The protein lysine methyltransferase SMYD2 has recently emerged as a new enzyme modulate gene transcription or signaling pathways, and involved into tumor progression. However, the role of SMYD2 in ...drug resistant is still not known. Here, we found that inhibition of SMYD2 by specific inhibitor could enhance the cell sensitivity to cisplatin (CDDP), but not paclitaxel, NVB, and VCR in non-small cell lung cancer (NSCLC). Further study showed that SMYD2 and its substrates were overexpressed in NSCLC resistant cells, and the inhibition of SMYD2 or knockdown by specific siRNA could reverse the cell resistance to cisplatin treatment in NSCLC/CDDP cells. In addition, our data indicated that the inhibition or knockdown SMYD2 inhibit tumor sphere formation and reduce cell migration in NSCLC/CDDP cells, but not in NSCLC parental cells. Mechanistically, inhibition of SMYD2 could enhance p53 pathway activity and induce cell apoptosis through regulating its target genes, including p21, GADD45, and Bax. On the contrary, the sensitivity of cells to cisplatin was decreased after knockdown p53 or in p53 deletion NSCLC cells. The synergistically action was further confirmed by
experiments. Taken together, our results demonstrate SMYD2 is involved into cisplatin resistance through regulating p53 pathway, and might become a promising therapeutic target for cisplatin resistance in NSCLC.
Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology ...of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.
This paper contributes to giving physical insights into stability of DC-link voltage control in multi-wind turbines integrated to weak grid. Wind farm stability operation will suffer from integrating ...to weak AC grid, due to strong coupling between the wind turbines control and grid dynamics. Multi-VSCs model is presented for DC-link voltage control stability analysis with effect of coupling among VSCs and grid strength. Based on the model, self-impact components and interaction-impact components are presented to study interactions among VSCs. Impacts of VSCs interactions on stability of DC-link voltage control are studied by investigating self-impact and interaction-impact components variations with considering grid strength, operating point and control loop bandwidth. It is found that interactions between VSC1 and VSC2 become more serious with decline of grid strength, decaying stability of VSCs. Theoretical analysis is verified with simulation of two parallel wind turbines connected to weak grid.
Hollow AuPd (hAuPd) alloy nanoparticles (NPs) were prepared through simultaneous reduction of HAuCl4 and Na2PdCl4 using Co NPs as sacrificial template (i.e., reductant). Then, the hAuPd NPs were ...assembled on nitrogen-doped graphene (NG) to prepare an NG–hAuPd hybrid film. The obtained NG–hAuPd composite showed higher electrocatalytic activity toward the reduction of H2O2, compared with graphene–hAuPd hybrid, NG–solid AuPd hybrid, and hAuPd NPs. The enhanced performance was related to the hollow structure of hAuPd NPs and the synergistic effect between NG and hAuPd NPs. Under optimum conditions, the NG–hAuPd hybrid film showed a linear response to H2O2 in the range of 0.1–20 μM, with a sensitivity of 5095.5 μA mM–1 cm–2and a comparable detection limit of 0.02 μM (S/N = 3). These results demonstrated that the NG–hAuPd composite was a promising electrocatalytic material for constructing sensors, etc.
Functional gastrointestinal disorders (FGIDs) are common among the aircrew due to their arduous working environment. This study investigated the prevalence of FGIDs in Chinese male pilots and ...assessed the effects of trigger factors on the FGIDs. A cross-sectional study including 212 male pilots was performed in a Chinese large civil airline company. FGIDs were diagnosed according to the Rome IV diagnostic criteria. The psychological performance, dietary pattern, sleep situation, and physical activity of the respondents were assessed. Logistic regression analysis and structural equation modeling were used to explore the association between these trigger factors and FGIDs. FGIDs were observed in 83 (39.22%) respondents, of which 31 (37.35%) had overlap syndromes. Age, flight level, flight time, high-salt food pattern, anxiety, and sleep performance were found to be associated with FGIDs (all P < 0.05). Stepwise logistic regression analysis revealed that the flight level (OR 0.59, 95% CI 0.31-0.080), high-salt food pattern (OR 2.31, 95% CI 1.28-4.16), and sleep performance (OR 2.39, 95% CI 1.11-5.14) were the influencing factors associated with FGIDs. Structural equation modeling confirmed the correlations between FGIDs and the occupational, dietary, and psychological factors with a reasonable fit. The preventive strategies were necessitated according to occupational and psychological characteristics.
