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Channel Interactions and Robust Inference for Ratiometric β-lactamase Assay Data: a Tox21 Library Analysis.
ACS Sustainable Chemistry & Engineering ( IF 7.1 ) Pub Date : 2018-01-15 00:00:00 , DOI: 10.1021/acssuschemeng.7b03394
Fjodor Melnikov 1 , Jui-Hua Hsieh 2 , Nisha S Sipes 3 , Paul T Anastas 1, 4
Affiliation  

Ratiometric β-lactamase (BLA) reporters are widely used to study transcriptional responses in a high-throughput screening (HTS) format. Typically, a ratio readout (background/target fluorescence) is used for toxicity assessment and structure–activity modeling efforts from BLA HTS data. This ratio readout may be confounded by channel-specific artifacts. To maximize the utility of BLA HTS data, we analyzed the relationship between individual channels and ratio readouts after fitting 10,000 chemical titration series screened in seven BLA stress–response assays from the Tox21 initiative. Similar to previous observations, we found that activity classifications based on BLA ratio readout alone are confounded by interference patterns for up to 85% (50% on average) of active chemicals. Most Tox21 analyses adjust for this issue by evaluating target and ratio readout direction. In addition, we found that the potency and efficacy estimates derived from the ratio readouts may not represent the target channel effects and thus complicates chemical activity comparison. From these analyses, we recommend a simpler approach using a direct evaluation of the target and background channels as well as the respective noise levels when using BLA data for toxicity assessment. This approach eliminates the channel interference issues and allows for straightforward chemical assessment and comparisons.

中文翻译:


比例 β-内酰胺酶测定数据的通道相互作用和稳健推断:Tox21 库分析。



比例 β-内酰胺酶 (BLA) 报告基因广泛用于以高通量筛选 (HTS) 形式研究转录反应。通常,比率读数(背景/目标荧光)用于 BLA HTS 数据的毒性评估和结构-活性建模工作。该比率读数可能会受到特定于通道的伪影的影响。为了最大限度地利用 BLA HTS 数据,我们在拟合了 Tox21 计划的 7 个 BLA 应激反应测定中筛选的 10,000 个化学滴定系列后,分析了各个通道和比率读数之间的关系。与之前的观察结果类似,我们发现仅基于 BLA 比率读数的活性分类会被高达 85%(平均 50%)的活性化学物质的干扰模式所混淆。大多数 Tox21 分析通过评估目标和比率读数方向来调整此问题。此外,我们发现从比率读数得出的效力和功效估计可能不代表目标通道效应,从而使化学活性比较复杂化。根据这些分析,我们建议采用一种更简单的方法,在使用 BLA 数据进行毒性评估时,直接评估目标通道和背景通道以及各自的噪声水平。这种方法消除了通道干扰问题,并允许直接进行化学评估和比较。
更新日期:2018-01-15
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