Interchenar retrotransfer of aureothin intermediates in an iterative polyketide synthase module

The course of the enigmatic iterative use of a polyketide synthase module was deduced from targeted domain inactivation in the aureothin assembly line. Mutational analyses revealed that the N-terminus of AurA is not involved in the iteration process, ruling out an ACP-ACP shuttle. Furthermore, an AurA(KS°, ACP°)-AurA(AT(0)) heterodimer proved to be nonfunctional, whereas aureothin production was restored in a ΔaurA mutant complemented with AurA(KS°)-AurA(ACP°). This finding supports a model according to which the ACP-bound polyketide intermediate is transferred back to the KS domain on the opposite PKS strand.     

Melting of cubic boron nitride at extreme pressures

Due to its large pressure range of stability and inert nature, cubic boron nitride has been proposed as a potential pressure standard for high pressure experiments. It is extremely refractive upon compression, although its melting temperature is not known beyond 10 GPa. We apply first-principles molecular dynamics to evaluate the thermodynamics of zincblende structured (cubic) and liquid boron nitride at extreme temperatures and pressures, and compute the melting curve up to 1 TPa by integration of the Clapeyron equation. The resulting equations of state reveal that liquid boron nitride becomes denser than the solid phase at pressures of around 0.5 TPa. This is expressed as a turnover in the melting curve, which reaches a maximum at 510 GPa and 6550 ± 700 K. The origin of this density crossover is explained in terms of the underlying liquid structure, which diverges from that of the zincblende structured solid as the phases are compressed.     

Air-coupled ultrasonic investigation of stacked cylindrical rods

Measurement of the periodicities of diffraction gratings composed of stacked cylindrical rods is explored using an air-coupled ultrasonic technique. Acoustic Bragg scattering from three periodic structures is investigated by means of a polar scan. Consequently, Bragg angles and corresponding frequencies are obtained from angular spectrograms, using two different data acquisition approaches. According to the principle of Bragg scattering, the periodicities of the three periodic structures, which are equal to the diameter of the cylindrical rods, are determined. In order to evaluate the reliability of the technique and its accuracy, the obtained diameters are compared with those directly measured with a digital caliber. To show the robustness of the technique measurements are done with transducers of different quality.     

The role of mass spectrometric methods in ionic reaction mechanistic studies

The role of various mass spectrometric methods, including electron ionization, collisional activation, metastable peak shapes, analysis of neutrals from ionic unimolecular dissociations, field ionization kinetics, drift cell, and Fourier transform ion cyclotron resonance spectrometry, in ionic reaction mechanistic studies is described. This is illustrated by selected examples of research performed in the author’s group over the last three decades. They comprise inter alia intramolecular acid–base, anchimeric assistance, nucleophilic attack, isomerization, cycloaddition, S_N2, and hydride ion transfer reactions.     

A Queueing Framework for Routing Problems with Time-dependent Travel Times

Assigning and scheduling vehicle routes in a dynamic environment is a crucial management problem. Despite numerous publications dealing with efficient scheduling methods for vehicle routing, very few addressed the inherent stochastic and dynamic nature of travel times. In this paper, a vehicle routing problem with time-dependent travel times due to potential traffic congestion is considered. The approach developed introduces the traffic congestion component based on queueing theory. This is an innovative modelling scheme to capture the stochastic behavior of travel times as it generates an analytical expression for the expected travel times as well as for the variance of the travel times. Routing solutions that perform well in the face of the extra complications due to congestion are developed. These more realistic solutions have the potential to reduce real operating costs for a broad range of industries which daily face routing problems. A number of datasets are used to illustrate the appropriateness of the novel approach. Moreover it is shown that static (or time-independent) solutions are often infeasible within a congested traffic environment which is generally the case on European road networks. Finally, the effect of travel time variability (obtained via the queueing approach) is quantified for the different datasets.      

Developing a platform for comparison of hospital admission systems: An illustration

There is an increasing need to develop a platform for comparing hospital admission planning systems due to a shift in the service paradigm in the health sector. The current service concept of hospital admission planning aims at optimising the use of scarce hospital resources without paying much attention to the level of service offered to patients. As patients nowadays do not accept long waiting times for hospital admission, it becomes necessary to consider alternative admission service concepts. Waiting lists have also become a political issue, and alternative concepts have been advocated such as giving all patients an appointment for admission. A simulation model was built to examine the impacts of extreme admission service concepts in a simplified hospital setting. The alternative concepts considered are based on the ‘zero waiting time’ principle (immediate treatment), and the ‘booked admissions’ principle (using an appointment for admission). The results of these admission service concepts are compared with the results of the current concept, based on the ‘maximising resource use’ principle. The paper deals with the development of a framework and tool that allows evaluating different, somehow conflicting, hospital admission planning concepts and the usefulness of such framework and tool for more refined/real-life approaches to hospital admission planning.     

Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2

Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds. Using our recently introduced reliability estimation metrics, we could classify predictions with higher confidence by featuring an applicability domain (AD) analysis in combination with protein–ligand interaction profiling. The outcomes of and agreement between our AD and interaction-profile analyses to distinguish and rationalize the performance of our predictions highlighted the relevance of sufficiently exploring protein–ligand interactions during training and it demonstrated the possibility to quantitatively and efficiently evaluate if this is achieved by using simulation data only.     

Collision-Induced consecutive dissociation reactions of the monocarboxylate anions generated from the dimethyl and diethyl esters of glutaric acid and its 3,3-dimethyl analogue

The collision-induced dissociation reactions of the monocarboxylate anions, generated from the dimethyl and diethyl esters of glutaric acid and its 3,3-dimetbyl analogue in a chemical ionization source, were studied as a function of the potential applied to the collision cell in combination with ²H labelling experiments. It was shown that many of the product anions are formed in consecutive steps. The mechanisms associated with these steps appear to be initiated by a functional group interaction between the carboxylate anion and the ester group, 1,5-hydrogen migrations both to the carboxylate anion and the uncharged ester group and charge remote fragmentation. In one of the collision-induced dissociation channels a methyl anion is generated as a granddaughter product anion, which contains the hydrogen atoms exclusively originating from positions 2 and 4 as shown by the applied ²H labelling.