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Lytic replication of Epstein-Barr virus (EBV) is not only essential for its cell-to- cell spread and host-to-host transmission, but it also contributes to EBV-induced oncogenesis. Thus, blocking EBV lytic replication could be a strategy for managing EBV-associated diseases. Previously, we identified a series of natural lignans isolated from the roots of Saururus chinensis (Asian lizard's tail) that efficiently block EBV lytic replication and virion production with low cytotoxicity. In this study, we attempted to elucidate the molecular mechanism by which these lignans inhibit EBV lytic replication. We found that a representative compound, CSC27 (manassantin B), inhibits EBV lytic replication by suppressing the expression of EBV immediateearly gene BZLF1 via disruption of AP-1 signal transduction. Further analysis revealed that manassantin B specifically blocks the mammalian target of rapamycin complex 2 (mTORC2)-mediated phosphorylation of AKT Ser/Thr protein kinase at Ser-473 and protein kinaseCα (PKCα) at Ser-657. Using phosphoinositide 3-kinase-AKT-specific inhibitors for kinase mapping and shRNA-mediated gene silencing, we validated that manassantin B abrogates EBV lytic replication by inhibiting mTORC2 activity and thereby blocking the mTORC2-PKC/AKT-signaling pathway. These results suggest thatmTORC2mayhave utility as an antiviral drug target against EBV infections and also reveal that manassantin B has potential therapeutic value for managing cancers that depend on mTORC2 signaling for survival. [ABSTRACT FROM AUTHOR]

Hypertension is a major risk factor for human cardiovascular health, which can damage heart, brain, kidneys, etc. In this study we aimed to develop novel angiotensin II receptor blockers (ARBs) that prevent the increase of blood pressure for treatment of hypertension. (2-(4-((2-Amyl-5-nitro-1H-benzo[d]-imidazol-1-yl) methyl)-1H-indol-1-yl) tetrazole; compound 1a) was one of the ARBs designed and synthesized. It was prepared and orally administered to spontaneous hypertensive rats to study the antihypertensive effects. The maximum reduction in blood pressure reached 50 mmHg after dosing compound 1a for 5 h. Acute toxicity test was carried out on healthy 4 week old 30 male and 30 female ICR mice and LD50 for 1a was found to be 2864.03 mg/kg. High performance liquid chromatography was employed to determine the level of 1a plasma concentration at various time points after administration. The plasma concentration of 1a increased after 2 h, declined gradually and was still detectable in the plasma after 72 h. The drug distribution analysis of 1a was performed on healthy Wistar rats. It was present in the liver with the highest concentration, in kidney with a lower concentration, and in the spleen, lung, heart and brain with the lowest concentration. It displayed high affinity to AT1 receptor, and had an efficient and long-lasting effect in reducing blood pressure, which lasted for more than 12 h. Due to its biological safety, 1a could be absorbed quickly, metabolized smoothly, and can be distributed in important organs. Therefore, 1a could be considered as a suitable ARB candidate for further studies. [ABSTRACT FROM AUTHOR]

Buried depth of grounding grids is one of the important factors to determine the grounding performance in substations, however, the real buried depth of grounding grids is changed and unknown due to the drawing loss and backfill during the reconstruction of the grounding grids. This paper proposes a derivative-based method to detect the buried depth of different metal conductors. First, the theoretical basis for the derivative-based method to detect the buried depth is described, and an example calculation on buried depth detection according to the magnetic derivation characteristic is carried out for a single conductor case. The results indicate that the main-side-peaks characteristic of the derivative method can determine the buried depth of metal conductor effectively. Then, the analysis of grounding grids is carried out to verify its validation in grounding grid buried depth detection, and results indicate that the method is effective in the cases of magnetic field superimposing, different buried depths of grounding grid, and nonuniform distribution of current in grounding grid. Finally, the experimental results prove that the derivative method works well with low error. [ABSTRACT FROM AUTHOR]

The topology and breakpoints of the grounding grid will directly affect its working performance. This paper proposed a resistivity reconstruction method based on magnetic detection electrical impedance tomography (MDEIT) to measure the topology and breakpoints of the grounding grid. First, this paper describes the forward problem of grounding grid detection in MDEIT, and calculates the magnetic-field distribution above the grounding grid. Then, the resistivity reconstruction method based on the least squares method is proposed. Finally, this paper verifies the feasibility of the proposed method by a numerical example, which shows that the proposed method can be applied to measure the topology and breakpoints of the grounding grid. [ABSTRACT FROM AUTHOR]