Understanding the molecular mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and ...multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous analysis methods and for which relevant molecular interaction profiles of the drugs involved are available. Analysis of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of molecular interaction profiles in the discovery of novel multicomponent therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objectives
The circRNAs–miRNAs–mRNAs competing endogenous RNA (ceRNA) networks involve in regulating the development of various inflammation-associated diseases, including allergic rhinitis (AR), and ...the present study aimed to identify novel AR-associated ceRNA networks.
Methods
The mRNA and protein levels of the associated genes were, respectively, examined by real-time qPCR and western blot analysis. The targeting sites in miR-556-5p and NLRP3 were validated by performing dual-luciferase reporter gene system assay. ELISA was used to measure inflammatory cytokines secretion, and CCK-8 assay was conducted to determine cell proliferation.
Results
Here, we first identified a hsa_circ_0000520/miR-556-5p/NLRP3 signaling cascade triggered epithelium pyroptosis and inflammation to regulate the development of AR in cellular and mice models. Specifically, the pyroptosis-associated biomarkers (NLRP3, ASC, IL-1β and IL-18) and pro-inflammatory cytokines (OVA-specific IgE, TNF-α, IL-4 and IL-5) were upregulated in the nasal subjects collected from AR patients and ovalbumin (OVA)-induced AR mice models, compared to their normal counterparts. Next, using the ceRNA networks analysis software, we screened out a hsa_circ_0000520/miR-556-5p axis that potentially regulated NLRP3 in the human nasal epithelial cell line. Mechanistically, miR-556-5p targeted both hsa_circ_0000520 and 3′ untranslated region (3′UTR) of NLRP3, and knock-down of hsa_circ_0000520 inactivated NLRP3-mediated epithelium pyroptosis through miR-556-5p in a ceRNA-dependent manner. Furthermore, we proved that both hsa_circ_0000520 ablation and miR-556-5p overexpression suppressed NLRP3-mediated cell pyroptosis to attenuate AR in mice models.
Conclusions
Taken together, we evidenced that targeting the hsa_circ_0000520/miR-556-5p/NLRP3 signaling pathway was a novel AQ1strategy to ameliorate AR progression; however, future clinical data are still required to validate our preliminary results.
Joint operation of the Longyangxia and Liujiaxia reservoirs (Long-Liu operation) is of great significance for water and sediment regulation in the Yellow River. The water-sediment-electricity ...coupling system is a giant system with complex nonlinear relationships. A reliable Long-Liu operation scheme facilitates maximization of the benefits of the water-sediment-electricity system. Based on systems thinking, this paper quantitatively evaluated the reliability of different Long-Liu operation schemes and coordination of the water-sediment-electricity coupling system through the entropy weight method and dissipative structure model. The results indicated that the current operation scheme is more reliable than the adjusted scheme at the inter-annual scale and during the summer-autumn flood season and ice flood season within a year. However, the operation scheme should be improved during the spring irrigation period. The key factors influencing the quality of the water-sediment-electricity system include the outflow of the Liujiaxia reservoir, incoming sediment load into the Yellow River at Toudaoguai, sediment inflow-outflow difference in the Ningxia-Inner Mongolia Reach, water flow at Lanzhou and power generation upstream of Toudaoguai. The water-sediment-electricity system under the current Long-Liu operation scheme is more coordinated than that in the adjusted state, but the overall coordinated development of the system remains at a low activity level.
Multispectral pedestrian detection, which consists of a color stream and thermal stream, is essential under conditions of insufficient illumination because the fusion of the two streams can provide ...complementary information for detecting pedestrians based on deep convolutional neural networks (CNNs). In this paper, we introduced and adapted a simple and efficient one-stage YOLOv4 to replace the current state-of-the-art two-stage fast-RCNN for multispectral pedestrian detection and to directly predict bounding boxes with confidence scores. To further improve the detection performance, we analyzed the existing multispectral fusion methods and proposed a novel multispectral channel feature fusion (MCFF) module for integrating the features from the color and thermal streams according to the illumination conditions. Moreover, several fusion architectures, such as Early Fusion, Halfway Fusion, Late Fusion, and Direct Fusion, were carefully designed based on the MCFF to transfer the feature information from the bottom to the top at different stages. Finally, the experimental results on the KAIST and Utokyo pedestrian benchmarks showed that Halfway Fusion was used to obtain the best performance of all architectures and the MCFF could adapt fused features in the two modalities. The log-average miss rate (MR) for the two modalities with reasonable settings were 4.91% and 23.14%, respectively.
