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With the progress of face manipulation techniques, synthesized faces are spreading on the Internet, which raises concerns about potential threats. To prevent these techniques’ abuse, various detection algorithms have been proposed. In this paper, we consider the image’s frequency information, then propose an adaptive filtering algorithm named spatial and adaptive filtering (SAF) Network. SAF is a dual-stream network that considers spatial and frequency domains. In the frequency domain, wavelet transform is used to divide the image into different frequency bands, then an adaptive filter is introduced, which aims to capture more decisive information by giving different weights to different frequencies. To fuse spatial and frequency features, spatial pyramid pooling fusion (SPPF) is proposed, which solves the mismatch of feature maps, and considers the relationship between different patches by attention mechanism. Experiment results show that the performance of SAF is better than the comparison algorithm.

The load-displacement curves of six types of roof-to-wall connection joints were obtained through uplift experiments, while the mechanical properties of each type of joint were compared and analyzed, and the applicability of each joint was verified by the Foschi load-displacement curve model simulation. The specimens were made of three kinds of wood (Pinus sylvestris (PS), Spruce-Pine-Fir (SPF), and Douglas fir (DF)) and two different metal connectors (A-type and B-type), and then the monotonic pullout tests were conducted on each specimen. The failure modes of each group of specimens were analyzed, and the characteristic values analysis method was used to analyze and compare the characteristic values of the load-displacement curves of each specimen, including six characteristic values: maximum load, yield load, deformation capacity, energy dissipation capacity, ductility ratio, and initial stiffness. The results showed that the load capacity of TA group (specimens with A-type metal connectors) was much greater than that of TB group (specimens with B-type metal connectors). The specimens made of DF had the best mechanical performance, but the specimens of DF group were prone to brittle failure. Finally, the fitting parameters of the Foschi model applicable to such joints were obtained.

Three kinds of typical Chinese traditional mortise-tenon joints were tested. The effects of sparging on the deformation, hysteretic behavior, strength and stiffness degradation, and energy dissipation of the mortise-tenon joints were studied via low-cycle reversed loading tests with and without a ‘Que-Ti’ component. The results showed the following: the bearing capacity of the straight-tenon joint was the strongest, and the hysteretic loop of the through-tenon joint and half-tenon joint were asymmetric due to the asymmetry of the tenon form. The half-tenon joint was most likely to pull out the tenon, and the tenon pulling condition of the half-tenon joint can be effectively alleviated by adding a ‘Que-Ti’ component. From the perspective of energy consumption, it was found that the energy consumption capacity of the mortise-tenon joints after adding a ‘Que-Ti’ component was stronger than the joints without a ‘Que-Ti’ component. This shows that the ‘Que-Ti’ can be used as an effective component in terms of enhancing the mechanical properties of the mortise-tenon joints.

The shear capacity was evaluated for specimens connected by beech dowels and composite dowels. The bearing capacities were calculated by the shear capacity formulas of metal dowel connectors in the GB 50005 (2017), NDS (2018), and EN 1995-1-1 (2014) standards. The results showed that, except for the specimen connected by one composite dowel calculated by the GB 50005 standard (2017), the remaining calculation differences were larger. Based on the failure mode, the force analysis of the beech dowels and the composite dowels was carried out. A calculation formula for the shear bearing capacity of the beech dowels and the composite dowels was proposed. The calculated results were in strong agreement with the test results, and the margins of difference were less than 10%. Furthermore, the formulas for two and four connectors were investigated. When the number of effective connectors was calculated by the GB 50005 standard (2017), the differences between the test values and the calculated values were less than 9.36%.

Background Among hospitalized children suffering from community-acquired pneumonia, Mycoplasma pneumoniae (MP) is one of the most common pathogens. MP often exists as a co-infection with bacteria or viruses, which can exacerbate the clinical symptoms. We investigated the pathogen spectrum in MP-positive and MP-negative samples from hospitalized children with respiratory tract infections in Beijing, China. Method This study included 1038 samples of nasopharyngeal aspirates obtained between April, 2017 and March, 2018 from hospitalized children under 6 years of age with respiratory tract infections. To explore the impact of MP infection on the composition of the pathogen spectrum, 185 nasopharyngeal aspirates (83 MP-positive/102 MP-negative) were randomly selected for next-generation sequencing and comprehensive metagenomics analysis. Real-time PCR was used to detect and verify common respiratory viruses. Results Of the 1038 samples, 454 (43.7%) were infected with MP. In children Pneumoviridae, and the number of reads for human respiratory syncytial virus (HRSV) in MP-positive samples was higher than that in MP-negative samples. Among the 83 MP-positive samples, 47 (56.63%) were co-infected with viruses, the most common of which was influenza virus (IFV). The durations of hospitalization and fever were higher in patients with MP co-infection than MP single infection, but the difference was not statistically significant. Conclusion The viral family with the highest number of reads in both groups was Pneumoviridae, and the number of reads matched to HRSV in MP-positive samples was much higher than MP-negative samples. Co-infection of MP and IFV infection were the most cases.

Pits in ray parenchyma cells are important to understand the functional anatomy of the ray parenchyma network in the xylem but have been less studied. Herein, pits in two types of ray parenchyma cells, contact cells and isolation cells, across different developmental stages were qualitatively studied using 48-year-old Populus tomentosa trees. The timing of differentiation and death was determined by histochemical staining and polarized light microscopy. The dimension, shape and density of pits as well as cell wall thickness were measured using SEM and optical microscopy images of semi-thin radial sections and macerated ray parenchyma cells, and analyzed by multi-factor analyses of variance. Results showed that secondary wall thickening and lignification of contact cells begun near the cambium, contrarily those of isolation cells have started until the transition zone. But even in the sapwood, contact cell walls were still much thinner than isolation cell walls. Moreover, district anatomical adaptions of pits during the xylem differentiation were present between horizontal walls and tangential walls, between contact cells and isolation cells. Ray pits were simple to slightly bordered, whereas sieve-like pits were only shown on tangential walls of isolation cells. Pit density of horizontal walls was similar between contact cells and isolation cells, nevertheless greater pits were present on tangential walls, especially for isolation cells. In addition, pits of ray parenchyma cells in the heartwood were smaller and more bordered than those in the sapwood, particularly on the horizontal walls. Moreover, isolation cells had pits with the smaller dimensions, greater pits on the tangential walls, more bordered pits on horizontal walls, as well as longer and narrower cell morphology with much thicker cell walls than contact cells. To a certain extent, all these anatomical adaptations were developed to ensure distinct functions of the two types of ray parenchyma cells in the xylem and finally to support tree growth in demand.

OBJECTIVE: The aim of this research was to investigate the effect of vascular endothelial growth factor A (VEGFA)-overexpressing rat dental pulp stem cells (rDPSCs) combined with laminin-coated and yarn-encapsulated poly((l)-lactide-co-glycolide) (PLGA) nerve guidance conduit (LC-YE-PLGA NGC) in repairing 10 mm facial nerve injury in rats. STUDY DESIGN: rDPSCs isolated from rat mandibular central incisor were cultured and identified in vitro and further transfected with the lentiviral vectors (Lv-VEGFA). To investigate the role and mechanisms of VEGFA in neurogenic differentiation in vitro, semaxanib (SU5416), Cell Counting Kit-8 (CCK-8), real-time quantitative polymerase chain reaction (qPCR) and Western blotting were performed. Ten-millimeter facial nerve defect models in rats were established and bridged by LC-YE-PLGA NGCs. The repair effects were detected by transmission electron microscopy (TEM), compound muscle action potential (CMAP), immunohistochemistry and immunofluorescence. RESULTS: Extracted cells exhibited spindle-shaped morphology, presented typical markers (CD44(+)CD90(+)CD34(−)CD45(−)), and presented multidirectional differentiation potential. The DPSCs with VEGFA overexpression were constructed successfully. VEGFA enhanced the proliferation and neural differentiation ability of rDPSCs, and the expression of neuron-specific enolase (NSE) and βIII-tubulin was increased. However, these trends were reversed with the addition of SU5416. This suggests that VEGFA mediates the above effects mainly through vascular endothelial growth factor receptor 2 (VEGFR2) binding. The LC-YE-NGC basically meet the requirements of facial nerve repair. For the in vivo experiment, the CMAP latency period was shorter in DPSCS-VEGFA-NGC group in comparison with other experimental groups, while the amplitude was increased. Such functional recovery correlated well with an increase in histological improvement. Further study suggested that VEGFA-modified DPSCs could increase the myelin number, thickness and axon diameter of facial nerve. NSE, βIII-tubulin and S100 fluorescence intensity and immunohistochemical staining intensity were significantly enhanced. CONCLUSION: VEGFA-modified rDPSCs combined with LC-YE-PLGA NGCs have certain advantages in the growth and functional recovery of facial nerves in rats.

Background: Periodontitis is associated with periodontal tissue damage and teeth loss. Nonalcoholic fatty liver disease (NAFLD) has an intimate relationship with periodontitis. Nevertheless, interacted mechanisms between them have not been clear. This study was intended for the exploration of shared gene signatures and latent therapeutic targets in periodontitis and NAFLD.Methods: Microarray datasets of periodontitis and NAFLD were obtained from the Gene Expression Omnibus (GEO) database. The weighted gene co-expression network analysis (WGCNA) was utilized for the acquisition of modules bound up with NAFLD and periodontitis. We used ClueGO to carry out biological analysis on shared genes to search their latent effects in NAFLD and periodontitis. Another cohort composed of differential gene analysis verified the results. The common microRNAs (miRNAs) in NAFLD and periodontitis were acquired in the light of the Human microRNA Disease Database (HMDD). According to miRTarbase, miRDB, and Targetscan databases, latent target genes of miRNAs were forecasted. Finally, the miRNAs–mRNAs network was designed.Results: Significant modules with periodontitis and NAFLD were obtained via WGCNA. GO enrichment analysis with GlueGo indicated that damaged migration of dendritic cells (DCs) might be a common pathophysiologic feature of NAFLD and periodontitis. In addition, we revealed common genes in NAFLD and periodontitis, including IGK, IGLJ3, IGHM, MME, SELL, ENPP2, VCAN, LCP1, IGHD, FCGR2C, ALOX5AP, IGJ, MMP9, FABP4, IL32, HBB, FMO1, ALPK2, PLA2G7, MNDA, HLA-DRA, and SLC16A7. The results of differential analysis in another cohort were highly accordant with the findings of WGCNA. We established a comorbidity model to explain the underlying mechanism of NAFLD secondary to periodontitis. Finally, the analysis of miRNA pointed out that hsa-mir-125b-5p, hsa-mir-17-5p, and hsa-mir-21-5p might provide potential therapeutic targets.Conclusion: Our study initially established a comorbidity model to explain the underlying mechanism of NAFLD secondary to periodontitis, found that damaged migration of DCs might be a common pathophysiological feature of NAFLD and periodontitis, and provided potential therapeutic targets.

Wood is highly regarded as the most sustainable resource that is widely used in structural applications. To extend its practicality in electrically conductive applications, it is necessary to confer electrical conductivity to the insulating wood. The most common strategy is to derive carbonized wood powder via an annealing process. Even though these carbonized wood powders are electrically conductive, they lost the ancestry characteristic of wood, that is, excellent mechanical properties. As such, it is of great importance to realize the concept of conductive wood while at the same time maintaining or even enhancing its mechanical properties further. By leveraging on the naturally formed transportation channels found in trees, conductive particles can be aligned along these ordered channels. To substitute active transport in living plants, a vacuum pressure impregnation process was used to infiltrate these conductive particles into the transportation channels. As a result, Cu/wood composite, denoted as Cu-SW, exhibited a minimum volume resistivity of 1.366 × 10

Background: TDI-induced asthma is characterized by neutrophil-dominated airway inflammation and often associated with poor responsiveness to steroid treatment. Both PI3Kδ and PI3Kγ have been demonstrated to play important proinflammatory roles in ovalbumin-induced asthma. We’ve already reported that blocking pan PI3K effectively attenuated TDI-induced allergic airway inflammation. Yet the specific functions of PI3Kδ and PI3Kγ in TDI-induced asthma are still unclear. Methods: Male BALB/c mice were first dermally sensitized and then challenged with TDI to generate an asthma model. Sellective inhibitors of PI3Kδ (IC-87114, AMG319) and PI3Kγ (AS252424, AS605240) as well as prednisone were respectively given to the mice after each airway challenge. Results: Treatment with IC-87114 or AMG319 after TDI exposure led to significantly decreased airway hyperresponsiveness (AHR), less neutrophil and eosinophil accumulation, attenuated airway smooth muscle (ASM) thickening, less M1 and M2 macrophages in lung, as well as lower levels of IL-4, IL-5, IL-6 and IL-18 in bronchoalveolar lavage fluid (BALF) and recovered IL-10 production. While mice treated with AS252424 or AS605240 had increased AHR, more severe ASM thickening, larger numbers of neutrophils and eosinophils, more M1 but less M2 macrophages, and higher BALF levels of IL-4, IL-5, IL-6, IL-10, IL-12, IL-18 when compared with those treated with vehicle. Conclusion: These data revealed that pharmacological inhibition of PI3Kδ attenuates TDI-induced steroid insensitive airway inflammation while PI3Kγ inhibition exacerbates TDI-induced asthma, indicating distinct biological functions of PI3Kδ and PI3Kγ in TDI-induced asthma.

Regulatory T cells (Tregs) are found to participate in the pathogenesis of cerebral ischemic stroke. Exosomes derived from Tregs (Treg-Exos) were found to mediate the mechanism of Tregs’ roles under various physiological and pathological conditions. But the roles of Treg-Exos in cerebral ischemic stroke are still unclear. Here, we explored the protective effects of Treg-Exos against microglial injury in response to oxygen-glucose deprivation/reperfusion (OGD/R) exposure. The results showed that Tregs-Exos relieved OGD/R-caused increases in LDH release and caspase-3 activity in BV-2 cells. The decreased cell viability and increased percentage of TUNEL-positive cells in OGD/R-exposed BV-2 cells were attenuated by Tregs-Exos treatment. Tregs-Exos also suppressed OGD/R-induced increase in production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in BV-2 microglia. Furthermore, Tregs-Exos induced the expression levels of phosphorylated phosphatidylinositol-3-kinase (p-PI3K) and phosphorylated protein kinase B (p-Akt) in BV-2 microglia under the challenge of OGD/R. Inhibition of the PI3K/Akt signaling by LY294002 partly reversed the effects of Tregs-Exos on cell apoptosis and inflammation in OGD/R-exposed BV-2 microglia. These results indicated that Tregs-Exos exerted protective effects against the OGD/R-caused injury of BV-2 microglia by activating the PI3K/Akt signaling.

A series of novel triazoloquinolinone and imidazoquinazolinone derivatives were designed and synthesised, and their biological activities against SHP2 protein and melanoma A357 cell line were evaluated in vitro. The results show that some target compounds have moderate to excellent inhibitory activity on SHP2 protein and melanoma A357 cell line. Structure-activity relationships (SARs) showed that both imidazoquinazolinone and triazoloquinazolinone derivatives have good SHP2 protein kinase and melanoma cell line A357 inhibitory activity. The results of molecular docking also showed that the cores of imidazoquinazolinone and triazoloquinazolinone have a certain affinity for SHP2 protein at the same time. Compared with SHP244, the target compounds have quite good liver microsomal stability and has more drug potential. The most promising compound B1 has a strong inhibitory effect on the melanoma cell line A357 at 100 µM (76.15% inhibition).

Background Human adenoviruse (HAdV) is a major pathogen of paediatric respiratory tract infections (RTIs). Mutation or recombination of HAdV genes may cause changes in its pathogenicity and transmission. We described the epidemiology and genotypic diversity of HAdV in hospitalized children with RTIs in Beijing, China. Methods Nasopharyngeal aspirates were collected from hospitalized children with RTIs from April 2018 to March 2019. HAdVs were detected by a quantitative real-time PCR, and the hexon gene was used for phylogenetic analysis. Results Among 1572 samples, 90 (5.72%) were HAdV-positive. The HAdV detection rate was highest in November and July. Among HAdV-positive children, 61.11% (55/90) were co-infected with other respiratory viruses, the most common of which were human respiratory syncytial virus and human rhinovirus. The main diagnosis was bronchopneumonia, most patient have cough and fever. Children with a high viral load were more likely to have a high fever (P = 0.041) and elevated WBC count (P = 0.000). Of 55 HAdV-positive specimens, HAdV-B (63.64%), HAdV-C (27.27%), and HAdV-E (9.09%) were main epidemic species. Phylogenetic analysis indicated that hexon sequences of three samples were on the same branch with the recombinant HAdV strain (CBJ113), which was circulating in Beijing since 2016. Conclusion The HAdV-B3 and HAdV-B7 are the main epidemic strains in Beijing, and the recombinant HAdV-C strain CBJ113 has formed an epidemic trend.

Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1β signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased TH2/TH17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased TH2 response and lower levels of IL-18 and IL-1β. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1β, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed TH2/TH17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.

Face manipulation techniques have raised concern over potential threats, which demand effective images forensic methods. Various approaches have been proposed, but when detecting higher-quality manipulated faces, the performance of previous method is not good enough. To prevent the abuse of these techniques and improve the detection ability, this paper proposes a new algorithm named Squeeze-Excitation Euclidean Distance Network (SE_EDNet) to detect manipulated faces, which is suitable for Deepfakes and GANs detection. SE_EDNet use Euclidean distance to describe similaity of vectors, which gives higher weights to important areas than traditional self-attention mechanism. Further, we take frequency into account and extract residuals information, which are obtained by a second-order filter. Then residuals are combined with original images as the input features for the network. Comparison experiment shows SE_EDNet performs better than existing algorithms. Extensive robustness experiments on Celeb-DF and DFFD demonstrate that proposed algorithm is robust against attacking on AUC scores and Recalls.

TDI-induced asthma is characterized by neutrophil-dominated airway inflammation and often associated with poor responsiveness to steroid treatment. Both PI3Kδ and PI3Kγ have been demonstrated to play important proinflammatory roles in ovalbumin-induced asthma. We've already reported that blocking pan PI3K effectively attenuated TDI-induced allergic airway inflammation. Yet the specific functions of PI3Kδ and PI3Kγ in TDI-induced asthma are still unclear. Male BALB/c mice were first dermally sensitized and then challenged with TDI to generate an asthma model. Sellective inhibitors of PI3Kδ (IC-87114, AMG319) and PI3Kγ (AS252424, AS605240) were respectively given to the mice after each airway challenge. Treatment with IC-87114 or AMG319 after TDI exposure led to significantly decreased airway hyperresponsiveness (AHR), less neutrophil and eosinophil accumulation, attenuated airway smooth muscle (ASM) thickening, less M1 and M2 macrophages in lung, as well as lower levels of IL-4, IL-5, IL-6 and IL-18 in bronchoalveolar lavage fluid (BALF) and recovered IL-10 production. While mice treated with AS252424 or AS605240 had increased AHR, more severe ASM thickening, larger numbers of neutrophils and eosinophils, more M1 but less M2 macrophages, and higher BALF levels of IL-4, IL-5, IL-6, IL-10, IL-12, IL-18 when compared with those treated with vehicle. These data revealed that pharmacological inhibition of PI3Kδ attenuates TDI-induced airway inflammation while PI3Kγ inhibition exacerbates TDI-induced asthma, indicating distinct biological functions of PI3Kδ and PI3Kγ in TDI-induced asthma.

Face morphing attack has become an increasingly serious problem since the widely applying of face recognition techniques. This type of attack becomes a serious security issue to face recognition systems, especially in widely deployed border control applications. In this paper, a face morphing attack detection method is proposed based on a multi-features Convolutional Neural Network (CNN) with micro-texture and color features. In this method, HSV color space transformation, Local Binary Patterns (LBP) is applied to preprocess images as well as and Histogram of Oriented Gradients (HOG) to enhance the traces of morphing attacks in aspect of micro-texture and color. Then, above mentioned features and the original image are fed into a well-designed multi-features convolutional neural network and obtain the final detection results. Experimental results illustrate that micro-texture and color features are efficient for face morphing detection. The proposed scheme achieves better detection accuracy compared with previous proposed method. The influence of different network structures and hyper parameters are investigated.

