RESUMO
Access to C,C-glycosyl amino acids as a novel class of glycomimetics is reported by means of radical generation, intermolecular addition and stereoselective reduction via a metal-induced hydrogen atom transfer (MHAT) sequence. The 'matched' coupling of exo-D-glycals with an enantiopure dehydroalanine bearing a (R)-configured benzyl oxazolidinone enables a singular case of two-fold diastereocontrol under iron catalysis. In the common exo-D-glucal series, the nature of the C-2 substituent was found to play a key role from both reactivity and stereocontrol aspects.
RESUMO
EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.
Assuntos
Ciclo Celular/genética , Linhagem da Célula/genética , Células Matadoras Naturais/imunologia , Proteínas com Domínio T/genética , Animais , Sequência de Bases , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/imunologia , Diferenciação Celular , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/imunologia , Epigênese Genética/imunologia , Interleucina-12/farmacologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas , Ligação Proteica , Baço/citologia , Baço/imunologia , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/imunologia , Transcrição Gênica , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologiaRESUMO
We describe herein a convenient strategy for the construction of C,C-glycoside building blocks via the intermediacy of tertiary pseudoanomeric radicals. Application of an iron-mediated hydrogen atom transfer/Michael-Giese coupling enables the anomeric quaternization of readily available exo-glycals with good to complete stereocontrol in the pyranose and furanose series. Carefully optimized conditions allow the use of challenging trisubstituted derivatives prone to undergo further elaboration to stable neoglycoconjugates. Preliminary results for direct C-disaccharide synthesis are also discussed.