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

Measurement of the c-axis optical reflectance of AFe2_2As2_2 (A=Ba, Sr) single crystals: Evidence of different mechanisms for the formation of two energy gaps

We present the c-axis optical reflectance measurement on single crystals of BaFe$_2$As$_2$ and SrFe$_2$As$_2$, the parent compounds of FeAs based superconductors. Different from the ab-plane optical response where two distinct energy gaps were observed in the SDW state, only the smaller energy gap could be seen clearly for \textbf{E}$\parallel$c-axis. The very pronounced energy gap structure seen at a higher energy scale for \textbf{E}$\parallel$ab-plane is almost invisible. We propose a novel picture for the band structure evolution across the SDW transition and suggest different driving mechanisms for the formation of the two energy gaps.Comment: 4 page

New Approach on the General Shape Equation of Axisymmetric Vesicles

The general Helfrich shape equation determined by minimizing the curvature free energy describes the equilibrium shapes of the axisymmetric lipid bilayer vesicles in different conditions. It is a non-linear differential equation with variable coefficients. In this letter, by analyzing the unique property of the solution, we change this shape equation into a system of the two differential equations. One of them is a linear differential equation. This equation system contains all of the known rigorous solutions of the general shape equation. And the more general constraint conditions are found for the solution of the general shape equation.Comment: 8 pages, LaTex, submit to Mod. Phys. Lett.

SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication.

Accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. Ubiquitination and SUMOylation are extensively studied posttranslational modifications (PTMs) that play critical roles in diverse biological processes. Cross talk between ubiquitination and SUMOylation of both host and viral proteins has been reported to result in distinct functional consequences. Enterovirus 71 (EV71), an RNA virus belonging to the family Picornaviridae, is a common cause of hand, foot, and mouth disease. Little is known concerning how host PTM systems interact with enteroviruses. Here, we demonstrate that the 3D protein, an RNA-dependent RNA polymerase (RdRp) of EV71, is modified by small ubiquitin-like modifier 1 (SUMO-1) both during infection and in vitro Residues K159 and L150/D151/L152 were responsible for 3D SUMOylation as determined by bioinformatics prediction combined with site-directed mutagenesis. Also, primer-dependent polymerase assays indicated that mutation of SUMOylation sites impaired 3D polymerase activity and virus replication. Moreover, 3D is ubiquitinated in a SUMO-dependent manner, and SUMOylation is crucial for 3D stability, which may be due to the interplay between the two PTMs. Importantly, increasing the level of SUMO-1 in EV71-infected cells augmented the SUMOylation and ubiquitination levels of 3D, leading to enhanced replication of EV71. These results together suggested that SUMO and ubiquitin cooperatively regulated EV71 infection, either by SUMO-ubiquitin hybrid chains or by ubiquitin conjugating to the exposed lysine residue through SUMOylation. Our study provides new insight into how a virus utilizes cellular pathways to facilitate its replication. IMPORTANCE: Infection with enterovirus 71 (EV71) often causes neurological diseases in children, and EV71 is responsible for the majority of fatalities. Based on a better understanding of interplay between virus and host cell, antiviral drugs against enteroviruses may be developed. As a dynamic cellular process of posttranslational modification, SUMOylation regulates global cellular protein localization, interaction, stability, and enzymatic activity. However, little is known concerning how SUMOylation directly influences virus replication by targeting viral polymerase. Here, we found that EV71 polymerase 3D was SUMOylated during EV71 infection and in vitro Moreover, the SUMOylation sites were determined, and in vitro polymerase assays indicated that mutations at SUMOylation sites could impair polymerase synthesis. Importantly, 3D is ubiquitinated in a SUMOylation-dependent manner that enhances the stability of the viral polymerase. Our findings indicate that the two modifications likely cooperatively enhance virus replication. Our study may offer a new therapeutic strategy against virus replication

Zika virus promotes CCN1 expression via the CaMKIIα-CREB pathway in astrocytes.