Background There is an increasing application of moderately hypofractionated radiotherapy for prostate cancer. We presented our outcomes and treatment-related toxicities with moderately hypofractionated (67.5 Gy in 25 fractions) radiotherapy for a group of advanced prostate cancer patients from China. Methods From November 2006 to December 2018, 246 consecutive patients with prostate cancer confined to the pelvis were treated with moderately hypofractionated radiotherapy (67.5 Gy in 25 fractions). 97.6% of the patients received a different duration of androgen deprivation therapy. Failure-free survival (FFS), prostate cancer-specific survival (PCSS), overall survival (OS), and cumulative grade ≥ 2 late toxicity were evaluated using the Kaplan–Meier actuarial method. Prognostic factors for FFS, PCSS, and OS were analyzed. Results The median follow-up time was 74 months (range: 6–150 months). For all patients, the 5- and 10-year FFS rates were 80.0% (95% CI: 74.7–85.7%) and 63.5% (95% CI 55.4–72.8%). The failure rates for the intermediate, high-risk, locally advanced, and N1 groups were 6.1%, 13.0%, 18.4%, and 35.7%, respectively (P = 0.003). Overall, 5- and 10-year PCSS rates were 95.7% (95% CI 93.0–98.5%) and 88.2% (95% CI 82.8–93.8%). Prostate cancer-specific mortality rates for the high-risk, locally advanced, and N1 groups were 4.0%, 8.2%, and 23.8%, respectively (P P P P Conclusions Moderately hypofractionated radiotherapy (67.5 Gy in 25 fractions) for this predominantly high-risk, locally advanced, or N1 in Chinese patients demonstrates encouraging long-term outcomes and acceptable toxicity. This fractionation schedule deserves further evaluation in similar populations.

There is increasing evidence that microRNA (miRNA) abnormity is involved in the occurrence and the development of various malignancies, including colon cancer. MiRNA-524–5p has been reported to possess anticancer activity in various tumors, which function is seldom investigated in colon cancer cells. The aim of this study was to explore the effect of the miRNA-524–5p/with-no-lysine kinase 1 (WNK1) system on angiogenesis in a colon cancer cell line (HT-29 and COLO205 cells) and further investigate the potential mechanisms. We found miRNA-524–5p expression was relatively high in COLO205 cells and relatively low in HT-29 cells. Elevating miRNA-524–5p expression inhibited proliferation, induced cycle arrest, diminished vascular endothelial growth factor production, and thereby suppressed angiogenesis in HT-29 cells. WNK1 silencing exerted the ability of antiangiogenesis in HT-29 cells. Besides, miRNA-524–5p deficiency-induced angiogenesis was impeded by WNK1 silence in COLO205 cells. In a murine tumor model, miRNA-524–5p agomir treatment significantly suppressed colon cancer tumorigenicity with the downregulation of WNK1 expression. In summary, our results indicated that miRNA-524–5p inhibited angiogenesis in colon cancer cells via targeting WNK1. NEW & NOTEWORTHY MiRNA-524–5p inhibited angiogenesis in colon cancer cells via targeting with-no-lysine kinase 1.

Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We’ve previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and β-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3β, tyrosine phosphorylation of β-catenin, as well as activation and nuclear transport of β-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and β-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.

We previously demonstrated receptor for advanced glycation end products (RAGE) was required for β-catenin stabilization in a toluene diisocyanate (TDI)-induced asthma model, suggesting it plays an important role in TDI-induced airway inflammation. The aim of this study was to examine whether RAGE mediates β-catenin stabilization via activation of the Src/p-Cav-1 axis in TDI-induced asthma model. To generate a chemical-induced asthma model, male BALB/c mice were sensitized and challenged with TDI. Before each challenge, FPS-ZM1 (RAGE inhibitor) and PP2 (Src inhibitor) was given via intraperitoneal injection. In the TDI-exposed mice, airway reactivity, airway inflammation, goblet cell metaplasia, and the release of Th2 cytokines and IgE increased significantly. The level of membrane β-catenin decreased but was increased in the cytoplasm. Increased expression of RAGE, p-Src, and p-Cav-1 was also detected in TDI-exposed lungs. However, all these changes were inhibited by FPS-ZM1 and PP2. In TDI-HSA stimulated human airway epithelial (16HBE) cells, the expression of p-Src and p-Cav-1, and the abnormal distribution of β-catenin were significantly increased, and then inhibited in RAGE knockdown cells. Similarly, PP2 or non-phosphorylatable Cav-1 mutant (Y14F-Cav-1) treated 16HBE cells had the same effect on the distribution of β-catenin. In addition, blockage of RAGE signaling and phosphorylation of Cav-1 eliminated the translocation of β-catenin from cytomembrane to cytoplasm. Our results showed that RAGE modulates β-catenin aberrant distribution via activation of Src/p-Cav-1 in a chemical-induced asthma model.

Profiled hollow core sandwich panels (SPs) and their components (outer layers and core) were manufactured with ponderosa and lodgepole pine wood strands to determine the effects of low-velocity impact forces and to observe their energy absorption (EA) capacities and failure modes. An instrumented drop weight impact system was applied and the tests were performed by releasing the impact head from 500 mm for all the specimens while the impactors (IMPs) were equipped with hemispherical and flat head cylindrical heads. SPs with cavities filled with a rigid foam insulation material (SPfoam) were also tested to understand the change in EA behavior and failure mode. Failure modes induced by both IMPs to SPs were found to be splitting, perforating, penetrating, core crushing and debonding between the core and the outer layers. SPfoams absorbed 26% more energy than unfilled SPs. SPfoams with urethane foam suffer less severe failure modes than SPs. SPs in a ridge-loading configuration absorbed more impact energy than those in a valley-loading configuration, especially when impacted by a hemispherical IMP. Based on the results, it is evident that sandwich structure is more efficient than a solid panel concerning impact energy absorption, primarily due to a larger elastic section modulus of the core’s corrugated geometry.

Background We have previously demonstrated that the receptor for advanced glycation end products (RAGE)/β-catenin axis plays a vital role in regulating airway inflammation and airway remodeling in a toluene diisocyanate (TDI)-induced murine asthma model. However, the exact mechanism of β-catenin activation remains unclear. Given that phosphorylation of the low-density lipoprotein receptor-related protein 6 (Lrp6) is a key step in mediating β-catenin stabilization in canonical wnt/β-catenin signaling, we explored the possible relationship between RAGE and Lrp6 in regulating β-catenin stabilization in TDI-induced asthma. Methods In this study, a TDI-induced murine asthma model was generated, and mice were treated with a specific inhibitor of RAGE. In vitro, the human bronchial epithelial cell line 16HBE was treated with TDI-human serum albumin (TDI-HSA). RAGE overexpression or knockdown cells were also constructed and assessed. Results The results showed that RAGE inhibition or RAGE knockdown decreased β-catenin nuclear accumulation and the expression of relevant β-catenin targeted genes (VEGF, MMP9, TGF-β1) in the TDI-induced murine asthma model and TDI-HSA-treated 16HBE cells, respectively. Silencing of RAGE reversed the TDI-induced increase in phospho-ERK1/2 (p-ERK) and phospho-Lrp6 (p-Lrp6) in 16HBE cells. Pretreatment with the extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 suppressed TDI-induced Lrp6 phosphorylation. Furthermore, knockdown of Lrp6 in 16HBE cells decreased β-catenin nuclear translocation and the expression of VEGF, MMP9, and TGF-β1. Conclusion These data suggested that the RAGE/ERK axis modulates Lrp6 phosphorylation, contributing to β-catenin stabilization in a TDI-induced murine model.

