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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

BackgroundRadiation therapy (RT) is a standard treatment for the local control of primary pelvic cancers (PPC), yet the risk of second corpus uteri cancer (SCUC) in PPC patients undergoing RT is still controversial. This study investigated the impact of RT on the risk of SCUC and assessed the survival outcome.MethodsWe queried nine cancer registries for PPC cases in the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence of SCUC was analyzed using Cox regression and Fine–Gray competing risk regression analysis. The Poisson regression analysis was employed to assess the standardized incidence ratios (SIRs) and radiation-attributed risk (RR) for SCUC. We evaluated the overall survival of patients with SCUC using the Kaplan–Meier method.ResultsReceiving radiotherapy was strongly associated with a higher risk of developing SCUC for PPC patients in Fine–Gray competing risk regression (No-RT vs. RT: adjusted HR = 1.77; 95% CI, 1.40–2.28; p < 0.001). The incidence of SCUC in PPC patients who received RT was higher than in the US general population (SIR, 1.66; 95% CI, 1.41–1.93; p < 0.05), but the incidence of SCUC in patients who did not receive RT was lower than with the US general population (SIR, 0.68; 95% CI, 0.61–0.75; p < 0.05). The dynamic SIR and RR for SCUC decreased with decreasing age at PPC diagnosis and decreased with time progress. In terms of overall survival, 10-year survival rates with SCUC after No-RT (NRT) and SCUC after RT were 45.9% and 25.9% (HR = 1.82; 95% CI, 1.46–2.29; p < 0.001), respectively.ConclusionRadiotherapy for primary pelvic cancers is associated with a higher risk of developing SCUC than patients unexposed to radiotherapy. We suggest that patients with pelvic RT, especially young patients, should receive long-term monitoring for the risk of developing SCUC.

Background: The type 2 mannose receptor C (MRC2) is involved in tumor biological processes and plays a new role in the remodeling of the extracellular matrix turnover. Previous studies have demonstrated MRC2 expression profiling and prognostic relevance in some tumor types. However, the clinical and immunotherapeutic value of MRC2 in pan-cancers remains controversial. Our study aimed to evaluate MRC2 expression pattern, clinical characteristics and prognostic significance in 33 cancers, explore the relationship between MRC2 and immune-related characteristics, and assess the prediction of MRC2 for the immunotherapeutic response.Methods: Transcriptional and clinical data of 33 cancers were downloaded from The Cancer Genome Atlas database (TCGA) database and two independent immunotherapeutic cohorts were obtained from GSE67501 and the IMvigor210 study. Next, patients stratified by MRC2 expression levels were displayed by Kaplan-Meier plot to compare prognosis-related indexes. Meanwhile, immune infiltrates of different cancers were estimated by tumor immune estimation resources (TIMER) and CIBERSORT. The ESTIMATE algorithm was used to estimate the immune and stromal scores in tumor tissues. MRC2 expression and immunological modulators, including immune inhibitors, immune stimulators, and MHC molecules, were screened through the TISIDB portal. Gene-set enrichment analysis analyses were performed to explore the underlying biological process of MRC2 across different cancers. The immunotherapeutic response prediction was performed in two independent cohorts (GSE78220: metastatic melanoma with pembrolizumab treatment and IMvigor210: advanced urothelial cancer with atezolizumab intervention).Results: MRC2 is expressed differently in many cancers and has been shown to have potential prognostic predicting significance. MRC2 was significantly associated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Notably, the immunotherapeutic response group was associated with lower MRC2 expression in metastatic melanoma and advanced urothelial carcinoma cohort.Conclusion: This study demonstrated that MRC2 could be a prognostic indicator for certain cancer and is critical for tumor immune microenvironments. MRC2 expression level may influence and predict immune checkpoint blockade response as a potential indicator.

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.

BackgroundRadiation therapy (RT) is a crucial modality for the local control of pelvic cancer (PC), but the effect of pelvic RT on the development of secondary malignancy is still unclear. This study aimed to identify the relationship between radiation therapy received for the treatment of primary PC and subsequent secondary bladder cancer (SBC).MethodsThe Surveillance, Epidemiology, and End Results (SEER) database (from 1975 to 2015) was queried for PC. Fine-gray competing risk regression and Cox regression analyses were employed to assess the cumulative incidence of SBC. Poisson regression and multiple primary standardized incidence ratios (SIR) were used to evaluate the radiotherapy-associated risk for patients receiving RT. Subgroup analyses of patients stratified by latency time since PC diagnosis, calendar year of PC diagnosis stage, and age at PC diagnosis were also performed. Overall survival (OS) was compared among different treatment groups with SBC by Kaplan–Meier analysis.ResultsA total of 318,165 observations showed that the primary cancers were located in pelvic cavity, 256,313 patients did not receive radiation therapy (NRT), 51,347 patients who underwent external beam radiation therapy (EBRT), and 10,505 patients receiving a combination of EBRT and brachytherapy (EBRT–BRT) who developed SBC. Receiving two types of radiotherapy was strongly consistent with a higher risk of developing SBC for PC patients in Fine-Gray competing risk regression (NRT vs. EBRT, adjusted HR= 1.71, 95% CI: 1.54-1.90, PConclusionRadiotherapy for primary PC was associated with higher risks of developing SBC than patients unexposed to radiotherapy. Different pelvic RT treatment modalities had different effects on the risk of SBC.

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.

Background: 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. Methods: 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 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 CD8+T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells. Conclusions: BMI1 is an unfavorable prognostic biomarker of CCA. Our data demonstrate 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

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.

Background: Cholangiocarcinoma is a highly malignant cancer with very dismal prognosis. Perihilar cholangiocarcinoma(pCCA) accounts for more than 50% of all cholangiocarcinoma and is well-characterized for its low rate of radical resection. Effects of radiotherapy and chemotherapy of pCCA are very limited. Methods: Here we screened potential biomarkers of pCCA with transcriptome sequencing and evaluated the prognostic significance of HMGA1 in a large cohort pCCA consisting of 106 patients. With bioinformatics and in vitro/vivo experiments, we showed that HMGA1 induced tumor cell stemness and epithelial-mesenchymal-transition(EMT), and thus facilitated proliferation, migration and invasion by promoting TRIP13 transcription. Moreover, TRIP13 was also an unfavorable prognostic biomarker of pCCA, and double high expression of HMGA1/TRIP13 could predict prognosis more sensitively. TRIP13 promoted pCCA progression by suppressing FBXW7 transcription and stabilizing c-Myc. c-Myc in turn induced the transcription and expression of both HMGA1 and TRIP13, indicating that HMGA-TRIP13 axis facilitated pCCA stemness and EMT in a positive feedback pathway. Conclusions: HMGA1 and TRIP13 were unfavorable prognostic biomarkers of pCCA. HMGA1 enhanced pCCA proliferation, migration, invasion, stemness and EMT, by inducing TRIP13 expression, suppressing FBXW7 expression and stabilizing c-Myc. Moreover, c-Myc can induce the transcription of HMGA1 and TRIP13, suggesting that HMGA-TRIP13 axis promoted EMT and stemness in a positive feedback pathway dependent on c-Myc.

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.

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.

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 type of cholangiocarcinoma with the worst prognosis. Radical resection of PHCC is difficult; thus, few effective biomarkers or useful molecular profiles for PHCC have been reported in recent years. Methods: In this study, we screened potential biomarkers for PHCC using exon and transcriptome sequencing with PHCC tissues and paired normal tissues, and confirmed that transcription factor 7(TCF7) was upregulated in PHCC using qRT-PCR, western blotting and immunohistochemistry. The correlations between TCF7 and clinicopathological factors were analyzed with Chi-square test, and the prognostic significance of TCF7 was evaluated with univariate and multivariate analysis in two independent cohorts. Moreover, the functions of TCF7 and its main effectors in PHCC cells proliferation, invasion, and migration were investigated with in vitro and in vivo experiments. Findings: TCF7 expression was upregulated in PHCC and it was an unfavorable prognostic biomarker. c-Myc was a main effector of TCF7 in PHCC cells and responsible for TCF7-induced proliferation, invasion, and migration of PHCC cells. With qRT-PCR screening, FOSL1 was also identified as a downstream target gene of TCF7 and was required in TCF7-induced PHCC proliferation. Triple-positive expression of TCF7, c-Myc, and FOSL1 predicted a much worse prognosis in patients with PHCC than TCF7 expression alone. Interpretation: TCF7 correlated with poor prognosis of PHCC by promoting proliferation, invasion, and migration of PHCC, which required the participation of its target gene c-Myc and FOSL1. Triple-positive expression of TCF7, c-Myc, and FOSL1 was a more sensitive factor to predict prognosis than TCF7 expression alone in patients with PHCC. These results suggested that postoperative detection of TCF7, c-Myc, and FOSL1 may be useful for stratifying patients with a high risk of unfavorable prognosis and that suppressing TCF7 or its downstream effectors may be a promising strategy for the treatment of PHCC. Funding: 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 Interest: We declare no conflicts of interest. Ethical Approval: This study was approved by the Qilu Hospital of Shandong Univeristy. The Laboratory Animal Care and Use Committees of the hospital approved all experimental procedures. Written informed consents were received from all patients.

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.

Preparation of new type coal-based carbon nanomaterials and its application in Fenton-like photocatalytic organic pollutant degradation was presented here. The study promoted the high value-added use of coal and extended Fenton-like research system. The coal with high silicon content from Wucaiwan, Xinjiang, China was used as carbon and silicon source. The coal-based graphene oxide (GO) was obtained via the oxidation and exfoliation of crystal graphite in coal under the ultrasonic oxidation treatment by the modified Hummers method. In this way, the natural silicon in coal was converted into the silica dioxide (SiO2) and in situ linked to the surface of the GO sheet by the surface hydroxyl deprotonation bonding to forme GO/SiO2 nanosheet. After all, the composite photocatalyst ZnO/GO/SiO2 was formed by loading the ZnO nanorods on the GO/SiO2 surface via the hydrothermal synthesis. Meanwhile, the photocatalytic Fenton-like system was constructed with H2O2 and ZnO/GO/SiO2. The property and mechanism of the photocatalytic Fenton-like oxidative degradation of methylene blue (MB) was characterized in detail. The results indicating that the photocatalyst can promote the degradation efficiently, with the photogenerated electron replacing the metal ions as activator for H2O2. On account of the property of adsorption and photogenerated electron transfer, the coal-based GO/SiO2 as carrier of ZnO immensely increased the production of active radicals from H2O2, resulting in the promotion of oxidative degradation.

