Severe Acute Respiratory Coronavirus (SARS-CoV-2) has been emerging in the form of different variants since its first emergence in early December 2019. A new Variant of Concern (VOC) named the Omicron variant (B.1.1.529) was reported recently. This variant has a large number of mutations in the S protein. To date, there exists a limited information on the Omicron variant. Here we present the analyses of mutation distribution, the evolutionary relationship of Omicron with previous variants, and probable structural impact of mutations on antibody binding. Our analyses show the presence of 46 high prevalence mutations specific to Omicron. Twenty-three of these are localized within the spike (S) protein and the rest localized to the other 3 structural proteins of the virus, the envelope (E), membrane (M), and nucleocapsid (N). Phylogenetic analysis showed that the Omicron is closely related to the Gamma (P.1) variant. The structural analyses showed that several mutations are localized to the region of the S protein that is the major target of antibodies, suggesting that the mutations in the Omicron variant may affect the binding affinities of antibodies to the S protein.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been rapidly evolving in the form of new variants. At least eleven known variants have been reported. The objective of this study was to delineate the differences in the mutational profile of Delta and Delta Plus variants. High-quality sequences (n = 1756) of Delta (B.1.617.2) and Delta Plus (AY.1 or B.1.617.2.1) variants were used to determine the prevalence of mutations (≤20 %) in the entire SARS-CoV-2 genome, their co-existence, and change in prevalence over a period of time. Structural analysis was conducted to get insights into the impact of mutations on antibody binding. A Sankey diagram was generated using phylogenetic analysis coupled with sequence-acquisition dates to infer the migration of the Delta Plus variant and its presence in the United States. The Delta Plus variant had a significant number of high-prevalence mutations (≤20 %) than in the Delta variant. Signature mutations in Spike (G142D, A222V, and T95I) existed at a more significant percentage in the Delta Plus variant than the Delta variant. Three mutations in Spike (K417N, V70F, and W258L) were exclusively present in the Delta Plus variant. A new mutation was identified in ORF1a (A1146T), which was only present in the Delta Plus variant with ∼58 % prevalence. Furthermore, five key mutations (T95I, A222V, G142D, R158G, and K417N) were significantly more prevalent in the Delta Plus than in the Delta variant. Structural analyses revealed that mutations alter the sidechain conformation to weaken the interactions with antibodies. Delta Plus, which first emerged in India, reached the United States through England and Japan, followed by its spread to more than 20 the United States. Based on the results presented here, it is clear that the Delta and Delta Plus variants have unique mutation profiles, and the Delta Plus variant is not just a simple addition of K417N to the Delta variant. Highly correlated mutations may have emerged to keep the structural integrity of the virus.

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Cigarette smoke contains numerous chemical compounds, including abundant reactive oxygen/nitrogen species and aldehydes, and many other carcinogens. Long-term cigarette smoking significantly increases the risk of various lung diseases, including chronic obstructive pulmonary disease and lung cancer, and contributes to premature death. Many in vitro and in vivo studies have elucidated mechanisms involved in cigarette smoke-induced inflammation, DNA damage, and autophagy, and the subsequent cell fates, including cell death, cellular senescence, and transformation. In this Translational Review, we summarize the known pathways underlying these processes in airway epithelial cells to help reveal future challenges and describe possible directions of research that could lead to better management and treatment of these diseases.

Human tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type proteinase inhibitor that regulates a variety of serine proteinases involved in coagulation and fibrinolysis through their non-productive interaction with a P 1 residue (Arg-24) in its first Kunitz-type domain (KD1). Previous kinetic studies revealed that TFPI-2 was a more effective inhibitor of plasmin than several other serine proteinases, but the molecular basis for this specificity was unclear. In this study, we employed molecular modeling and mutagenesis strategies to produce several variants of human TFPI-2 KD1 in an effort to identify interactive site residues other than the P 1 Arg that contribute significantly to its inhibitory activity and specificity. Molecular modeling of KD1 based on the crystal structure of bovine pancreatic trypsin inhibitor revealed that KD1 formed a more energetically favorable complex with plasmin versus trypsin and/or the factor VIIa-tissue factor complex primarily due to strong ionic interactions between Asp-19 (P 6 ) and Arg residues in plasmin (Arg-644, Arg-719, and Arg-767), Arg-24 (P 1 ) with Asp-735 in plasmin, and Arg-29 (P 5 ) with Glu-606 in plasmin. In addition, Leu-26 through Leu-28 (P 2 -P 4 ) in KD1 formed strong van der Waals contact with a hydrophobic cluster in plasmin (Phe-583, Met-585, and Phe-587). Mutagenesis of Asp-19, Tyr-20, Arg-24, Arg-29, and Leu-26 in KD1 resulted in substantial reductions in plasmin inhibitory activity relative to wild-type KD1, but the Asp-19 and Tyr-20 mutations revealed the importance of these residues in the specific inhibition of plasmin. In addition to the reactive site residues in the P 6 -P 5 region of KD1, mutation of a highly conserved Phe at the P 18 position revealed the importance of this residue in the inhibition of serine proteinases by KD1. Thus, together with the P 1 residue, the nature of other residues flanking the P 1 residue, particularly at P 6 and P 5 , strongly influences the inhibitory activity and specificity of human TFPI-2.