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Epilepsy treatment with antiepileptic drugs (AEDs) is usually requires for many years. Q808 is an innovative antiepileptic chemical. It exerts effective antiepileptic effect against various epilepsy models. Exploring the gene transcriptomic profile of long-term treatment of Q808 is necessary. In the present study, hippocampus RNA-sequencing was performed to reveal the transcriptome profile of rats before and after treatment of Q808 for 28 d. Results confirmed 51 differentially expressed genes (DEGs) between Q808 and healthy control groups. Gene cluster analysis showed that most upregulated DEGs linked to response to drug and nucleus, most downregulated DEGs linked to locomotory, neuronal cell body, and drug binding. Most of DEGs were enriched in the signaling transduction, substance dependence, nervous system, and neurodegenerative disease pathways. Furthermore, quantitative real-time PCR analysis confirmed that Q808 significantly increased the expression of neuroprotective genes, such as Mdk, and decreased the mRNA levels of Penk, Drd1, and Adora2a, which are highly expressed in epilepsy models. In addition, Q808 decreased the mRNA expression of Pde10A and Drd2, which are known to be closely associated with schizophrenia. Our study may provide a theoretical basis to explore the effect of Q808 on the susceptibility to epilepsy and other neurological diseases.

Cholangiocarcinoma (CCA) is a type of highly malignant tumor originating from bile ducts. The prognosis of CCA is poor and the treatment options are limited. The biomarker study of CCA has made little progresses in recent years because of the difficulty to obtain CCA specimens. SOX9 is an important regulator of cholangiocyte proliferation and differentiation. We performed mRNA sequencing of CCA, retrieved TCGA data, and detected SOX9 expression in a large CCA cohort. With WNT3A stimulation, SOX9 expression and transcription was elevated by TCF7. Moreover, SOX9 was substantially up-regulated in CCA tissues and was identified as a prognostic biomarker of CCA. With mRNA sequencing and in vitro/vivo validation, we demonstrated that SOX9 enhanced the transcription and expression of FGF7 and FGFR2. FGF7 was significantly up-regulated in the bile and serum of CCA patients, and may promote CCA proliferation by activating FGFR2 in an autocrine pathway. co-expression of FGF7 and FGFR2 was a more sensitive marker for poor prognosis. SOX9-induced overexpression of FGF7 and FGFR2 was the key reason of SOX9-involved pemigatinib resistance. In conclusion, SOX9 and FGF7 were prognostic biomarkers of CCA. WNT3A-TCF7-SOX9 axis could induce pemigatinib resistance in two independent pathways: (1)SOX9 directly promotes FGFR2 transcription and expression; (2)SOX9 elevates FGF7 expression, which could be secreted from CCA cells and activates FGFR2 phosphorylation in an autocrine pathway.

In this paper, the application of equivalent simplified calculation model of isolated structure in super high-rise building is studied. In this paper, the characteristics of isolation structures with different height width ratio are analyzed, and the relationship curve between the limit value of height width ratio of isolation structure and the distance of isolation support is established. From the curve, we can estimate the limit height of the isolated structure when the bearing does not produce tensile stress under different seismic intensities. This paper also analyzes the influencing factors of the height width ratio limit, and puts forward the method of increasing the height width ratio limit. In this paper, a vertical stiffness correction model of isolation bearing is proposed. Compared with the shaking table test results and time history analysis, the modified model can truly reflect the mechanical properties of the isolation bearing.

In this paper, the exterior envelope of prefabricated buildings in alpine areas is studied. This paper compares the wind resistance of the fabricated structure composed of two different connection modes, connectors with different thickness, lightweight ceramsite concrete peripheral wall panel and wood composite peripheral wall panel. The test results show that the wind resistance of the fabricated structure composed of wood wallboard mainly depends on the thickness of wallboard, connection mode and connector thickness. Whether sand packing is filled or not has no effect on the improvement of wind resistance of this prefabricated enclosure structure. For meeting the wind resistance of the fabricated enclosure used in the support room, it is recommended to use thick wooden wallboard and connect up and down. The wind resistance of the fabricated enclosure composed of wood wallboard mainly depends on the strength of the wood wallboard itself. The use of wood wallboards with higher thickness can improve the wind resistance of this fabricated structure.

