Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
Cell ; 187(9): 2209-2223.e16, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38670073

RESUMO

Nuclear factor κB (NF-κB) plays roles in various diseases. Many inflammatory signals, such as circulating lipopolysaccharides (LPSs), activate NF-κB via specific receptors. Using whole-genome CRISPR-Cas9 screens of LPS-treated cells that express an NF-κB-driven suicide gene, we discovered that the LPS receptor Toll-like receptor 4 (TLR4) is specifically dependent on the oligosaccharyltransferase complex OST-A for N-glycosylation and cell-surface localization. The tool compound NGI-1 inhibits OST complexes in vivo, but the underlying molecular mechanism remained unknown. We did a CRISPR base-editor screen for NGI-1-resistant variants of STT3A, the catalytic subunit of OST-A. These variants, in conjunction with cryoelectron microscopy studies, revealed that NGI-1 binds the catalytic site of STT3A, where it traps a molecule of the donor substrate dolichyl-PP-GlcNAc2-Man9-Glc3, suggesting an uncompetitive inhibition mechanism. Our results provide a rationale for and an initial step toward the development of STT3A-specific inhibitors and illustrate the power of contemporaneous base-editor and structural studies to define drug mechanism of action.


Assuntos
Sistemas CRISPR-Cas , Hexosiltransferases , Lipopolissacarídeos , Proteínas de Membrana , NF-kappa B , Transdução de Sinais , Receptor 4 Toll-Like , Hexosiltransferases/metabolismo , Hexosiltransferases/genética , NF-kappa B/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Humanos , Receptor 4 Toll-Like/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Células HEK293 , Inflamação/metabolismo , Inflamação/genética , Glicosilação , Microscopia Crioeletrônica , Domínio Catalítico , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética
2.
Clin Pract Cases Emerg Med ; 2(4): 283-285, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30443606

RESUMO

In this article, we present two medicolegal cases illustrating medical and diagnostic pitfalls that can lead to litigation for missed testicular torsion. Testicular torsion (TT) is a urologic emergency with potentially devastating consequences and costs, for providers and patients alike. TT occurs in approximately 4.5 per 100,000 males under the age of 25. While uncommon, TT is the third most common cause of medical malpractice suits in this demographic. As a consequence of varying presentations and physical exam findings, and diagnostic imaging subject to individual interpretation, this time-sensitive diagnosis may be missed by emergency department providers. Delays in diagnosis significantly increases the morbidity associated with TT, and 31.9%-41.9% of such cases result in testicular loss. The average reported settlement for TT malpractice litigation is $60,000. This article discusses two actual malpractice cases involving TT and provides insight and caveats to ensure an optimal evaluation and diagnostic approach to this often-elusive condition.

SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa