Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Unreliable numbers: error and harm induced by bad design can be reduced by better design

Number entry is a ubiquitous activity and is often performed in safety- and mission-critical procedures, such as healthcare, science, finance, aviation and in many other areas. We show that Monte Carlo methods can quickly and easily compare the reliability of different number entry systems. A surprising finding is that many common, widely used systems are defective, and induce unnecessary human error. We show that Monte Carlo methods enable designers to explore the implications of normal and unexpected operator behaviour, and to design systems to be more resilient to use error. We demonstrate novel designs with improved resilience, implying that the common problems identified and the errors they induce are avoidable.     

Time reversibility of the discrete element method

An algorithm is presented for discrete element method simulations of energy-conserving systems of frictionless, spherical particles in a reversed-time frame. This algorithm is verified, within the limits of round-off error, through implementation in the LAMMPS code. Mechanisms for energy dissipation such as interparticle friction, damping, rotational resistance, particle crushing, or bond breakage cannot be incorporated into this algorithm without causing time irreversibility. This theoretical development is applied to critical-state soil mechanics as an exemplar. It is shown that the convergence of soil samples, which differ only in terms of their initial void ratio, to the same critical state requires the presence of shear forces and frictional dissipation within the soil system.     

Reality-based interaction affecting mental workload in virtual reality mental arithmetic training

ABSTRACT

The concept of digital game-based learning (DGBL) evolves rapidly together with technological enhancements of virtual reality (VR) and smart phones. However, the mental workload (MWL) that VR-training applications demand and motivational qualities originating from user experience (UX) should be identified in order to create effective and enjoyable training/learning challenges that fit with individual users’ capabilities. This study examined the effects of reality-based interaction (RBI) and VR on measures of student motivation and MWL, in a mental arithmetic game for secondary school pupils. In a randomised controlled trial with sixty school children, a mental arithmetic game was tested with three different interaction and two different presentation methods – VR RBI, VR head-mounted-display tapping and tablet flick-gesture. Results found a significant effect of RBI on MWL but no differences in enjoyment of training were found between VR-experience and tablet training-experience. In fact, adding the gaming-context to the mental arithmetic task created an enjoyable, motivating experience regardless of presentation or interaction-style.     

Damage evolution in polymer due to exposure to high-pressure hydrogen gas

The use of hydrogen as a fuel is increasing exponentially, and the most economical way to store and transport hydrogen for fuel use is as a high-pressure gas. Polymers are widely used for hydrogen distribution and storage systems because they are chemically inert towards hydrogen. However, when exposed to high-pressure hydrogen, some hydrogen diffuses through polymers and occupies the preexisting cavities inside the material. Upon depressurization, the hydrogen trapped inside polymer cavities can cause blistering or cracking by expanding these cavities. A continuum mechanics–based deformation model was deployed to predict the stress distribution and damage propagation while the polymer undergoes depressurization after high-pressure hydrogen exposure. The effects of cavity size, cavity location, and pressure inside the cavity on damage initiation and evolution inside the polymer were studied. The stress and damage evolution in the presence of multiple cavities was also studied, because interaction among cavities alters the damage and stress field. It was found that all these factors significantly change the stress state in the polymer, resulting in different paths for damage propagation. The effect of adding carbon black filler particles and plasticizer on the damage was also studied. It was found that damage tolerance of the polymer increases drastically with the addition of carbon black fillers, but decreases with the addition of the plasticizer.     

Evaluating the Use of Daily Care Notes Software for Older People with Dementia

There has been little research to investigate the impact of software to support the care for older people with dementia care. This article reports the evaluation of software adapted to support one key person-centered task for the care of older residents with dementia – recording and sharing daily care notes. The evaluation on the dementia wing of 1 residential home for over 6 months revealed that use of the software on mobile devices carried by the carers increased the number and volume of daily care notes recorded, but only for the types of content that were already being recorded by carers. Carers reported more advantages that resulted from daily care notes once in digital form than from the documenting task, as well as barriers to the use of mobile digital software to record daily care notes.     

Alteration of the Route to Menaquinone towards Isochorismate-Derived Metabolites

Chorismate and isochorismate constitute branch-point intermediates in the biosynthesis of many aromatic metabolites in microorganisms and plants. To obtain unnatural compounds, we modified the route to menaquinone in Escherichia coli. We propose a model for the binding of isochorismate to the active site of MenD ((1R,2S, 5S,6S)-2-succinyl-5-enolpyruvyl-6-hydroxycyclohex-3-ene-1-carboxylate (SEPHCHC) synthase) that explains the outcome of the native reaction with α-ketoglutarate. We have rationally designed variants of MenD for the conversion of several isochorismate analogues. The double-variant Asn117Arg–Leu478Thr preferentially converts (5S,6S)-5,6-dihydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHD), the hydrolysis product of isochorismate, with a >70-fold higher ratio than that for the wild type. The single-variant Arg107Ile uses (5S,6S)-6-amino-5-hydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHA) as substrate with >6-fold conversion compared to wild-type MenD. The novel compounds have been made accessible in vivo (up to 5.3 g L⁻¹). Unexpectedly, as the identified residues such as Arg107 are highly conserved (>94 %), some of the designed variations can be found in wild-type SEPHCHC synthases from other bacteria (Arg107Lys, 0.3 %). This raises the question for the possible natural occurrence of as yet unexplored branches of the shikimate pathway.