miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

Background/Aims: MicroRNAs (miRNAs) are a group of non-coding RNAs that play diverse roles in pancreatic carcinogenesis. In pancreatic ductal adenocarcinoma (PDAC), NF-kB is constitutively activated in most patients and is linked to a mutation in KRAS via IkB kinase complex 1 (IKK1, also known as IKKa). We investigated the link between PDAC aggressiveness and miR-1290. Methods: We used miRCURYTM LNA Array and in situ hybridization to investigate candidate miRNAs and validated the findings with PCR. The malignant behavior of cell lines was assessed with Cell Counting Kit-8, colony formation, and Transwell assays. A dual-luciferase reporter assay was used to evaluate the interaction between miR-1290 and IKK1. Protein expression was observed by western blotting. Results: In this study, 36 miRNAs were dysregulated in high-grade pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues compared with low-grade PanIN tissues. The area under the curve values of miR-1290 and miR-31-5p were 0.829 and 0.848, respectively (95% confidence interval, 0.722–0.936 and 0.749–0.948, both P < 0.001). There was a significant correlation between miR-1290 and histological differentiation (P = 0.029), pT stage (P = 0.006), and lymph node metastasis (P = 0.001). In addition, the in vitro work showed that miR-1290 promoted PDAC cell proliferation, invasion, and migration. Western blotting and the dual-luciferase reporter assay showed that miR-1290 promoted cancer aggressiveness by directly targeting IKK1. The synergist effect of miR-1290 on the proliferation and metastasis of PDAC cells was attenuated and enhanced by IKK1 overexpression and knockdown, respectively. Consistent with the in vitro results, a subcutaneous tumor mouse model showed that miR-1290 functioned as a potent promoter of PDAC in vivo. Conclusion: MiR-1290 may act as an oncogene by directly targeting the 3’-untranslated region of IKK1, and the miR-1290/IKK1 pathway may prove to be a novel diagnostic and therapeutic target for PDAC

Study on the effect of different pre-excitation factors on the output characteristics of MCSR

This paper takes the BKFSZT-30000/400 three-phase eight-limb magnetically controlled shunt reactor as the research object. Firstly, an electromagnetic transient simulation model is established based on the parity principle to verify the operating characteristics of the MCSR during direct energization and pre-excitation energization. On this basis, the influence of the pre-excitation capacity and the target capacity on the output characteristics of the MCSR is investigated. The results show that during the pre-excitation process the currents of working and control winding produce a DC component and a harmonic component dominated by the second harmonic, with the size of both DC components mainly influenced by the pre-excitation capacity and the attenuation determined by MCSR; the variation of the working harmonics is mainly influenced by the target capacity, while the size and attenuation of the control harmonics are determined by the pre-excitation capacity and the target capacity respectively. The results of the study clarify the output characteristics of the MCSR when energization with pre-excitation and provide a reference for further analysis of the interaction with the grid. Finally, to solve the problem of no reliable external power supply for pre-excitation, a fast excitation energization method with short-connected of the compensation winding is provided and verified by simulation

Design and analysis of 12 MW offshore wind turbine

Permanent magnet synchronous motors are widely used in various fields for the advantages of high power density, high efficiency and high reliability. This paper analyzes the cogging torque of generators with different slot and pole coordination, and selects the optimal pole–slot ratio. Then, this paper analyzes the structural differences between the outer rotor and the inner rotor of permanent magnet synchronous motor, and selects the structural form of the outer rotor for analysis. Based on the electromagnetic design parameters of the motor, a two-dimensional finite element model is established in Maxwell to simulate and analyze the performance at no-load, rated load and short-circuit. The internal magnetic field, the distortion rate of voltage waveform, torque and short circuit current of the motor are studied, and the demagnetization of the permanent magnet under the worst operating condition is investigated. The simulation results show that the design scheme meets the design objectives

Modeling and analysis for group delay mismatch effect on wideband adaptive spatial interference cancellation

