Search

Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve patients with GAC poses a significant challenge, limiting the scope of current research, which has focused predominantly on localized tumors. This gap hinders deeper insight into the metastatic dynamics of GAC. We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, using cell lines and multiple patient-derived xenograft and novel mouse models of GAC. Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of tumor microenvironment phenotypes, supporting the notion that cancer cells and their local tumor microenvironments co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 up-regulation during GAC progression. Conditional depletion of Gpx4 or pharmacologic inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. In addition, ferroptosis-resensitizing treatments augmented the efficacy of chimeric antigen receptor T-cell therapy. This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with chimeric antigen receptor T-cell therapy as a novel therapeutic strategy with potential immense clinical implications. A comprehensive single-cell tumor and immune atlas of metastatic gastric adenocarcinomas is presented, uncovering molecular and cellular dynamics during metastasis and proposing a novel therapeutic strategy with potential clinical implications. [ABSTRACT FROM AUTHOR]

Age is a significant predictor of papillary thyroid carcinoma (PTC). At present, the available evidence shows that age at diagnosis has an important impact on the recurrence of PTC. The objective of our investigation was to examine the relationship between age at diagnosis and recurrence in patients with PTC. The medical records of patients with PTC who were treated between January 2010 and December 2018 at a single institute in a cancer referral center in China were retrospectively reviewed. The hazard ratios (HRs) and 95 % confidence intervals (CIs) for recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) were assessed using Cox proportional hazard models and restricted cubic splines (RCSs). A total of 13758 patients were included in the study. With a median follow-up of 60 months (range 12–277), a total of 687 patients experienced recurrence, and 90 patients died. The 5-year RFS, LRRFS and DMFS rates were 95.0 % (95 % CI 94.6%–95.4 %), 95.8 % (95 % CI 95.4%–96.2 %) and 98.8 % (95 % CI 98.6%–99.0 %), respectively. The adjusted smooth RCS curves revealed a U-shaped association between age at diagnosis and RFS, LRRFS, and DMFS. After adjusting for potential confounding variables, both younger (≤30 years) and older (≥55 years) patients exhibited significantly lower RFS and LRRFS rates than did middle-aged patients (31–54 years). Older patients had significantly lower DMFS rates. This study confirmed a U-shaped association between age at diagnosis and the risk of both locoregional recurrence and distant metastasis. [ABSTRACT FROM AUTHOR]

The water content in the Earth's interior is of great significance for material circulation and the dynamic evolution of the planet. The water content in mantle minerals significantly affects their conductivities. By measuring the variations in conductivity within the Earth, we can infer the water content in the mantle and study the movement and processes of materials within the Earth. The geomagnetic depth sounding is a widely used method for imaging the mantle conductivity as it has large sounding depth. However, the ocean induction effects can seriously impact geomagnetic data that can't be well corrected using conventional methods. Here, we present a novel three-dimensional inversion method for geomagnetic depth sounding to overcome the ocean induction effects by directly adopt the real earth surface conductivity into the inverse model. In this method, the unstructured tetrahedral grids are used to represent the model in multi-scale and the vector finite-element method is adopted to accurately compute the geomagnetic responses. The synthetic model tests show that the earth surface conductivity has serious effect on the inversion results, but it can be well suppressed by directly modeling it in the inverse model. We further invert the data from 128 geomagnetic stations around the world and obtain a more accurate new model of global mantle conductivity. • Innovative finite element approach for geomagnetic depth sounding. • Global and Local Data Processing. • Employs a multi-scale, unstructured tetrahedral mesh for model discretization. • Obtains a new global mantle resistivity model. [ABSTRACT FROM AUTHOR]

[Display omitted] • Establishing a Single-Channel EEG Dataset for Driving Fatigue: The research involves collecting single-channel EEG data related to driving fatigue, and the model proposed in this paper has demonstrated favorable classification results using our custom dataset. • Incorporation of a Novel Semi-Supervised Approach: A novel semi-supervised approach enhances the collected EEG data. This method involves the generation of pseudo-labels, combining self-training with high-confidence pseudo-labeling, resulting in a significant improvement in model accuracy. • Enhanced Recognition Model: The research incorporates a multi-scale fuzzy entropy algorithm based on complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN). This approach significantly enhances recognition accuracy by approximately 8 % compared to existing methods. The model is trained on a combination of labeled and pseudo-labeled data, making it more effective for intelligent vehicle systems. Fatigue-induced driving remains a prominent contributing factor to frequent traffic accidents. Extensive research has demonstrated the efficacy of utilizing Electroencephalogram (EEG) for accurate fatigue detection. However, the laborious and cost-intensive process of EEG labeling, compounded by the issue of label reliability, poses a substantial challenge. Most of the current studies are based on multi-channel EEG signals, which are not conducive to the application of intelligent vehicle systems because they require abundant complex wiring. Based on the EEG signals of the left forehead, this paper proposes a self-training semi-supervised method to transform unlabeled data into pseudo-labeled data and combines the fuzzy entropy feature after scale-transformation of the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) to establish a driving fatigue recognition model. In this work, three kinds of features of EEG in the time domain, frequency domain, and entropy were extracted to train the semi-supervised model of self-training. Unlabeled data is predicted using this model, and high-confidence pseudo-labeled data is amalgamated with the labeled data. The multi-scale fuzzy entropy algorithm based on CEEMDAN was used to establish the classification model. The results show that the CEEMDAN fuzzy entropy method can improve the recognition accuracy by about 8 %, and the use of pseudo-labeled data with high confidence obtained by single self-training for model training can improve the recognition accuracy. Compared with other recognition methods based on single-channel forehead EEG, this method has higher accuracy. Meanwhile, our methodology's effectiveness has been further validated through testing on publicly accessible datasets, underscoring its robustness and applicability. [ABSTRACT FROM AUTHOR]