Background Colorectal cancer (CRC) is a common malignant cancer with a poor prognosis. Liver metastasis is the dominant cause of death in CRC patients, and it often involves changes in various gene expression profiling. This study proposed to construct and validate a risk model based on differentially expressed genes between primary and liver metastatic tumors from CRC for prognostic prediction. Methods Transcriptomic and clinical data of CRC were downloaded from The Cancer Genome Atlas database (TCGA) and Gene Expression Omnibus database (GEO). Identification and screening of candidate differentially expressed genes (DEGs) between liver metastatic tissues and corresponding primary tumors were conducted by R package “limma” and univariate Cox analysis in the GSE50760 and TCGA cohort. Last, absolute shrinkage and selection operator (LASSO) Cox regression was carried out to shrink DEGs and develop the risk model. CRC patients from the GSE161158 cohort were utilized for validation. Functional enrichment, CIBERSORT algorithm, and ESTIMATE algorithm for further analysis. Results An 8-gene signature risk model, including HPD, C8G, CDO1, FGL1, SLC2A2, ALDOB, SPINK4, and ITLN1, was developed and classified the CRC patients from TCGA and GEO cohorts into high and low-risk groups. The high-risk group has a worse prognosis compared with the low-risk group. The model was verified as an independent indicator for prognosis. Moreover, tumor immune infiltration analyses demonstrated that monocytes (P = 0.006), macrophage M0 (P

Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1-/- mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway.

The lightweight design makes thin-plate welded structures used widely, especially for the aluminum alloy thin-plate welded structure, it is very important to study the fatigue fracture properties of the structure considering the influence of residual stress. A solid model of a butt joint of aluminum alloy with a double-pass weld is established. Both the welding temperature fields and residual stress fields are simulated through the thermal elastic–plastic method. The welding experiment is also performed with the corresponding joint, which is welded by means of metal inert-gas (MIG) welding. Consequently, the computational and experimental results of residual stress are in good agreement. Moreover, the thermal elastic–plastic method is employed to calculate the residual stress fields of typical welded joints. Based on the inherent strain theory, the transverse and longitudinal inherent strain of the joints are decomposed from the total strains and applied to both solid and shell models of the three types of joints to calculate the residual stress fields of them. The results of the solid and shell models using the two methods are practically consistent, which indicates that the inherent strain method can predict the residual stress on the shell model efficiently and accurately. Thus, the method of predicting the welding residual stress of thin-plate structures based on the inherent strain is proposed, which provides a reference for the structural fatigue assessment under the influence of residual stress.

Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. BMI1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of BMI1 in cholangiocarcinoma (CCA) are not well elucidated.In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected BMI1 expression in a large CCA cohort. We demonstrated that BMI1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of BMI1 promoted CCA proliferation, migration, and invasion. And BMI1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain BMI1 proteins, which can transfer BMI1 between CCA cells. The unique BMI1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that BMI1 inhibits CD8BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA.

Our study aims at developing an interferon-stimulated genes (ISGs) signature that could predict overall survival (OS) in cancer patients, which enrolled a total of 5643 pan-cancer patients. Linear models for microarray data method analysis were conducted to identify the differentially expressed prognostic genes in the global ISGs family. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival analysis were used to test the efficiency of a multi-gene signature in predicting the prognosis of pan-cancer patients. The prognostic performance and potential biological function of gene signature were verified by quantitative real-time PCR in a pan-cancer independent cohort. Three ISGs genes were finally identified to build a classifier, a specific risk score formula, with which patients were classified into the low- or high-risk groups. Time-dependent ROC analyses proved prognostic accuracy. Then, its prognostic value was validated in seven external validation series. A nomogram was constructed to guide the individualized treatment of patients with lung adenocarcinoma. Biological pathway and tumor immune infiltration analysis showed that the signature might cause poor prognosis by blocking NK cell activation. Finally, the signature in our centers was confirmed by real-time quantitative PCR. A robust ISGs-related feature was discovered to effectively classify pan-cancer patients into subgroups with different OS.

