Biocatalytic Friedel-Crafts Reactions

Friedel-Crafts alkylation and acylation reactions are important methodologies in synthetic and industrial chemistry for the construction of aryl-alkyl and aryl-acyl linkages that are ubiquitous in bioactive molecules. Nature also exploits these reactions in many biosynthetic processes. Much work has been done to expand the synthetic application of these enzymes to unnatural substrates through directed evolution. The promise of such biocatalysts is their potential to supersede inefficient and toxic chemical approaches to these reactions, with mild operating conditions - the hallmark of enzymes. Complementary work has created many bio-hybrid Friedel-Crafts catalysts consisting of chemical catalysts anchored into biomolecular scaffolds, which display many of the same desirable characteristics. In this Review, we summarise these efforts, focussing on both mechanistic aspects and synthetic considerations, concluding with an overview of the frontiers of this field and routes towards more efficient and benign Friedel-Crafts reactions for the future of humankind

On the effectiveness of run-time checks

Run-time checks are often assumed to be a cost-effective way of improving the dependability of software components, by checking required properties of their outputs and flagging an output as incorrect if it fails the check. However, evaluating how effective they are going to be in a future application is difficult, since the effectiveness of a check depends on the unknown faults of the program to which it is applied. A programming contest, providing thousands of programs written to the same specifications, gives us the opportunity to systematically test run-time checks to observe statistics of their effects on actual programs. In these examples, run-time checks turn out to be most effective for unreliable programs. For more reliable programs, the benefit is relatively low as compared to the gain that can be achieved by other (more expensive) measures, most notably multiple-version diversity

Multi-Time-Scale Convolution for Emotion Recognition from Speech Audio Signals

Robustness against temporal variations is important for emotion recognition from speech audio, since emotion is expressed through complex spectral patterns that can exhibit significant local dilation and compression on the time axis depending on speaker and context. To address this and potentially other tasks, we introduce the multi-time-scale (MTS) method to create flexibility towards temporal variations when analyzing time-frequency representations of audio data. MTS extends convolutional neural networks with convolution kernels that are scaled and re-sampled along the time axis, to increase temporal flexibility without increasing the number of trainable parameters compared to standard convolutional layers. We evaluate MTS and standard convolutional layers in different architectures for emotion recognition from speech audio, using 4 datasets of different sizes. The results show that the use of MTS layers consistently improves the generalization of networks of different capacity and depth, compared to standard convolution, especially on smaller datasets

Unlocking Iminium Catalysis in Artificial Enzymes to Create a Friedel-Crafts Alkylase

[Image: see text] The construction and engineering of artificial enzymes consisting of abiological catalytic moieties incorporated into protein scaffolds is a promising strategy to realize non-natural mechanisms in biocatalysis. Here, we show that incorporation of the noncanonical amino acid para-aminophenylalanine (pAF) into the nonenzymatic protein scaffold LmrR creates a proficient and stereoselective artificial enzyme (LmrR_pAF) for the vinylogous Friedel–Crafts alkylation between α,β-unsaturated aldehydes and indoles. pAF acts as a catalytic residue, activating enal substrates toward conjugate addition via the formation of intermediate iminium ion species, while the protein scaffold provides rate acceleration and stereoinduction. Improved LmrR_pAF variants were identified by low-throughput directed evolution advised by alanine-scanning to obtain a triple mutant that provided higher yields and enantioselectivities for a range of aliphatic enals and substituted indoles. Analysis of Michaelis–Menten kinetics of LmrR_pAF and evolved mutants reveals that different activities emerge via evolutionary pathways that diverge from one another and specialize catalytic reactivity. Translating this iminium-based catalytic mechanism into an enzymatic context will enable many more biocatalytic transformations inspired by organocatalysis

Rodent Research: Implementation of an Immunology Experiment on the ISS

No abstract availabl

Media outlets and their moguls: why concentrated individual or family ownership is bad for editorial independence

This article investigates the levels of owner influence in 211 different print and broadcast outlets in 32 different European media markets. Drawing on the literature from industrial organisation, it sets out reasons why we should expect greater levels of influence where ownership of individual outlets is concentrated; where it is concentrated in the hands of individuals or families; and where ownership groups own multiple outlets in the same media market. Conversely, we should expect lower levels of influence where ownership is dispersed between transnational companies. The articles uses original data on the ownership structures of these outlets, and combines it with reliable expert judgments as to the level of owner influence in each of the outlets. These hypotheses are tested and confirmed in a multilevel regression model of owner influence. The findings are relevant for policy on ownership limits in the media, and for the debate over transnational versus local control of media

How explicit are the barriers to failure in safety arguments?