The fracture and damage evolution patterns of hydraulic asphalt concrete (HAC) under cyclic tensile loading determine the performance of asphalt concrete impermeable structures in embankment dams under seismic loading. Therefore, in this study, the whole fatigue tensile damage process of HAC under different loading conditions was studied with the help of acoustic emission (AE) technique. The results indicated that the fatigue behaviors of the HAC and AE signals follow the same evolutionary pattern, experiencing the initial deformation stage, the stability stage, the acceleration stage, and the failure stage. The b value, obtained from the least square fit between AE event number and magnitude, decreases to its lowest point upon specimen failure, and this decrease corresponds to a sudden increase in the peak frequency of the AE. The parametric analysis of relative amplitude-average frequency values classified for different cracking modes revealed that the tensile cracking dominates during the fatigue damage process, while the proportion of shear cracking events increases during the failure stage. Moreover, the peak value of the proportion of shear cracking events appears within the range near the point of failure, making it a useful indicator for providing critical warnings of HAC fatigue damage. • The failure evolution of hydraulic asphalt concrete (HAC) was investigated. • The HAC fatigue process includes initial deformation, stability, acceleration, and failure stage. • The tensile cracking dominates the failure during the fatigue damage process. • The drop of b value curve can be used as a critical indicator for the HAC fatigue failure in engineering. [ABSTRACT FROM AUTHOR]

• A special subset of immune cells which expressed both CD19 and CD3 (named B-T cells) in human peripheral blood was found. • The percentage of B-T cells in cancer patients was significantly higher than that of healthy donors. • B-T cells may be a potential novel tumor immune marker. CD3 and CD19 are the characteristic surface markers of mature T lymphocytes and B lymphocytes of human respectively. A special subset of immune cells that characteristically expressed the surface markers CD19+ of B lymphocytes and CD3+ of T lymphocytes simultaneously (CD19+CD3+ cells, hereinafter referred to as B-T cells) was found in the peripheral blood of human, yet it has not been reported in cancer research before. Our aims were to characterize the expression and possible value of B-T cells in cancer patients. Flow cytometry was applied to analyse the CD19+CD3+ cells, and laser scanning confocal microscope was utilized to prove co-expressing CD19+ of B lymphocytes and CD3+ of T lymphocytes simultaneously on the surface of the cells. Then a total of 523 patients with malignant tumor were enrolled in this study, and 177 healthy donors were recruited as the control group. The levels of CD19+CD3+ cells in peripheral blood were measured by flow cytometry, and the differences between the two groups were compared. The healthy donors and cancer patients all had B-T cells in their peripheral blood, but the percentage of B-T cells was 0.16 % ± 0.11 % and 0.58 % ± 0.38 % respectively, showing statistically significant (P < 0.0001). There was no significant correlation between the percentage of B-T cells and lymphocyte subsets (P > 0.05). The percentages of B-T cells in different tumor species were different. The proportion of B-T cells was high in esophageal cancer, non-Hodgkin's lymphoma and lung cancer, but it was low in pancreatic cancer, ovarian cancer and kidney cancer. Meanwhile, there was significant difference between esophageal cancer and kidney cancer (P < 0.001). The distribution of B-T cells in pancreatic cancer and kidney cancer was more concentrated, yet more dispersed in other cancers. Although there was a trend of increase in clinical stage Ⅲ+Ⅳ and a trend of decrease in age above 60 years for breast cancer, gastric cancer and liver cancer, there was no significant difference in the percentage of B-T cells in age, gender, different clinical stages, tumor metastasis, lymph node metastasis, and splenomegaly (P > 0.05). The percentage of B-T cells in cancer patients was significantly higher than that of healthy donors. B-T cells maybe play a very complicated role in tumor, whether it could be a potential tumor immune marker or not and what are the specific phenotypes and functions of it to need be further verified. [ABSTRACT FROM AUTHOR]

Background: Microvascular invasion (MVI) relates to poor survival in hepatocellular carcinoma (HCC) patients. In this study, we aim at developing a nomogram for MVI prediction and potential assistance in surgical planning.Methods: A total of 357 patients were assigned to training (n = 257) and validation (n = 100) cohort. Univariate and multivariate analyses were used to reveal preoperative predictors for MVI. A nomogram incorporating independent predictors was constructed and validated. Disease-free survival was compared between patients, and the potential of the predicted MVI in making surgical procedure was also explored.Results: Pathological examination confirmed MVI in 140 (39.2%) patients. Imaging features including larger tumor, intra-tumoral artery, tumor type, and higher serum AFP independently correlated with MVI. The nomogram showed desirable performance with an AUROC of 0.803 (95% CI, 0.746-0.860) and 0.814 (95% CI, 0.720-0.908) in the training and validation cohorts, respectively. Good calibration were also revealed by calibration curve in both cohorts. The decision curve analysis indicated that the prediction nomogram was of promising usefulness in clinical work. In addition, survival analysis revealed that patients with positive-predicted MVI suffered a higher risk of early recurrence (P < 0.01). There was no difference in disease-free survival between anatomic or non-anatomic resection in large HCC or small HCC without nomogram-predicted MVI. However, anatomic resection improved disease-free survival in small HCC with nomogram-predicted MVI.Conclusions: The nomogram obtained desirable results in predicting MVI. Patients with predicted MVI were associated with early recurrence and anatomic resection was recommended for small HCC patients with predicted MVI. [ABSTRACT FROM AUTHOR]

