulfonate (STS) has shown significant clinical therapeutic effects in cerebral ischemic stroke (CIS), but the molecular mechanisms of neuroprotection remain partially known. The purpose of this study was to explore whether STS plays a protective role in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury by regulating microglia autophagy and inflammatory activity. Co-cultured microglia and neurons were subjected to OGD/R injury, an in vitro model of ischemia/reperfusion (I/R) injury with or without STS treatment. Expression of protein phosphatase 2 A (PP2A) and autophagy-associated proteins Beclin 1, autophagy related 5 (ATG5), and p62 in microglia was determined by Western blotting. Autophagic flux in microglia was observed with confocal laser scanning microscopy. Neuronal apoptosis was measured by flow cytometric and TUNEL assays. Neuronal mitochondrial function was determined via assessments of reactive oxygen species generation and mitochondrial membrane potential integrity. STS treatment markedly induced PP2A expression in microglia. Forced overexpression of PP2A increased levels of Beclin 1 and ATG5, decreased the p62 protein level, and induced autophagic flux. Silencing of PP2A or administration of 3-methyladenine inhibited autophagy and decreased the production of anti-inflammatory factors (IL-10, TGF-ß and BDNF) and induced the release of proinflammatory cytokines (IL-1ß, IL-2 and TNF-α) by STS-treated microglia, thereby inducing mitochondrial dysfunction and apoptosis of STS-treated neurons. STS exerts protection against neuron injury, and the PP2A gene plays a crucial role in improving mitochondrial function and inhibiting neuronal apoptosis by regulating autophagy and inflammation in microglia.

Genome-wide mapping of regulatory variants for temperature- and salinity-adaptive genes reveals genetic basis of genotype-by-environment interaction in Crassostrea ariakensis.

Regulatory variants in gene expression serve as bridges linking genetic variation and phenotypic plasticity. Environmental conditions typically influence the effects of regulatory variants on phenotypic plasticity; however, such genotype-by-environment interactions (G × E) are poorly understood. This study aimed to investigate the genetic basis of G × E in estuarine oyster (Crassostrea ariakensis), which is an important model animal for studying environmental adaption owing to its high plasticity and large intraspecific divergence. Genome-wide mapping of expression quantitative trait loci (eQTLs) for 23 environmental adaptive genes was performed for 256 estuarine oysters. We identified 1194 eQTL single nucleotide polymorphisms (eSNPs), including 433 cis-eSNPs in four genes and 722 trans-eSNPs in eight genes. The expression variation explanation of cis-eSNPs (9.95%) was significantly higher than that of trans-eSNPs (9.15%). We specifically showed cis- and trans-eSNPs with high linkage disequilibrium (LD) for Traf7, Slc6a5, Ggt, and Dap3. For example, we identified a cis-regulatory LD block containing 68 cis-eSNP and a trans-regulatory LD block, including 20 trans-eSNPs in Traf7. A high proportion (85%) of 40 vital eSNPs exhibited significant G × E effects. We identified crossing and nonparallel interactions of G × E, with the tag cis-eSNPs of Baat and Slc6a5 as representatives. Our results indicated that cis-eQTLs are highly conserved. This study provides insights into the understanding of adaptive evolutionary mechanisms and phenotypic response prediction to variable environments, as well as the genetic improvement for superior adaptive traits for genetic resource conservation and aquaculture.

Comparative proteomic and phosphoproteomic analysis reveals differential heat response mechanism in two congeneric oyster species.

High-temperature stress caused by global climate change poses a significant threat to marine ectotherms. This study investigated the role of protein phosphorylation modifications in the molecular regulation network under heat stress in oysters, which are representative intertidal organisms that experience considerable temperature changes. Firstly, the study compared the extent of thermal damage between two congeneric oyster species, the relative heat-tolerant Crassostrea angulata (C. angulata) and heat-sensitive Crassostrea gigas (C. gigas), under sublethal temperature (37 °C) for 12 h, using various physiological and biochemical methods. Subsequently, the comparative proteomic and phosphoproteomic analyses revealed that high-temperature considerably regulated signal transduction, energy metabolism, protein synthesis, cell survival and apoptosis, and cytoskeleton remodeling through phosphorylation modifications of related receptors and kinases. Furthermore, the protein kinase A, mitogen-activated protein kinase 1, tyrosine-protein kinase Src, and serine/threonine kinase AKT, exhibiting differential phosphorylation modification patterns, were identified as hub regulators that may enhance glycolysis and TCA cycle to increase the energy supply, distribute protein synthesis, inhibit Caspase-dependent apoptosis activated by endogenous mitochondrial cytochrome release and maintain cytoskeletal stability, ultimately shaping the higher thermal resistance of C. angulata. This study represents the first investigation of protein phosphorylation dynamics in marine invertebrates under heat stress, reveals the molecular mechanisms underlying the differential thermal responses between two Crassostrea oysters at the phosphorylation level, and provides new insights into understanding phosphorylation-mediated molecular responses in marine organisms during environmental changes and predicting the adaptive potential in the context of global warming.

MiRNA-1976 Regulates the Apoptosis of Dopaminergic Neurons by Targeting the PINK1 Gene.

INTRODUCTION: Parkinson's disease (PD), which is a neurodegenerative disease, requires urgently needed biomarkers to explore its mechanism. We screened for differences in the expression of microRNAs (miRNAs) and identified miR-1976 as a possible biomarker. METHODS: Twenty-three patients and 30 controls were included in this study. Dopaminergic neurons from C57/BL mice were cultured. The miRNA expression profiles were analyzed using an miRNA microarray. MiR-1976 was identified as an miRNA that was differentially expressed between PD patients and age-matched controls. Lentiviral vectors were constructed, then apoptosis in dopaminergic neurons was analyzed using MTS (multicellular tumor spheroids) and flow cytometry. Transfection of miR-1976 mimics into MES23.5 cells was performed, and target genes and biological effects were analyzed. RESULTS: Overexpression of miR-1976 increased apoptosis and mitochondrial damage in dopaminergic neurons. PINK1 (PINK1-induced kinase 1) was the most common target protein of miR-1976, and silencing of PINK1 caused mitochondrial damage and increased apoptosis of MES23.5 cells. CONCLUSIONS: MiR-1976 is a newly discovered miRNA that exhibits a high degree of differential expression with respect to the apoptosis of dopaminergic neurons. Given these results, increased expression of miR-1976 may increase the risk of PD by targeting PINK1 and may therefore be a useful biomarker for PD.