BackgroundMacrophage extracellular traps (METs) and tumor-infiltrating macrophages contribute to the progression of several diseases. But the role of METs and tumor-infiltrating macrophages in colon cancer (CC) has not been illuminated. In this study, we aimed to clarify the prognostic value of METs for CC patients and to explore the interaction between CC cells and METs in vitro and in vivo.MethodsA training cohort consisting of 116 patients and a validation cohort of 94 patients were enrolled in this study. Immunofluorescence (IF) staining was conducted to determine METs formation in CC patients. Cox regression was used to perform prognostic analysis and screen out the best prognostic model. A nomogram was established to predict 5-year overall survival (OS). The correlation between METs with clinicopathological features and inflammatory markers was analyzed. The formation of METs in vitro was detected by SYTOX® green and IF staining, and the effect of METs on CC cells was detected by transwell assays. PAD2-IN-1, a selective inhibitor of peptidylarginine deiminase 2 (PAD2), was introduced to destroy the crosstalk between CC cells and METs in vitro and in vivo.ResultsMETs levels were higher in CC tissues and were an independent prognostic factor for CC patients. The prognostic model consisting of age, tumors local invasion, lymph node metastasis and METs were confirmed to be consistent and accurate for predicting the 5-year OS of CC patients. Besides, METs were correlated with distant metastasis and inflammation. Through in vitro experiments, we confirmed that there was a positive feedback loop between CC cells and METs, in that METs promoted the invasion of CC cells and CC cells enhanced the production of METs, in turn. This interaction could be blocked by PAD2-IN-1 inhibitors. More importantly, animal experiments revealed that PAD2-IN-1 inhibited METs formation and CC liver metastasis in vivo.ConclusionsMETs were the potential biomarker of CC patient prognosis. PAD2-IN-1 inhibited the crosstalk between CC cells and METs in vitro and in vivo, which should be emphasized in CC therapy.

Cholangiocarcinoma (CCA), consisting of three subtypes-intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA), is a highly aggressive cancer arising from the bile duct and has an extremely poor prognosis. Pemigatinib is the only FDA-approved targeted drug for CCA, and the CCA treatment options are substantially insufficient considering its poor prognosis and increasing morbidity. Here, we performed next-generation sequencing (NGS) of 15 pCCAs and 16 dCCAs and detected the expression of SMAD4, a frequently mutated gene, in 261 CCAs. By univariate and multivariate analyses, we identified Smad4 as a favorable prognostic biomarker in iCCA and pCCA. With in vitro and in vivo experiments, we demonstrated that Smad4 suppressed CCA proliferation, migration and invasion by inhibiting β-catenin-S675 phosphorylation and intranuclear translocation. We applied LC-MS/MS and multiple biochemical techniques and identified PP1A as the phosphatase in Smad4-mediated dephosphorylation of PAK1-T423, which is responsible for β-catenin-S675 phosphorylation. Moreover, we demonstrated that MYO18A is the PP1-interacting protein of PP1A for substrate recognition in CCA. MYO18A interacts with PP1A via its RVFFR motif and interacts with Smad4 via CC domain. Patients with coexpression of MYO18A and Smad4 have a more favorable prognosis than other patients. Smad4 enhances Pemigatinib efficiency, and Smad4 knockdown results in Pemigatinib resistance. In conclusion, coexpression of Smad4 and MYO18A is a favorable prognostic indicator for iCCA and pCCA. The Smad4-MYO18A-PP1A complex dephosphorylates PAK1-T423 and thus inhibits β-catenin-S675 phosphorylation and its intranuclear localization. Smad4 suppresses CCA proliferation, migration, invasion, and sensitivity to Pemigatinib by governing the phosphorylation and intracellular localization of β-catenin.

Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster The chronic stress-induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/β neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress-induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.

Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted.

Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster. The chronic stress–induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/β neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress–induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.

Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. In our study, ANXA10 upregulation was revealed by exome and transcription sequencing in 5 pairs of PHCCA and adjacent tissues. The clinical significance and prognostic value of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables and survival rates. As a result, ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and unfavorable prognosis. With in vitro and in vivo experiments, we demonstrated that ANXA10 promoted the epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of the PHCCA cell line QBC939. The key molecule in ANXA10-induced CCA progression was screened by mRNA sequencing. Consequently, PLA2G4A expression was regulated by ANXA10 and it was required in ANXA10-induced metastasis. High PLA2G4A expression also predicted poor prognosis in PHCCA and DCCA. With multiple in vivo experiments, we showed that ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. In conclusion, ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the proliferation, migration and invasion of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. Our results suggested that ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA. Funding Statement: Our study was supported by National Natural Science Foundation of China (Grant no. 81601668), Shandong Province Major Research and Design Program (Grant No. 2018GSF118169), Jinan City Science and Technology Development Program(Grant No. 201805017, 201805013), and Hengrui Hepatobiliary and Pancreatic Foundation (Grant No.Y-2017-144). Declaration of Interests: The authors declare no conflicts of interests. Ethics Approval Statement: All experiments were approved by the Ethics Committee of Qilu Hospital of Shandong University.

Durability fatigue tests for full-scale structures are essential to ensure the fatigue reliability and operational safety of high-speed trains. An accelerated life test (ALT) method is first used to predict the fatigue life of a full-scale bogie frame. Three step-up acceleration load spectrum is compiled for an ALT on the basis of the failure mechanism consistency principle. The ALT of a full-scale bogie frame is conducted. Then, the acceleration coefficient and cycle times from the accelerated load level to the working load level are calculated. Based on the equal damage principle, combined with the finite element calculation, the fatigue life of the bogie frame under acceleration load spectrum is extrapolated. The ALT method is used to compile the acceleration load spectrum and to perform fatigue tests to analyze the acceleration coefficients and predict the fatigue life for a full-scale bogie frame, which provides a reference for the reliability evaluation of large structures.

With the wide application of ballastless track on high-speed railway, the load on the structure of the high-speed train exhibits the characteristics of high frequency and small amplitude. It is the...

The welding deformation of a single-side double-pass welding T-joint is simulated by using a thermal elastic-plastic method (TEPM) and inherent strain method (ISM) respectively, and comparisons are made. Consequently, the numerical simulation results using the two methods are approximately consistent; thus, the application of the thermal elastic-plastic method and inherent strain method for predicting the welding deformation of T-joints is validated. Then, the inherent strain method based on empirical formulas is applied to simulate the welding deformation of a shell model and solid model of the side beam of a bogie frame. A comparative analysis of the two models shows that the simulated result of the solid model is more accurate than that of the shell model. However, the two results are basically consistent with the measured welding deformation of the side beam of the frame, further demonstrating the effectiveness of the inherent strain method in predicting the welding deformation of large complex structures. The prediction methods provided in this paper give a reference to the welding deformation correction and the corresponding welding process optimization for large-scale welded structures.

Additional file 1: Supplementary Figure 1. HMGA1 expression in cell lines. Supplementary Figure 2. HMGA1 promoted pCCA progression. Supplementary Figure 3. TRIP13 promoted pCCA migration, invasion and stemness. Supplementary Figure 4. TRIP13 was required in HMGA1-induced pCCA progression. Supplementary Figure 5. FBXW7 suppressed TRIP13-induced progression. Supplementary Figure 6. HMGA1 and TRIP13 expression was correlated with FBXW7 in xenografts. Supplementary Figure 7. FBXW7 induced c-Myc degradation by promoting its ubiquitination. Supplementary Figure 8. HMGA1-TRIP13 axis promotes stemness and EMT in a positive feedback pathway dependent on c-Myc. Supplementary Figure 9. HMGA1 regulated the expression of TCF family. Supplementary Table 1. The Expression of HMGA1 and TRIP13 in primary cohort and validated cohort. Supplementary Table 2. Primers for qRT-PCR. Supplementary Table 3. The information of sh/siRNA sequences. Supplementary Table 4. The promoter region sequences. Supplementary Table 5. Proteomic HMGA1-linked signature genes and up-regulated genes in exome and transcriptome sequencing profiles. Supplementary Table 6. The prognostic significance of HMGA1/TRIP13 and clinicopathological factors in pCCA. Supplementary Table 7. Correlation between TRIP13 and clinicopathological factors.

Cholangiocarcinoma (CCA) is a highly aggressive malignancy with extremely poor prognoses. The oncogenic role and prognostic value of c-Myc in CCA is not well elucidated. WD repeat domain 5 (WDR5) is a critical regulatory factor directly interacting with c-Myc to regulate c-Myc recruitment at chromosomal locations, but the interaction of WDR5 and c-Myc in CCA was uncovered. In our study, we detected WDR5 and c-Myc expression in all CCA types, including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA, and evaluated their prognostic significance. Consequently, we demonstrated that WDR5 was significantly correlated with poor prognosis of CCA and that WDR5 and c-Myc co-expression was a more sensitive prognostic factor. With in vitro and in vivo experiments and bioinformatics, we showed that WDR5 interacted with the Myc box IIIb (MBIIIb) motif of c-Myc and facilitated Myc-induced HIF1A transcription, thereby promoting the epithelial-mesenchymal transition (EMT), invasion, and metastasis of CCA. Moreover, WDR5 enhanced hypoxia-inducible factor 1 subunit α (HIF-1α) accumulation by binding with histone deacetylase 2 (HDAC2) and increasing histone 3 lysine 4 acetylation (H3K4ac) deacetylation of the prolyl hydroxylase domain protein 2 (PHD2) promoter, resulting in the attenuation of chromatin opening and PHD2 expression, and eventually leading to HIF-1α stabilization and accumulation. In conclusion, WDR5 facilitated EMT and metastasis of CCA by increasing HIF-1α accumulation in a Myc-dependent pathway to promote HIF-1α transcription and a Myc-independent pathway to stabilize HIF-1α.

Background Perihilar cholangiocarcinoma (PHCCA) is the most common type of human cholangiocarcinoma with a very dismal prognosis. Tumor markers and target drugs of PHCCA are desperately needed. Protein phosphatase N3 (PTPN3) has dual roles in the progression of human cancers, but its expression and functions in PHCCA have not been elucidated. Materials and methods The expression of PTPN3 in PHCCA was detected with western blotting, qRT-PCR and immunohistochemistry. The clinical significance of PTPN3 was identified by analyzing the correlations between its expression and the clinicopathological variables, and the prognostic value was evaluated by univariate and multivariate analyses. The functions of PTPN3 in the progression of PHCCA were estimated with both in vitro and in vivo experiments. Results PTPN3 expression was down-regulated in PHCCA compared with normal bile duct. Low PTPN3 expression was markedly associated with large tumor size and unfavorable prognosis. After knocking down PTPN3, the percentages of G2/S phase of PHCCA cells were elevated, and the proliferation increased significantly. Moreover, we demonstrated that the phosphorylation of AKT was elevated by PTPN3 knockdown, and it was required in PTPN3-involved proliferation of PHCCA. Within vivo experiments, PTPN3 and AKT inhibitor MK-2206 were demonstrated to suppress tumor size of PHCCA. Conclusion PTPN3 was a favorable prognostic biomarker of PHCCA. PTPN3 suppressed the proliferation of PHCCA by inhibiting AKT phosphorylation and arresting cell cycle. Our results suggested thatpost-operative detection of PTPN3 would be a helpful approach to stratify the PHCCA patients with high-risk.

Waste resulting from consumers’ confusion about foods’ date labels is a multi-billion-dollar problem in the United States. The present study examines the mechanisms underlying such labels’ influence on people’s willingness to consume, and whether exposure to additional information regarding sensory assessment of food products or storage practices could help to reduce food waste. We conducted a mixed-design experiment in which the between-subjects variable comprised five commonly used food date labels (i.e., “Best if Used By”, “Use By”, “Sell By”, “Enjoy By”, and a date without any explanatory phrase), and the within-subjects variable consisted of three information conditions (i.e., basic information, sensory information, and food-storage information). Our data indicate that date labels affected consumers’ willingness to eat yogurt through two mediators, quality concerns and safety concerns. The direct effects on willingness to consume of variation in date-label wording were non-significant after controlling for the two mediators. Additionally, when the participants were told that the yogurt had a normal color and odor, or that it had been stored in accordance with best practices, their intention to eat it rose significantly. These findings enhance our understanding of how food date labels affect consumer-level food waste, and provide insights that can aid the development of educational campaigns to reduce it.

