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Abstract Background Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. Methods C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. Results Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3–5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. Conclusions Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

Rockburst plays a serious threat to personnel and equipment during underground engineering construction. The study of the rockburst mechanism is helpful to its prediction and prevention. Based on the characteristic analysis of a large number of rockburst cases, Li et al. proposed three stress-type and three stress-structural rockbursts and obtained the geological characteristics and occurrence criteria of these rockbursts, but the evolution process of rockbursts is still unclear. Based on the continuous-discontinuous element method, the characteristics of failure process, surrounding rock stress, motion, and energy of three stress-rockburst blocks are analyzed. The results show that rockburst failure generally goes through several stages, such as a few surfaces tensile failure, shallow shear failure, deep extension of tensile failure, shear failure communication, and rockburst occurrence. The total volume of rockburst blocks and the main distribution intervals of block diameters for different types of rockbursts are quite different, which are mainly affected by stress state and geological structure. The ejection velocity of the small block is always higher than that of the large block during the same one rockburst simulation, and the ejection velocity of the small block is from the surface. In the process of rockburst, not only the elastic strain energy is released but also the elastic strain energy is accumulated. The greater the rockburst intensity, the more the elastic strain energy is released, and the steeper the prepeak curve of elastic strain energy. The research results provide a reference for further understanding the mechanism of rockburst and lay a theoretical basis for the prevention and control of rockburst in underground engineering.

Abstract Engineered extracellular vesicles (EVs) are considered excellent delivery vehicles for a variety of therapeutic agents, including nucleic acids, proteins, drugs, and nanomaterials. Recently, several studies have indicated that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated 9 (Cas9) delivered by EVs enable efficient DNA editing. However, an RNA editing tool delivered by EVs is still unavailable. Here, a signal peptide‐optimized and EVs‐delivered guide RNA (gRNA) and CRISPR/CasRx (Cas13d) system capable of rapidly inhibiting the expression of targeted genes with quick catabolism after performing their functions is developed. EVs with CRISPR/CasRx and tandem gRNAs targeting pivotal cytokines are further packed whose levels increase substantially over the course of acute inflammatory diseases and find that these engineered EVs inhibit macrophage activation in vitro. More importantly, this system attenuates lipopolysaccharide (LPS)‐triggered acute lung injury and sepsis in the acute phase, mitigating organ damage and improving the prognosis in vivo. In summary, a potent tool is provided for short‐acting RNA editing, which could be a powerful therapeutic platform for the treatment of acute diseases.

Several engineering practices have shown that the excavation of shallow-buried tunnels beneath major roads, as well as the selection of appropriate engineering measures and construction methods, has a significant impact on road surface settlement. Therefore, field monitoring and numerical simulation are adopted in this study to analyze the effect of the cross diaphragm (CRD) excavation method on surface settlement for the under-construction Yüan 1 railroad tunnel. The findings show that during the excavation of the four divisions of the CRD excavation method for shallow-buried tunnels, the amount of surface settlement caused by the excavation of part 1 accounts for 40% of the total surface settlement, followed by the excavation of part 3, accounting for 30% of the total surface settlement, and the difference between the excavation of parts 2 and 4 is insignificant, with part 2 slightly larger than part 4. The main influence of the CRD method on surface settlement for shallow-buried tunnels is 0.64–0.86 times the cavity diameter from the tunnel median, within which the final surface settlement caused by excavation is within the same horizontal range, and beyond which the surface settlement is prone to dramatically decline. By applying advanced grouting and adjusting the construction method of CRD based on the monitoring data, the effect of the CRD excavation method on surface settlement can be controlled.

The rockburst phenomenon occurs in dry red sandstone under high in situ stress, and the rockburst effect is weaker for a water-bearing rock. The rockburst effect on red sandstone with different water contents is analyzed in this paper. A true triaxial testing machine is used to conduct the loading, and acoustic emission recording equipment and a high-speed camera are used to monitor the acoustic signal inside the rock and the rock-caving situation throughout the entire process in order to analyze the characteristics of the acoustic emissions and the ejection form of the rockburst. The results show that rockburst occurs in dry red sandstone and 50% saturated red sandstone but not in saturated red sandstone. The phrase characteristics of the stress–strain curve of the dry rock vary more significantly than those of the water-bearing rock, and the elastic strain energy inside the rock decreases gradually as the water content increases. The double peak of the acoustic emissions curve occurs during the failure process of the dry rock and gradually transitions to a stepped pattern as the water content increases. The ejected fragments of dry red sandstone during the rockburst are abundant and large. The true triaxial test results illustrate the characteristic effect of the rockburst on red sandstone with different water contents, reveal the failure mode and ejection characteristics of red sandstone with different water contents, and demonstrate the influence of the water content on the rockburst characteristics of red sandstone. The results of this study provide a theoretical reference for the study of the rockburst mechanisms of similar hard rocks.