The mobile edge computing (MEC) technology can simultaneously provide high-speed computing services for multiple vehicular users (VUs) in vehicular edge computing (VEC) networks. Nevertheless, due to ...the open feature of the wireless offloading channels and the high mobility of the vehicles, the security and stability of the offloading process would be seriously degraded. In this paper, by utilizing the physical layer security (PLS) technique and spectrum sharing architecture, we propose a deep reinforcement learning based joint secure offloading and resource allocation (SORA) scheme to improve the secrecy performance and resource efficiency of the multi-user VEC networks, where the VU offloading links share the frequency spectrum preoccupied with the vehicle-to-vehicle (V2V) communication links. We use Wyner's wiretap coding scheme to obtain the achievable secrecy rate and guarantee that confidential information cannot be decoded by multiple mobile eavesdroppers. We aim at minimizing the system processing delay while securing the wireless offloading process, by jointly optimizing the transmit power, the frequency spectrum selection and the computation resource allocation. We formulate the optimization problem as a multi-agent collaborative optimal decision problem and solve it with a double deep Q-learning algorithm. Besides, we set a punishment mechanism for the rate degradation to guarantee the communication quality of each V2V link. Simulation results demonstrate that multiple VU agents adopting the SORA scheme can rapidly adapt to the highly dynamic VEC networks and cooperate to improve the system delay performance while increasing the secrecy probability.
Nonylphenol (NP) can be widely used as a plasticizer, surfactant, antioxidant, textile printing, dyeing additive, and pesticide emulsifier. Animal studies have shown that NP aggravates ovalbumin ...(OVA)-induced allergic rhinitis (AR); however, the exact mechanism underlying its action has not yet been detailed. This study aimed to explore the aggravation of the AR inflammatory response following NP exposure and its possible mechanism. The AR mouse model was constructed using OVA. Under NP exposure, allergic nasal symptoms were observed, eosinophil infiltration was assessed by Sirius red staining, and the levels of IL-4, IL-5, and IL-13 in nasal mucosa samples were detected using cytometric bead array. The mRNA levels of OX40/OX40L and GATA3 in nasal mucosa were detected by qPCR, and the expression levels of the TSLP and JAK1/2-STAT3 signaling pathway components were also identified. Our results suggest that NP exposure exacerbated allergic nasal symptoms and that eosinophils accumulated in nasal mucosa after OVA challenge. The levels of the typical T helper 2 cytokines, as well as the mRNA levels of OX40/OX40L and GATA3, were elevated in the nasal mucosa of OVA-challenged mice exposed to NP. In addition, NP exposure elevated the TSLP, TSLPR, IL-7R, p-JAK1, p-JAK2, and p-STAT3 levels in the nasal mucosa after OVA stimulation. Overall, the present study suggests NP can exacerbate OVA-induced AR inflammatory responses; furthermore, this aggravating effect of NP may be related to the TSLP-TSLPR/IL-7R and JAK1/2-STAT3 signaling pathways.
Purpose
Previous studies suggest that triglyceride-glucose index (TyG) index, as a marker of insulin resistance, may have associations with the risk of cardiovascular diseases (CVD) in elderly ...population. Given the paucity of data, it remains controversial, especially in general Chinese population. We aimed to further assess whether TyG index is an independent risk factor for CVD.
Methods
We conducted a prospective cohort study that enrolled a total of 96,541 participants from the Kailuan Study. TyG index was calculated as ln (fasting triglyceride mg/dL × fasting glucose mg/dL/2). Participants were divided into four groups (Q1, Q2, Q3, and Q4) by quartiles of the TyG index. Any CVD events occurred during 2006–2017 were recorded, including myocardial infarction (MI) and stroke. We assessed the association of TyG index with the risk of CVD and the subtypes of CVD by using Cox models estimated hazard ratios (HRs) and 95% confidence interval (CIs).
Results
During a median follow-up of 10.33 years, totally 6421 CVD events, 1493 MIs, and 5083 stroke events occurred. Multivariate Cox regression analysis showed that compared with Q1, HR (95% CI) for CVD events was 1.12 (95%, 1.03–1.21) in Q2, 1.28 (95%, 1.18–1.38) in Q3, and 1.34 (95%, 1.23–1.45) in Q4. In a time-dependent Cox Model we also found that compared with Q1, HR (95% CI) for CVD events was 1.09 (95%, 1.02–1.18) in Q2, 1.18 (95%, 1.09–1.27) in Q3, and 1.20 (95%, 1.11–1.30) in Q4. Similar results were showed in MI and stroke.
Conclusions
TyG index as a marker of insulin resistance was an independent risk factor for CVD. This may help in the early identification of people at high risk of CVD and be applicable to the primordial and primary prevention.
