Infectious bursal disease virus (IBDV) is a bi-segmented double-strand RNA (dsRNA) virus of the family. While IBDV genomic dsRNA lacks a 5' cap, the means by which the uncapped IBDV genomic RNA is translated effectively is unknown. In this study, we describe a cap-independent pathway of translation initiation of IBDV uncapped RNA that relies on VP1 and VP3. We show that neither purified IBDV genomic dsRNA nor the uncapped viral plus-sense RNA transcripts was directly translated and rescued into infectious viruses in host cells. This defect in translation of the uncapped IBDV genomic dsRNA was rescued by-supplementation of the viral proteins VP1 and VP3, which was dependent on both the intact polymerase activity of VP1 and the dsRNA binding activity of VP3. Deletion analysis showed that both 5' - and 3' -UTRs of IBDV dsRNA were essential for the VP1/VP3-dependent translation initiation. Significantly, VP1 and VP3 could also mediate the recovery of infectious IBDV from the authentic minus-sense strand of IBDV dsRNA. Moreover, down-regulation or inhibition of the cap-binding protein eIF4E did not decrease, but rather enhanced the VP1/VP3-mediated translation of the uncapped IBDV RNA. Collectively, our findings for the first time reveal that VP1 and VP3 compensate for the deficiency of 5' cap and replace eIF4E to confer upon the uncapped IBDV RNA the ability to be translated and rescued into infectious viruses.A key point of control for virus replication is the viral translation initiation. The current study shows that the uncapped IBDV RNA cannot be translated into viral proteins directly by host translation machinery, and is thus noninfectious. Our results constitute the first direct experimental evidence that the VP1 and VP3 are required and sufficient to initiate translation of uncapped IBDV genomic RNA by acting as a substitute of cap and replacing the cap-binding protein eIF4E. Significantly, the VP1/VP3 mediate the recovery of infectious IBDV not only from the plus-sense but also from the minus-sense strand of the IBDV dsRNA. These findings provide not only new insights into the molecular mechanisms of the life cycle of IBDV, but also a new tool for an alternative strategy for the recovery of IBDV from both the plus- and the minus-sense strand of the viral genomic dsRNA.

While the entry of infectious bursal disease virus (IBDV) is initiated by the binding of the virus to the two major receptors integrin and HSP90, the signaling events after receptor binding and how they contribute to virus entry remain elusive. We show here that IBDV activates c-Src by inducing the phosphorylation of the Y416 residue in c-Src both in DF-1 chicken fibroblasts and in vivo in the bursa of Fabricius from specific-pathogen-free (SPF) chickens. Importantly, inactivated IBDV fails to stimulate c-Src Y416 phosphorylation, and a very virulent IBDV strain induces a much higher level of c-Src Y416 phosphorylation than does an attenuated strain. Inhibition of c-Src activation by an Src kinase inhibitor or expression of a c-Src dominant negative mutant results in a significant decrease in the internalization of IBDV but has little effect on virus adhesion. Furthermore, short hairpin RNA (shRNA) downregulation of integrin, either the ␣4 or ␤1 subunit, but not HSP90 remarkably attenuates IBDV-induced c-Src Y416 phosphorylation, resulting in a decrease in IBDV internalization but not virus adhesion. Moreover, interestingly, inhibition of either c-Src downstream of the phosphatidylinositol 3-kinase (PI3K)/Akt-RhoA signaling cascade or actin rearrangement leads to a significant decrease in IBDV internalization irrespective of the IBDV-induced high levels of c-Src phosphorylation. Cumulatively, our results suggest a novel feed-forward model whereby IBDV activates c-Src for benefiting its cell entry via an integrin-mediated pathway by the activation of downstream PI3K/Akt-RhoA signaling and cytoskeleton actin rearrangement.IMPORTANCE While IBDV-caused immunosuppression is highly related to viral invasion, the molecular basis of the cellular entry of IBDV remains elusive. In this study, we demonstrate that IBDV activates c-Src by inducing the phosphorylation of the Y416 residue in c-Src to promote virus internalization but not virus adhesion. The ability to induce the level of c-Src Y416 phosphorylation correlates with the pathogenicity of an IBDV strain. IBDV-induced c-Src Y416 activation is ␣4␤1 integrin but not HSP90 dependent and involves the activation of the downstream PI3K/Akt-RhoA GTPase-actin rearrangement cascade. Thus, our findings provide new insights into the IBDV infection process and the potential for c-Src as a candidate target for the development of IBDV therapeutic drugs.

