Directed evolution and predictive modelling of galactose oxidase towards bulky benzylic and unactivated secondary alcohols

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Subjective Benefits of Bimodal Listening in Cochlear Implant Recipients with Asymmetric Hearing Loss

Objective: To investigate the influence of cochlear implant (CI) use on subjective benefits in quality of life in cases of asymmetric hearing loss (AHL). Study Design: Prospective clinical trial. Setting: Tertiary academic center. Subjects and Methods: Subjects included CI recipients with AHL (n = 20), defined as moderate-to-profound hearing loss in the affected ear and mild-to-moderate hearing loss in the contralateral ear. Quality of life was assessed with the Speech, Spatial, and Qualities of Hearing Scale (SSQ) pragmatic subscales, which assess binaural benefits. Subjective benefit on the pragmatic subscales was compared to word recognition in quiet and spatial hearing abilities (ie, masked sentence recognition and localization). Results: Subjects demonstrated an early, significant improvement (P <.01) in abilities with the CI as compared to preoperative abilities on the SSQ pragmatic subscales by the 1-month interval. Perceived abilities were either maintained or continued to improve over the study period. There were no significant correlations between results on the Speech in Quiet subscale and word recognition in quiet, the Speech in Speech Contexts subscale and masked sentence recognition, or the Localization subscale and sound field localization. Conclusions: CI recipients with AHL report a significant improvement in quality of life as measured by the SSQ pragmatic subscales over preoperative abilities. Reported improvements are observed as early as 1 month postactivation, which likely reflect the binaural benefits of listening with bimodal stimulation (CI and contralateral hearing aid). The SSQ pragmatic subscales may provide a more in-depth insight into CI recipient experience as compared to behavioral sound field measures alone

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours.

PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts

Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study

A41 Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study In: Addiction Science & Clinical Practice 2017, 12(Suppl 1): A4

Directed Evolution and Predictive Modelling of Galactose Oxidase towards Bulky Benzylic and Unactivated Secondary Alcohols

The growth of industrial biocatalysis for sustainable chemical manufacturing has been limited by the narrow range of chemistries associated with natural enzymes and experiment-intensive regimes of enzyme engineering. Consequently, there has been deep interest to expand enzyme substrate scopes for broader synthetic utility, and to streamline the enzyme engineering process. In the field of alcohol oxidation, galactose oxidase (GOase) is one of the most established enzymes capable of this important chemical transformation under benign conditions. However, the applicability of GOase towards more complex molecules such as those frequently found in the pharmaceutical, or agrochemical industries remains restricted. Here, by employing a combined approach of directed evolution and predictive modelling, we have identified new GOases with significantly expanded substrate specificity toward both bulky benzylic and unactivated secondary alcohols, showing activity enhancements of up to 2,400-fold compared to the reported benchmark M3-5 mutant. Beneficial mutations conveying relaxed substrate enantioselectivity biases (R/S ratios down to 1.05) and higher thermostabilities (up to 20-fold versus benchmark) have also been identified. We have developed predictive models based on computational tools YASARA, FoldX, SCWRL and Glide that are well correlated with features related to enzyme structure, selectivity, protein stability and catalytic activity. The generated enzyme activity models based on Glide-MM/GBSA (r = -0.85) and YASARA (r = -0.89) have successfully predicted the activity trend of a family of related substrates based on the 1-phenyl-1-alkyl alcohol scaffold with varying alkyl chain lengths. It is envisioned that these in silico models can serve as valuable tools to explore desirable enzyme characteristics, establish enzyme substrate scopes, and accelerate biocatalyst development, thus promoting it as a competitive and competent solution for sustainable chemical manufacturing