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Background Sepsis is defined as a systemic inflammatory response to microbial infections with multiple organ dysfunction. This study analysed untargeted metabolomics combined with proteomics of serum from patients with sepsis to reveal the underlying pathological mechanisms involved in sepsis. Methods A total of 63 patients with sepsis and 43 normal controls were enrolled from a prospective multicentre cohort. The biological functions of the metabolome were assessed by coexpression network analysis. A molecular network based on metabolomics and proteomics data was constructed to investigate the key molecules. Results Untargeted metabolomics analysis revealed widespread dysregulation of amino acid metabolism, which regulates inflammation and immunity, in patients with sepsis. Seventy-three differentially expressed metabolites (|log 2 fold change| > 1.5, adjusted P value < 0.05 and variable importance in the projection (VIP) > 1.5) that could predict sepsis were identified. External validation of the hub metabolites was consistent with the derivation results (area under the receiver operating characteristic curve (AUROC): 0.81–0.96/0.62–1.00). The pentose phosphate pathway was found to be related to sepsis-associated encephalopathy. Phenylalanine metabolism was associated with sepsis-associated acute kidney injury. The key molecular alterations of the multiomics network in sepsis compared to normal controls implicate acute inflammatory response, platelet degranulation, myeloid cell activation involved in immune response and phenylalanine, tyrosine and tryptophan biosynthesis, and arginine biosynthesis. Conclusions Integrated analysis of untargeted metabolomics and proteomics revealed characteristic metabolite and protein alterations in sepsis, which were mainly involved in inflammation-related pathways and amino acid metabolism. This study depicted the pathological characteristics and pathways involved in sepsis and potential therapeutic targets.

The similarity test of ship stiffened plate structures under underwater explosions is a cost-effective and efficient method to evaluate the vitality of ships and guide the design of their shock resistance. This study focuses on the nonlinear impact response model tests of ship stiffened plate structures and their similarity laws with actual ships. The vertical motion of the ship stiffened plate structure is characterized by the Hurst index, and an equivalent relationship between the Hurst index of the model and the prototype is derived from classical similarity law. Based on the Hurst index, a similarity transformation relationship between the strain signals of the model and prototype is established. To verify the conclusions, similarity experiments of underwater explosions were conducted on both the model and the prototype. The original signals were grouped by the natural vibration period to determine the variation of the Hurst index over time. The model experiment strain signals for each natural vibration period were converted and compared with the prototype experiment results to verify the method's effectiveness. Simultaneously, the Hurst index of the stiffened plate structure under explosive shock load and its similarity transformation relationship with the prototype were simulated and analyzed. This provides theoretical and technical support for conducting analogous nonlinear response experiments for ship underwater explosions.

Background Chemokines and chemokine receptors cooperate to promote immune cell recruitment to the central nervous system (CNS). In this study, we investigated the roles of CXCR2 and CXCL1 in leukocyte recruitment to the CNS using a murine model of neuroinflammation. Methods Wild-type (WT), CXCL1 −/− , and CXCR2 −/− mice each received an intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS). Esterase staining and intravital microscopy were performed to examine neutrophil recruitment to the brain. To assess endothelial activation in these mice, the expression of adhesion molecules was measured via quantitative real-time polymerase chain reaction (PCR) and Western blotting. To identify the cellular source of functional CXCR2, chimeric mice were generated by transferring bone marrow cells between the WT and CXCR2 −/− mice. Results Expression levels of the chemokines CXCL1, CXCL2, and CXCL5 were significantly increased in the brain following the i.c.v. injection of LPS. CXCR2 or CXCL1 deficiency blocked neutrophil infiltration and leukocyte recruitment in the cerebral microvessels. In the CXCR2 −/− and CXCL1 −/− mice, the cerebral endothelial expression of adhesion molecules such as P-selectin and VCAM-1 was dramatically reduced. Furthermore, the bone marrow transfer experiments demonstrated that CXCR2 expression on CNS-residing cells is essential for cerebral endothelial activation and leukocyte recruitment. Compared with microglia, cultured astrocytes secreted a much higher level of CXCL1 in vitro. Astrocyte culture conditioned medium significantly increased the expression of VCAM-1 and ICAM-1 in cerebral endothelial cells in a CXCR2-dependent manner. Additionally, CXCR2 messenger RNA (mRNA) expression in cerebral endothelial cells but not in microglia or astrocytes was increased following tumor necrosis factor-α (TNF-α) stimulation. The intravenous injection of the CXCR2 antagonist SB225002 significantly inhibited endothelial activation and leukocyte recruitment to cerebral microvessels. Conclusions CXCL1 secreted by astrocytes and endothelial CXCR2 play essential roles in cerebral endothelial activation and subsequent leukocyte recruitment during neuroinflammation.

Bubbles in pipes are widely present in marine engineering, transmission, and fluid systems with complex environments. This paper divides tubes into short, longer, and long tubes due to different lengths. In short tubes, the formation, development, and stability of spark bubbles are deeply analyzed through numerical simulation and experimental measurement, and the morphology and period of vortex rings generated in the surrounding fluid are studied. The results show that bubbles in tubes are significantly elongated compared with those in free fields. Changing the parameters of tubes can affect the size and oscillation speed of vortex rings. Secondary cavitation is found in asymmetric positions in longer tubes. The conditions, positions, and periods of multiple secondary cavitations are summarized in a series of experiments on long tubes. It is found that bubbles in tubes are related to the γt and γL tube parameters. More secondary cavitation is easily generated in thinner and longer tubes. In addition, the pumping effect brought about by the movement of bubbles in tubes is studied. By designing reasonable tube parameters, the life cycle of bubbles can be changed, and the pumping efficiency can be improved. This study provides important theoretical support for the reliability of the movement of bubbles and surrounding fluid in tubes and lays a foundation for the optimization and promotion of this technology in practical applications.

To improve the evaluation efficiency of failure probability in RBDO models with uncertainty, many RIA-based, PMA-based methods have evolved as a powerful procedure, including the modified reliability index approach (MRIA), PMA two-level, PMA with sequential approximate programming (SAP). However, MRIA may encounter inefficiency and instability when applied to complex concave performance functions, and so does PMA two-level, not for PMA with SAP. The active set strategy-based SAP (ASS-based SAP) for PMA is proposed to accelerate computational efficiency through establishing an active set strategy and a deciding factor. The active set strategy defined by using inequality is to identify the feasible most probable target point (MPTP) in the inner loop. The decision factor integrates the reliability index and the active set strategy to quickly renew the active constraints in the outer loop. The reliability assessment and outer optimization are driven simultaneously, thereby the computational efficiency is strengthened. Numerical examples are compared with other reliability methods to demonstrate the excellent performance of the proposed method in efficiency and robustness. Results also show that the proposed method has the ability to solve complex RBDO problems.

Self-excited oscillating pulsed cavitation jet has many advantages, such as easy operation, simply maintenance, and low investment costs. Based on the structural parameters of the traditional Helmholtz and organ pipe single-chamber self-excited oscillating pulsed nozzles, Helmholtz + Helmholtz, organ pipe + organ pipe, and Helmholtz + organ pipe dual-chamber self-excited oscillating pulsed nozzles with different structures are established in series, and the internal flow field of the dual chamber is studied to obtain the best combination nozzle by comparing numerical simulation and erosion experiments. The results indicate that the cleaning effect is the best when adopting the combined structure of Helmholtz + organ pipe, which brings out the largest volume fraction of the nozzle cavity with higher gas content and higher kinetic energy with larger jet velocity. By comparing the erosion experiments, it is found that the flushing area and erosion depth of the nozzle with the ratio of cavity and wall (D/a) of 2.50 is significantly higher than the nozzle with the ratio of cavity and wall (D/a) of 5.00. The pulse pressure of the flushing target increases by 0.0044 MPa, the pressure amplitude of the former changes significantly in the same cavitation cycle, and the cleaning effect is best.

The shape of a bubble changes near an elastic boundary, and this alteration also influences the boundary itself. This study investigates bubble shape and boundary displacement near an elastic cylindrical boundary through an electric spark bubble experiment. Three parameters—dimensionless distance, elastic cylinder tension, and dimensionless size—are discussed and analyzed in relation to bubble shape. For studying elastic cylinder boundary displacement, a displacement formula is proposed by establishing a motion model, and impulse is used for verification. Furthermore, the elastic cylinder tension employed in this study has negligible impact on boundary displacement. Understanding how bubble shape changes near an elastic boundary, along with the corresponding boundary displacement, provides valuable insights into the stability and durability of materials and structures under similar conditions. The elasticity of the cylinder and its displacement response to external forces can help predict long-term behavior, contributing to the reliability assessment of engineering systems involving elastic boundaries and fluid dynamics.

Background Interleukin-33 (IL-33) is increasingly being recognized as a key immunomodulatory cytokine in many neurological diseases. Methods In the present study, wild-type (WT) and IL-33 −/− mice received intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS) to induce neuroinflammation. Intravital microscopy was employed to examine leukocyte–endothelial interactions in the brain vasculature. The degree of neutrophil infiltration was determined by myeloperoxidase (MPO) staining. Real-time PCR and western blotting were used to detect endothelial activation. Enzyme-linked immunosorbent assay and quantitative PCR were conducted to detect pro-inflammatory cytokine levels in the brain. Results In IL-33 −/− mice, neutrophil infiltration in the brain cortex and leukocyte–endothelial cell interactions in the cerebral microvessels were significantly decreased as compared to WT mice after LPS injection. In addition, IL-33 −/− mice showed reduced activation of microglia and cerebral endothelial cells. In vitro results indicated that IL-33 directly activated cerebral endothelial cells and promoted pro-inflammatory cytokine production in LPS-stimulated microglia. Conclusions Our study indicated that IL-33/ST2 signaling plays an important role in the activation of microglia and cerebral endothelial cells and, therefore, is essential in leukocyte recruitment in brain inflammation. Graphical abstract The role of IL-33/ST2 in LPS induced neuroinflammation

An analytical model of laminated composite double-plate system (LCDPS) is established, which efficiently analyzes the common 3D plate structure in engineering applications. The proposed model combines the first-order shear deformation theory (FSDT) and the classical delamination theory, and then the LCDPS’s vibration characteristics are investigated. In the process of analysis, the improved Fourier series method (IFSM) is used to describe the displacement admissible function of the LCDPS, which can remove the potential discontinuities at the boundaries. Five sets of artificial springs are introduced to simulate the elastic boundary constraints, and the restraints of the Winkler elastic layer can be adjustable. The improved Fourier series is substituted into the governing equations and boundary conditions; then, applying the Rayleigh–Ritz method, we take all the series expansion coefficients as the generalized coordinates. After that, a set of standard linear algebraic equations was obtained. On this basis, the natural frequency and mode shapes of the LCDPS can be obtained by solving the standard eigenvalue problem. By the discussion of numerical examples and the comparison with those of the reports in the literature, the convergence and the reliability of the present approach are validated. Finally, the parametric investigations of the free vibration with complex boundary conditions are carried out, including the influence of boundary conditions, lamination scheme, plate geometric parameters, and elastic coefficient between two plates.

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons and excessive microglial activation in the substantia nigra pars compacta (SNpc). In the present study, we aimed to demonstrate the therapeutic effectiveness of the potent sphingosine-1-phosphate receptor antagonist fingolimod (FTY720) in an animal model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and to identify the potential mechanisms underlying these therapeutic effects. C57BL/6J mice were orally administered FTY720 before subcutaneous injection of MPTP. Open-field and rotarod tests were performed to determine the therapeutic effect of FTY720. The damage to dopaminergic neurons and the production of monoamine neurotransmitters were assessed using immunohistochemistry, high-performance liquid chromatography, and flow cytometry. Immunofluorescence (CD68- positive) and enzyme-linked immunosorbent assay were used to analyze the activation of microglia, and the levels of activated signaling molecules were measured using Western blotting. Our findings indicated that FTY720 significantly attenuated MPTP-induced behavioral deficits, reduced the loss of dopaminergic neurons, and increased dopamine release. FTY720 directly inhibited MPTP-induced microglial activation in the SNpc, suppressed the production of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in BV-2 microglial cells treated with 1-methyl-4-phenylpyridinium (MPP + ), and subsequently decreased apoptosis in SH-SY5Y neuroblastoma cells. Moreover, in MPP + -treated BV-2 cells and primary microglia, FTY720 treatment significantly attenuated the increases in the phosphorylation of PI3K/AKT/GSK-3β, reduced ROS generation and p65 activation, and also inhibited the activation of NLRP3 inflammasome and caspase-1. In conclusion, FTY720 may reduce PD progression by inhibiting NLRP3 inflammasome activation via its effects on ROS generation and p65 activation in microglia. These findings provide novel insights into the mechanisms underlying the therapeutic effects of FTY720, suggesting its potential as a novel therapeutic strategy against PD. Graphical Abstract FTY720 may reduce ROS production by inhibiting the PI3K/AKT/GSK-3β signaling pathway, while at the same time reducing p65 phosphorylation, thus decreasing NLRP3 inflammasome activation through these two pathways, ultimately reducing microglia activation-induced neuronal damage.