Reactivation of Epstein–Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function

EBNA1 is the only Epstein–Barr virus (EBV) latent protein responsible for viral genome maintenance and is expressed in all EBV-infected cells. Zn2+ is essential for oligomerization of the functional EBNA1. We constructed an EBNA1 binding peptide with a Zn2+ chelator to create an EBNA1-specific inhibitor (ZRL5P4). ZRL5P4 by itself is sufficient to reactivate EBV from its latent infection. ZRL5P4 is able to emit unique responsive fluorescent signals once it binds with EBNA1 and a Zn2+ ion. ZRL5P4 can selectively disrupt the EBNA1 oligomerization and cause nasopharyngeal carcinoma (NPC) tumor shrinkage, possibly due to EBV lytic induction. Dicer1 seems essential for this lytic reactivation. As can been seen, EBNA1 is likely to maintain NPC cell survival by suppressing viral reactivation

Peak wind pressures on roof claddings of regular railway stations

Small or medium-scales regular railway stations are being widely built. Through an extensive survey of actual modern railway stations, the common ranges of building parameters were determined. Wind pressure measurements of 18 models were conducted by wind tunnel tests to systematically investigate the influence of the canopy width, opening width and waiting hall building height on peak wind pressure coefficients on roof claddings of the canopies and waiting hall building. According to the distribution law of the most critical minimum wind pressure coefficients, roofs of the two canopies and waiting hall building are divided into 19 zones for the convenience of engineering applications. The dependency of the area-averaged most critical minimum wind pressure coefficients on the tributary area in all roof zones of the canopies and waiting hall building are investigated. The fitted formulas to calculate the area-averaged most critical wind pressure coefficients are proposed as a function of the tributary area, which can be used as the reference for determining wind loads during the design of roof claddings of regular railway stations

EBNA1-targeted probe for the imaging and growth inhibition of tumours associated with the Epstein–Barr virus

Epstein–Barr nuclear antigen 1 (EBNA1), a dimeric oncoprotein of the Epstein–Barr virus (EBV), is essential for both viral-genome maintenance and the survival of infected cells. Despite EBNA1’s potential as a therapeutic target, tools for the direct monitoring of EBNA1 in vitro and in vivo are lacking. Here, we show that a peptide-based inhibitor that luminesces when bound to EBNA1 inside the nucleus of EBV+ cells can regulate EBNA1 homodimer formation and selectively inhibit the growth of EBV+ tumours of nasopharyngeal carcinoma cells (C666-1 and NPC43) and Burkitt’s lymphoma Raji cells. We also show that the peptide-based probe leads to 93% growth inhibition of EBV+ tumours in mice. Our findings support the hypothesis that selective inhibition of EBNA1 dimerization can be used to afford better EBV-related cancer differentiation, and highlight the potential application of the probe as a new generation of biotracers for investigating the fundamental biological function of EBNA1 and for exploring its application as a therapeutic target

Erratum: Reactivation of Epstein–Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function (Proceedings of the National Academy of Sciences of the United States of America (2019) 116 (26614-26624) DOI: 10.1073/pnas.1915372116)

Correction for “Reactivation of Epstein–Barr virus by a dualresponsive fluorescent EBNA1-targeting agent with Zn2+- chelating function,” by Lijun Jiang, Hong Lok Lung, Tao Huang, Rongfeng Lan, Shuai Zha, Lai Sheung Chan, Waygen Thor, Tik-Hung Tsoi, Ho-Fai Chau, Cecilia Boreström, Steven L. Cobb, Sai Wah Tsao, Zhao-Xiang Bian, Ga-Lai Law, Wing-Tak Wong, William Chi-Shing Tai, Wai Yin Chau, Yujun Du, Lucas Hao Xi Tang, Alan Kwok Shing Chiang, Jaap M. Middeldorp, Kwok-Wai Lo, Nai Ki Mak, Nicholas J. Long, and Ka-Leung Wong, which was first published December 10, 2019; 10.1073/pnas.1915372116 (Proc. Natl. Acad. Sci. U.S.A. 116, 26614–26624). The authors note that Fig. 6 appeared incorrectly. Part of panel D of the published figure was inadvertently omitted. The corrected figure and its legend appear below. (Figure Presented)

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV proteinspecific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency