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PLoS One ; 14(5): e0215221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120888


Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.

Avaliação Pré-Clínica de Medicamentos/normas , Relatório de Pesquisa/normas , Analgésicos/uso terapêutico , Animais , Bases de Dados Factuais , Guias como Assunto , Dor/tratamento farmacológico
Structure ; 23(4): 615-27, 2015 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-25728927


Activation-induced cytidine deaminase (AID) mutates cytidine to uridine at immunoglobulin loci to initiate secondary antibody diversification but also causes genome-wide damage. We previously demonstrated that AID has a relatively low catalytic rate. The structure of AID has not been solved. Thus, to probe the basis for its catalytic lethargy we generated a panel of free or DNA-bound AID models based on eight recently resolved APOBEC structures. Docking revealed that the majority of AID:DNA complexes would be inactive due to substrate binding such that a cytidine is not positioned for deamination. Furthermore, we found that most AID conformations exhibit fully or partially occluded catalytic pockets. We constructed mutant and chimeric AID variants predicted to have altered catalytic pocket accessibility dynamics and observed significant correlation with catalytic rate. Data from modeling simulations and functional tests of AID variants support the notion that catalytic pocket accessibility is an inherent bottleneck for AID activity.

Domínio Catalítico , Citidina Desaminase/química , Sequência de Aminoácidos , Animais , Citidina/química , Citidina/metabolismo , Citidina Desaminase/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Humanos , Camundongos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Mutagênese , Ligação Proteica