The unprecedented outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the WHO, with >34 million people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and with>1 million COVID-19-related deaths worldwide 1. COVID-19 can lead to a disease spectrum ranging from mild respiratory symptoms to acute respiratory distress syndrome (ARDS) and death 2-4. SARS-CoV-2 is now the third highly pathogenic and transmissible coronavirus identified in humans. Human coronaviruses were first dis covered in the 1960s 5 , but it was not until the 21st century that coronaviruses were recognized as major threats to public health. SARS-CoV 6-9 , Middle East respiratory syndrome coronavirus (MERS-CoV) 10 and SARS-CoV-2 all cause severe respiratory tract infections and have been associated with global pandemics. SARS-CoV was first reported in China in 2003 and infected >8,000 indivi duals, causing 774 deaths worldwide 11. A decade later, MERS was first reported in Saudi Arabia and infected >2,494 individuals and caused 858 deaths, with an extremely high death rate of 34% in part owing to the lack of effective therapies 12,13. SARS-CoV, MERS-CoV and SARS-CoV-2 belong to the Betacoronavirus genus, which is one of four genera of coronavirus 14. Phylogenetic analysis revealed that SARS-CoV-2 is closely related to two bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21 (with around 88% sequence identity), SARS-CoV (approximately 79% sequence identity) and MERS-CoV (approximately 50% sequence identity) 15. Homology modelling revealed that the receptor-binding domain structures in SARS-CoV and SARS-CoV-2 are similar, despite some amino acid variations 15. MERS-CoV infects human cells by binding to the dipeptidyl peptidase 4 receptor 16 , whereas both SARS-CoV 17 and SARS-CoV-2 (refs 18,19) use angiotensin-converting enzyme 2 (ACE2) as a receptor to infect cells. For SARS-CoV-2 infection, in addition to ACE2, one or more proteases including transmembrane protease serine 2 (TMPRSS2), basigin (also known as CD147) and potentially cathepsin B or cathepsin L are required 18,19. Acute respiratory distress syndrome (ArDs). A syndrome characterized by severe acute respiratory failure arising from inflammation and fluid build-up in the lungs.

Supramolecular processes that result in the formation of covalent bonds and occur in solution are expected to be difficult to achieve in the absence of solvent owing to the restricted conformational and translational degrees of freedom of molecules in solids. Diffusion rates of molecules in the crystalline state are in the order of 10 À15 m 2 s À1 , [1] which is at least six orders of magnitude less than in solution. In this context, organic molecules that act as supramolecular catalysts make up much of the current chemistry of molecular recognition.[2] Supramolecular catalysts are inspired by the dynamic mode of action of enzymes and take advantage of processes of molecular recognition to afford transformations that are highly stereoselective, environmentally friendly, and cost effective. Small-molecule supramolecular catalysts are typically endowed with hydrogen-bond-donor and -acceptor groups that assemble two simultaneously bound substrates (e.g. ditopic receptors) within a molecular complex for reaction.[3] Relatively high catalyst loadings are often required for these catalysts owing to effects of entropy, the reversibility and relative weakness of intermolecular forces in a liquid, as well as product inhibition.[4] All small-molecule supramolecular catalysts reported to date operate in the liquid phase, typically an organic solvent.[5]Here we report a ditopic supramolecular receptor, [6] in the form of the bifunctional hydrogen-bond donor 4,6-dichlororesorcinol (4,6-diCl-res) that operates as a supramolecular catalyst in the absence of solvent (Figure 1). The catalytic reaction is a [2+2] photodimerization of trans-1,2-bis(4-pyridyl)ethylene (4,4'-bpe). [6b,c] The reaction directed by the catalyst occurs in a close-packed environment where molecular movement is at a minimum. The reaction results in the stereospecific formation of rctt-tetrakis(4-pyridyl)cyclobutane (4,4'-tpcb) in near quantitative yield. To achieve dynamic turnover between the catalyst, reactants, and product in the absence of molecular movement assisted by solvent, we employ mechanochemical energy, [7] in the form of dry mortarand-pestle grinding, [8] in a two-step process that we demonstrate results in reactions between different crystalline phases. The mechanochemistry in the first step forms a reactive hydrogen-bonded catalyst-reactant complex and in the second step disassembles the catalyst and product to make the small-molecule catalyst available to bind additional reactants. The mechanochemistry is used, in effect, to enable the catalyst to "hop" from one set of olefins to another to direct product formation and facilitate turnover. The release of the product in the second grinding results in stereospecific recombination of the catalyst and olefin, which means that the interaction between the catalyst and product does not inhibit the course of the mechanochemical catalytic process.The supramolecular catalysis originates from a molecular co-crystal composed of 4,6-diCl-res and 4,4'-bpe, specifically, 2(4,6-diCl-res)·2(4,4'-bpe). Th...

Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis.

Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) ( < .0001). Clinical laboratory-based thrombophilia testing identified a heritable thrombophilia in only 14 of 54 study patients (25.9%). The majority of WES variants were either associated with thrombosis based on prior reports in the literature or predicted to affect protein structure based on protein modeling performed as part of this study. Variants were found in major thrombophilia genes, various genes, and highly conserved areas of other genes with established or potential roles in coagulation or fibrinolysis. Ten patients (15.6%) had>1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias.

Supramolecular processes that result in the formation of covalent bonds and occur in solution are expected to be difficult to achieve in the absence of solvent owing to the restricted conformational and translational degrees of freedom of molecules in solids. Diffusion rates of molecules in the crystalline state are in the order of 10 À15 m 2 s À1 , [1] which is at least six orders of magnitude less than in solution. In this context, organic molecules that act as supramolecular catalysts make up much of the current chemistry of molecular recognition.[2] Supramolecular catalysts are inspired by the dynamic mode of action of enzymes and take advantage of processes of molecular recognition to afford transformations that are highly stereoselective, environmentally friendly, and cost effective. Small-molecule supramolecular catalysts are typically endowed with hydrogen-bond-donor and -acceptor groups that assemble two simultaneously bound substrates (e.g. ditopic receptors) within a molecular complex for reaction.[3] Relatively high catalyst loadings are often required for these catalysts owing to effects of entropy, the reversibility and relative weakness of intermolecular forces in a liquid, as well as product inhibition.[4] All small-molecule supramolecular catalysts reported to date operate in the liquid phase, typically an organic solvent.[5]Here we report a ditopic supramolecular receptor, [6] in the form of the bifunctional hydrogen-bond donor 4,6-dichlororesorcinol (4,6-diCl-res) that operates as a supramolecular catalyst in the absence of solvent (Figure 1). The catalytic reaction is a [2+2] photodimerization of trans-1,2-bis(4-pyridyl)ethylene (4,4'-bpe). [6b,c] The reaction directed by the catalyst occurs in a close-packed environment where molecular movement is at a minimum. The reaction results in the stereospecific formation of rctt-tetrakis(4-pyridyl)cyclobutane (4,4'-tpcb) in near quantitative yield. To achieve dynamic turnover between the catalyst, reactants, and product in the absence of molecular movement assisted by solvent, we employ mechanochemical energy, [7] in the form of dry mortarand-pestle grinding, [8] in a two-step process that we demonstrate results in reactions between different crystalline phases. The mechanochemistry in the first step forms a reactive hydrogen-bonded catalyst-reactant complex and in the second step disassembles the catalyst and product to make the small-molecule catalyst available to bind additional reactants. The mechanochemistry is used, in effect, to enable the catalyst to "hop" from one set of olefins to another to direct product formation and facilitate turnover. The release of the product in the second grinding results in stereospecific recombination of the catalyst and olefin, which means that the interaction between the catalyst and product does not inhibit the course of the mechanochemical catalytic process.The supramolecular catalysis originates from a molecular co-crystal composed of 4,6-diCl-res and 4,4'-bpe, specifically, 2(4,6-diCl-res)·2(4,4'-bpe). Th...