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Lactonization as a general route to beta-C(sp(3))-H functionalization 期刊论文
NATURE, 2020, 577 (7792) : 656-+
作者:  Washington, Harriet A.
收藏  |  浏览/下载:27/0  |  提交时间:2020/07/03

Functionalization of the beta-C-H bonds of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions(1-5). Despite efforts for beta-C-H functionalization in carbon-carbon and carbon-heteroatom bond-forming reactions, these have numerous crucial limitations, especially for industrial-scale applications, including lack of mono-selectivity, use of expensive oxidants and limited scope(6-13). Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C-H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here we report a Pd-catalysed beta-C(sp(3))-H lactonization of aliphatic acids enabled by a mono-N-protected beta-amino acid ligand. The highly strained and reactive beta-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl and amino groups at the beta position of the parent acid, thus providing a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide as the oxidant to promote the desired selective reductive elimination from the Pd(IV) centre, as well as the ease of product purification without column chromatography, render this reaction amenable to tonne-scale manufacturing.


  
MAFG-driven astrocytes promote CNS inflammation 期刊论文
NATURE, 2020, 578 (7796) : 593-+
作者:  Clark, Peter U.;  He, Feng;  Golledge, Nicholas R.;  Mitrovica, Jerry X.;  Dutton, Andrea;  Hoffman, Jeremy S.;  Dendy, Sarah
收藏  |  浏览/下载:64/0  |  提交时间:2020/07/03

Multiple sclerosis is a chronic inflammatory disease of the CNS1. Astrocytes contribute to the pathogenesis of multiple sclerosis(2), but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2 alpha to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2 alpha and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.


Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed.


  
Anthropogenic Control Over Wintertime Oxidation of Atmospheric Pollutants 期刊论文
GEOPHYSICAL RESEARCH LETTERS, 2019
作者:  Haskins, J. D.;  Lopez-Hilfiker, F. D.;  Lee, B. H.;  Shah, V;  Wolfe, G. M.;  DiGangi, J.;  Fibiger, D.;  McDuffie, E. E.;  Veres, P.;  Schroder, J. C.;  Campuzano-Jost, P.;  Day, D. A.;  Jimenez, J. L.;  Weinheimer, A.;  Sparks, T.;  Cohen, R. C.;  Campos, T.;  Sullivan, A.;  Guo, H.;  Weber, R.;  Dibb, J.;  Green, J.;  Fiddler, M.;  Bililign, S.;  Jaegle, L.;  Brown, S. S.;  Thornton, J. A.
收藏  |  浏览/下载:45/0  |  提交时间:2020/02/17
oxidation  radical budget  winter  pollution  anthropogenic  oxidant