The CRISPR-Cas9 system provides unprecedented genome editing capabilities. However, off-target effects lead to sub-optimal usage and additionally are a bottleneck in the development of therapeutic uses. Herein, we introduce the first machine learning-based approach to off-target prediction, yielding a state-of-the-art model for CRISPR-Cas9 that outperforms all other guide design services. Our approach, Elevation, consists of two interdependent machine learning models—one for scoring individual guide-target pairs, and another which aggregates these guide-target scores into a single, overall summary guide score. Through systematic investigation, we demonstrate that Elevation performs substantially better than competing approaches on both tasks. Additionally, we are the first to systematically evaluate approaches on the guide summary score problem; we show that the most widely-used method performs no better than random at times, whereas Elevation consistently outperformed it, sometimes by an order of magnitude. We also introduce an evaluation method that balances errors between active and inactive guides, thereby encapsulating a range of practical use cases; Elevation is consistently superior to other methods across the entire range. Finally, because of the large scale and computational demands of off-target prediction, we have developed a cloud-based service for quick retrieval. This service provides end-to-end guide design by also incorporating our previously reported on-target model, Azimuth. (https://crispr.ml:please treat this web site as confidential until publication).

A mixed-integer nonlinear program (MINLP) algorithm to optimize catalyst turnover number (TON) and product yield by simultaneously modulating discrete variables—catalyst types—and continuous variables—temperature, residence time, and catalyst loading—was implemented and validated.

Abstract-Analog beamforming with phased arrays is a promising technique for 5G wireless communication at millimeter wave frequencies. Using a discrete codebook consisting of multiple analog beams, each beam focuses on a certain range of angles of arrival or departure and corresponds to a set of fixed phase shifts across frequency due to practical hardware considerations. However, for sufficiently large bandwidth, the gain provided by the phased array is actually frequency dependent, which is an effect called beam squint, and this effect occurs even if the radiation pattern of the antenna elements is frequency independent. This paper examines the nature of beam squint for a uniform linear array (ULA) and analyzes its impact on codebook design as a function of the number of antennas and system bandwidth normalized by the carrier frequency. The criterion for codebook design is to guarantee that each beam's minimum gain for a range of angles and for all frequencies in the wideband system exceeds a target threshold, for example 3 dB below the array's maximum gain. Analysis and numerical examples suggest that a denser codebook is required to compensate for beam squint. For example, 54% more beams are needed compared to a codebook design that ignores beam squint for a ULA with 32 antennas operating at a carrier frequency of 73 GHz and bandwidth of 2.5 GHz. Furthermore, beam squint with this design criterion limits the bandwidth or the number of antennas of the array if the other one is fixed.

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