(–)-Syringaresinol (SYR), a natural lignan with significant antioxidant and anti-inflammatory activities, possesses various pharmacological benefits including cardio-protective, antibacterial, anticancer, and anti-aging effects. It was shown that the effectiveness of (+)-syringaresinol diglucoside on the ulcerative colitis (UC) was attributed to the active metabolite (+)-syringaresinol (the enantiomor of SYR). However, the efficacy of SYR against UC remains unclear, and the associated molecular mechanism has not been revealed yet This study aimed to assess the protective effect of SYR in UC and its underlying mechanism We examined SYR's protective impact on the intestinal epithelial barrier and its ability to inhibit inflammatory responses in both a lipopolysaccharide (LPS)-induced Caco-2 cell model and a dextran sodium sulfate (DSS)-induced UC mouse model. We also explored the potential signaling pathways regulated by SYR using transcriptome analysis and western blot assay In Caco-2 cells, SYR significantly increased trans-epithelial electrical resistance, reduced tumor necrosis factor- α (TNF- α) , interleukin-6 (IL-6), interferon- γ (IFN- γ) , and cyclooxygenase-2 (COX-2) levels, and enhanced cellular tight junction protein expression and distribution. In mice with UC, oral treatment with SYR (10, 20, 40 mg·kg−1) dose-dependently increased body weight, colon length, and expression of tight junction proteins, decreased disease activity index score, spleen coefficient, cytokine serum levels, bacterial translocation, and intestinal damage, and also preserved the ultrastructure of colonic mucosal cells. Transcriptomics indicated that the anti-UC effect of SYR is mediated via the PI3K-Akt/MAPK/Wnt signaling pathway. Conclusion : In summary, SYR effectively mitigated the development of UC by enhancing the intestinal epithelial barrier function and attenuating the inflammatory response. The plant-derived product SYR might be a potentially effective therapeutical agent against UC. [Display omitted] [ABSTRACT FROM AUTHOR]

This study investigates the crack propagation and internal non-uniform deformation field of hydraulic asphalt concrete (HAC) under triaxial compression. Utilizing in situ triaxial compression tests at temperatures of 5 °C and 20 °C, the investigation incorporated X-ray computed tomography (CT) scanning to observe internal changes. Through digital volume correlation (DVC), the deformation field within HAC was analyzed in detail. Results indicated that the crack fraction of longitudinal sections at 20 °C was smaller across various deformation stages than that at 5 °C. The displacement and strain fields within the material displayed increased heterogeneity with increasing deformation. It was observed that the probability density distributions of both equivalent and volumetric strains conformed to a normal distribution at different deformation stages. By analyzing the crack propagation and the internal non-uniform deformation field, the progressive failure process of HAC with sub-voxel accuracy at 5 °C and 20 °C was clarified. This research confirmed the presence of both shear deformation failure and volumetric deformation characteristics, which undergo a transition from shear shrinkage to shear expansion at the meso scale. • An CT scanning in situ triaxial compressive test of HAC was conducted. • The crack propagation and the progressive failure process was investigated. • The evolution process of internal non-uniform deformation field was elucidated. • The probability density distribution model of the strain field were established. [ABSTRACT FROM AUTHOR]

• Shikonin induces necroptosis and impaired autophagic flux via ROS generation. • RIP3 may be involved in autophagosomes and be degraded by autolysosomes. • Necroptosis connected with the accumulation of p62/RIP3 complex may disturb the autophagic flux, inhibiting necroptosis could further activate autophagy. • Combining shikonin with autolysosome inhibitor could further activate necroptosis via disturbing RIP3 degradation in vitro and in vivo. Shikonin, a natural naphthoquinone compound, has a wide range of pharmacological effects, but its anti-tumor effect and underlying mechanisms in bladder cancer remain unclear. We aimed to investigate the role of shikonin in bladder cancer in vitro and in vivo in order to broaden the scope of shikonin's clinical application. We performed MTT and colony formation to detect the inhibiting effect of shikonin on bladder cancer cells. ROS staining and flow cytometry assays were performed to detect the accumulation of ROS. Western blotting, siRNA and immunoprecipitation were used to evaluate the effect of necroptosis in bladder cancer cells. Transmission electron microscopy and immunofluorescence were used to examine the effect of autophagy. Nucleoplasmic separation and other pharmacological experimental methods described were used to explore the Nrf2 signal pathway and the crosstalk with necroptosis and autophagy. We established a subcutaneously implanted tumor model and performed immunohistochemistry assays to study the effects and the underlying mechanisms of shikonin on bladder cancer cells in vivo. The results showed that shikonin has a selective inhibitory effect on bladder cancer cells and has no toxicity on normal bladder epithelial cells. Mechanically, shikonin induced necroptosis and impaired autophagic flux via ROS generation. The accumulation of autophagic biomarker p62 elevated p62/Keap1 complex and activated the Nrf2 signaling pathway to fight against ROS. Furthermore, crosstalk between necroptosis and autophagy was present, we found that RIP3 may be involved in autophagosomes and be degraded by autolysosomes. We found for the first time that shikonin-induced activation of RIP3 may disturb the autophagic flux, and inhibiting RIP3 and necroptosis could accelerate the conversion of autophagosome to autolysosome and further activate autophagy. Therefore, on the basis of RIP3/p62/Keap1 complex regulatory system, we further combined shikonin with late autophagy inhibitor(chloroquine) to treat bladder cancer and achieved a better inhibitory effect. In conclusion, shikonin could induce necroptosis and impaired autophagic flux through RIP3/p62/Keap1 complex regulatory system, necroptosis could inhibit the process of autophagy via RIP3. Combining shikonin with late autophagy inhibitor could further activate necroptosis via disturbing RIP3 degradation in bladder cancer in vitro and in vivo. Shikonin induces necroptosis, impaired autophagic flux via ROS and activates antioxidant stress signaling pathways to fight against ROS. Necroptosis inhibits autophagy through RIP3/p62/Keap1 complex regulatory system. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A comprehensive investigation of the chemical compositions and bioactivity of Oviductus Ranae and Rana chensinensis ovum. • About 138 compounds have been identified from Oviductus Ranae and Rana chensinensis ovum. • The relationships between the chemical compositions and anti-fatigue effect of Oviductus Ranae and Rana chensinensis ovum have been illustrated. • The anti-fatigue markers of Oviductus Ranae and Rana chensinensis ovum have been revealed using an integrated strategy. This work is the first attempt to reveal the chemical compositions, as well as the relationships between the chemical compositions and anti-fatigue effect of Oviductus Ranae (OR) and Rana chensinensis ovum (RCO). In this work, an integrated strategy was applied containing comprehensive chemical profiling analysis, extraction methods, in vivo study, multivariate statistics, and network pharmacology. Here, 138 compounds were identified or briefly characterized using UPLC-Q/TOF-MS. About 24 and 35 variables were considered to be discriminating compounds from petroleum ether and ethanol extracts of OR and RCO, respectively. In addition, 41 identified compounds in OR and RCO were significantly correlated with anti-fatigue parameters. Finally, 22 candidate markers in OR and RCO were screened. Network pharmacology analysis was employed to verify those markers and screen the potential targets for anti-fatigue effect. Screened targets were further validated using RT-PCR. In muscle tissues, AKT mRNA, PI3K mRNA, and mTOR mRNA were upregulated following OR and RCO administration. This work not only paved the way for further study of OR and RCO in anti-fatigue function, but also provided essential information for their products quality control. [ABSTRACT FROM AUTHOR]

