Tick-borne encephalitis virus induces chemokine RANTES expression via activation of IRF-3 pathway.

BACKGROUND: Tick-borne encephalitis virus (TBEV) is one of the most important flaviviruses that targets the central nervous system (CNS) and causes encephalitides in humans. Although neuroinflammatory mechanisms may contribute to brain tissue destruction, the induction pathways and potential roles of specific chemokines in TBEV-mediated neurological disease are poorly understood. METHODS: BALB/c mice were intracerebrally injected with TBEV, followed by evaluation of chemokine and cytokine profiles using protein array analysis. The virus-infected mice were treated with the CC chemokine antagonist Met-RANTES or anti-RANTES mAb to determine the role of RANTES in affecting TBEV-induced neurological disease. The underlying signaling mechanisms were delineated using RANTES promoter luciferase reporter assay, siRNA-mediated knockdown, and pharmacological inhibitors in human brain-derived cell culture models. RESULTS: In a mouse model, pathological features including marked inflammatory cell infiltrates were observed in brain sections, which correlated with a robust up-regulation of RANTES within the brain but not in peripheral tissues and sera. Antagonizing RANTES within CNS extended the survival of mice and reduced accumulation of infiltrating cells in the brain after TBEV infection. Through in vitro studies, we show that virus infection up-regulated RANTES production at both mRNA and protein levels in human brain-derived cell lines and primary progenitor-derived astrocytes. Furthermore, IRF-3 pathway appeared to be essential for TBEV-induced RANTES production. Site mutation of an IRF-3-binding motif abrogated the RANTES promoter activity in virus-infected brain cells. Moreover, IRF-3 was activated upon TBEV infection as evidenced by phosphorylation of TBK1 and IRF-3, while blockade of IRF-3 activation drastically reduced virus-induced RANTES expression. CONCLUSIONS: Our findings together provide insights into the molecular mechanism underlying RANTES production induced by TBEV, highlighting its potential importance in the process of neuroinflammatory responses to TBEV infection

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

A unique distant submillimeter galaxy with an X-ray-obscured radio-luminous active galactic nucleus

We present a multiwavelength study of an atypical submillimeter galaxy in the GOODS-North field, with the aim to understand its physical properties of stellar and dust emission, as well as the central AGN activity. Although it is shown that the source is likely an extremely dusty galaxy at high redshift, its exact position of submillimeter emission is unknown. With the new NOEMA interferometric imaging, we confirm that the source is a unique dusty galaxy. It has no obvious counterpart in the optical and even NIR images observed with HST at lambda~<1.4um. Photometric-redshift analyses from both stellar and dust SED suggest it to likely be at z~>4, though a lower redshift at z~>3.1 cannot be fully ruled out (at 90% confidence interval). Explaining its unusual optical-to-NIR properties requires an old stellar population (~0.67 Gyr), coexisting with a very dusty ongoing starburst component. The latter is contributing to the FIR emission, with its rest-frame UV and optical light being largely obscured along our line of sight. If the observed fluxes at the rest-frame optical/NIR wavelengths were mainly contributed by old stars, a total stellar mass of ~3.5x10^11Msun would be obtained. An X-ray spectral analysis suggests that this galaxy harbors a heavily obscured AGN with N_H=3.3x10^23 cm^-2 and an intrinsic 2-10 keV luminosity of L_X~2.6x10^44 erg/s, which places this object among distant type 2 quasars. The radio emission of the source is extremely bright, which is an order of magnitude higher than the star-formation-powered emission, making it one of the most distant radio-luminous dusty galaxies. The combined characteristics of the galaxy suggest that the source appears to have been caught in a rare but critical transition stage in the evolution of submillimeter galaxies, where we are witnessing the birth of a young AGN and possibly the earliest stage of its jet formation and feedback.Comment: 13 pages in printer format, 10 figures, 1 table, accepted for publication in the A&

Feasibility study of SiCp reinforced TC11 titanium alloy under selective laser melting

In order to improve the comprehensive performance of titanium alloy, the mechanical ball milling method was used to optimize the preparation of composite powder by different ball milling time, rotation speed and SiCp content. SiCp/TC11 composites were prepared by selective laser melting (SLM) technology. The results show that the milling speed, time and SiC content have an effect on the morphology, size and distribution of the composite powder. Compared with TC11, the hardness of the composite prepared by SLM process is 426,723 HV, which is increased by 15,10 %, and the enhancement effect of SiCp is successfully realized.The research results provide a theoretical basis for obtaining high-quality aerospace titanium alloy parts

Feasibility study of SiCp reinforced TC11 titanium alloy under selective laser melting

In order to improve the comprehensive performance of titanium alloy, the mechanical ball milling method was used to optimize the preparation of composite powder by different ball milling time, rotation speed and SiCp content. SiCp/TC11 composites were prepared by selective laser melting (SLM) technology. The results show that the milling speed, time and SiC content have an effect on the morphology, size and distribution of the composite powder. Compared with TC11, the hardness of the composite prepared by SLM process is 426,723 HV, which is increased by 15,10 %, and the enhancement effect of SiCp is successfully realized.The research results provide a theoretical basis for obtaining high-quality aerospace titanium alloy parts

Optical loss compensation in a bulk left-handed metamaterial by the gain in quantum dots

A bulk left-handed metamaterial with fishnet structure is investigated to show the optical loss compensation via surface plasmon amplification, with the assistance of a Gaussian gain in PbS quantum dots. The optical resonance enhancement around 200 THz is confirmed by the retrieval method. By exploring the dependence of propagation loss on the gain coefficient and metamaterial thickness, we verify numerically that the left-handed response can endure a large propagation thickness with ultralow and stable loss under a certain gain coefficient.Comment: 6 pages with 4 figure

Study on cold spinning deformation behavior and load mechanism of conical thin-walled aluminum alloy parts

Aiming at the problem that the wall thickness uniformity of conical thin-walled aluminum alloy parts formed by single-pass spinning is difficult to control, this paper systematically studies the influence of different spinning parameters on the material evolution law and load mechanism during the forming process of 1070 thin-walled aluminum alloy. The effects of slab thickness, roller gap and feed ratio on the macroscopic forming quality and mechanical load of 1070 thin-walled aluminum alloy conical parts were simulated by Simufact.forming software. Finally, the optimal spinning parameters of 1070 thin-walled aluminum alloy conical parts were obtained. The final results show that increasing the diameter-thickness ratio of the blank can prevent wrinkling, and reasonable spinning parameters can improve the uniformity of the wall thickness of the product