Infectious bursal disease virus (IBDV) infection triggers the induction of type I IFN, which is mediated by melanoma differentiation-associated protein 5 recognition of the viral genomic double-stranded RNA (dsRNA). However, the mechanism of IBDV overcoming the type I IFN antiviral response remains poorly characterized. Here, we show that IBDV genomic dsRNA selectively binds to the host cellular RNA binding protein Staufen1 (STAU1) in vitro and in vivo. The viral dsRNA binding region was mapped to the N-terminal moiety of STAU1 (residues 1-468). Down-regulation of STAU1 impaired IBDV replication and enhanced IFN-β transcription in response to IBDV infection, while having little effect on the viral attachment to the host cells and cellular entry. Conversely, overexpression of STAU1 but not the IBDV dsRNA-binding deficient STAU1 mutant (469-702) led to a suppression of IBDV dsRNA-induced IFN-β promoter activity. Moreover, we found that the binding of STAU1 to IBDV dsRNA decreased the association of melanoma differentiation-associated protein 5 but not VP3 with the IBDV dsRNA in vitro. Finally, we showed that STAU1 and VP3 suppressed IFN-β gene transcription in response to IBDV infection in an additive manner. Collectively, these findings provide a novel insight into the evasive strategies used by IBDV to escape the host IFN antiviral response.-Ye, C., Yu, Z., Xiong, Y., Wang, Y., Ruan, Y., Guo, Y., Chen, M., Luan, S., Zhang, E., Liu, H. STAU1 binds to IBDV genomic double-stranded RNA and promotes viral replication via attenuation of MDA5-dependent β interferon induction.

Hollow CoS x nanoparticles grown on FeCo-LDH microtubes (FeCo-LDH@CoS x ) were successfully developed as a highly efficient and lowcost electrocatalyst for the oxygen evolution reaction (OER) in an alkaline solution. The as-prepared FeCo-LDH@CoS x microtubes were characterized by X-ray powder diffraction, field emission scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy, and high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM)-EDS elemental mapping. Experiments showed that the as-obtained hollow FeCo-LDH@CoS x electrocatalyst required low overpotentials of 229, 270, and 308 mV to deliver current densities of 10, 100, and 400 mA cm −2 in a 1 M KOH distilled water solution, respectively. Also, the as-obtained catalyst exhibited good durability in various alkaline electrolytes, including distilled water, tap water, and natural river water. In a twoelectrode water-splitting device with nickel foams separately coated by FeCo-LDH@CoS x and 20% Pt/C as the anode and the cathode, respectively, using distilled water as the electrolyte, voltages of 1.495, 1.600, and 1.785 V were separately required for achieving current densities of 10, 100, and 400 mA cm −2 . Simultaneously, the present two-electrode system continuously worked for 50 h at a current density of 50 mA cm −2 in various alkaline electrolytes, including distilled water, tap water, and natural river water, and no obvious voltage fluctuation was detected, implying remarkable stability. Obviously, the present FeCo-LDH@CoS x microstructure provides a catalyst selection for the OER in practical applications.

Discovering the common modules that are co-expressed across various stages can lead to an improved understanding of the underlying molecular mechanisms of cancers. There is a shortage of efficient tools for integrative analysis of gene expression and protein interaction networks for discovering common modules associated with cancer progression. To address this issue, we propose a novel regularized multi-view subspace clustering (rMV-spc) algorithm to obtain a representation matrix for each stage and a joint representation matrix that balances the agreement across various stages. To avoid the heterogeneity of data, the protein interaction network is incorporated into the objective of rMV-spc via regularization. Based on the interior point algorithm, we solve the optimization problem to obtain the common modules. By using artificial networks, we demonstrate that the proposed algorithm outperforms state-of-the-art methods in terms of accuracy. Furthermore, the rMV-spc discovers common modules in breast cancer networks based on the breast data, and these modules serve as biomarkers to predict stages of breast cancer. The proposed model and algorithm effectively integrate heterogeneous data for dynamic modules.

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Hypergraph partitioning is critical for dividing and conquering intractable problems in many complex systems, which is an NP-hard problem. In the paper, a novel hypergraph bipartitioning algorithm is proposed, which partitions the hypergraph by separating the intersection graph. The new approach completely eliminates the adverse effects of hyperedges with large cardinality on the performance of the vertex-oriented refinement algorithms, and enhances the hill-climbing ability of the move-based refinement algorithms. Our approach also simplifies the vertex designation. Experiments on the industrial testing benchmark datasets indicate that our approach achieves an average of 7% improvement in performance over FM family partitioning algorithms.