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1.
Front Immunol ; 13: 918551, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248901

RESUMO

The complement system is an ancient and critical part of innate immunity. Recent studies have highlighted novel roles of complement beyond lysis of invading pathogens with implications in regulating the innate immune response, as well as contributing to metabolic reprogramming of T-cells, synoviocytes as well as cells in the CNS. These findings hint that complement can be an immunometabolic regulator, but whether this is also the case for the terminal step of the complement pathway, the membrane attack complex (MAC) is not clear. In this study we focused on determining whether MAC is an immunometabolic regulator of the innate immune response in human monocyte-derived macrophages. Here, we uncover previously uncharacterized metabolic changes and mitochondrial dysfunction occurring downstream of MAC deposition. These alterations in glycolytic flux and mitochondrial morphology and function mediate NLRP3 inflammasome activation, pro-inflammatory cytokine release and gasdermin D formation. Together, these data elucidate a novel signalling cascade, with metabolic alterations at its center, in MAC-stimulated human macrophages that drives an inflammatory consequence in an immunologically relevant cell type.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
3.
Anal Chem ; 90(4): 2970-2975, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29369625

RESUMO

We demonstrate a high-throughput chemoprinting platform that confirms the consistency in the higher-order structure of protein biologics and is sensitive enough to detect single-point mutations. This method addresses the quality and consistency of the tertiary and quaternary structure of biologic drug products, which is arguably the most important, yet rarely examined, parameter. The method described uses specific small-molecule ligands as molecular probes to assess protein structure. Each library of probe molecules provides a "fingerprint" when taken holistically. After proof-of-concept experiments involving enzymes and antibodies, we were able to detect minor conformational perturbations between four 48 kDa protein mutants that only differ by one amino acid residue.


Assuntos
Produtos Biológicos/química , Ensaios de Triagem em Larga Escala , Proteínas/química , Proteínas/genética , Cromatografia Líquida , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular
4.
Nat Commun ; 8: 16081, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28714473

RESUMO

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Biblioteca Gênica , Mycobacterium tuberculosis/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Staphylococcus aureus/efeitos dos fármacos , Acinetobacter baumannii/metabolismo , Avaliação Pré-Clínica de Medicamentos , Terapia de Alvo Molecular , Mycobacterium tuberculosis/metabolismo , Staphylococcus aureus/metabolismo
5.
Appl Opt ; 41(17): 3404-11, 2002 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-12074511

RESUMO

We present a method for determining the refractive-index profile of polymer optical fiber preforms through a direct-deflection measurement. The method is simple to use, compact, and has good resolution. The profile is obtained from the deflection data by numerically integrating the differential-ray equation for a radial refractive-index gradient. Corrections for topographical deviations are also discussed. Results for both graded-index and step-index fibers are presented.

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