When two high-speed trains pass through a tunnel, the aerodynamic changes are more complex and drastic than in open air owing to the interference of the tunnel wall and the entry effect. The impact on the carbody fatigue strength is very significant in the fatigue reliability design of the carbody. In this paper, the sequential coupling method was used for the first time to study the effect of pressure waves on the fatigue strength in a large-scale and complex carbody structure. The computational fluid dynamics method was used to calculate and analyze the aerodynamic pressure wave of the intersection of the trains in a long and short tunnel. A full-scale finite element shell model of the carbody structure was established. Then, the time integration method was used to convert the transient pressure wave into the aerodynamic loads bearing by the side wall of the carbody. The inhomogeneous stress concentrations at the restraint points were eliminated by the inertial release method; moreover, a finite element analysis of the carbody was carried out under the combined aerodynamic and mechanical loads. The Goodman fatigue strength curve of the aluminum alloy carbody was drawn. The influence of the aerodynamic load on the fatigue strength of the vehicle body was analyzed and compared under the entry effect of the short tunnel. The results show that the aerodynamic load of the short tunnel has a significant impact on the fatigue strength of the carbody owing to the train's entry effect. The safety factor of the fatigue strength is 15% less than that of the long tunnel aerodynamic load. In this paper, computational fluid dynamics and finite element method were used to analyze and evaluate the impact of the pressure wave on the fatigue strength of the carbody, which is of great reference value in the structural design of the carbody subjected to complex aerodynamic loads.

Ginsengs, has long been used as one medicinal herb in China for more than two thousand years. Many studies have shown that ginsengs have preventive and therapeutic roles for cancer, and play a good complementary role in cancer treatment. Ginsenosides, as most important constituents of ginseng, have been extensively investigated and emphasized in cancer chemoprevention and therapeutics. However, the functional mechanism of Ginsenosides on cancer is not well known. This review will focus on introducing the functional mechanisms of ginsenosides and their metabolites, which regulate signaling pathways related with tumor growth and metastasis. Ginsenosides inhibit tumor growth via upregulating tumor apoptosis, inducing tumor cell differentiation and targeting cancer stem cells. In addition, Ginsenosides regulate tumor microenvironment via suppressing tumor angiogenesis-related proteins and pathways. Structural modification of ginsenosides and their administration alone or combinations with other Chinese medicines or chemical medicines have recently been developed to be a new therapeutic strategy for cancer. Keywords: Functional mechanism, Ginsenosides, Tumor growth, Tumor metastasis

Ethnopharmacological relevance Liangxue Tongyu Prescription (LTP) is a traditional Chinese medicine formula composed of 8 crude drugs that is widely used to treat acute intracerebral hemorrhage (AICH). Aim of the study To verify the efficacy of LTP on the survival time in the treatment of acute intracerebral hemorrhagic rats (AICHs), and to elucidate its network pharmacodynamic mechanism of multi-component, multi-target, and multi-signaling pathways. Materials and methods Survival analysis was used to evaluate the survival time of AICH rats induced by different doses of collagenase and the efficacy of three doses of LTP in the treatment of AICH rats. The Kaplan-Meier curves for survival time were produced and compared with the Log-rank test and Wilcoxon (Gehan) χ2. Differential mRNA-seq combined with network pharmacology was used to disclose the network effect mechanism of LTP on AICH, and the obtained differential genes were mapped into the predictive empirical compound-target network model (ECT network model) and the empirical compound-target-pathogenesis (disease) network model (ECTP network model). Results The median survival time of four different doses of LTP-treated groups (0.00 g/kg, 5.78 g/kg, 11.55 g/kg, 23.10 g/kg) for adult AICH rats by 0.18 U collagenase was 14 h, 37 h, 150 h, and 51 h respectively, and the 7-day survival rates were 33.3%, 41.7%, 50.0%, and 38.5%, of which the medium-dose group (MD) had a longer survival time and higher survival rate. Through further validation experiments, the MD group had a better efficacy trend with a median survival time of 168 h vs 23 h in the model control group (MC) (Wilcoxon Gehan Test, χ2 = 3.478, P = 0.062). The transcriptomic analysis of mRNA showed that 583 significant differential genes were found between the MC and MD group and 7 key therapeutic targets regulated by 29 compounds in LTP on AICH were screened out by VCT and VCTP network model. These targets were involved in 5 regulatory models or pathways. Conclusion Our study confirmed the exact efficacy of the LTP in the treatment of AICH and revealed the potential pharmacodynamic components and mode of action of the LTP on AICH. Using differential transcriptome of mRNA combined with network pharmacology, we screened out 29 chemical compounds as the potential effective ingredients of LTP which acted on 7 targets of AICH involving 5 pathological pathways, mainly including repairing the brain function defect, improving neural function, protecting blood-brain barrier from damage, reducing inflammatory factors, and inhibiting apoptosis. The present study not only provides a new explanation for the ‘multi-component, multi-target, multi-pathway’ effects of the LTP on AICH but also screened out some major compounds of LTP and their potential targets which will facilitate the development of new drugs for AICH.