Local buckling may occur in the straight portion of a corrugated steel plate (CSP) pipe-arch with a deep wave section that is used in a buried structure. In this study, the soil support of the pipe-arch structure is considered, and the local buckling of the straight portion of the CSP is investigated. The corresponding theoretical formulae are derived using the Rayleigh-Ritz method. The simplified mechanical model with the soil support is used for derivation. Then, the finite element models for the invert of the pipe-arch with several waves are established to analyze the actual rotational restraints of the straight portion. The influences of plate thickness, corrugation, aspect ratio and curvature on the local buckling load of the invert are investigated. The relationships of plate thickness and local buckling load for three types of deep corrugations are obtained. These relationships reveal that the actual rotational restraints are negative, i.e., the straight portion provides restraint for the corrugated portion. Based on numerical simulations, the theoretical formulae are modified to account for the actual rotational restraints of the straight portion. Then, the finite element model of the global pipe-arch structure is built. The corresponding analysis matches well with the revised formula, which validates the modified derivation. Finally, according to the yield criterion, a reasonable limit value for the width-to-thickness ratio for the straight portion of the CSP is suggested. This limit can be used to prevent local buckling of CSP buried pipe-arch structures in practice.

Purpose The aim of the study was to investigate the functional role of L1.2, the zebrafish paralog of L1.1 and ortholog of mammalian L1CAM in adult zebrafish spinal cord regeneration after injury. L1CAM and L1.1 have shown beneficial features in ameliorating nervous system dysfunctions in different experimental paradigms. It thus deemed important to characterize the L1.2 member of the L1CAM family, the functions of which are unknown. Methods Spinal cord transection of adult zebrafish, application of anti-sense morpholino to reduce L1.2 expression, qPCR, immunohistology, immunoblotting, in situ hybridization, retrograde tracing, anterograde tracing. Results Similar to L1.1, L1.2 expression in adult zebrafish is upregulated after spinal cord transection. By co-localization of in situ hybridization and immunohistology, L1.2 is expressed in neurons and, in contrast to L1.1, it is also expressed in GFAP-immunoreactive glia. Reducing L1.2 protein levels leads to impaired locomotor recovery and reduction of regrowth of severed descending axons from a brain stem nucleus which is composed of neurons innately capable of axonal regrowth. Conclusions Our findings support the speculation that paralogs of duplicated genes can exert similar functions and may thus represent an advantage over other species that do not carry duplicated genes.

The calculation of the dynamic stress of a large and complex welded carbody is the key to the fatigue design and the durability evaluation of the carbody. Adopting the advanced structural stress based on the finite element method, a new finite element transformation method between random loads and dynamic stresses is proposed to be applied in carbody for high-speed trains. The multi-axial random dynamic load spectrums of full-scale carbody are obtained by the vehicle system dynamics method, and the shell finite element model of a full-scale carbody is established. Adopting the concept of a surrogate model, the finite element transformation relationship between the random load and the dynamic structural stress at concerned points is constructed by using multidisciplinary methods to compute the dynamic stress spectrums of concerned points at the welding seam, and dynamic structural stresses are compared and validated through carbody rig-test. The analysis methods of dynamic structural stress are performed systematically for a full-scale welded structure, which provides reference methods for the fatigue durability evaluation of large-scale welded structures.

The title compound, C12H10N2O2, was obtained unintentionally during the synthesis of 2-amino-5-(4-methoxyphenyl)furan-3-carbonitrile. In the crystal, weak intermolecular C—H...N and C—H...π interactions link the molecules into columns propagating in [010].

The preparation and characterization of carbon nanotubes (CNTs)/epoxy composites were studied for microwave absorption, which frequency is from 2 to 6 GHz. The absorbing coating with a loading of 15 wt % CNTs/epoxy resin, which thickness is 3 mm, exhibited an absorbing peak of 10.5 dB at 3.85GHz. After being treated by HNO3–H2SO4 acid at the temperature of 100 °C, the real and imaginary part values of permittivity of CNTs have a larger increase in quantity, and the absorbing peak position moves to lower frequency of 3.35 GHz showing an increasing the dielectric loss in lower microwave frequency. Two-layer coating with CNTs/epoxy resin and graphite/epoxy resin composites have been also investigated in order to widen the frequencies range of CNTs microwave sorbent in the low microwave frequency application. The results indicated that two-layer coating (15 wt % loading CNTs/epoxy resin and 9 wt % loading graphite/epoxy resin) can obtain 2.4 GHz broad frequencies band for absorption of 5.0 dB. The absorbing p...