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An overview on the identification of MAIT cell antigens
Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I‐like molecule, MHC‐related protein‐1 (MR1). Until 2012, the origin of the MAIT cell antigens (Ags) was unknown, although it was established that MAIT cells could be activated by a broad range of bacteria and yeasts, possibly suggesting a conserved Ag. Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and small molecule chemistry, we discovered MR1 ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). While the folate derivative 6‐formylpterin generally inhibited MAIT cell activation, two riboflavin pathway derivatives, 5‐(2‐oxopropylideneamino)‐6‐D‐ribitylaminouracil and 5‐(2‐oxoethylideneamino)‐6‐D‐ribitylaminouracil, were potent MAIT cell agonists. Other intermediates and derivatives of riboflavin synthesis displayed weak or no MAIT cell activation. Collectively, these studies revealed that in addition to peptide and lipid‐based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αβ T‐cell receptors, and here we recount this discovery. Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I‐like molecule, MHC‐related protein‐1 (MR1). Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and chemistry, we discovered MAIT cell ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). Collectively, these studies revealed that in addition to peptide and lipid‐based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αβ T‐cell receptors, and here we recount this discovery.
Journal Article
A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity
To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54,
P
= 7 × 10
−8
), hospitalization (OR = 0.61,
P
= 8 × 10
−8
) and susceptibility (OR = 0.78,
P
= 8 × 10
−6
). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.
A variant of the
OAS1
gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.
Journal Article
Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis
In a trial, patients with moderate to severely advanced idiopathic pulmonary fibrosis were treated with nintedanib plus sildenafil or nintedanib alone, with the goal of decreasing IPF symptoms. There were no between-group differences in any of three symptom measures.
Journal Article
Synthesis and Properties of α-Phosphate-Modified Nucleoside Triphosphates
This review article is focused on the progress made in the synthesis of 5′-α-P-modified nucleoside triphosphates (α-phosphate mimetics). A variety of α-P-modified nucleoside triphosphates (NTPαXYs, Y = O, S; X = S, Se, BH3, alkyl, amine, N-alkyl, imido, or others) have been developed. There is a unique class of nucleoside triphosphate analogs with different properties. The main chemical approaches to the synthesis of NTPαXYs are analyzed and systematized here. Using the data presented here on the diversity of NTPαXYs and their synthesis protocols, it is possible to select an appropriate method for obtaining a desired α-phosphate mimetic. Triphosphates’ substrate properties toward nucleic acid metabolism enzymes are highlighted too. We reviewed some of the most prominent applications of NTPαXYs including the use of modified dNTPs in studies on mechanisms of action of polymerases or in systematic evolution of ligands by exponential enrichment (SELEX). The presence of heteroatoms such as sulfur, selenium, or boron in α-phosphate makes modified triphosphates nuclease resistant. The most distinctive feature of NTPαXYs is that they can be recognized by polymerases. As a result, S-, Se-, or BH3-modified phosphate residues can be incorporated into DNA or RNA. This property has made NTPαXYs a multifunctional tool in molecular biology. This review will be of interest to synthetic chemists, biochemists, biotechnologists, or biologists engaged in basic or applied research.
Journal Article
Conventional wisdom : the alternate Article V mechanism for proposing amendments to the U.S. Constitution
\"Article V of the Constitution allows two-thirds majorities of both houses of Congress to propose amendments to the document and a three-fourths majority of the states to ratify them. Scholars and frustrated advocates of constitutional change have often criticized this process for being too difficult. Despite this, state legislatures have yet to use the other primary method that Article V outlines for proposing amendments: it permits two-thirds of the state legislatures to petition Congress to call a convention to propose amendments that, like those proposed by Congress, must be ratified by three-fourths of the states. In this book, John R. Vile surveys more than two centuries of scholarship on Article V and concludes that the weight of the evidence (including a much-overlooked Federalist essay) indicates that states and Congress have the legal right to limit the scope of such conventions to a single subject and that political considerations would make a runaway convention unlikely. Charting a prudent course between those who fail to differentiate revolutionary change from constitutional change, those who fear ever using the Article V convention mechanism that the Framers clearly envisioned, and those who would vest total control of the convention in Congress, the states, or the convention itself, Vile's work will enhance modern debates on the subject.\" -- Back cover.
Book
Investigation of Cissus populnea as a Potential Therapeutic Agent for Erectile Dysfunction
Cissus populnea
(CP) is a plant reported to possess an erection-enhancing ability, though mechanisms remain unclear. Drugs targeting phosphodiesterase 5 (PDE5) inhibition, such as sildenafil, have been employed to treat erectile dysfunction (EDRF), but they are associated with several complications. This study investigated the effect of
C. populnea
extracts (aqueous and saponin-rich) on the activity and gene expressions of proteins related to erection. PDE5, Nitric oxide synthase (NOS) and androgen receptor (AR) genes were studied using RT-PCR on CP-treated paroxetine-induced ERDF-rats. It also employed Schrödinger suites for investigations such as molecular and induced-fit docking, MMGBSA, ADMET, and QSAR profiling of CP-phytocompounds.
C. populnea
extracts reduce the activity and downregulate the expression of the PDE5 gene while upregulating the expressions of AR and NOS genes in the ERDF-rats relative to the control group. Five (leading) compounds with induced-fit docking (IFD) scores in kcal/mol, namely, stigmasterol (−638.73), daucosterol (−644.73), furostanol (−639.29), papaverine (−639.03), and capsaicin (−642.88), had better docking scores of −9.936, −9.824, −9.064, −8.863, and −8.736 kcal/mol, respectively, compared with those of sildenafil (−8.611 kcal/mol). They also showed an excellent ADMET profile, satisfying Lipinski’s rule of five. The MMGBSA predictions revealed that stigmasterol, daucosterol, papaverine, and capsaicin had binding free energies of −45.29, −59.14, −50.63, and −50.47 kcal/mol, respectively, suggesting that they are significant inhibitors of PDE5. The QSAR model revealed that lead compounds possess good pIC50 values. These results indicate that
C. populnea
is a more promising possible treatment for controlling EDRF and deserves further research.
Journal Article