Boolean logic and arithmetic through DNA excision (BLADE) is a recently developed platform for implementing inducible and logical control over gene expression in mammalian cells, which has the potential to revolutionise cell engineering for therapeutic applications. This 2-input 2-output platform can implement 256 different logical circuits that exploit the specificity and stability of DNA recombination. Here, we develop the first mechanistic mathematical model of the 2-input BLADE platform based on Cre- and Flp-mediated DNA excision. After calibrating the model on experimental data from two circuits, we demonstrate close agreement between model outputs and data on the other 111 circuits that have so far been experimentally constructed using the 2-input BLADE platform. Model simulations of the remaining 143 circuits that have yet to be tested experimentally predict excellent performance of the 2-input BLADE platform across the range of possible circuits. Circuits from both the tested and untested subsets that perform less well consist of a disproportionally high number of STOP sequences. Model predictions suggested that circuit performance declines with a decrease in recombinase expression and new experimental data was generated that confirms this relationship.

中文翻译：

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BLADE平台的机械模型可预测256种不同的合成DNA重组电路的性能特征

通过DNA切除术（BLADE）进行的布尔逻辑和算术是一种最近开发的平台，用于对哺乳动物细胞中的基因表达实施诱导和逻辑控制，这可能会彻底改变用于治疗应用的细胞工程。这个2输入2输出平台可以实现256个不同的逻辑电路，这些逻辑电路利用了DNA重组的特异性和稳定性。在这里，我们开发基于Cre-和Flp介导的DNA切除的2输入BLADE平台的第一个力学数学模型。在对来自两个电路的实验数据进行模型校准之后，我们证明了模型输出与到目前为止使用2输入BLADE平台通过实验构建的其他111个电路的数据之间的紧密一致性。尚待测试的其余143条电路的模型仿真可以预测2输入BLADE平台在所有可能电路范围内的出色性能。来自测试和未测试子集的电路表现较差，它们包含大量不成比例的STOP序列。模型预测表明，电路性能随着重组酶表达的降低而降低，并且产生了新的实验数据来证实这种关系。