The exploration of drug combinations presents an opportunity to amplify therapeutic effectiveness while alleviating undesirable side effects. Nevertheless, the extensive array of potential ...combinations poses challenges in terms of cost and time constraints for experimental screening. Thus, it is crucial to narrow down the search space. Deep learning approaches have gained widespread popularity in predicting synergistic drug combinations tailored for specific cell lines in vitro settings. In the present study, we introduce a novel method termed GTextSyn, which utilizes the integration of gene expression data and chemical structure information for the prediction of synergistic effects in drug combinations. GTextSyn employs a sentence classification model within the domain of Natural Language Processing (NLP), wherein drugs and cell lines are regarded as entities possessing biochemical relevance. Meanwhile, combinations of drug pairs and cell lines are construed as sentences with biochemical relational significance. To assess the efficacy of GTextSyn, we conduct a comparative analysis with alternative deep learning approaches using a standard benchmark dataset. The results from a five-fold cross-validation demonstrate a 49.5% reduction in Mean Square Error (MSE) achieved by GTextSyn, surpassing the performance of the next best method in the regression task. Furthermore, we conduct a comprehensive literature survey on the predicted novel drug combinations and find substantial support from prior experimental studies for many of the combinations identified by GTextSyn.
Graphical Abstract
Fine-grained Al2O3/SiC composite ceramic tool materials were synthesized by two-step microwave sintering. The effects of first-step sintering temperature (T1), content and particle size of SiC on the ...microstructure and mechanical properties were studied. It was found that the sample with higher content of SiC was achieved with finer grains, and the incorporation of SiC particles could bridge, branch and deflect the cracks, thus improving the fracture toughness. Higher T1 was required for the densification of the samples with higher content of SiC (>5 wt%). The sample containing 3 wt% SiC particles with the mean particle size of 100 nm, which was sintered at 1600 °C (T1) and 1100 °C (T2) for 5 min had the fine microstructure and optimal properties. Its relative density, grain size, Vickers hardness and fracture toughness obtained were 98.37%, 0.78 ± 0.31 μm, 18.40 ± 0.24 GPa and 4.97 ± 0.30 MPa m1/2, respectively. Compared to the sample prepared by single-step microwave sintering, although near full densification can be achieved in both two methods, the grain size was reduced by 36% and the fracture toughness was improved by 28% in two-step microwave sintering.
Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by ...functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe
mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR's effects. In addition, AUR induces IL-6 via the NF-κB pathway. In C57BL/6J mice, acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating male Hfe
mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in female Hfe
mice. Notably, high-dose AUR (25 mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.
Tool life and failure mechanisms of a microwave-sintered sub-crystal Al2O3/SiC ceramic tool (AS) in dry turning hardened steel were studied. The AS tool with plane face shows better cutting ...performance and wear resistance than the commercial ceramic tool SW500 and cemented carbide tool YG8 at both low and high cutting speeds. It's suitable for dry cutting at high speed (210–270 m/min), the cutting distance is 5–8 times longer than that of other two tools. The results indicate that the ceramic tool fabricated by this pressureless sintering technology can satisfy the requirements of high-speed machining. Wear forms of AS tool at low cutting speed are slight crater wear and groove wear, which were mainly caused by abrasion. At high cutting speed, tool failure forms are cater wear, groove wear and slight chipping caused by severe abrasion and adhesion.
One kind of TiB2/TiC composite ceramic tool material toughened by graphene nanosheets was fabricated by spark plasma sintering. Effects of graphene nanosheets on microstructure, mechanical properties ...and toughening mechanisms were investigated. The results indicated that TiB2/TiC with 0.1 wt% graphene nanosheets sintered at 1800 °C with the holding time of 5 min obtained full densification and optimal mechanical properties. Its fracture toughness and Vickers hardness were 7.9 ± 1.2 MPa m1/2 and 20.0 ± 0.7 GPa, respectively. Excess graphene nanosheets had no effects to toughness improvement. Fracture toughness was increased by 31.7% in comparison with the TiB2/TiC without graphene nanosheets. Toughness enhancement mainly benefited from crack bridging, also slip-stick effect of graphene made it hard to detach and effectively restrained crack extension.
Online learning resources (OLR) play an important role in teaching and learning in the process of online learning. Teachers will be satisfied with selectable and suitable online learning resources, ...which can promote their self-efficacy to facilitate online teaching and learning. This study proposed a model to examine the effects of the selectivity of online learning resources (SE-OLR) and the suitability of online learning resources (SU-OLR) on teachers' online teaching satisfaction, and the mediating role of technology self-efficacy (TECHN-SE) and online teaching self-efficacy (OT-SE) between them. The results indicated that SE-OLR and SU-OLR positively affected teachers' online teaching satisfaction; TECHN-SE and OT-SE positively influenced teachers' online teaching satisfaction, while TECHN-SE and OT-SE played mediating roles between SE-OLR and SU-OLR and teachers' online teaching satisfaction. The findings have implications for the design and development of online learning resources to improve teachers' satisfaction and facilitate students' learning effectiveness and teachers' online teaching.
