TRPing the switch on pain: an introduction to the chemistry and biology of capsaicin and TRPV1

Capsaicin has elicited great interest for many centuries due to its noticeable culinary and medical properties. The discovery of its receptor, TRPV1, sparked an explosion of interest in TRPV1 and the development of TRPV1 agonists and antagonists. This tutorial review provides an introduction to the history of both capsaicin and TRPV1. Two TRPV1 antagonists that are undergoing clinical trials are highlighted, as are some light-activated molecular tools that are enabling the intracellular study of this protein. This article will be of interest to chemists and biologists with an interest in TRPV1, cell signalling, or medicinal and biological chemistry.     

A Survey of Methods Available for the Numerical Optimization of Continuous Dynamic Systems

There has been significant progress in the development of numerical methods for the determination of optimal trajectories for continuous dynamic systems, especially in the last 20 years. In the 1980s, the principal contribution was new methods for discretizing the continuous system and converting the optimization problem into a nonlinear programming problem. This has been a successful approach that has yielded optimal trajectories for very sophisticated problems. In the last 15–20 years, researchers have applied a qualitatively different approach, using evolutionary algorithms or metaheuristics, to solve similar parameter optimization problems. Evolutionary algorithms use the principle of “survival of the fittest” applied to a population of individuals representing candidate solutions for the optimal trajectories. Metaheuristics optimize by iteratively acting to improve candidate solutions, often using stochastic methods. In this paper, the advantages and disadvantages of these recently developed methods are described and an attempt is made to answer the question of what is now the best extant numerical solution method.     

Effects of thermal impact on a thin spherical cap

Because of the importance of thin shells as structural elements in all aircraft and missile vehicles, the response of the shell to transient thermal loads is of extreme interest. At very high heating rates, as can be produced by the absorption of intense radiation energy, dynamic mechanical response of the structure may be produced. This paper describes a brief exploratory investigation of the effects of short-duration, high-intensity thermal radiation exposure of a thin-shell structure. Exposure of a spherical cap in a arc-image furnance failed to produce buckling under the test conditions. Rapid thermal rupture, however, did result in interesting failure surfaces.     

Ammonium formate-based one-pot reductive Heck reactions for the construction of cyclic sulfonamides

A modified method is reported for the conversion of unsaturated sulfonamides into their cyclic saturated counterparts. This method utilises a single palladium catalyst for an intramolecular Heck reaction and subsequent transfer hydrogenation, which is achieved in one-pot following the addition of ammonium formate. Accordingly, a range of fourteen structural variations are reported and under optimal conditions the adducts were generated in typically good to excellent yields. Notably, discrimination of differentially substituted dienes can be accomplished in the case of compounds 28 and 29 and the process was only observed to fail with the more sterically hindered precursor 32.     

Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2

N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine N-acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamine N-acetyltransferase NAT2 also acetylates aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed increased intracellular concentrations of mono- and diacetylated spermidine in human cell lines expressing the rapid compared to the slow acetylator NAT2 phenotype. The regioselective N⁸-acetylation of monoacetylated spermidine by NAT2 answers the long-standing question of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine-containing drugs by NAT2, which may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2, and we suggest that this enzyme should be considered for re-classification.     

Kinetic Monte Carlo simulation of electrodeposition of polycrystalline Cu

A two-dimensional cross-sectional poly-lattice kinetic Monte Carlo (2DCSP-KMC) model has been developed for simulation of the electrodeposition of polycrystalline copper on a copper and gold substrate. The mis-orientation and higher energetic state of grain boundaries are taken into account by introducing a ‘strange’ coordination number and a correction coefficient while determining the diffusion rate. The evolution of the microstructure, the average grain size, the variance of grain size and the distribution of grain-boundary mis-orientation of the deposit are also considered in simulations. The model has proven capable of capturing some key aspects of nucleation and growth mechanism including the nucleation type (e.g. homogeneous or heterogeneous), texture development, the growth of grains and higher energetic state of grain boundaries. The simulated microstructure qualitatively agrees with our experimental observation on the copper deposition on gold.