ABSTRACT
The COVID-19 pandemic highlights the importance of efficient and safe vaccine development. Vaccine adjuvants are essential to boost and tailor the immune response to the corresponding pathogen. To allow for an educated selection, we assessed the effect of different adjuvants on human monocyte-derived dendritic cells (DCs) and their ability to polarize innate and adaptive immune responses. In contrast to commonly used adjuvants, such as aluminum hydroxide, Toll-like receptor (TLR) agonists induced robust phenotypic and functional DC maturation. In a DC-lymphocyte coculture system, we investigated the ensuing immune reactions. While monophosphoryl lipid A synthetic, a TLR4 ligand, induced checkpoint inhibitors indicative for immune exhaustion, the TLR7/8 agonist Resiquimod (R848) induced prominent type-1 interferon and interleukin 6 responses and robust CTL, B-cell, and NK-cell proliferation, which is particularly suited for antiviral immune responses. The recently licensed COVID-19 vaccines, BNT162b and mRNA-1273, are both based on single-stranded RNA. Indeed, we could confirm that the cytokine profile induced by lipid-complexed RNA was almost identical to the pattern induced by R848. Although this awaits further investigation, our results suggest that their efficacy involves the highly efficient antiviral response pattern stimulated by the RNAs' TLR7/8 activation.
Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19/immunology , Dendritic Cells/immunology , Immunity, Cellular/drug effects , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Female , Humans , Imidazoles/pharmacology , Lipid A/analogs & derivatives , Lipid A/pharmacology , Male , Middle Aged , Toll-Like Receptors/immunologyABSTRACT
A novel chemoenzymatic three-component synthesis of (hetero)arylated propargyl amides in good yields based upon Novozyme® 435 (Candida antarctica lipase B (CAL-B)) catalyzed aminolysis of methyl carboxylates followed by Sonogashira coupling with (hetero)aryliodides in a consecutive one-pot fashion has been presented. This efficient methodology can be readily concatenated with a CuAAC (Cu catalyzed alkyne azide cycloaddition) as a third consecutive step to furnish 1,4-disubstituted 1,2,3-triazole ligated arylated propargyl amides. This one-pot process can be regarded as a transition metal catalyzed sequence that takes advantage of the copper source still present from the cross-coupling step.
Subject(s)
Amides/chemistry , Amides/chemical synthesis , Fungal Proteins/metabolism , Lipase/metabolism , Amines/chemistry , Biocatalysis , Chemistry Techniques, Synthetic , Pargyline/chemistryABSTRACT
Cyclic secondary amines and 2-hydroxybenzaldehydes or related ketones react to furnish benzo[e][1,3]oxazine structures in generally good yields. This overall redox-neutral amine α-C-H functionalization features a combined reductive N-alkylation/oxidative α-functionalization and is catalyzed by acetic acid. In contrast to previous reports, no external oxidants or metal catalysts are required. Reactions performed under modified conditions lead to an apparent reductive amination and the formation of o-hydroxybenzylamines in a process that involves the oxidation of a second equivalent of amine. A detailed computational study employing density functional theory compares different mechanistic pathways and is used to explain the observed experimental findings. Furthermore, these results also reveal the origin of the catalytic efficiency of acetic acid in these transformations.
Subject(s)
Amines/chemistry , Oxygen/chemistry , Catalysis , Ketones/chemistry , Models, Molecular , Molecular Conformation , Oxidation-Reduction , Toluene/chemistryABSTRACT
Researchers assessed 58 preschoolers' reactions to an unfamiliar person and unfamiliar objects in their familiar home environment. Children participated in a 30-min procedure designed to elicit behavioral inhibition, including (a) a free-play period with a stranger present, (b) a structured interaction with the stranger, and (c) uncertainty-eliciting tasks. Behaviors representing the child's reactions toward the mother, stranger, and novel objects were coded. Mothers completed a temperament scale. Preschoolers exhibited behaviors indicative of inhibition toward unfamiliar social and nonsocial stimuli; behaviors remained stable across increasingly intrusive episodes. The approach/withdrawal component of temperament was related to behavioral inhibition. Individual differences in mood did not appear to be related to differences in inhibition. Parent reported temperament was related to researcher-observed behaviors.
