Advancements in the Development of non-BET Bromodomain Chemical Probes

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high-quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non-BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non-BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non-BET bromodomains as tractable therapeutic targets.     

Characterization of sea water ageing effects on mechanical properties of carbon/epoxy composites for tidal turbine blades

In recent years, many tidal turbine projects have been developed using composites blades. Tidal turbine blades are subject to ocean forces and sea water aggressions, and the reliability of these components is crucial to the profitability of ocean energy recovery systems. The majority of tidal turbine developers have preferred carbon/epoxy blades, so there is a need to understand how prolonged immersion in the ocean affects these composites. In this study the long term behaviour of different carbon/epoxy composites has been studied using accelerated ageing tests. A significant reduction of composite strengths has been observed after saturation of water in the material. For longer immersions only small further changes in these properties occur. No significant changes have been observed for moduli nor for composite toughness. The effect of sea water ageing on damage thresholds and kinetics has been studied and modelled. After saturation, the damage threshold is modified while kinetics of damage development remain the same.     

Biocatalytic Alkylation Cascades: Recent Advances and Future Opportunities for Late-Stage Functionalization

This Concept article describes the latest developments in the emerging area of late-stage biocatalytic alkylation. Central to these developments is the ability to efficiently prepare S-adenosyl methionine (SAM) cofactor analogues and couple this with enzymatic alkyl transfer. Recent developments in the enzymatic synthesis of SAM cofactor analogues are summarized first, followed by their application as alkyl transfer agents catalyzed by methyltransferases (MTases). Second, innovative methods to regenerate SAM cofactors by enzymatic cascades is reported. Finally, future opportunities towards establishing a generalized platform for late-stage alkylation are described.     

An element-based displacement preconditioner for linear elasticity problems

Finite element analysis of problems in structural and geotechnical engineering results in linear systems where the unknowns are displacements and rotations at nodes. Although the solution of these systems can be carried out using either direct or iterative methods, in practice the matrices involved are usually very large and sparse (particularly for 3D problems) so an iterative approach is often advantageous in terms of both computational time and memory requirements. This memory saving can be further enhanced if the method used does not require assembly of the full coefficient matrix during the solution procedure. One disadvantage of iterative methods is the need to apply preconditioning to improve convergence. In this paper, we review a range of established element-based preconditioning methods for linear elastic problems and compare their performance with a new method based on preconditioning with element displacement components. This new method appears to offer a significant improvement in performance.     

Iodo-2'-deoxyuridine (IUdR) and 125IUdR loaded biodegradable microspheres for controlled delivery to the brain

The aim of this work was to develop sustained local release systems for radioiodinated iodo-2'-deoxyuridine (125IUdR) from biodegradable polymeric microspheres to facilitate the controlled delivery of 125IUdR to brain tumours. The selective uptake of IUdR into the cell nucleus results in cell disruption over the short range of the low energy Auger electrons. The biodegradable microspheres can be precisely implanted in the brain by stereotactic techniques and the IUdR within the microspheres is protected from degradation and thus a sustained source of radiolabelled IUdR is available in the vicinity of the residual tumour cells. Poly(lactic-co-glycolic acid), PLGA (85:15), microspheres containing cold IUdR and the Auger-electron emitter 125I, as 125IUdR were prepared using the O/W, O/O and W/O/W emulsion-solvent evaporation methods. The W/O/W emulsion method was most effective in achieving good drug loading with the use of bovine plasma in the internal water phase. Also effective in improving the drug loading was the use of 20% acetone in the dichloromethane and the presence of Span 40 in the organic phase. Electrolytes (NaCl and IUdR) in the external aqueous phase also improved drug loading. After an initial rapid release from the microspheres, a sustained release was observed over 15 days for the 'cold' IUdR. The sustained release portions of the release curves showed Higuchi (t1/2), diffusion controlled release kinetics. The radiolabelled IUdR microspheres showed a burst release effect of 30-40% followed by a sustained release over 35 days.     

Similarity coefficient methods applied to the cell formation problem: a comparative investigation

Although many similarity coefficients have been proposed, very few comparative studies have been done to evaluate the performance of various similarity coefficients. In this paper, we compare the performance of 20 well-known similarity coefficients. Two hundred and fourteen numerical cell formation problems, which are selected from the literature or generated deliberately, are used for the comparative study. Nine performance measures are used for evaluating the goodness of cell formation solutions. Two characteristics, discriminability and stability of the similarity coefficients are tested under different data conditions. From the results, three similarity coefficients are found to be more discriminable. Jaccard is found to be the most stable similarity coefficient. Four similarity coefficients are not recommendable due to their poor performances.     

Influence of lips on thin-walled sections

Turning the free edge of an unstiffened flange inwards or outwards to form a ‘lip’, can substantially improve the local buckling resistance of a member. The lip is the most common type of edge stiffener used in cold-rolled, thin-walled sections. In this paper the behaviour of plate elements of thin-walled sections stiffened by compound lips (i.e. lips which are folded twice to form ‘lips on the lips’) is examined both theoretically and experimentally. An outline of a series of tests on compound edge-stiffened thin-walled sections of various geometries is given and some load-end compression displacement paths are compared with the theoretical predictions. Reasonably good agreement is obtained between the experimental and theoretical results. Comparisons of the theoretical predictions with experimental results of other researchers are also presented in this paper.     

Stimulatory effects of tannins and cholic acid on tryptic hydrolysis of proteins: Ecological implications

The biochemical basis for considering tannins as digestion inhibitors has been reexamined. Both stimulatory and inhibitory effects of tannins on tryptic hydrolysis are reported. We show how stimulation may result from tannin-induced structural changes in the substrate protein, effectively denaturing it. The surfactant and bile constituent cholic acid also produced similar stimulatory effects. These results have considerable implications for normal digestive physiology as well as for the impact of tannins on argicultural and natural herbivore populations.