ObjectiveTo our knowledge, the impact of area-level socioeconomic status (SES) has not yet been described in primary central nervous system lymphomas (PCNSLs). Current study sought to explore the association of socioeconomic deprivation, measured using the Area Deprivation Index (ADI), with PCNSL outcomes.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to identify PCNSL patients diagnosed between 2006 and 2015 for our analyses. The impact of ADI on overall survival (OS) and cancer-specific survival (CSS) were investigated. Survival analyses were conducted using Kaplan-Meier method with log-rank tests. The Inverse Probability Weighting (IPW) analysis and multivariate cox proportional hazards regression analysis were employed to make covariate adjustments. Multiple mediation analysis (MMA) was performed to estimate the mediating effects.ResultsA total of 3159 PCNSL patients classified into low and high ADI subgroups according to the median ADI score were studied. The Kaplan-Meier analyses showed that low ADI was significantly associated with higher OS rates (HR 1.15, 95%CI 1.06-1.26, P

Slope cutting is becoming more common in engineering construction to obtain a large floor area. Slope cutting disrupts a slope’s inherent stability, causing instability and sliding. To solve the problem of geological disasters caused by artificial slope cutting, Cangxi County is used as an example to analyze the cutting slope and the height of different slope structures in the county, to study the disaster mode and disaster factors caused by slope cutting, and to analyze the influence of slope cutting height and slope cutting gradient on the disaster process. This study demonstrates that the stability of cutting on different types of slopes is weakened to different degrees, with mixed rocky-soil slopes having the strongest resistance to weakening, thick-soil slopes the second strongest, and thin-soil slopes the weakest. Slope cutting is the main factor of disaster, and rainwater infiltration promotes landslide formation. Numerical simulation is employed to determine the proximities of the slope cutting height and slope cutting gradient, and 75% of the critical value is taken as the proposed threshold value of slope cutting. The recommended cut slope threshold value corresponds to the real stable cut slope gradient on site, and the research findings can be used to guide engineering cut slope decisions in Cangxi County and other red-layer areas.

The B7-CD28 gene family plays a crucial role in modulating immune functions and has served as potential targets for immunotherapeutic strategies. Therefore, we systematically analyzed B7-CD28 family gene expression profiles and constructed a B7-CD28 family-based prognostic signature to predict survival and immune host status in diffuse gliomas. The TCGA dataset was used as a training cohort, and three CGGA datasets (mRNAseq_325, mRNAseq_693 and mRNA-array) were employed as validation cohorts to intensify the findings that we have revealed in TCGA dataset. Ultimately, we developed a B7-CD28 family-based signature that consisted of CD276, CD274, PDCD1LG2 and CD80 using LASSO Cox analysis. This gene signature was validated to have significant prognostic value, and could be used as a biomarker to distinguish pathological grade and IDH mutation status in diffuse glioma. Additionally, we found that the gene signature was significantly related to intensity of immune response and immune cell population, as well as several other important immune checkpoint genes, holding a great potential to be a predictive immune marker for immunotherapy and tumor microenvironment. Finally, a B7-CD28 family-based nomogram was established to predict patient life expectancy contributing to facilitate personalizing therapy for tumor sufferers. In summary, this is the first mathematical model based on this gene family with the aim of providing novel insights into immunotherapy for diffuse glioma.

The study on the failure difference of deep hard rock based on the comparison between conventional and true triaxial tests can help us better understand the fracture processes and failure characteristics of the deep rock mass. Therefore, this article carries out a comparative analysis of the failure of hard rock under conventional and true triaxial stress states. Within the scope of this study, it is found that the brittle–ductile transformation properties can be intuitively reflected in the rock stress–strain curve and failure mode. The brittle–ductile transition point of rock can also be determined by the difference between peak and residual strengths. The rock failure strength increases with the increase of σ2, the peak strain decreases with the increase of σ2, the stress drop of the post-peak curve becomes more obvious with the increase of σ2, and the rock tends toward Class II brittle failure after the peak with the increase of σ2. When σ3 is relatively high, the rock fracture angle increases with the increase of σ2 with obvious regularity. Compared with conventional triaxial stress conditions, the differential stress-induced anisotropy failure is the biggest difference in rock fracture characteristics between true and conventional triaxial stress states. This study can supply useful references to the study of failure properties of hard rock under complex stress states.

Polystyrene nanoparticles (PS-NPs) are organic pollutants that are widely detected in the environment and organisms, posing potential threats to both ecosystems and human health. PS-NPs have been proven to penetrate the blood–brain barrier and increase the incidence of neurodegenerative diseases. However, information relating to the pathogenic molecular mechanism is still unclear. This study investigated the neurotoxicity and regulatory mechanisms of PS-NPs in human neuroblastoma SHSY-5Y cells. The results show that PS-NPs caused obvious mitochondrial damages, as evidenced by inhibited cell proliferation, increased lactate dehydrogenase release, stimulated oxidative stress responses, elevated Ca2+ level and apoptosis, and reduced mitochondrial membrane potential and adenosine triphosphate levels. The increased release of cytochrome c and the overexpression of apoptosis-related proteins apoptotic protease activating factor-1 (Apaf-1), cysteinyl aspartate specific proteinase-3 (caspase-3), and caspase-9 indicate the activation of the mitochondrial apoptosis pathway. In addition, the upregulation of autophagy markers light chain 3-II (LC3-II), Beclin-1, and autophagy-related protein (Atg) 5/12/16L suggests that PS-NPs could promote autophagy in SHSY-5Y cells. The RNA interference of Beclin-1 confirms the regulatory role of autophagy in PS-NP-induced neurotoxicity. The administration of antioxidant N-acetylcysteine (NAC) significantly attenuated the cytotoxicity and autophagy activation induced by PS-NP exposure. Generally, PS-NPs could induce neurotoxicity in SHSY-5Y cells via autophagy activation and mitochondria dysfunction, which was modulated by mitochondrial oxidative stress. Mitochondrial damages caused by oxidative stress could potentially be involved in the pathological mechanisms for PS-NP-induced neurodegenerative diseases.