Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances in order to interpret and predict their effects upon humans. Experimental log D7.4, pKa and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3‐hydroxyphenazepam, 4’‐chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam) and compared with values generated by various software packages (ACD/I‐lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I‐LAB returned the most accurate values for log D7.4 and plasma protein binding while ADMET Predictor returned the most accurate values for pKa. Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future ‘training’ of predictive models for these new psychoactive substances

Local and global instabilities of flow in a flexible-walled channel

We consider laminar high-Reynolds-number flow through a long finite-length planar channel, where a segment of one wall is replaced by a massless membrane held under longitudinal tension. The flow is driven by a fixed pressure difference across the channel and is described using an integral form of the unsteady boundary-layer equations. The basic flow state, for which the channel has uniform width, exhibits static and oscillatory global instabilities, having distinct modal forms. In contrast, the corresponding local problem (neglecting boundary conditions associated with the rigid parts of the system) is found to be convectively, but not absolutely, unstable to small-amplitude disturbances in the absence of wall damping. We show how amplification of the primary global oscillatory instability can arise entirely from wave reflections with the rigid parts of the system, involving interacting travelling wave flutter and static-divergence modes that are convectively stable; alteration of the mean flow by oscillations makes the onset of this primary instability subcritical. We also show how distinct mechanisms of energy transfer differentiate the primary global mode from other modes of oscillatory instability

Evolutionary history of LINE-1 in the major clades of placental mammals

BACKGROUND: LINE-1 constitutes an important component of mammalian genomes. It has a dynamic evolutionary history characterized by the rise, fall and replacement of subfamilies. Most data concerning LINE-1 biology and evolution are derived from the human and mouse genomes and are often assumed to hold for all placentals. METHODOLOGY: To examine LINE-1 relationships, sequences from the 3′ region of the reverse transcriptase from 21 species (representing 13 orders across Afrotheria, Xenarthra, Supraprimates and Laurasiatheria) were obtained from whole genome sequence assemblies, or by PCR with degenerate primers. These sequences were aligned and analysed. PRINCIPAL FINDINGS: Our analysis reflects accepted placental relationships suggesting mostly lineage-specific LINE-1 families. The data provide clear support for several clades including Glires, Supraprimates, Laurasiatheria, Boreoeutheria, Xenarthra and Afrotheria. Within the afrotherian LINE-1 (AfroLINE) clade, our tree supports Paenungulata, Afroinsectivora and Afroinsectiphillia. Xenarthran LINE-1 (XenaLINE) falls sister to AfroLINE, providing some support for the Atlantogenata (Xenarthra+Afrotheria) hypothesis. SIGNIFICANCE: LINEs and SINEs make up approximately half of all placental genomes, so understanding their dynamics is an essential aspect of comparative genomics. Importantly, a tree of LINE-1 offers a different view of the root, as long edges (branches) such as that to marsupials are shortened and/or broken up. Additionally, a robust phylogeny of diverse LINE-1 is essential in testing that site-specific LINE-1 insertions, often regarded as homoplasy-free phylogenetic markers, are indeed unique and not convergent

Communications software performance prediction

Software development can be costly and it is important that confidence in a software system be established as early as possible in the design process. Where the software supports communication services, it is essential that the resultant system will operate within certain performance constraints (e.g. response time). This paper gives an overview of work in progress on a collaborative project sponsored by BT which aims to offer performance predictions at an early stage in the software design process. The Permabase architecture enables object-oriented software designs to be combined with descriptions of the network configuration and workload as a basis for the input to a simulation model which can predict aspects of the performance of the system. The prototype implementation of the architecture uses a combination of linked design and simulation tools

The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines

The illicit market for new psychoactive substances is forever expanding. Benzodiazepines and their derivatives are one of a number of groups of these substances and thus far their number has grown year upon year. For both forensic and clinical purposes it is important to be able to rapidly understand these emerging substances. However as a consequence of the illicit nature of these compounds, there is a deficiency in the pharmacological data available for these ‘new’ benzodiazepines. In order to further understand the pharmacology of ‘new’ benzodiazepines we utilised a quantitative structure-activity relationship (QSAR) approach. A set of 69 benzodiazepine-based compounds was analysed to develop a QSAR training set with respect to published binding values to GABAA receptors. The QSAR model returned an R2 value of 0.90. The most influential factors were found to be the positioning of two H-bond acceptors, two aromatic rings and a hydrophobic group. A test set of nine random compounds was then selected for internal validation to determine the predictive ability of the model and gave an R2 value of 0.86 when comparing the binding values with their experimental data. The QSAR model was then used to predict the binding for 22 benzodiazepines that are classed as new psychoactive substances. This model will allow rapid prediction of the binding activity of emerging benzodiazepines in a rapid and economic way, compared with lengthy and expensive in vitro/in vivo analysis. This will enable forensic chemists and toxicologists to better understand both recently developed compounds and prediction of substances likely to emerge in the future

TIDieR-PHP: a reporting guideline for population health and policy interventions

We lack guidance on how to describe population health and policy (PHP) interventions in reports of evaluation studies. PHP interventions are legal, fiscal, structural, organisational, environmental, and policy interventions such as the regulation of unhealthy commodities, health service reorganisation, changes in welfare policy, and neighbourhood improvement schemes. Many PHP interventions have characteristics that are important for their implementation and success but are not adequately captured in the original Template for Intervention Description and Replication (TIDieR) checklist. This article describes the development of a revised reporting template for PHP interventions (TIDieR-PHP) and presents the checklist with examples for each ite

Is the Donnan effect sufficient to explain swelling in brain tissue slices?

Brain tissue swelling is a dangerous consequence of traumatic injury and is associated with raised intracranial pressure and restricted blood flow. We consider the mechanical effects that drive swelling of brain tissue slices in an ionic solution bath, motivated by recent experimental results that showed that the volume change of tissue slices depends on the ionic concentration of the bathing solution. This result was attributed to the presence of large charged molecules that induce ion concentration gradients to ensure electroneutrality (the Donnan effect), leading to osmotic pressures and water accumulation. We use a mathematical triphasic model for soft tissue to characterize the underlying processes that could lead to the volume changes observed experimentally. We suggest that swelling is caused by an osmotic pressure increase driven by both non-permeating solutes released by necrotic cells, in addition to the Donnan effect. Both effects are necessary to explain the dependence of the tissue slice volume on the ionic bath concentration that was observed experimentally

Wrinkling, creasing, and folding in fiber-reinforced soft tissues

Many biological tissues develop elaborate folds during growth and development. The onset of this folding is often understood in relation to the creasing and wrinkling of a thin elastic layer that grows whilst attached to a large elastic foundation. In reality, many biological tissues are reinforced by fibres and so are intrinsically anisotropic. However, the correlation between the fiber directions and the pattern formed during growth is not well understood. Here, we consider the stability of a two-layer tissue composed of a thin hyperelastic strip adhered to an elastic half-space in which are embedded elastic fibers. The combined object is subject to a uniform compression and, at a critical value of this compression, buckles out of the plane — it wrinkles. We characterize the wrinkle wavelength at onset as a function of the fiber orientation both computationally and analytically and show that the onset of surface instability can be either promoted or inhibited as the fiber stiffness increases, depending on the fibre angle. However, we find that the structure of the resulting folds is approximately independent of the fiber orientation. We also explore numerically the formation of large creases in fiber-reinforced tissue in the post-buckling regime