Trichloroethylene (TCE) triggers a severe hypersensitivity syndrome in the occupational population dependent on dendritic cells (DCs). Chloral hydrate (CH), the major oxidative metabolite of TCE, has ...been proved to be the culprit causative substance of TCE-induced hypersensitivity by human patch tests. Because redox imbalance is essential for chemical sensitizers-induced maturation of DCs, we predicted that CH would activate DCs by the nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant response. This study selected THP-1 cells as the in vitro DC model, and we evaluated the cell activation markers, intracellular oxidative stress, and Nrf2 pathway related genes expression in response to CH in THP-1 cells. CH displayed significant stimulation of THP-1 cells activation, including CD54 and CD86 expression, IL-8 release, and cell migration, and damaged the redox balance by triggering ROS generation, GSH consumption, and antioxidase activities modulation. The levels of Nrf2 and its downstream genes (HO-1 and NQO1) in mRNA and protein expressions were upregulated by CH, and CH also promoted the nuclear translocation of Nrf2. Subsequently, we investigated the effects of antioxidant on Nrf2-mediated cell defense in CH treated cells. Pretreatment with curcumin dramatically reduced cell activation and oxidative stress triggered by CH in THP-1 cells. We also confirmed the specific role of Nrf2 in CH-induced cell activation using NRF2-knockout cells. Deficiency of Nrf2 inhibited cell activation and downregulated HO-1 and NQO1 expression in CH-challenged cells. These findings suggest that Nrf2-dependent redox homeostasis plays a pivotal role in CH-induced activation of THP-1 cells, thereby providing new knowledge of the allergen as well as the molecular mechanism involving in TCE-induce hypersensitivity syndrome.
•CH activated THP-1 cells and damaged intracellular redox balance.•NRF2 and downstream genes HO-1 and NQO1 were upregulated by CH.•Curcumin alleviated the cell activation and oxidative stress caused by CH.•Nrf2 pathway was the key regulator for THP-1 cell activation.
•One waveform centroid algorithm combing EMD and intensity-weighted method for accurate Lidar detecting under low SNR was proposed.•A combination of EMD,DCT and IDCT were utilized to filter out the ...high-frequency interference in Lidar pulse.•The effectiveness of the proposed algorithm under the condition of low reflectivity and background clutter interference was confirmed.
In this study, we report on a self-adaptive waveform centroid algorithm combing EMD and intensity-weighted (IW) method for the accurate Lidar ranging under low signal-to-noise ratio (SNR) conditions. Empirical mode decomposition (EMD), discrete cosine transformation (DCT) and inverse discrete cosine transformation (IDCT) are utilized to filter out the high-frequency interference in Lidar pulse signal. A time window is set to adaptive select the effective data. The centroid points are calculated by the intensity-weighted (IW) waveform centroid algorithm with the selected data. The proposed algorithm is experimentally tested, achieving an average error of about 153 ps, 209 ps and 232 ps under the SNR of 5.1 dB, 2.7 dB and 1.8 dB, respectively, which exerts better precision compared to the wavelet soft thresholding with intensity-weighted (WL-IW) algorithm and EMD with peak selection (EMD-PK) algorithm. Furthermore, the proposed algorithm is fairly robust with remarkable detection success rates of above 96% under low SNR conditions. The proposed waveform centroid algorithm has the potential for pulsed Lidar’s ranging tasks in harsh environment.
In this work a novel strategy has been developed to prepare well-dispersed amine-functionalized SiO2 nanodot-coated layered double hydroxide nano- composite （NH2-SiO2@LDH） via electrostatic ...interactions and condensation of （3-aminopropyl）triethoxysilane （APTES）. This nanocomposite system is well dispersed in culture media and phosphate buffered saline, and exhibits low cytotoxicity and good biocompatibility. The fluorescence microscopy images and flow cytometry data indicate that such an NH2-SiO2@LDH nanocomposite is able to efficiently deliver small interfering RNA （siRNA） into the U2OS cell line to inhibit cell proliferation. Thus, NH2-SiOR@LDH nanocomposite has a great potential as a nanocarrier for efficient gene delivery.
Walking error has been problematic for pulsed LiDAR based on a single threshold comparator. Traditionally, walk error must be suppressed by some time discrimination methods with extremely complex ...electronic circuits and high costs. In this paper, we propose a compact and flexible method for reducing walk error and achieving distance-intensity imaging. A single threshold comparator and commercial time digital converter chip are designed to measure the laser pulse’s time of flight and pulse width. In order to obtain first-class measurement accuracy, we designed a specific pulse width correction method based on the Kalman filter to correct the laser recording time, significantly reducing the ranging walk error by echo intensity fluctuation. In addition, the pulse width obtained by our method, which is a recording of the laser intensity, is conducive to target identification. The experiment results verified plane point clouds of various targets obtained by the proposed method with a plane flatness less than 0.34. The novel contribution of the study is to provide a highly integrated and cost-effective solution for the realization of high-precision ranging and multi-dimensional detection by pulsed LiDAR. It is valuable for realizing multi-dimension, outstanding performance, and low-cost LiDAR.
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