Safety cases embody arguments that demonstrate how safety properties of a system are upheld. Such cases implicitly document the barriers that must exist between hazards and vulnerable components of a system. For safety certification, it is the analysis of these barriers that provide confidence in the safety of the system. The explicit representation of hazard barriers can provide additional insight for the design and evaluation of system safety. They can be identified in a hazard analysis to allow analysts to reflect on particular design choices. Barrier existence in a live system can be mapped to abstract barrier representations to provide both verification of barrier existence and a basis for quantitative measures between the predicted barrier behaviour and performance of the actual barrier. This paper explores the first stage of this process, the binding between explicit mitigation arguments in hazard analysis and the barrier concept. Examples from the domains of computer-assisted detection in mammography and free route airspace feasibility are examined and the implications for system certification are considered

Systems-theoretic Safety Assessment of Robotic Telesurgical Systems

Robotic telesurgical systems are one of the most complex medical cyber-physical systems on the market, and have been used in over 1.75 million procedures during the last decade. Despite significant improvements in design of robotic surgical systems through the years, there have been ongoing occurrences of safety incidents during procedures that negatively impact patients. This paper presents an approach for systems-theoretic safety assessment of robotic telesurgical systems using software-implemented fault-injection. We used a systemstheoretic hazard analysis technique (STPA) to identify the potential safety hazard scenarios and their contributing causes in RAVEN II robot, an open-source robotic surgical platform. We integrated the robot control software with a softwareimplemented fault-injection engine which measures the resilience of the system to the identified safety hazard scenarios by automatically inserting faults into different parts of the robot control software. Representative hazard scenarios from real robotic surgery incidents reported to the U.S. Food and Drug Administration (FDA) MAUDE database were used to demonstrate the feasibility of the proposed approach for safety-based design of robotic telesurgical systems.Comment: Revise based on reviewers feedback. To appear in the the International Conference on Computer Safety, Reliability, and Security (SAFECOMP) 201

An Exercise in Reverse Engineering for Safety-Critical Systems: An Experience for the Classroom

Since the Y2K crisis, reverse engineering has become a major area of work in industrial software application development, but lacks emphasis in US academia. This issue is exemplified by the high demand for software systems in new and expanding software application areas, which has resulted in systems being implemented before the requirements and design phases have been completed. Towards the maintenance of such systems, it is necessary to conducted reverse engineering for the derivation of software documentation for requirements and high-level and low-level design. When this scenario exists in the domain of safety-critical system, particularly in the aviation industry, reverse engineering takes on greater value because such software systems have to undergo development regulations and certification restrictions. This work reports on the pedagogical revelations gained from conducting reverse engineering on a software system that was developed and deployed for use in managing the assignment of commercial aircrafts to airport terminal gates. The software system incorporated genetic algorithms solutions and was implemented on a high-speed multi-processor system. The reverse engineering methodology applied was based on the RTCA DO-178C Software Considerations in Airborne Systems and Equipment Certification specification for onboard avionic software systems

Evaluation of ADAS with a supported-driver model for desired allocation of tasks between human and technology performance

Partly automated driving is relevant for solving mobility problems, but also causes concerns with respect to the driver‟s reliability in task performance. The supported driver model presented in this paper is therefore intended to answer the question, what type of support and in which circumstances, will enhance the driver‟s ability to control the vehicle. It became apparent that prerequisites for performing tasks differ per driving task‟s type and require different support. The possible support for each driving task‟s type, has been combined with support-types to reduce the error causations from each different performance level (i.e. knowledge-based, rule-based and skill-based performance). The allocation of support in relation to performance level and driving task‟s type resulted in a supported driver model and this model relates the requested circumstances to appropriate support types. Among three tested ADAS systems, semi-automated parking showed best allocation of support; converting the demanding parallel parking task into a rather routine-like operation