The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABAA receptor

A Catalyst pharmacophore model has been developed for the benzodiazepine site within the GABA(A) receptor complex. The model is based on a pharmacophore model originally proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) and further developed by Kahnberg et al. (J. Med. Chem. 2002, 45, 4188-4201). The Catalyst pharmacophore model has been validated by using a series of flavonoids with varying affinities for the benzodiazepine receptor and has then been used as a search query in database searching with the aim of finding novel structures which have the possibility to be modified into novel lead compounds. Five of the hits from the database searching were purchased and their affinities for the benzodiazepine site of the GABA(A) receptor were determined. Two of the compounds displayed K(i) values below 10 microM. The substance showing highest potency in-vitro displayed an affinity of 121 nM making it an interesting compound for optimization. The false positive compounds (K(i) values >10 microM affinities) have been analysed in terms of conformational energy penalties and possibilities for hydrogen bond interactions. The analysis clearly demonstrates the need for post processing of Catalyst hits.     

A Controlled Experiment Comparing the Maintainability of Programs Designed with and without Design Patterns—A Replication in a Real Programming Environment

Software design patterns seek to package proven solutions to design problems in a form that makes it possible to find, adapt and reuse them. To support the industrial use of design patterns, this research investigates when, and how, using patterns is beneficial, and whether some patterns are more difficult to use than others. This paper describes a replication of an earlier controlled experiment on design patterns in maintenance, with major extensions. Experimental realism was increased by using a real programming environment instead of pen and paper, and paid professionals from multiple major consultancy companies as subjects. Measurements of elapsed time and correctness were analyzed using regression models and an estimation method that took into account the correlations present in the raw data. Together with on-line logging of the subjects work, this made possible a better qualitative understanding of the results. The results indicate quite strongly that some patterns are much easier to understand and use than others. In particular, the Visitor pattern caused much confusion. Conversely, the patterns Observer and, to a certain extent, Decorator were grasped and used intuitively, even by subjects with little or no knowledge of patterns. The implication is that design patterns are not universally good or bad, but must be used in a way that matches the problem and the people. When approaching a program with documented design patterns, even basic training can improve both the speed and quality of maintenance activities.     

Melt penetration and chemical reactions in 16 industrial aluminum carbon cathodes

The study shows examples of the distribution of melt components in spent carbon cathodes from 16 industrial aluminum electrolysis cells shut down after 10 to 2534 days. The concentration of the phases was determined by quantitative X-ray diffraction (XRD), and the distribution was found by analyzing series of samples from several vertical cores from each cathode. The results show that the analysis is useful for characterizing phases in spent potlining, and the detailed distribution graphs are suitable for comparing different parts of a cathode, or different cathodes. The composition of the melt in the 16 cathodes changed systematically over time, and the stages in the evolution, the effect of the cathode material type, and the effect of the melt on the lining are discussed.     

Preparation and characterization of Au/CeO2–Al2O3 monoliths

Porous CeO₂–Al₂O₃ monoliths with hierarchical pore structure were prepared by mixing boehmite particles with solutions containing different amounts of cerium chloride and aluminum nitrate. The monoliths were functionalized with gold nanoparticles using the incipient wetness method. The resulting materials were characterized by X-ray diffraction, nitrogen sorption, mercury porosimetry, UV–vis spectroscopy and transmission electron microscopy. The catalysts were tested in liquid phase glucose oxidation, comparing continuously stirred batch reactor and continuous-flow fix-bed reactor setups.     

Van der Waals density functional calculations of binding in molecular crystals

A recent paper [J. Chem. Phys. 132 (2010) 134705] illustrated the potential of the van der Waals density functional (vdW-DF) method [Phys. Rev. Lett. 92 (2004) 246401] for efficient first-principle accounts of structure and cohesion in molecular crystals. Since then, modifications of the original vdW-DF version (identified as vdW-DF1) have been proposed, and there is also a new version called vdW-DF2 [Phys. Rev. B 82 (2010) 081101(R)], within the vdW-DF framework. Here we investigate the performance and nature of the modifications and the new version for the binding of a set of simple molecular crystals: hexamine, dodecahedrane, C60, and graphite. These extended systems provide benchmarks for computational methods dealing with sparse matter. We show that a previously documented enhancement of non-local correlations of vdW-DF1 over an asymptotic atom-based account close to and a few Å beyond binding separation persists in vdW-DF2. The calculation and analysis of the binding in molecular crystals require appropriate computational tools. In this paper, we also present details on our real-space parallel implementation of the vdW-DF correlation and on the method used to generate asymptotic atom-based pair potentials based on vdW-DF.     

