ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells.

BACKGROUND: Many viruses depend on the extensive membranous network of the endoplasmic reticulum (ER) for their translation, replication, and packaging. Certain membrane modifications of the ER can be a trigger for ER stress, as well as the accumulation of viral protein in the ER by viral infection. Then, unfolded protein response (UPR) is activated to alleviate the stress. Zika virus (ZIKV) is a mosquito-borne flavivirus and its infection causes microcephaly in newborns and serious neurological complications in adults. Here, we investigated ER stress and the regulating model of UPR in ZIKV-infected neural cells in vitro and in vivo. METHODS: Mice deficient in type I and II IFN receptors were infected with ZIKV via intraperitoneal injection and the nervous tissues of the mice were assayed at 5 days post-infection. The expression of phospho-IRE1, XBP1, and ATF6 which were the key markers of ER stress were analyzed by immunohistochemistry assay in vivo. Additionally, the nuclear localization of XBP1s and ATF6n were analyzed by immunohistofluorescence. Furthermore, two representative neural cells, neuroblastoma cell line (SK-N-SH) and astrocytoma cell line (CCF-STTG1), were selected to verify the ER stress in vitro. The expression of BIP, phospho-elF2α, phospho-IRE1, and ATF6 were analyzed through western blot and the nuclear localization of XBP1s was performed by confocal immunofluorescence microscopy. RT-qPCR was also used to quantify the mRNA level of the UPR downstream genes in vitro and in vivo. RESULTS: ZIKV infection significantly upregulated the expression of ER stress markers in vitro and in vivo. Phospho-IRE1 and XBP1 expression significantly increased in the cerebellum and mesocephalon, while ATF6 expression significantly increased in the mesocephalon. ATF6n and XBP1s were translocated into the cell nucleus. The levels of BIP, ATF6, phospho-elf2α, and spliced xbp1 also significantly increased in vitro. Furthermore, the downstream genes of UPR were detected to investigate the regulating model of the UPR during ZIKV infection in vitro and in vivo. The transcriptional levels of atf4, gadd34, chop, and edem-1 in vivo and that of gadd34 and chop in vitro significantly increased. CONCLUSION: Findings in this study demonstrated that ZIKV infection activates ER stress in neural cells. The results offer clues to further study the mechanism of neuropathogenesis caused by ZIKV infection

On the existence of almost periodic solutions of neutral functional differential equations

This paper discusses the existence of almost periodic solutions of neutral functional differential equations. Using a Liapunov function and the Razumikhin's technique, we obtain the existence, uniqueness and stability of almost periodic solutions

Excitation of nonlinear ion acoustic waves in CH plasmas

Excitation of nonlinear ion acoustic wave (IAW) by an external electric field is demonstrated by Vlasov simulation. The frequency calculated by the dispersion relation with no damping is verified much closer to the resonance frequency of the small-amplitude nonlinear IAW than that calculated by the linear dispersion relation. When the wave number $k\lambda_{De}$ increases, the linear Landau damping of the fast mode (its phase velocity is greater than any ion's thermal velocity) increases obviously in the region of $T_i/T_e < 0.2$ in which the fast mode is weakly damped mode. As a result, the deviation between the frequency calculated by the linear dispersion relation and that by the dispersion relation with no damping becomes larger with $k\lambda_{De}$ increasing. When $k\lambda_{De}$ is not large, such as $k\lambda_{De}=0.1, 0.3, 0.5$, the nonlinear IAW can be excited by the driver with the linear frequency of the modes. However, when $k\lambda_{De}$ is large, such as $k\lambda_{De}=0.7$, the linear frequency can not be applied to exciting the nonlinear IAW, while the frequency calculated by the dispersion relation with no damping can be applied to exciting the nonlinear IAW.Comment: 10 pages, 9 figures, Accepted by POP, Publication in August 1