Zika virus (ZIKV) infection in the human central nervous system (CNS) causes Guillain-Barre syndrome, cerebellum deformity, and other diseases. Astrocytes are immune response cells in the CNS and an important component of the blood-brain barrier. Consequently, any damage to astrocytes facilitates the spread of ZIKV in the CNS. Connective tissue growth factor/Nephroblastoma overexpressed gene family 1 (CCN1), an important inflammatory factor secreted by astrocytes, is reported to regulate innate immunity and viral infection. However, the mechanism by which astrocyte viral infection affects CCN1 expression remains undefined. In this study, we demonstrate that ZIKV infection up-regulates CCN1 expression in astrocytes, thus promoting intracellular viral replication. Other studies revealed that the cAMP response element (CRE) in the CCN1 promoter is activated by the ZIKV NS3 protein. The cAMP-responsive element-binding protein (CREB), a transacting factor of the CRE, is also activated by NS3 or ZIKV. Furthermore,a specific inhibitor of CREB, i.e. SGC-CBP30, reduced ZIKV-induced CCN1 up-regulation and ZIKV replication. Moreover, co-immunoprecipitation, overexpression, and knockdown studies confirmed that the interaction between NS3 and the regulatory domain of CaMKIIα could activate the CREB pathway, thus resulting in the up-regulation of CCN1 expression and enhancement of virus replication. In conclusion, the findings of our investigations on the NS3-CaMKIIα-CREB-CCN1 pathway provide a foundation for understanding the infection mechanism of ZIKV in the CNS

Discussion on Event Horizon and Quantum Ergosphere of Evaporating Black Holes in a Tunnelling Framework

In this paper, with the Parikh-Wilczek tunnelling framework the positions of the event horizon of the Vaidya black hole and the Vaidya-Bonner black hole are calculated respectively. We find that the event horizon and the apparent horizon of these two black holes correspond respectively to the two turning points of the Hawking radiation tunnelling barrier. That is, the quantum ergosphere coincides with the tunnelling barrier. Our calculation also implies that the Hawking radiation comes from the apparent horizon.Comment: 8 page

Robust interface between flying and topological qubits

Hybrid architectures, consisting of conventional and topological qubits, have recently attracted much attention due to their capability in consolidating the robustness of topological qubits and the universality of conventional qubits. However, these two kinds of qubits are normally constructed in significantly different energy scales, and thus this energy mismatch is a major obstacle for their coupling that supports the exchange of quantum information between them. Here, we propose a microwave photonic quantum bus for a direct strong coupling between the topological and conventional qubits, in which the energy mismatch is compensated by the external driving field via the fractional ac Josephson effect. In the framework of tight-binding simulation and perturbation theory, we show that the energy splitting of the topological qubits in a finite length nanowire is still robust against local perturbations, which is ensured not only by topology, but also by the particle-hole symmetry. Therefore, the present scheme realizes a robust interface between the flying and topological qubits. Finally, we demonstrate that this quantum bus can also be used to generate multipartitie entangled states with the topological qubits.Comment: Accepted for publication in Scientific Report

Aeroelastic Performance Analysis of Wind Turbine in the Wake with a New Elastic Actuator Line Model

The scale of a wind turbine is getting larger with the development of wind energy recently. Therefore, the effect of the wind turbine blades deformation on its performances and lifespan has become obvious. In order to solve this research rapidly, a new elastic actuator line model (EALM) is proposed in this study, which is based on turbinesFoam in OpenFOAM (Open Source Field Operation and Manipulation, a free, open source computational fluid dynamics (CFD) software package released by the OpenFOAM Foundation, which was incorporated as a company limited by guarantee in England and Wales). The model combines the actuator line model (ALM) and a beam solver, which is used in the wind turbine blade design. The aeroelastic performances of the NREL (National Renewable Energy Laboratory) 5 MW wind turbine like power, thrust, and blade tip displacement are investigated. These results are compared with some research to prove the new model. Additionally, the influence caused by blade deflections on the aerodynamic performance is discussed. It is demonstrated that the tower shadow effect becomes more obvious and causes the power and thrust to get a bit lower and unsteady. Finally, this variety is analyzed in the wake of upstream wind turbine and it is found that the influence on the performance and wake flow field of downstream wind turbine becomes more serious