Abstract The adaptive interference cancellation technique has been widely utilized in radar, GPS, data link, etc., systems to address challenges from external interference, such as co-site and hostile interference. Since the anti-jamming performance of the adaptive interference cancellation technique is sensitive to group delay mismatch between channels, the group delay mismatch becomes one of the main factors that limit the system’s anti-jamming capability. However, the traditional adaptive interference cancellation system’s mathematical model cannot quantitatively characterize the group delay mismatch effect on the wideband interference cancellation performance. In this paper, the mathematical model of the wideband adaptive spatial interference cancellation (ASIC) system is established, which considers the group delay mismatch, to quantitatively analyze the impact of group delay mismatch on the hostile interference cancellation. The mathematical model utilizes the weighted multi-tone signals to fit the wideband interference, and then, delay differences are attached to each tone signal to simulate the group delay mismatch. Then, the analytic expressions of weight and interference cancellation ratio are derived, which consider the interference bandwidth and group delay mismatch, to quantitatively analyze the group delay mismatch effect on the anti-jamming performance of the wideband ASIC system. Simulation results indicate that the theoretical analysis based on the mathematical model of wideband ASIC system are accurate, which can achieve the quantitative analysis of the group delay mismatch effect on the WIC performance

Purification and Functional Characterization of a Soluble Trehalase in <i>Lissorhoptrus oryzophilus</i> (Coleoptera: Curculionidae)

Trehalase is the only enzyme known for the irreversible splitting of trehalose and plays a major role in insect growth and development. In this report, we describe a basic study of the trehalase gene fragment encoding a soluble trehalase from Lissorhoptrus oryzophilus (LoTRE1). Sequence alignment and phylogenetic analysis suggested that LoTRE1 was similar to some known insect trehalases and belongs to the Coleoptera trehalase group. Additionally, LoTRE1 was expressed mainly in the fat body. Purified protein was obtained using heterologous expression of LoTRE1 in Escherichia coli, and the recombinant protein exhibited the ability to decompose trehalose. Enzyme–substrate docking indicated the potential involvement of other residues in the catalytic activity, in addition to Asp 333. Moreover, feeding of adults on LoTRE1 dsRNA silenced the transcription of LoTRE1 and thereby reduced the activity of trehalase and increased the trehalose content; it also led to a 12% death rate. This study reveals essential molecular features of trehalase and offers insights into the structural aspects of this enzyme, which might be related to its function. Taken together, the findings demonstrate that LoTRE1 is indispensable for adults of this pest and provide a new target for the control of L. oryzophilus

MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin

The long non-coding RNA maternally expressed gene 3 (MEG3) is frequently dysregulated in human cancers; however, its roles in colorectal cancer (CRC) development are largely unknown. Here, we reported that MEG3 was down-regulated in CRC tissues and CRC patients with lower MEG3 showed poorer overall survival and disease-free survival than those with higher MEG3 level. MEG3 over-expression represses CRC cells proliferation and migration in vivo and in vitro, while MEG3 knockdown leads to the enhanced proliferation and metastasis of CRC cells. In CRC cells, MEG3 over-expression is related to decreased Clusterin mRNA and the corresponding protein levels, and it also directly binds to Clusterin protein through its 732–1174 region. In further, Clusterin over-expression rescues the compromised abilities of proliferation and metastasis induced by MEG3 over-expression, suggesting that MEG3 inhibits the CRC progression through regulating the Clusterin activities. Additionally, we found that 1α,25-(OH)2D and vitamin D receptor (VDR) stimulate MEG3 expression in CRC cells through directly binding to its promoter. These results suggested that MEG3 functions as a tumor suppressor in CRC via regulating the Clusterin activities and may underlie the anticancer activities of vitamin D on CRC cells. The VDR/MEG3/Clusterin signaling pathway may serve as potential therapeutic targets and prognosis biomarkers for CRC patients in future. Keywords: lncRNA, CRC, MEG3, Clusterin, Vitamin

Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca2+-dependent gap junction intercellular communication

Abstract. Background:. Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. Methods:. Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca2+-related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. Results:. Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca2+ is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. Conclusions:. Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy