To improve the comprehensive structural performance and optimize the structural quality of the aluminum alloy subway car body, a multi-objective structural optimization method based on a response ...surface approximate proxy model was proposed. On the basis of the sensitivity calculation of the objective response to the thickness changes of profiles in different regions of the car body, 21 groups of plate variables with the highest optimization potential were selected for optimization. The optimization experiments were performed on the design variables, and sufficient sample points were selected for the target analysis. Based on the calculated data, second-order response surface models for the bending modal frequency, bending stiffness, and complete mass of the subway car body were constructed considering the optimized profile thickness. After verifying the accuracy of the model, it was used to replace the finite element model for optimization analysis. To achieve feasible optimization results, two schemes with the profile thickness varied in steps of 0.1 and 0.5 mm in the design space were used. After the completion of the calculation, experimental evaluation of the two optimal schemes indicated that the structural performance was consistent with the numerical results.
This study aimed to determine whether the lotus leaf extract (LLE) had the effect of treating salpingitis in laying hens. First, the salpingitis model was established by the method of bacterial ...infection. Differential genes between salpingitis and healthy laying hens were identified by transcriptome sequencing, and GO and KEGG enrichment analyses were performed. Groups of treatment of antibiotics and LLE were established to verify the feasibility of the lotus leaf extract in treating salpingitis. Furthermore, the active component and pharmacological effects of LLE were identified using the UPLC-Q-TOF-MS and network pharmacology technique. At last, the mechanism of LLE treating salpingitis was further evaluated by DF-1 cells infected with bacteria. The results showed that LLE significantly reduced the levels of TLR4 and IFN-γ (P < 0.05), accelerated the levels of IgA and IgG (P < 0.05), regulated the levels of SOD and MDA (P < 0.05) in laying hens with salpingitis. A total of 1,874 differential genes were obtained according to the transcriptome sequencing. It was revealed a significant role in cell cycle and apoptosis by enrichment analysis. In addition, among the 28 components identified by UPLC-Q-TOF-MS, 20 components acted on 58 genes, including CDK1, BIRC5, and CA2 for treating salpingitis. After bacterial infection, cells were damaged and unable to complete the normal progression of the cell cycle, leading to cell cycle arrest and further apoptosis formation. However, with the intervention of LLE, bacterial infection was resisted. The cells proliferation was extensively restored, and the expression of NO was increased. The addition of LLE significantly decreased cell apoptosis. The G1 phase increased, the S phase and the G2 phase decreased in the model group; after the intervention of LLE, the G1 phase gradually returned to the average level, and G2 and S phases increased. The mRNA expression levels of BIRC5, CDK1, and CA2 were consistent with the predicted results in network pharmacology. At the same time, the mRNA expression levels of Caspase-3 and Caspase-7 were reduced after added with LLE. The mRNA expression levels of TNF-α, TRADD, FADD, Caspase-8, Caspase-10, and Caspase-9 (P < 0.05), which would inhibit death receptor activation and decrease the apoptotic cascade, were upregulated after bacterial infection. However, the results in LLE groups were downregulated (P < 0.05). Meanwhile, the mRNA expression levels of BCL-2 in LLE groups were increased significantly compared with it in model group (P < 0.05). Notably, LLE administration inhibited apoptosis and regulated the cell cycle distribution in the salpingitis induced by bacterial infection. These results indicated that the LLE attenuated bacterial-induced salpingitis by modulating apoptosis and immune function in laying hens.
Alarmins are endogenous mediators capable of promoting the recruitment and activation of antigen-presenting cells (APCs), including dendritic cells (DCs), that can potentially alert host defense ...against danger signals. However, the relevance of alarmins to the induction of adaptive immune responses remains to be demonstrated. In this study, we report the identification of HMGN1 (high-mobility group nucleosome-binding protein 1) as a novel alarmin and demonstrate that it contributes to the induction of antigen-specific immune responses. HMGN1 induced DC maturation via TLR4 (Toll-like receptor 4), recruitment of APCs at sites of injection, and activation of NF-κB and multiple mitogen-activated protein kinases in DCs. HMGN1 promoted antigen-specific immune response upon co-administration with antigens, and Hmgn1(-/-) mice developed greatly reduced antigen-specific antibody and T cell responses when immunized with antigens in the presence of lipopolysaccharide (LPS). The impaired ability of Hmgn1(-/-) mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from nonleukocytes was critical for the induction of antigen-specific antibody and T cell responses. Thus, extracellular HMGN1 acts as a novel alarmin critical for LPS-induced development of innate and adaptive immune responses.
To explore the strategy of acute cerebral artery embolism after radiofrequency catheter ablation (RFA) for atrial fibrillation (AF). Reporting two cases with acute cerebral infarction after RFA for ...AF. Two patients were both with AF, and intracardiac thrombus was excluded through transesophageal echocardiogram (TEE) before procedure. Approach of ablation: circumferential pulmonary vein ablation in left atrium to isolate pulmonary vein plus linear ablation in the top and bottom of left atrium (BOX procedure). They both received Dabigatran Etexilate 110 mg twice daily, starting 6 hr after ablation. Symptoms of major stroke appeared 30 hr after ablation in Case 1. Occlusion was detected in M1 segment of the left middle cerebral artery by MRI 2 hr after symptoms onset. Intravenous thrombolysis was given immediately. In Case 2, the patient presented symptoms of major stroke 34 hr after ablation and occlusion in the basilar artery was confirmed by MRI 4.5 hr after symptoms onset. Although it was beyond the thrombolysis time window, mechanical thrombectomy was taken 7 hr after the symptoms onset. The culprit artery was successfully revascularized in both cases. In Case 1, NIHSS score was reduced from 8 (before thrombolysis) to 0 (24 hr after thrombolysis). In Case 2, NIHSS score decreased from 18 (before embolectomy) to 3 (24 hr after embolectomy). Both of the patients live a normal life without brain function impairment and hemorrhage until the last follow‐up. Timely recanalization could attained a good cure effect when acute stoke was happened after RFA for AF.