Finite element analysis has been applied to a large aqueduct to investigate the efficiency of lead rubber bearings (LRBs) in reducing the effects of earthquake shocks. Theoretical relationships have been derived for dynamic interaction of a coupled fluid-solid system such as an aqueduct. A numerical program has been developed by considering the coupled fluid-structure dynamics between the water in the aqueduct and the side wall of the aqueduct and the bilinear deformation characteristics of LRB. The numerical analysis shows that the incorporation of LRBs is a valuable technique in creating aseismicity for a variety of conditions. Since aseismic efficiency varies with LRB type, it is feasible to have an optimal design. The analyses show that LRBs work best with large earthquakes, however, the displacement of the trough sat on top of the LRBs is enhanced so the design of joints within the aqueduct needs special attention. [ABSTRACT FROM AUTHOR]

• HS-GC-IMS was first used to identify volatile fingerprints of WP and BP bacons. • The type of raw meat play more vital role on flavor of bacon than storage. • Volatile compounds detected in WP bacon were much abundant than BP bacon. The oxidation and volatile constituents of bacon (which made of white pig (Duroc × Landrace × Yorkshire) and black pig (Beijing Black × Yorkshire)) during refrigerated storage were analyzed by thiobarbituric acid reactive substances (TBARS), total thiol groups, gas chromatography-mass spectrometry (GC–MS) and gas chromatography coupling with ion mobility spectrometry (GC-IMS). The TBARS value of tested samples increased while the total thiol groups decreased during 60 days storage (P < 0.05). Volatile fingerprint results were obtained by GC–MS and GC-IMS detector, the classes and contents of volatile compounds detected in WP bacon were much abundant than BP bacon. Higher phenols and acids concentrations were observed in WP bacon, while alcohols, ketones, and nitrogen-containing compounds were more determined in BP bacon. Besides, WP bacon was more notably affected by storage rather than BP bacon, and the difference of raw material is the main reason for the flavor in WP and BP bacon comparing with the storage process. [ABSTRACT FROM AUTHOR]

The study takes into account the working temperature of the asphalt hydraulic asphalt concrete of the impermeable body as well as possible structural tensile cracking problems. The test temperature range is selected with the working temperature of hydraulic asphalt concrete impermeable body as a reference, while taking into account the strain rate effect of the ground concrete material. Therefore, in the tensile property test of recycled aggregate hydraulic asphalt concrete, the temperature is −10–10℃, and the strain rate is 10−51/s ∼ 10−21/s. The results indicated that the decrease of temperature and the increase of strain rate could both cause the same pattern, inducing an increase in tensile strength and tensile modulus of the specimens but a decrease in peak strain. The phenomenon of cross-sectional failure was similar and visible, which were a large proportion of aggregate fracture. To refine the results of this test,on the basis of the test, the evolution law of the fine mechanical parameters of the recycled aggregate hydraulic asphalt concrete model under specific working conditions were analyzed by PFC3D. The influence laws of different temperatures and strain rates on the damage morphology, fracture evolution, and particle displacement development of the recycled aggregate hydraulic asphalt concrete model were obtained. The tensile damage mechanism of recycled aggregate hydraulic asphalt concrete is revealed from the fine viewpoint. In which the numerical analysis results are in good agreement with the test results. It is properties still meet the specification design requirements, and can be used in engineering construction. • The tensile properties of recycled aggregate hydraulic asphalt concrete at different temperatures and strain rates. • Evolution law of tensile mechanical properties of recycled aggregate hydraulic asphalt concrete was revealed. • Failure mechanism of recycled aggregate hydraulic asphalt concrete was revealed from the mesoscopic perspective by using PFC3D. [ABSTRACT FROM AUTHOR]