Formal Vulnerability Assessment of a maritime transportation system

World trade increasingly relies on longer, larger and more complex supply chains, where maritime transportation is a vital backbone of such operations. Long and complex supply chain systems are more prone to being vulnerable, though through reviews, no specific methods have been found to assess vulnerabilities of a maritime transportation system. Most existing supply chain risk assessment frameworks require risks to be foreseen to be mitigated, rather than giving transportation systems the ability to cope with unforeseen threats and hazards. In assessing cost-efficiency, societal vulnerability versus industrial cost of measures should be included.This conceptual paper presents a structured Formal Vulnerability Assessment (FVA) methodology, seeking to transfer the safety-oriented Formal Safety Assessment (FSA) framework into the domain of maritime supply chain vulnerability. To do so, the following two alterations are made: (1) The focus of the assessment is defined to ensure the ability of the transportation to serve as a throughput mechanism of goods, and to survive and recover from disruptive events. (2) To cope with low-frequency high-impact disruptive scenarios that were not necessarily foreseen, two parallel tracks of risk assessments need to be pursued—the cause-focused risk assessment as in the FSA, and a consequence-focused failure mode approach.     

Self‐perceived quality of sleep and mortality in Norwegian dialysis patients

Sleep complaints are prevalent and associated with poor health‐related quality of life (HRQoL), depression and possibly mortality in dialysis patients. This study aimed to explore possible associations between sleep quality, daytime sleepiness and mortality in dialysis patients. In this study, 301 dialysis patients were followed up to 4.3 years. HRQoL was evaluated at baseline with the Kidney Disease and Quality of Life—Short Form (KDQoL‐SF), depression with Beck Depression Inventory (BDI), sleep quality with Pittsburgh Sleep Quality Index and daytime sleepiness with Epworth Sleepiness Scale. The single item “on a scale from 0–10, how would you evaluate your sleep?” in the sleep subscale in KDQoL‐SF was used to identify poor (0–5) and good sleepers (6–10). A total of 160 patients (53.3%) were characterized as poor sleepers. They were younger (r = 0.241, P < 0.001), had more depression (BDI: 8.72 ± 6.79 vs. 13.60 ± 8.04, P < 0.001), a higher consumption of hypnotics and antidepressants and reduced HRQoL (Mental Component Summary score: 45.4 ± 11.0 vs. 50.0 ± 10.4, P < 0.001. Physical Component Summary score: 35.0 ± 9.9 vs. 38.5 ± 10.5, P = 0.004). In multivariate analyses, poor sleepers had nearly a twofold increase in mortality risk (hazard ratio [HR] 1.92, confidence interval [CI] 1.10‐3.35, P = 0.022). Daytime sleepiness was not related to mortality (HR 1.01, CI 0.95‐1.08, P = 0.751). Sleep complaints predicted increased mortality risk in dialysis patients and should therefore be routinely assessed. Further studies are needed to find suitable treatment options for poor sleep in dialysis patients as it may affect both HRQoL and survival.     

Presence and Persistence of White Phosphorus On Military Training Ranges

The use of obscurants is a common practice by militaries worldwide. One of the most effective of these is white phosphorus (WP). WP is the elemental form of phosphorus that does not occur in nature and is highly toxic. The use of WP rounds on training ranges has led to a number of die‐offs of grazing land animals and dabbling waterfowl, the first recorded in 1930. In the 1980s, thousands of waterfowl were dying annually at an impact range in Alaska, leading to the first large‐scale investigation of WP as a lethal range contaminant. Tests were conducted at an upland impact range in New York to determine the quantity and persistence of WP in a typical environment. At all sites cited in this paper, WP was persistent for months to years following the detonation of WP munitions. At the Eagle River Flats range in AK, WP was identified from rounds fired in the 1950s, persisting over 45 years in a non‐saturated environment. In New York, dispersal of gram quantities of WP occurred at detonation, and high concentrations of WP were found in the detonation craters a year after firing. Caution needs to be exercised when using white phosphorus munitions on ranges.