COVID-19 pandemic continues worldwide with many variants arising, especially those of variants of concern (VOCs). A recent VOC, Omicron (B.1.1.529), which obtains a large number of mutations in the receptor-binding domain (RBD) of the spike protein, has risen to intense scientific and public attention. Here we studied the binding properties between the human receptor ACE2 (hACE2) and the VOC RBDs and resolved the crystal and cryo- EM structures of the Omicron RBD-hACE2 complex, as well as the crystal structure of Delta RBD-hACE2 complex. We found that, unlike Alpha, Beta and Gamma, Omicron RBD binds to hACE2 at a similar affinity compared to that of the prototype RBD, which might be due to compensation of multiple mutations for both immune escape and transmissibility. The complex structures of Omicron-hACE2 and Delta-hACE2 reveal the structural basis of how RBD-specific mutations bind to hACE2.

We recently reported the critical importance of Rac GTPase-dependent cortical actin rearrangement in the augmentation of pulmonary endothelial cell (EC) barrier function by sphingosine 1-phosphate (S1P). We now describe functional roles for the actin-binding proteins cortactin and EC myosin light chain kinase (MLCK) in mediating this response. Antisense down-regulation of cortactin protein expression significantly inhibits S1P-induced barrier enhancement in cultured human pulmonary artery EC as measured by transendothelial electrical resistance (TER). Immunofluorescence studies reveal rapid, Rac-dependent translocation of cortactin to the expanded cortical actin band following S1P challenge, where colocalization with EC MLCK occurs within 5 min. Adenoviral overexpression of a Rac dominant negative mutant attenuates TER elevation by S1P. S1P also induces a rapid increase in cortactin tyrosine phosphorylation (within 30 s) critical to subsequent barrier enhancement, since EC transfected with a tyrosinedeficient mutant cortactin exhibit a blunted TER response. Direct binding of EC MLCK to the cortactin Src homology 3 domain appears essential to S1P barrier regulation, since cortactin blocking peptide inhibits both S1P-induced MLC phosphorylation and peak S1P-induced TER values. These data support novel roles for the cytoskeletal proteins cortactin and EC MLCK in mediating lung vascular barrier augmentation evoked by S1P.The pulmonary endothelium is a functionally dynamic tissue that serves as a semipermeable barrier between circulating vascular contents and the interstitium and airspaces of the lung. The regulatory mechanisms involved in maintenance of this barrier are poorly understood; however, we recently reported that sphingosine 1-phosphate (S1P), 1 a potent phospholipid angiogenic factor released from activated platelets (1), produces significant endothelial cell (EC) barrier enhancement through Edg receptor ligation and Rac GTPase-dependent cortical actin rearrangement (2). Although the rapid, sustained, and dose-dependent increase in EC transmonolayer electrical resistance (TER) generated by S1P requires an intact actin cytoskeleton capable of undergoing dynamic rearrangement (2), the specific mediators and regulatory mechanisms that effect these actin cytoskeletal changes remain unclear.The 80/85-kDa actin-binding protein, cortactin, has been implicated in cortical actin rearrangement (3). Ideally suited for integrating multiple signals at sites of dynamic actin rearrangement, the amino acid structure of cortactin contains an N-terminal acidic region that stimulates actin polymerization by the Arp2-Arp3 complex (murine AA 1-90), a unique tandem repeat site for actin binding (AA 91-326), a Pro-and Tyr-rich area containing sites for p60 src phosphorylation (AA 401-495), and a C-terminal SH3 domain (AA 496 -546) (3). Cortactin stimulates and stabilizes Arp2-Arp3-mediated polymerization of branched actin filaments at peripheral sites of cytoskeletal rearrangement (4, 5), but regulation of cortactin's activity ...

Since April 2010, a severe outbreak of duck viral infection, with egg drop, feed uptake decline and ovary-oviduct disease, has spread around the major duck-producing regions in China. A new virus, named BYD virus, was isolated in different areas, and a similar disease was reproduced in healthy egg-producing ducks, infecting with the isolated virus. The virus was re-isolated from the affected ducks and replicated well in primary duck embryo fibroblasts and Vero cells, causing the cytopathic effect. The virus was identified as an enveloped positive-stranded RNA virus with a size of approximately 55 nm in diameter. Genomic sequencing of the isolated virus revealed that it is closely related to Tembusu virus (a mosquito-borne Ntaya group flavivirus), with 87–91% nucleotide identity of the partial E (envelope) proteins to that of Tembusu virus and 72% of the entire genome coding sequence with Bagaza virus, the most closely related flavivirus with an entirely sequenced genome. Collectively our systematic studies fulfill Koch's postulates, and therefore, the causative agent of the duck egg drop syndrome occurring in China is a new flavivirus. Flavivirus is an emerging and re-emerging zoonotic pathogen and BYD virus that causes severe egg-drop, could be disastrous for the duck industry. More importantly its public health concerns should also be evaluated, and its epidemiology should be closely watched due to the zoonotic nature of flaviviruses.