The seismic input is the basis for the seismic safety analysis of dams, but current seismic input methods have not reasonably considered the influence of canyon scattering effects on the dynamic response of dams. In this paper, the total motion field of the canyon is deconstructed into the free field of a uniform half space and the scattering field of the canyon and they are obtained separately. The indirect boundary integral equation method (IBIEM) is used to determine the scattering field of the canyon, which is superimposed with the free field to obtain the seismic ground motion field (total motion field) of the canyon. The accuracy of the total motion field of the canyon is verified through reference solutions. In the finite element analysis of seismic ground motion field in the canyon, the total motion field at the truncation boundary of the canyon foundation is transformed into the equivalent seismic input loads and the interior of the canyon are simulated using the finite element method (FEM). Then, based on the wave input for the free field combined with the viscoelastic artificial boundary, a new wave input method for the total motion field combined with the viscoelastic artificial boundary is established. The seismic wave input method based on the finite element-indirect boundary integral equation method is applied to numerically determine the seismic response of a trapezoidal canyon. The differences in the seismic response of the canyon under free-field input and total motion field input are discussed. The results show that there is a certain deviation between the displacement and waveform obtained from the free-field input and the solutions obtained from the indirect boundary integral equation method. There is a large error for a large angle of incidence, and the errors increase with increasing seismic wave frequency. When the incident angle is 60°, the maximum error in the frequency domain reaches 92.3 %, and the maximum error in the time domain reaches 250 %. The displacement amplitude and waveform of the canyon obtained from the total motion field input showed agreement with the results of the indirect boundary integral equation method. The wave input method established in this paper has high calculation accuracy and reasonably considers the scattering effect of canyons, which provides a basis for more accurate predictions of the seismic response of dams on canyon foundations. • The scattering field motion of canyon sites is determined. • The earthquake ground motion field of canyon sites is determined based on IBIEM. • The influence mechanisms of scattering effects of canyon sites are revealed. • A new wave input method considering the scattering effect of canyons is established. • The wave input method suiting for canyon sites has high calculation accuracy. [ABSTRACT FROM AUTHOR]

• A total of 32 novel fatty acid ester derivatives of pyxinol were synthesized. • Compounds 2e and 3b displayed excellent ACE inhibitory activity in vitro. • Compounds 2e and 3b exhibited good activity in zebrafish heart failure model. • The preliminary mechanism of compound 2e on heart failure was studied by using untargeted metabolomics Heart failure (HF) is an important and leading cause of substantial morbidity and mortality globally. The angiotensin-converting enzymatic (ACE) is the causative source for congestive heart failure. Natural products and its derivatives play a vital role in drug discovery and development owing to their efficacy and low toxicity. Pyxinol is a potent natural agent for cardiovascular disease. Thus we investigated the effect on ACE and HF of pyxinol derivatives. We designed and synthesized 32 novel fatty acid ester derivatives of pyxinol via esterification. Among them, compounds 2e (IC 50 =105 nM) and 3b (IC 50 =114 nM) displayed excellent ACE inhibitory activity in vitro , and exhibited non-toxic to H9c2 cells. The interactions between ACE and compounds were predicted by molecular docking respectively. In verapamil-induced zebrafish HF model, the activity assay showed that these two derivatives could improve cardiovascular physiological indexes including heart beats, venous congestion, heart dilation, cardiac output, ejection fraction and fractional shortening in a dose-dependent manner. A UPLC-QTOF-MS-based serum metabolomics approach was applied to explore the latent mechanism. A total of 25 differentiated metabolites and 8 perturbed metabolic pathways were identified. These results indicated that pyxinol fatty acid ester derivatives 2e and 3b might be considered as potent drug candidates against heart failure and deserved further research and development. [ABSTRACT FROM AUTHOR]

• Ginsenoside Rg5 displayed excellent ACE inhibitory activity in vitro. • Ginsenoside Rg5 exhibited good activity in zebrafish heart failure model. • The preliminary mechanism of Rg5 on heart failure was studied by using untargeted metabolomics. Heart failure (HF), with a high fatality rate, is seriously harmful to human health. Ginsenoside Rg5 (Rg5) is the major active component in black ginseng. The effect and mechanism of Rg5 on HF were investigated for the first time. Firstly, the in vitro angiotensin-converting enzyme (ACE) inhibitory activity was evaluated. Then, the verapamil-induced zebrafish HF model was used to assay the effect of Rg5. Finally, the untargeted metabolomics based on UPLC-QTOF-MS was applied to explore the latent mechanism by analyzing the metabolic perturbation. The results showed that Rg5 had a similar ACE-inhibitory activity (IC 50 = 0.124 μM) to the reference drug enalapril. Rg5 could dramatically improve cardiac function in a dose-dependent manner. A total of 22 differentiated metabolites and 8 perturbed metabolic pathways were identified. In summary, this study indicated that Rg5 could be a potential agent for protecting heart function in the clinical treatment of heart failure. [ABSTRACT FROM AUTHOR]