Fatigue is an important factor affecting modern flight safety. It can easily lead to a decline in pilots' operational ability, misjudgments, and flight illusions. Moreover, it can even trigger ...serious flight accidents. In this paper, a wearable wireless physiological device was used to obtain pilots' electrocardiogram (ECG) data in a simulated flight experiment, and 1440 effective samples were determined. The Friedman test was adopted to select the characteristic indexes that reflect the fatigue state of the pilot from the time domain, frequency domain, and non-linear characteristics of the effective samples. Furthermore, the variation rules of the characteristic indexes were analyzed. Principal component analysis (PCA) was utilized to extract the features of the selected feature indexes, and the feature parameter set representing the fatigue state of the pilot was established. For the study on pilots' fatigue state identification, the feature parameter set was used as the input of the learning vector quantization (LVQ) algorithm to train the pilots' fatigue state identification model. Results show that the recognition accuracy of the LVQ model reached 81.94%, which is 12.84% and 9.02% higher than that of traditional back propagation neural network (BPNN) and support vector machine (SVM) model, respectively. The identification model based on the LVQ established in this paper is suitable for identifying pilots' fatigue states. This is of great practical significance to reduce flight accidents caused by pilot fatigue, thus providing a theoretical foundation for pilot fatigue risk management and the development of intelligent aircraft autopilot systems.
This paper proposes a new direct active and reactive power control (DPC) for the three-phase grid connected dc/ac converters. The proposed DPC strategy employs a nonlinear sliding mode control (SMC) ...scheme to directly calculate the required converter's control voltage so as to eliminate the instantaneous errors of active and reactive powers without involving any rotating coordinate transformations. Meanwhile, there are no extra current control loops involved, which simplifies the system design and enhances the transient performance. Constant converter switching frequency is achieved by using space vector modulation, which eases the design of the ac harmonic filter. Simulation and experimental results are provided and compared with those of the classic voltage-oriented vector control (VC) and conventional lookup table (LUT) DPC strategies. The proposed SMC-DPC is capable of providing enhanced transient performance similar to that of the LUT-DPC, and keeps the steady-state harmonic spectra at the same level as those of the VC scheme. The robustness of the proposed DPC to line inductance variations is also inspected during active and reactive power changes.
Tetraethyl orthosilicate was selected as a matrix of heat insulating materials among three silanes, and an anti-infrared radiation fiber was chosen as a reinforcement for silica aerogel insulation ...composite. The silica aerogel was combined well and evenly distributed in the anti-infrared radiation fiber. The heat insulation effect was improved with the increase in thickness of the aerogel insulation material, as determined by the self-made aerospace insulation material insulation performance test equipment. The 15 mm and 30 mm thick thermal insulation material heated at 250 °C for 3 h, the temperatures at the cold surface were about 80 °C and 60 °C, respectively, and the temperatures at 150 mm above the cold surface were less than 60 °C and 50 °C, respectively. The silica aerogel composites with various thicknesses showed good thermal insulation stability. The silica insulation composite with a thickness of 15 mm exhibited good heat insulation performance, meets the thermal insulation requirements of general equipment compartments under low-temperature and long-term environmental conditions. The thermal conductivity of prepared silica aerogel composite was 0.0191 W·m
·k
at room temperature and 0.0489 W·m
·k
at 500 °C.
In the cathodic electrochemiluminescence (ECL) field, most reported luminophores produced ECL emission at high potentials (more than −1.3 V
vs.
Ag/AgCl), which was adverse for both fundamental ...studies and practical application. It was important to screen novel ECL luminophores and coreactants for the development of ECL. In this work,
N
,
N
′-dimethyl-3,4,9,10-perylenedicarboximide (PDI-CH
3
) is reported to produce ECL at −0.47 V using K
2
S
2
O
8
as a coreactant in an aqueous system. In addition, the ECL wavelength was 689 nm, which was interpreted with the emission of excited PDI-CH
3
dimers. Finally, this low-triggering-potential ECL system was used to construct sandwiched immunosensors to detect carcinoembryonic antigen (CEA) with the potential range from 0 to −0.8 V. In this immunosensor, PDI-CH
3
and gold nanoparticles (AuNPs) reduced by citrate were grafted onto graphite oxide (GO) to label secondary antibodies (Ab
2
). This immunosensor could sensitively detect CEA with the linear response range between 1 fg mL
−1
and 1 μg mL
−1
and detection limit 0.29 fg mL
−1
. In addition, this immunosensor showed good feasibility in various cancer serum samples.
N
,
N
′-Dimethyl-3,4,9,10-perylenedicarboximide emitted strong ECL at −0.47 V and was used to construct an ECL immunosensor for carcinoembryonic antigen detection.
•FGFR4 is significantly related with N stage in IHCC, with T stage and TNM stage in PHCC.•FGFR4 is an independent prognostic factor in IHCC and PHCC.•FGFR4 promotes proliferation, invasion and EMT in ...cholangiocarinoma cell lines.•Inhibitor AP24354 can decrease proliferation, invasion and induce apoptosis of CCA.
Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P=0.002) and PHCC (P=0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P=0.045) and PHCC (P=0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial–mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target.
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