Bisphenol A (BPA) is found in many plastics widely used in everyday life and affects the immune system. Previous studies found that the selective G protein coupled estrogen receptor (GPER) agonist ...G-1 can reduce the inflammation associated with asthma and allergic rhinitis (AR). BPA also interferes with the protective effect of estradiol against myocardial ischemia-reperfusion injury.
We explored whether BPA attenuates the effect of G-1 on inflammation in a mouse AR model.
The AR model was established by sensitizing and stimulating female BALB/c mice with ovalbumin (OVA) and G-1/BPA. Eosinophils, neutrophils, and lymphocyte subsets (including T and B cells) in nasal mucosa and Th2 and Treg cells in the spleen were detected by flow cytometry. Cytokines and transcription factors characteristic of Th2 and Treg cells in nasal mucosa were detected using cytometric bead arrays and quantitative PCR, respectively.
G-1 reduced OVA-induced nasal mucosal inflammation in mice. The proportions of eosinophils, neutrophils, Siglec-F+ neutrophils, lymphocytes, and T cell subsets were reduced by G-1, and this effect was attenuated by BPA. G-1 significantly decreased the Th2 population and levels of IL-4, IL-5, IL-13 and GATA-3; these effects were attenuated by BPA. The enhanced Treg response (as evidenced by an increased Treg population and higher IL-10 and Foxp3 levels) mediated by G-1 tended to be reduced by BPA.
We found that G-1 reduced OVA-induced nasal mucosal inflammation and significantly decreased the Th2 response, while increasing the Treg response. These effects were attenuated by BPA.
Display omitted
•GPER-specific agonist G-1 can reduce OVA-induced nasal mucosal inflammation in mice.•G-1 reduced eosinophils, neutrophils, Siglec-F+ neutrophils, lymphocytes and T cells.•G-1 decreased Th2 population, the levels of IL-4, IL-5, IL-13 and GATA-3.•G-1 increased Treg population, the levels of IL-10 and Foxp3.•BPA intervention can attenuate the therapeutic effects of G-1 in AR.
Capturing all-in-focus images with 3D scenes is typically a challenging task due to depth of field limitations, and various multi-focus image fusion methods have been employed to generate ...all-in-focus images. However, existing methods have difficulty simultaneously achieving real-time and superior fusion performance. In this paper, we propose a region- and pixel-based method that can recognize the focus and defocus regions or pixels by the neighborhood information in the source images. The proposed method can obtain satisfactory fusion results and achieve improved real-time performance. First, a convolutional neural network (CNN)-based classifier generates a coarse region-based trimap quickly, which contains focus, defocus and boundary regions. Then, precise fine-tuning is implemented at the boundary regions to address the boundary pixels that are difficult to discriminate by existing methods. Based on a public database, a high-quality dataset is constructed that provides abundant precise pixel-level labels, so that the proposed method can accurately classify the regions and pixels without artifacts. Furthermore, an image interpolation method called
NEAREST_Gaussian
is proposed to improve the recognition ability at the boundary. Experimental results show that the proposed method outperforms other state-of-the-art methods in visual perception and object metrics. Additionally, the proposed method has 80% improved to the conventional CNN-based methods.
Nasopharyngeal carcinoma (NPC) is a common malignant tumor. Ten-eleven translocation (TET) protein 2 (TET2), an evolutionarily conserved dioxygenases, is reported to be involved in various malignant ...tumor developments. Here, we aim to investigate the effect of TET2 on NPC progress in vitro and in vivo, and its detailed underlying mechanism.
Real-time PCR and western blotting were used to determine the expression levels of TET1/2/3 in NPC cell lines. The effects of TET2 on NPC progression were evaluated using CCK8 and invasion assays in vitro. Proteins interacted with TET2 in NPC cells were detected by immunoprecipitation and mass spectrometry. The effects of TET2 or pyruvate kinase, muscle (PKM) on glycolysis in NPC cells were examined by detecting glucose uptake and lactate production. The effects of TET2 on NPC progression were evaluated using xenograft tumor model in vivo.
TET2 expression was decreased in NPC cells, and TET2 overexpression inhibited proliferation and invasion of NPC cells, which is independent on TET2's catalytic activity. In mechanism, TET2 N-terminal domain interacts with PKM in cytoplasm to prevent PKM dimers from translocating into nucleus, suppressing glycolysis in NPC cells, thereby inhibiting proliferation and invasion of NPC cells. Moreover, using xenograft tumor model, we found that TET2 knockout promoted NPC progression and decreased survival rate. However, administration with the inhibitor of PKM, shikonin, decreased the tumor volume of TET2-cas9 group, and increased the survival rate.
TET2 suppresses NPC development through interacting with PKM to inhibit glycolysis.
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