Forward-directivity and fling-step effects of fault rupture generally cause large amplitude and long-period velocity pulses in near-fault ground motions, which impose severe damages on structures. In this paper, 30 typical near-fault impulsive and non-pulse records were selected as the input. The 3-dimensional finite element model with material nonlinearity of a reinforced concrete intake tower structure in hydraulic engineering was established to examine its elastoplastic dynamic responses and seismic performance. The distribution features of acceleration and displacement responses of intake tower along the height under the ground motions with forward-directivity and the fling-step effects were compared. The lateral curvature was proposed as damage index to identify the damage location and to quantify the damage degree of intake tower structure, which behaves like a shear wall. Numerical results indicated that the forward-directivity and fling-step pulses lead to great nodal displacements of intake tower, and large curvatures are generated at the lower part of the structure. Moreover, the damage of intake tower subjected to near-fault impulsive records is more severe. Finally, the dynamic responses of intake tower were examined by using peak ground acceleration (PGA) and improved effective peak acceleration (IEPA) as the scaling indices of the records. It is illustrated that the dispersions of seismic responses of intake tower structure with amplitude scaling is smaller than those without scaling, and the intensity measure IEPA is more appropriate for the scaling of near-fault impulsive records than PGA. • The elastoplastic seismic responses of intake tower structure under near-fault ground motion with forward-directivity and fling-step effects were examined. • The lateral curvature was proposed as an effective index to identify the damage location and quantify the damage degree of intake tower structure. • The fling-step impulsive ground motions more easily lead to the greater curvature and damage of lower structure of intake tower. • Intensity measure IEPA is more appropriate to scaling of impulsive records than PGA. [ABSTRACT FROM AUTHOR]

Hydraulic asphalt concrete (HAC) is extensively utilized as impervious interior core walls or upstream facings in embankment dams. This study examines the evolution of crack growth in HAC and its impact on its impervious performance under varying external loadings and temperatures. By employing X-ray computed tomography (CT) scanning in-situ triaxial compressive tests, the behavior of HAC specimens at 5 °C and 20 °C was analyzed. Statistical methods enabled the categorization of cracks by their equivalent diameter, revealing their evolution from shrinkage and initiation to expansion, interconnection, and convergence with increasing deformation. The fractal dimensions of these cracks initially decreased gradually, then stabilized, before increasing sharply. Furthermore, a logarithmic relationship between the fractal dimensions of cracks and the crack ratio was established. At equivalent deformation levels, crack development was more pronounced at 5 °C than at 20 °C. Notably, the specimens did not exhibit complete external interconnection of cracks at either temperature near the peak stress, highlighting HAC's robust impervious qualities at the meso scale. Compared to clay and concrete, HAC demonstrated superior deformation resistance and impervious capabilities in the anti-seepage structure of embankment dams. This research provides valuable insights for the application of HAC as a water barrier in complex geological settings. • A CT scanning in-situ loading test was conducted on HAC both at 5 °C and 20 °C. • The crack equivalent diameter was defined and categorized to analyze crack growth. • A relationship was established between the crack fractal dimension and crack ratio. • Impervious ability of HAC in various temperatures and deformation stages was studied. • The advantages of HAC as a water barrier in embankment dams were highlighted. [ABSTRACT FROM AUTHOR]

• A scoring models constructed by 6 prognosis-related genes selected by an algorithm. • The scores are independent and superior to the currently used clinical risk indicators. • Patients with poor scores are enriched with multiple cancer-related pathways. • The scores is related to immune infiltration of certain immune cells. Multiple myeloma is the second largest malignant tumor of the blood system. Proteasome inhibitors (PIs) currently are effective drugs for some myeloma patients, but their prognosis varies. We extracted the transcriptome expression data and clinical information of myeloma patients from MMRF CoMMpass database, and used the Random Survival Forest Variable Hunting (RSF-VH) algorithm to select 6 highly prognosis-related genes and to develop a 6-genes scoring model, by which the risk score predicted were significantly associated with the progress-free survival (PFS, P < 0.001). The median PFS of the high-risk group is 21 months, while it is 29 months in the low-risk group. The scoring model was further validated in the testing cohort. Furthermore, Analysis revealed that the risk score performed better in predicting the multiple myeloma patients' prognosis than the existed staging system, including R-ISS. The risk score is independent with the most existed clinical risk indicators, and the prognostic effectiveness of 6-genes scoring model is homogenous in patients with different clinical observations. Further bioinformatic analysis revealed that the risk score is not only significantly associated with multiple myeloma-related pathways, including immune response, but also with the infiltration of many kinds of immune cells that associated with clinical malignancy. Collectively, the model we developed using one lincRNA and five mRNAs is a robust and effective indicator for myeloma patients' prognosis undergoing proteasome inhibitors therapy. [ABSTRACT FROM AUTHOR]

• Low-voltage electrostatic field (LVEF) is directly used to assist frozen lamb meat to storage. • LVEF enhances frozen force at −12 °C achieving the same inhibition of the oxidative denaturation of protein as conventional frozen. • During 90–––150 d, the effect of LVEF assisting frozen storage at −9 °C disappears. The effect of low-voltage electrostatic field (LVEF) assisted −9 °C (LVEF-9) and −12 °C (LVEF-12) frozen, non-LVEF-assisted −9 °C (NLVEF-9) and −12 °C (NLVEF-12) frozen, and conventional frozen (CF-18, −18 °C) storage on the muscle microstructure and the oxidative denaturation of the lamb protein during the subsequent frozen storage process after finishing initial freezing was investigated. Compared with NLVEF-9, LVEF-9, and NLVEF-12, LVEF-12 maintained the better integrity of muscle microstructure, demonstrated by smaller holes, more complete Z-line and M-line, and no significant difference with CF-18 (P > 0.05). Furthermore, LVEF-12 effectively inhibited protein oxidative denaturation as shown by the lower carbonyl content, surface hydrophobicity, and higher total/active sulfhydryl groups and Ca2+-ATPase activity. Moreover, LVEF-12 effectively maintained the integrity of the secondary and tertiary structure of proteins, reduced cross-linking aggregation of proteins, and sustained better functional properties, as shown by higher α -helix content, fluorescence intensity, protein solubility, and lower R-value, disulfide bonds. [ABSTRACT FROM AUTHOR]