Background: Perihilar cholangiocarcinoma (PHCC) is the most common subtype of cholangiocarcinoma(CCA). We previously investigated the expression pattern of Sprouty(SPRY) in intrahepatic cholangiocarcinoma(ICC), but the expression and clinical significance of SPRY family members in PHCC are still unknown. Methods: The expression of SPRY family members(SPRY1-4) was detected in different subtypes of CCA and corresponding adjacent tissues. SPRY4 expression in 142 cases of PHCC was detected by immunohistochemistry, and its clinical significance was evaluated using univariate and multivariate analyses. The functions of SPRY4 in the FGFR-induced proliferation and migration of PHCC cells were investigated through in vitro and in vivo experiments. We further investigated the effects and mechanisms of SPRY4 on FGFR-induced ERK phosphorylation and cell cycle distribution in the presence of FGFR and ERK inhibitors. Findings: SPRY4 was the only SPRY family member associated with PHCC prognosis, and it was identified as an independent factor predicting favorable prognosis. In PHCC, SPRY4 expression was extensively associated with FGFR2, and its expression can be induced by ectopic FGFR2 activation. Through in vitro and in vivo experiments, we demonstrated that SPRY4 suppressed FGFR-induced proliferation and migration by inhibiting ERK phosphorylation. Moreover, SPRY4 knockdown was shown to decrease the percentage of cells in the G1 phase and promote the percentage of cells in the S and G2/M phases by increasing cyclin D1 expression, which also required FGFR-induced ERK phosphorylation. Interpretation: High expression of SPRY4 was an independent biomarker of favorable prognosis in PHCC. SPRY4 expression can be induced by ectopic FGFR2 activation in PHCC. SPRY4 arrested the cell cycle at G1 phase and suppressed FGFR-induced proliferation and migration by inhibiting ERK phosphorylation, indicating that SPRY4 may be a potential therapeutic target in PHCC. Keywords: Sprouty 4, Perihilar cholangiocarcinoma, Prognosis, Proliferation, Cell cycle

A simple design procedure is proposed for seismic retrofitting of existing structures using viscoelastic dampers (VEDs) based on the uniform damping ratio (UDR) concept to make full use of each damper. The UDR concept states that the equivalent damping ratios, which represent the energy dissipation capacities of the dampers, are the same for each installed VED. The stiffness and damping characteristic parameters of the damped structure can be formally decoupled using UDR-based derivations, which simplify the determination of the VEDs’ parameters. The generalized single-degree-of-freedom method and pushover analysis are adopted for a fast estimation of the seismic response of the damped elastoplastic structure. Taking the response reduction ratio as the design target, a seismic retrofit design procedure is proposed based on the UDR concept to meet the performance demand. Finally, a six-story frame is adopted to illustrate the proposed design method. The dynamic analysis results show that the seismic responses of the structure are well-controlled, as expected, and that the installed VEDs are used effectively. The conclusion can be drawn that the UDR-based design method for retrofitting an existing structure using VEDs is rational and effective.