This thesis investigates the problem of input–output finite-time stabilization for a class of nonlinear impulsive hybrid systems based on finite state machine (FSM). First, the concept of input–output finite-time stability (IO-FTS) is extended for such hybrid systems, then, the stability analysis is given by combining the multiple Lyapunov functions (MLFs) method and mode-dependent average dwell time (MDADT) technique, the corresponding sufficient conditions are derived and proved. Furthermore, a state feedback controller is designed to stabilize the hybrid systems. Finally, a numerical example is given to show the feasibility and effectiveness of the proposed controller.

Purpose Accumulating evidence has suggested that toll-like receptor 4 (TLR4) is critically involved in the pathogenesis of asthma. The aim of this study was to investigate the role of TLR4 in toluene diisocyanate (TDI)-induced allergic airway inflammation. Methods TLR4-/- and wild-type (WT) C57BL/10J mice were sensitized and challenged with TDI to generate a TDI-induced asthma model. B-cell lymphoma 2 (Bcl-2) inhibitors, ABT-199 (4 mg/kg) and ABT-737 (4 mg/kg), were intranasally given to TDI-exposed TLR4-/- mice after each challenge. Results TDI exposure led to increased airway hyperresponsiveness (AHR), granulocyte flux, bronchial epithelial shedding and extensive submucosal collagen deposition, which were unexpectedly aggravated by TLR4 deficiency. Following TDI challenge, TLR4-/- mice exhibited down-regulated interleukin-17A and increased colony-stimulating factor 3 in bronchoalveolar lavage fluid (BALF), while WT mice did not. In addition, TLR4 deficiency robustly suppressed the expression of NOD-like receptor family pyrin domain containing 3 and NLR family CARD domain containing 4, decreased caspase-1 activity in TDI-exposed mice, but had no effect on the level of high mobility group box 1 in BALF. Flow cytometry revealed that TDI hampered both neutrophil and eosinophil apoptosis, of which neutrophil apoptosis was further inhibited in TDI-exposed TLR4-/- mice, with marked up-regulation of Bcl-2. Moreover, inhibition of Bcl-2 with either ABT-199 or ABT-737 significantly alleviated neutrophil recruitment by promoting apoptosis. Conclusions These data indicated that TLR4 deficiency promoted neutrophil infiltration by impairing its apoptosis via up-regulation of Bcl-2, thereby resulting in deteriorated AHR and airway inflammation, which suggests that TLR4 could be a negative regulator of TDI-induced neutrophilic inflammation.

Academic impact is an important factor in the research assessment of a scholar. The prediction of the individual future academic impact is beneficial to detecting talented scholars and allocating the academic resources more reasonably. Recently, many evaluation indicators based on academic impact have been proposed, among which the G-index is more objective than the citations and H-index that used more frequently. At present, the main contradiction is formed between the great values of the individual future academic impact in practice and the imperfect evaluation and prediction methods. In order to solve this contradiction, this paper chooses the objective and comprehensive evaluation indicator G-index to measure individual academic impact and proposes the solution of how to predict the G-index at a given time interval for the first time in relevant research fields. Firstly, different characteristic features are extracted based on the structure of the academic social network. Then, a prediction model based on deep learning is proposed to learn the function mapping relationship between the future G-index time with the current feature set. Finally, the proposed model is validated with real academic social network dataset. The experiment results show that the individual G-index development is tightly related to the scholar's characteristic features in the current academic social network and the deep learning model performs well in predicting the future G index.

Natural Language Inference (NLI), which is also known as Recognizing Textual Entailment (RTE), aims to identify the logical relationship between a premise and a hypothesis. In this paper, a DCAE (Directly-Conditional-Attention-Encoding) feature based on Bi-LSTM and a new architecture named LIC (LSTM-Interaction-CNN) is proposed to deal with the NLI task. In the proposed algorithm, Bi-LSTM layers are used to modeling sentences to obtain a DCAE feature, then the DCAE feature is reconstructed into images through an interaction layer to enrich the relevant information and make it possible to be dealt with convolutional layers, finally the CNN layers are applied to extract high-level relevant features and relation patterns and the discriminant result obtained through a MLP (Multi-Layer Perceptron). Advantages of LSTM layers in sequence information processing and CNN layers in feature extraction are fully combined in this proposed algorithm. Experiments show this model achieving state-of-the-art results on the SNLI and Multi-NLI datasets.

Cell-cell junctions are critical for the maintenance of cellular as well as tissue polarity and integrity. Dysfunction of airway epithelial barrier has been shown to be involved in the pathogenesis of acute lung injury (ALI). Yet the role of phosphatidylinositol 3-kinase delta (PI3Kδ) in dysregulation of airway epithelial barrier integrity in ALI has not been addressed. Mice were subjected to intratracheal instillation of lipopolysaccharide (LPS) to generate a ALI model. Two pharmacological inhibitors of PI3Kδ, IC87114 and AMG319, were respectively given to the mice. Expression of p110δ and its downstream substrate phospho-AKT (Ser473) was increased in LPS-exposed lungs. These increases were inhibited by IC87114 or AMG319. LPS led to pronounced lung injury that was accompanied by significant airway neutrophil recruitment and bronchial epithelial morphological alterations 72 h after exposure. We also found compromised expression of adherens junction protein E-cadherin and tight junction protein claudin-2 in the airway epithelial cells. Treatment with either IC87114 or AMG319 not only attenuated LPS-induced edema, lung injury and neutrophilc inflammation, reduced total protein concentration and IL-6, TNF-α secretion in BALF, but also restored epithelial E-cadherin and claudin-2 expression. In summary, our results showed that LPS can induce a delayed effect on airway epithelial barrier integrity that is mediated by PI3Kδ in a mouse model of ALI.

BACKGROUND AND PURPOSE Cytoplasmic retention of β-catenin will lead to its nuclear translocation and subsequent interaction with the transcription factor TCF/LEF that regulates target gene expression. We have previously demonstrated aberrant expression of β-catenin in a model of asthma induced by toluene diisocyanate (TDI). The aim of this study was to examine whether the receptor for advanced glycation end products (RAGE) can regulate β-catenin expression in TDI-induced asthma. EXPERIMENTAL APPROACH Male BALB/c mice were sensitized and challenged with TDI to generate a chemically-induced asthma model. Inhibitors of RAGE, FPS-ZM1 and the RAGE antagonist peptide (RAP), were injected i.p. after each challenge. Airway resistance was measured in vivo and bronchoalveolar lavage fluid was analysed. Lungs were examined by histology and immunohistochemistry. Western blotting and quantitative PCR were also used. KEY RESULTS Expression of RAGE and of its ligands HMGB1, S100A12, S100B, HSP70 was increased in TDI-exposed lungs. These increases were inhibited by FPS-ZM1 or RAP. Either antagonist blunted airway reactivity, airway inflammation and goblet cell metaplasia, and decreased release of Th2 cytokines. TDI exposure decreased level of membrane β-catenin, phosphorylated Akt (Ser(473) ), inactivated GSK3β (Ser(9) ), dephosphorylated β-catenin at Ser(33) /(37) /Thr(41) , which controls its cytoplasmic degradation, increased phosphorylated β-catenin at Ser(552) , raised cytoplasmic and nuclear levels of β-catenin and up-regulated its targeted gene expression (MMP2, MMP7, MMP9, VEGF, cyclin D1, fibronectin), all of which were reversed by RAGE inhibition. CONCLUSION AND IMPLICATIONS RAGE was required for stabilization of β-catenin in TDI-induced asthma, identifying protective effects of RAGE blockade in this model.

Breast cancer stem cells (bCSCs) are considered an obstacle in breast cancer therapy because they exhibit long-term proliferative potential, phenotypic plasticity and high resistance to the current therapeutics. CXC chemokine receptor type 7 (CXCR7), which provides a growth advantage to breast cancer cells, has recently been demonstrated to play an important role in the maintenance of stem cell-like properties in the CSCs of glioblastoma and lung cancer, yet its role in bCSCs remains elusive. In this study, CD44+/CD24low bCSC-enriched cells (bCSCs for short) were isolated from MCF-7 cells, and CXCR7 was stably knocked down in bCSCs via lentivirus-mediated transduction with CXCR7 short hairpin RNA (shRNA). Knockdown of CXCR7 in bCSCs decreased the proportion of CD44+/CD24low cells, and markedly reduced the clonogenicity of the cells. Moreover, silencing of CXCR7 downregulated the expression of stem cell markers, such as aldehyde dehydrogenase 1 (ALDH1), Oct4, and Nanog. In addition, CXCR7 silencing in bCSCs suppressed cell proliferation and G1/S transition in vitro, and delayed tumor growth in vivo in a xenograft mouse model. In situ immunohistochemical analysis revealed a reduction in Ki-67 expression and enhanced apoptosis in the xenograft tumors as a result of CXCR7 silencing. Furthermore, combined treatment with CXCR7 silencing and epirubicin displayed an outstanding anti-tumor effect compared with either single treatment. Our study demonstrates that CXCR7 plays a critical role in the maintenance of stem cell-like properties and promotion of growth in bCSCs, and suggests that CXCR7 may be a candidate target for bCSCs in breast cancer therapy.

Recent studies have indicated that high-mobility group box 1 protein (HMGB1) and the receptor for advanced glycation end-products (RAGE) contribute to the pathogenesis of asthma. However, whether the activation of the HMGB1/RAGE axis mediates airway epithelial barrier dysfunction remains unknown. Thus, the aim of this study was to examine the effects of HMGB1 and its synergistic action with interleukin (IL)-1β on airway epithelial barrier properties. We evaluated the effects of recombinant human HMGB1 alone or in combination with IL-1β on ionic and macromolecular barrier permeability, by culturing air-liquid interface 16HBE cells with HMGB1 to mimic the differentiated epithelium. Western blot analysis and immunofluorescence staining were utilized to examine the level and structure of major junction proteins, namely E-cadherin, β-catenin, occludin and claudin-1. Furthermore, we examined the effects of RAGE neutralizing antibodies and mitogen-activated protein kinase (MAPK) inhibitors on epithelial barrier properties in order to elucidate the mechanisms involved. HMGB1 increased FITC-dextran permeability, but suppressed epithelial resistance in a dose- and time-dependent manner. HMGB1-mediated barrier hyperpermeability was accompanied by a disruption of cell-cell contacts, the selective downregulation of occludin and claudin-1, and the redistribution of E-cadherin and β-catenin. HMGB1 in synergy with IL-1β induced a similar, but greater barrier hyperpermeability and induced the disruption of junction proteins. Furthermore, HMGB1 elicited the activation of the RAGE/extracellular signal-related kinase (ERK)1/2 signaling pathway, which correlated with barrier dysfunction in the 16HBE cells. Anti-RAGE antibody and the ERK1/2 inhibitor, U0126, attenuated the HMGB1-mediated changes in barrier permeability, restored the expression levels of occludin and claudin-1 and pevented the redistribution of E-cadherin and β-catenin. Taken together, the findings of our study demonstrate that HMGB1 is capable of inducing potent effects on epithelial barrier function and that RAGE/ERK1/2 is a key signaling pathway involved in the crosstalk between formations of junction proteins and epithelial barrier dysfunction.

The oils extracted by hydro distillation from the aerial parts of Artemisia scoparia waldst. & kitag growing wild in two regions on Qinghai-Tibetan Plateau were analyzed by GC-MS. Eighty-three components were identified representing 97.5% of the total components detected. The major constituents of the oil from the samples obtained in the eastern of Riyue Mountain (2700 - 3200 m) were 2-ethenyl-naphthalene (45.1%), beta-pinene (11.2%), 3-carene (8.7%), 3,7-dimethyl-1,3,6- octatriene (7.9%), limonene (5.4%), alpha-pinene (3.5%) and beta-myrcene (2.0%). Whereas the oil from the plant collected in Qilian Mountain (3300 - 3500 m) was composed mainly of thujone (21.4%), 1,8-cineole (18.9%), camphor (9.1%), 4-methyl-1-(1-methyl ethyl)-3-cyclo hexen-1-ol (7.8%), 4-methyl-1-(1-methylethyl)-bicyclo[3.1.0]hexan-3-one (5.3%) and 2-isopropyl-5-methyl- 3-cyclohexen-1-one(5.0%).

The aim of this study is to evaluate the feasibility, safety, and clinical efficacy of CT-guided 125I seed interstitial brachytherapy in patients with recurrent spinal metastases after external beam radiotherapy (EBRT). Between August 2003 and September 2015, 26 spinal metastatic lesions (24 patients) were reirradiated by this salvage therapy modality. Treatment for all patients was preplanned using a three-dimensional treatment planning system 3–5 days before 125I seed interstitial brachytherapy; dosimetry verification was performed immediately after seed implantation. Median actual D90 was 99 Gy (range, 90–176), and spinal cord median Dmax was 39 Gy (range, 6–110). Median local control (LC) was 12 months (95% CI: 7.0–17.0). The 6- and 12-month LC rates were 52% and 40%, respectively. Median overall survival (OS) was 11 months (95% CI: 7.7–14.3); 6-month and 1-, 2-, and 3-year OS rates were 65%, 37%, 14%, and 9%, respectively. Pain-free survival ranged from 2 to 42 months (median, 6; 95% CI: 4.6–7.4). Treatment was well-tolerated, with no radiation-induced vertebral compression fractures or myelopathy reported. Reirradiation with CT-guided 125I seed interstitial brachytherapy appears to be feasible, safe, and effective as pain relief or salvage treatment for patients with recurrent spinal metastases after EBRT.