In order to evaluate the earthquake performance of new type prefabricated concrete frame joints, low-cycle loading tests were conducted on the eight specimens. The connection type and axial compression ratio were considered as the main design parameters for the above joints. The experimental failure process, characteristic loads and displacements, and ductility of the joints were analyzed. The hysteretic curve of the joint was relatively full, and the cumulative energy dissipation was 1.75 times that of the cast-in-place joint, which showed that the joints demonstrate good seismic performance. The joint specimens' surface strains and crack initiation trends were monitored through the VIC-3D system, and a strain-based damage model was defined accordingly. On the basis of the experimental results, a modified Park-Ang damage model was proposed, which was based on maximum deformation and cumulative energy dissipation. Combining experimental research, the damage process of the joint was divided into five categories: stage of no damage, initial damage stage, stable development stage of damage, rapid development stage of damage, and specimen failure stage. Corresponding quantitative indicators for each stage were provided. Moreover, the joint connection type and axial compression ratio on the seismic damage performance were analyzed comprehensively. After 10 mm, the damage index of the Z -shaped spliced joint was relatively small, with an average difference of 0.10 from the damage index of the bolted-welded joint, indicating a slower development of damage. The damage development rate of high axial compression joints (n = 0.54) was 1.25 times that of low axial compression joints (n = 0.18). • low-cycle loading tests were conducted on the prefabricated joint specimens. • A modified Park-Ang damage formula was proposed. • The strain on the joint specimens' surface were analyzed based on VIC-3D technology. [ABSTRACT FROM AUTHOR]

The dynamic nonlinearity, overburden stratification characteristics and oblique incidence of seismic waves in soil greatly increase the difficulty of determining the free field of a dam foundation, which restricts seismic input accuracy. Based on the potential function theory, this paper constructs a transfer relationship between the wave amplitude matrix at the top layer of a dam foundation with overburden and the wave amplitude matrix at any layer and obtains the shear strain of the soil through Fourier inverse transformation. Then, the equivalent linearization method is adopted to depict the nonlinearity of the soil. An analytical calculation method for the free field of a dam foundation with layered overburden under inclined seismic waves is proposed. This method can not only forward the free field according to the incident wave in the deep part of the foundation but also directly invert the free field according to the seismic motion on the ground surface, and the inversion efficiency is high. Using a nonlinear viscous-spring boundary element developed by the authors, combined with the free field, a wave input method for a dam foundation with a layered overburden under inclined seismic waves is established. The maximum error between the numerical solution under wave input and the analytical solution is only 5%. The computational precision of the method is high. Finally, the dynamic responses of a bituminous concrete core rockfill dam on a layered overburden are studied. The results show that an upstream buoyancy and oblique incidence are the main reasons for a larger acceleration on the upstream side of the dam than on the downstream side. As the incident angle increases, the differential distribution becomes more significant, and the amplification coefficient of the anti-seepage system also increases. When the incident angle is 25°, the horizontal and vertical amplification coefficients at the top of the core wall increase by 12.8% and 25.2% compared to the vertical incidence, respectively. The accelerations of the dam are overestimated under uniform seismic input, and the amplification coefficients of the dam crest are overestimated by 52.3% and 39.8% compared with the wave input, respectively. The wave input reasonably solves the problem of seismic input for a dam foundation with layered overburden, considers the inclined seismic waves, and can reflect the seismic waves propagation characteristics. The wave method provides a solid foundation for the seismic safety of rockfill dams with layered overburden. [ABSTRACT FROM AUTHOR]

Abstract In this paper, we present an experimental study of the fatigue performance of high-strength steels base materials, perforated plate, and bolted connection. The corresponding fatigue life was predicted. According to the stress concentration degree, the location of the initial crack was discussed, and the reduction degree in fatigue strength was quantitatively analyzed by the fatigue notch factor. Finally, the fatigue damage development process was analyzed on the basis of fatigue damage theory. Results indicated that the base materials and perforated plate showed good fatigue performance in the finite fatigue range. Their fatigue limit was clearly higher than the code value. The fatigue strengths of the Q690 base material and the perforated plate under the 95% survival probability were 1.3 and 1.2 times that of Q460, respectively. The fatigue performance of bolted connection Q690 was significantly higher than of Q460. Under the 95% survival probability, the fatigue strength of bolted connection Q690 was 1.5 times that of Q460. The stress concentration led to enhanced local stress and stress gradient. It also restricted crack initiation at maximum stress and reduced the fatigue strength of specimens. Damage value could better reflect the internal state changes of the components well in the process of fatigue failure. With the fatigue cycles times increased，the damage value gradually increased, whereas the effective bearing area and bearing capacity decreased, and the instantaneous fracture occurred. Highlights • The study on fatigue performance of high strength steels base materials, perforated plate, bolted connection were conducted. • A quantitative analysis on the degree of decrease in fatigue strength was conducted on the basis of the fatigue notch factor. • The experimental curves were fitted and compared with different standard curves. • Macroscopic and microscopic models of fatigue damage were discussed. • Influences of stress concentration on fatigue strength of specimens was discussed. [ABSTRACT FROM AUTHOR]