Alarmins are endogenous mediators that are elicited rapidly in response to danger signals, enhancing innate and adaptive immune responses by promoting the recruitment and maturation of ...antigen-presenting cells (APC). The nucleosome-binding protein HMGN1 is a potent alarmin that binds TLR4 and induces antigen-specific Th1 immune responses, but its contributions to antitumor immunity have not been explored. We found that ovalbumin (OVA)-expressing EG7 mouse thymoma cells grew much faster in Hmgn1-deficient mice than littermate-matched controls. Tumor-bearing Hmgn1(-/-) mice generated fewer OVA-specific CD8 cells in the spleen than EG7-bearing Hmgn1(+/+) mice, suggesting that HMGN1 supported T cell-mediated antitumor immunity. In addition, EG7 tumors expressing HMGN1 grew more slowly than control EG7 tumors, suggesting greater resistance to HMGN1-expressing tumors. This resistance relied on T cell-mediated immunity because it was abolished by in vivo depletion of CD4(+) and CD8(+) T cells. Moreover, mice vaccinated with a DNA vector expressing an HMGN1-gp100 fusion protein manifested gp100-specific, Th1-polarized immune responses, acquiring resistance to challenge with mouse B16F1 melanoma. Overall, our findings show that HMGN1 contributes to antitumor immunity and it may offer an effective adjuvant to heighten responses to cancer vaccines.
This paper aimed to evaluate the effect of 3 kinds of TCM polysaccharides instead of antibiotics in preventing salpingitis in laying hens. After feeding the laying hens with Lotus leaf ...polysaccharide, Poria polysaccharide, and Epimedium polysaccharide, mixed bacteria (E. coli and Staphylococcus aureus) were used to infect the oviduct to establish an inflammation model. Changes in antioxidant, serum immunity, anti-inflammatory, gut microbiota, and serum metabolites were evaluated. The results showed that the 3 TCM polysaccharides could increase the expression of antioxidant markers SOD, GSH, and CAT, and reduce the accumulation of MDA in the liver; the contents of IgA and IgM in serum were increased. Decreased the mRNA expression of TLR4, NFκB, TNF-α, IFN-γ, IL1β, IL6, and IL8, and increased the mRNA expression of anti-inflammatory factor IL5 in oviduct tissue. 16sRNA high-throughput sequencing revealed that the 3 TCM polysaccharides improved the intestinal flora disturbance caused by bacterial infection, increased the abundance of beneficial bacteria such as Bacteroides and Actinobacillus, and decreased the abundance of harmful bacteria such as Romboutsia, Turicibacter, and Streptococcus. Metabolomics showed that the 3 TCM polysaccharides could increase the content of metabolites such as 3-hydroxybutyric acid and isobutyl-L-carnitine, and these results could alleviate the further development of salpingitis. In conclusion, the present study has found that using TCM polysaccharides instead of antibiotics was a feasible way to prevent bacterial salpingitis in laying hens, which might make preventing this disease no longer an issue for breeding laying hens.
Pure copper was subjected to high-pressure surface rolling (HPSR) to obtain a surface gradient layer. Effects of HPSR parameters on the surface microstructure and microhardness of Cu were ...investigated by using optical microscopy, transmission electronic microscopy, X-ray diffraction, and the microhardness test. The HPSR surface layer has a gradient microstructure consisting of increasingly refined grains with decreasing depth from the treated surface (DFS). The thicknesses of the refined surface layer can be up to ~1.8 mm, and the grain size of the topmost surface is down to ~88 nm, depending on the HPSR parameters including pressure, time, and temperature. Microhardness of HPSR samples increases with decreasing DFS, with a maximum of ~2.4 times that of the undeformed matrix. The present results indicated that HPSR could be an effective method for the production of a mm-thick surface layer on Cu with gradient microstructure and property.
Tuberous sclerosis complex 1 (Tsc1) is known to regulate the development and function of various cell types, and RORγt is a critical transcription factor in the immune system. However, whether Tsc1 ...participates in regulating RORγt-expressing cells remains unknown.
We generated a mouse model in which Tsc1 was conditionally deleted from RORγt-expressing cells (Tsc1
) to study the role of RORγt-expressing cells with Tsc1 deficiency in brain homeostasis.
Type 3 innate lymphoid cells (ILC3s) in Tsc1
mice displayed normal development and function, and the mice showed normal Th17 cell differentiation. However, Tsc1
mice exhibited spontaneous tonic-clonic seizures and died between 4 and 6 weeks after birth. At the age of 4 weeks, mice in which Tsc1 was specifically knocked out in RORγt-expressing cells had cortical neuron defects and hippocampal structural abnormalities. Notably, over-activation of neurons and astrogliosis were observed in the cortex and hippocampus of Tsc1
mice. Moreover, expression of the γ-amino butyric acid (GABA) receptor in the brains of Tsc1
mice was decreased, and GABA supplementation prolonged the lifespan of the mice to some extent. Further experiments revealed the presence of a group of rare RORγt-expressing cells with high metabolic activity in the mouse brain.
Our study verifies the critical role of previously unnoticed RORγt-expressing cells in the brain and demonstrates that the Tsc1 signaling pathway in RORγt-expressing cells is important for maintaining brain homeostasis.
Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new ...anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ
NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation
PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.
Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through ...lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.
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