Network encryption traffic security censorship is an indispensable part of Internet security. The accuracy and speed of the censorship is a very important requirement. In the actual censorship environment, there is much unknown protocol traffic so that the existing method of artificial designing features cannot satisfy the classification of unknown protocols. CNN can automatically learn features and use them to construct the classification algorithm of the model. CNN has strict requirements on input and we divide the original traffic to numbers of sessions which have a size as large as 400 bytes for each. We do some experiments to get this result, 400-byte size and get a series of inspiring results. We get 64 feature maps automatically learned by CNN, which verify our thoughts on feature self-learning. The classification results meet the requirements of network traffic censorship. This is the first time that CNN has been used to classify botnet encrypted and unencrypted traffic, and the focus of research is on features self-learning. This has implications for the future research of artificial intelligence methods on botnet and provides a reference.

Steroid insensitivity constitutes a major problem for asthma management. Toluene diisocyanate (TDI) is one of the leading allergens of asthma that induces both T-helper Th2 and Th17 responses, and is often associated with poor responsiveness to steroid treatment in the clinic.We sought to evaluate the effects of inhaled and systemic steroids on a TDI-induced asthma model and to find how interleukin (IL)-17A and IL-17F function in this model. BALB/c mice were exposed to TDI for generating an asthma model and were treated with inhaled fluticasone propionate, systemic prednisone, anti-IL-17A, anti-IL-17F, recombinant IL-17A or IL-17F.Both fluticasone propionate and prednisone showed no effects on TDI-induced airway hyperresponsiveness (AHR), bronchial neutrophilia and eosinophilia, and epithelial goblet cell metaplasia. TDI-induced Th2 and Th17 signatures were not suppressed by fluticasone propionate or prednisone. Treatment with anti-IL-17A after TDI exposure led to increased AHR, aggravated mucus production and airway eosinophil recruitment, accompanied by amplified Th2 responses, whereas anti-IL-17F ameliorated TDI-induced AHR and airway neutrophilia, with decreased Th17 responses. Recombinant IL-17A and IL-17F showed opposite effects to the monoclonal antibodies.IL-17A and IL-17F exert distinct biological effects during airway inflammation of a TDI-induced asthma model, which is unresponsive to both inhaled and systemic steroids.

High mobility group box 1 (HMGB1) is a DNA-binding protein that is abundantly expressed in most tissues. Recently, HMGB1 has gained much attention for its regulation of immunity and inflammation. Yet its role in toluene diisocyanate (TDI)-induced asthma still remains poorly characterized. In this study, mice were sensitized and challenged with TDI to establish a TDI-induced asthma model. An IgY anti-HMGB1 antibody or isotype IgY was given intraperitoneally after each challenge. Airway reactivity to methacholine, airway inflammation, bronchial epithelial hyperplasia and shedding were unexpectedly aggravated after administration of the anti-HMGB1 antibody and was accompanied by increased pulmonary expression of HMGB1, especially in those mice treated with IgY. Levels of IL-4, IL-5, IL-13 and TNF-α were also elevated with TDI-induction. Primary lymphocytes from TDI sensitized and challenged mice demonstrated increased secretion of IL-4 after IgY stimulation. To confirm the effect of IgY, a cohort of mice exposed to TDI or vehicle was injected with IgY and the same results were observed after IgY treatment as in TDI asthmatic mice. Taken together, these results show that the IgY anti-HMGB1 antibody can facilitate TDI-induced allergic airway inflammation. Specifically, IgY, rather than anti-HMGB1, plays an important role in the process of exacerbated asthma, shedding light on an underappreciated role of avian IgY.

Purpose To evaluate the feasibility, efficacy, and safety of permanent 125 I seed interstitial brachytherapy reirradiation in patients with retroperitoneal lymph node recurrence under CT guidance. Methods and Materials Seventeen patients with 19 retroperitoneal lymph node recurrence after external beam radiotherapy underwent CT-guided 125 I seed implant brachytherapy from October 2007 to August 2014. Treatment for all patients was preplanned using a three-dimensional radiation therapy planning system 3–5 days before brachytherapy; dosimetry verification was performed immediately after brachytherapy. Results The actuarial D90 (dose delivered to 90% of the target volume) was 100–198 Gy (median, 126.5 Gy). In 9 patients, pain intensity decreased to mild pain 1–3 weeks after brachytherapy. Pain-free survival ranged 2–15 months (median, 5 months; 95% confidence interval [CI]: 0.1, 9.9). The overall response rate was 19 of 19 (100%). The median local control time was 15 months (95% CI: 2.3, 27.7). The 6-, 12-, and 24-month local control rate was 88.0%, 63.2%, and 42.1%, respectively. Twelve patients (70.6%) developed distant metastases and died. Two patients (11.8%) are alive with distant metastases but no evidence of local recurrence. Three patients (17.6%) are alive with no evidence of local recurrence. Median overall survival was 10 months (95% CI: 5.7, 14.3); the 1- and 2-year survival rates were 38.1% and 15.3%, respectively. No major complications related to the procedure occurred during or after brachytherapy. Conclusions Reirradiation with CT-guided permanent 125 I seed interstitial brachytherapy is feasible, safe, and effective as pain relief or salvage treatment for patients with recurrent retroperitoneal lymph nodes.

Introduction Fractional exhaled nitric oxide (FeNO) has been used as a marker of airway inflammation. Airway caliber is related to the level of FeNO in asthmatics. Objectives This study aimed to investigate whether airway obstruction could interfere with real FENO levels and if different FeNO changes after albuterol inhalation could assist in distinguishing asthma from chronic obstructive pulmonary disease (COPD). Methods FeNO and spirometry measurements were performed before and after albuterol inhalation in the following three patient groups: 30 steroid-naive asthmatics, 25 asthmatics inhaling corticosteroids/long-acting β(2)-adrenergic agonists for at least 1 month and 20 COPD patients. Bronchodilator test (BDT) results were positive in all patients enrolled. The correlations among FeNO levels, pulmonary function and sputum eosinophil counts were analyzed. Results FeNO increased significantly after albuterol inhalation in steroid-naive asthmatics but not in ICS-treated asthmatics or COPD patients. The FeNO levels demonstrated no significant correlation with spirometry results or sputum eosinophil counts before or after inhaling bronchodilator in all three groups. Both the levels of FeNO and changes in FENO after albuterol inhalation in steroid-naive asthma patients were higher than those in ICS-treated asthmatics and COPD patients (P

Cell-cell junctions are critical for the maintenance of cellular as well as tissue polarity and integrity. Yet the role of phosphatidylinositol 3-kinase (PI3K) in dysregulation of airway epithelial adherens junctions in toluene diisocyanate (TDI)-induced asthma has not been addressed. Male BALB/c mice were first dermally sensitized and then challenged with TDI by means of compressed air nebulization. The mice were treated intratracheally with PI3K inhibitor LY294002. Levels of phospho-Akt in airway epithelium and whole lung tissues were markedly increased in TDI group compared with control mice, which decreased after administration of LY294002. The dilated intercellular spaces of airway epithelium induced by TDI were partially recovered by LY294002. Both the protein expression and distribution of adherens junction proteins E-cadherin and β-catenin were altered by TDI. Treatment with LY294002 rescued the distribution of E-cadherin and β-catenin at cell-cell membranes, restored total β-catenin pool, but had no effect on protein level of E-cadherin. At the same time, LY294002 also inhibited phosphorylation of ERK, glycogen synthase kinase3β and tyrosine 654 of β-catenin induced by TDI. In summary, our results showed that the PI3K pathway mediates β-catenin dysregulation in a TDI-induced murine asthma model, which may be associated with increased tyrosine phosphorylation of β-catenin.

The issue of stability and stabilization for a class of nonlinear impulsive hybrid systems based on finite state machine (FSM) with mode-dependent average dwell time (MDADT) is investigated in this paper. The concepts of global asymptotic stability and global exponential stability are extended for the systems, and the multiple Lyapunov functions (MLFs) are constructed to prove the sufficient conditions of global asymptotic stability and global exponential stability, respectively. Furthermore, the method of stabilization is also given for the hybrid systems. The application of MLFs and MDADT leads to a reduction of conservativeness in contrast with classical Lyapunov function. Finally, a numerical example is given to show the feasibility and effectiveness of the proposed approach.

Background Diisocyanates are one of the leading causes of occupational asthma, which is dominated by granulocytic inflammation in the airway. In this study, we intended to explore the role of ethyl pyruvate (EP) on neutrophil infiltration in a toluene-2,4-diisocyanate (TDI)-induced murine asthma model. Methods The experimental mice were first dermally sensitized and then challenged with TDI via oropharyngeal aspiration. The mice were treated intraperitoneally with 100, 50 or 10 mg/kg EP 1 h before each challenge. One day after the last challenge, airway reactivity to methacholine was measured by a barometric plethysmographic chamber. Total and differential cell counts, along with levels of macrophage inflammatory protein-2 (MIP-2), TNF-α in bronchoalveolar lavage (BAL) fluid and mRNA expression of CXCR2 in the lung were assessed. To depict neutrophils, a naphthol AS-D chloroacetate esterase kit was used. High mobility group box 1 (HMGB1) was determined by western blot and immunohistochemistry. Results Treatment with EP dramatically decreased airway hyperresponsiveness in TDI-challenged mice, as well as numbers of neutrophils in BAL fluid and peribronchovascular regions. Both the TDI-induced raised protein level and abnormal distribution of HMGB1 were significantly recovered by EP in a dose-dependent manner. The concentration of MIP-2 in TDI-induced asthma mice was significantly higher than that of the control ones, while EP had few effects on MIP-2. The mRNA expression of CXCR2 didn't change significantly, and TNF-α was not detected in BAL fluids. Conclusion EP reduces airway neutrophil infiltration partly through downregulating HMGB1 in a chemical-induced murine asthma model.

Background Aberrant activation of β-catenin signaling by both WNT-dependent and WNT-independent pathways has been demonstrated in asthmatic airways, which is thought to contribute critically in remodeling of the airways. Yet, the exact role of β-catenin in asthma is very poorly defined. As we have previously reported abnormal expression of β-catenin in a toluene diisocyanate (TDI)-induced asthma model, in this study, we evaluated the therapeutic efficacy of two small molecules XAV-939 and ICG-001 in TDI-asthmatic male BALB/c mice, which selectively block β-catenin-mediated transcription. Methods Male BALB/c mice were sensitized and challenged with TDI to generate a chemically induced asthma model. Inhibitors of β-catenin, XAV-939, and ICG-001 were respectively given to the mice through intraperitoneally injection. Results TDI exposure led to a significantly increased activity of β-catenin, which was then confirmed by a luciferase assay in 16HBE transfected with the TOPFlash reporter plasmid. Treatment with either XAV-939 or ICG-001 effectively inhibited activation of β-catenin and downregulated mRNA expression of β-catenin-targeted genes in TDI-asthmatic mice, paralleled by dramatically attenuated TDI-induced hyperresponsiveness and inflammation of the airway, alleviated airway goblet cell metaplasia and collagen deposition, decreased Th2 inflammation, as well as lower levels of TGFβ1, VEGF, HMGB1, and IL-1β. Conclusion The results showed that β-catenin is a principal mediator of TDI-induced asthma, proposing β-catenin as a promising therapeutic target in asthma.

The aim of this study is to evaluate the feasibility, safety, and clinical efficacy of CT-guided 125I seed interstitial brachytherapy in patients with recurrent spinal metastases after external beam radiotherapy (EBRT). Between August 2003 and September 2015, 26 spinal metastatic lesions (24 patients) were reirradiated by this salvage therapy modality. Treatment for all patients was preplanned using a three-dimensional treatment planning system 3–5 days before 125I seed interstitial brachytherapy; dosimetry verification was performed immediately after seed implantation. Median actual D 90 was 99 Gy (range, 90–176), and spinal cord median D max was 39 Gy (range, 6–110). Median local control (LC) was 12 months (95% CI: 7.0–17.0). The 6- and 12-month LC rates were 52% and 40%, respectively. Median overall survival (OS) was 11 months (95% CI: 7.7–14.3); 6-month and 1-, 2-, and 3-year OS rates were 65%, 37%, 14%, and 9%, respectively. Pain-free survival ranged from 2 to 42 months (median, 6; 95% CI: 4.6–7.4). Treatment was well-tolerated, with no radiation-induced vertebral compression fractures or myelopathy reported. Reirradiation with CT-guided 125I seed interstitial brachytherapy appears to be feasible, safe, and effective as pain relief or salvage treatment for patients with recurrent spinal metastases after EBRT.

Cytoplasmic retention of β-catenin will lead to its nuclear translocation and subsequent interaction with the transcription factor TCF/LEF that regulates target gene expression. We have previously demonstrated aberrant expression of β-catenin in a model of asthma induced by toluene diisocyanate (TDI). The aim of this study was to examine whether the receptor for advanced glycation end products (RAGE) can regulate β-catenin expression in TDI-induced asthma.Male BALB/c mice were sensitized and challenged with TDI to generate a chemically-induced asthma model. Inhibitors of RAGE, FPS-ZM1 and the RAGE antagonist peptide (RAP), were injected i.p. after each challenge. Airway resistance was measured in vivo and bronchoalveolar lavage fluid was analysed. Lungs were examined by histology and immunohistochemistry. Western blotting and quantitative PCR were also used.Expression of RAGE and of its ligands HMGB1, S100A12, S100B, HSP70 was increased in TDI-exposed lungs. These increases were inhibited by FPS-ZM1 or RAP. Either antagonist blunted airway reactivity, airway inflammation and goblet cell metaplasia, and decreased release of Th2 cytokines. TDI exposure decreased level of membrane β-catenin, phosphorylated Akt (Ser(473) ), inactivated GSK3β (Ser(9) ), dephosphorylated β-catenin at Ser(33) /(37) /Thr(41) , which controls its cytoplasmic degradation, increased phosphorylated β-catenin at Ser(552) , raised cytoplasmic and nuclear levels of β-catenin and up-regulated its targeted gene expression (MMP2, MMP7, MMP9, VEGF, cyclin D1, fibronectin), all of which were reversed by RAGE inhibition.RAGE was required for stabilization of β-catenin in TDI-induced asthma, identifying protective effects of RAGE blockade in this model.