Abstract To reveal more information and understand the difference in failure mechanisms and mechanical behaviors of welded T-stub joints with different steel grades under bolt preloading cases, a systematic experimental study was conducted in this paper. The tensile performance of the welded T-stub joint with Q690 high strength steel (HSS) and Q345 normal steel (NS) was compared and evaluated. Especially, the properties of stiffness, resistance and ductility varying with the bolt diameter, strength grade and the ratio of bolt edge distance e to bolt distance d from the web. Moreover, the Faella stiffness formulations and the provisions of Eurocode 3 Part 1–8 were validated against the test results of HSS welded T-stub joints. It was found that, the failure of only the flange occurred near the weld toe can ensure a good ductility for the welded T-stub joints with NS, but for HSS welded T-stub joints there is still a brittle rupture mode due to little necking developed. The plastic resistance of welded T-stub joints with HSS is higher than that of those joints using NS by about 24–66%, while its ultimate bearing capacity is slightly more than that of those joints with NS by around 1–23%. The empirical stiffness coefficient ψ in Faella stiffness formulation significantly overestimates the bolt restraining action of the HSS welded T-stub joints. In addition, EC3 resistance equations may be not safe to predict the actual resistance of the HSS welded T-stub joints when the flange fracture near the weld toe governs the collapse, due to the influence of welding process. Highlights • Mechanical performance of welded T-stub joints with HSS and NS is compared and evaluated experimentally and theoretically. • HSS welded T-stub joints has the superior plastic resistance, while its ultimate resistance is quite limited. • The coefficient ψ in Faella stiffness formulations overestimates the bolt restraining action of HSS welded T-stub joints. • EC3 resistance equations may be not safe to predict the actual resistance of the HSS welded T-stub joints. [ABSTRACT FROM AUTHOR]

Abstract This paper proposes an intrinsic length scale with unambiguous physical significance for dimensional response analysis of inelastic systems, and establishes a versatile regression model for the self-similar response spectra of bilinear single-degree-of-freedom (SDOF) under near-fault ground motions. Firstly, according to the dimensional analysis of elastic SDOF systems subjected to analytical pulses, the intrinsic length scale is proposed to compare with the widely used energetic length scale. It is shown that the normalized displacement with respect to the intrinsic length scale is compatible with the analytical solution, and the overall absolute dispersion in the normalized responses is effectively reduced and is more evenly distributed in the entire frequency-ratio range. Then, the intrinsic length scale is adopted in the case of bilinear SDOF systems under analytical pulses, and similar results are observed. Finally, 30 near-fault ground motion records are selected as seismic input of the bilinear SDOF systems. Results indicate that both overall absolute and relative dispersions associated with intrinsic length scale are smaller than those with energetic length scale, when the normalized yield displacement is large. Therefore, the intrinsic length scale is recommended as an alternative length scale for dimensional analysis of elastoplastic structures. Moreover, it is illustrated that there exist two states of complete similarity in the normalized yield displacement. Accordingly, a versatile regression model is suggested for self-similar response spectrum, which can predict structural response. Highlights • An intrinsic length scale with unambiguous physical significance is proposed. • Intrinsic length scale is an alternative scale for dimensional response analysis. • Two complete self-similarities in the normalized yield displacement are found. • A versatile regression model for self-similar response spectrum is established. [ABSTRACT FROM AUTHOR]

Abstract Based on static tensile test of 20 Q460D high-strength steel bolted connection joints, influences of high-strength steel material strength and bolt arrangement pattern on bearing capacity and deformation of connections were analyzed. According to differences of end distance, edge distance, and pitch between bolts, finite element modeling, theoretical calculation, and test results were compared, a quantitative analysis was carried out for mechanical property of high-strength steel bolted connections, and applicability of relevant standards was investigated. The study showed that bearing capacity and deformation of specimens for Q460D high-strength steel increased as pitch increased when bolts were under transversal arrangement. Influence of increased edge and end distance on bearing capacity of the connection was minimal after standard value of the structure was reached. Stress nephogram obtained from numerical analysis and plastic region presented symmetrical distribution with two holes bearing balanced stress, fitted curve points were dispersedly distributed, and margin of theoretically calculated value was large when EC3 standard was used. When bolts were under longitudinal arrangement, bearing capacity of the specimens only presented a linearly increasing trend as pitch increased, two holes bore unbalanced stress in stress distribution, stress borne by bolt hole at end part and its deformation were both large, and bearing capacities of end and middle bolts calculated according to the EC3 standard were relatively accurate. This study can provide a theoretical basis for design and connection structure of Q460D high-strength steel bolted connection joints. Highlights • The mechanical property of Q460 HSS bolt connection joint was investigated experimentally and numerically. • The bearing capacity of Q460 HSS bolt connection joint was underestimated by EC3 application. • The plastic zone development law of each bolt was discussed through finite element method. • The bearing capacity of end bolts and inner bolts is discussed. [ABSTRACT FROM AUTHOR]

The welded joint of steel structure is prone to occur fatigue fracture under dynamic loads. In this paper, an experimental study on the fatigue performance of base material, butt weld, and cross fillet weld of high-strength steels were investigated. The S-N curve was fitted, and the corresponding fatigue life was predicted. Results corroborate that the base material of high-strength steel possess high fatigue resistance. AISC360 and EC3 standard design curves are applicable for the evaluation of the butt weld fatigue performance of Q460D and possess adequate safety margin, but only suitable for low-fatigue life estimation of Q690D butt weld. With respect to cross fillet weld, AISC360 design curve not only is suitable for the fatigue life analysis of Q460D and Q690D but also has enough safety margins, while EC3 and BS7608 codes possess relatively low fatigue limit. In addition, a quantitative analysis on fatigue fracture was conducted on the basis of fatigue damage theory, and the fatigue crack propagation law was disclosed on the basis of fracture morphology. The crack propagation law before instant fracture is consistent with damage development, and the fatigue striation width increases gradually with damage development. The fast crack propagation stage accounts for a small proportion in the fatigue life, thereby indicating that this stage is insufficiently developed. [ABSTRACT FROM AUTHOR]