MAOS ls for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines

General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative analog library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.     

A study on the interactions of Aurein 2.5 with bacterial membranes

Aurein 2.5 (GLFDIVKKVVGAFGSL-NH₂) is an uncharacterised antimicrobial peptide. At an air/water interface, it exhibited strong surface activity (maximal surface pressure 25 mN m⁻¹) and molecular areas consistent with the adoption of α-helical structure orientated either perpendicular (1.72 nm² molecule⁻¹) or parallel (3.6 nm² molecule⁻¹) to the interface. Aurein 2.5 was strongly antibacterial, exhibiting a minimum inhibitory concentration (MIC) of 30 μM against Bacillus subtilis and Escherichia coli. The peptide induced maximal surface pressure changes of 9 mN m⁻¹ and 5 mN m⁻¹, respectively, in monolayers mimicking membranes of these organisms whilst compression isotherm analysis of these monolayers showed ΔG_Mix > 0, indicating destabilisation by Aurein 2.5. These combined data suggested that toxicity of the peptide to these organisms may involve membrane invasion via the use of oblique orientated α-helical structure. The peptide induced strong, comparable maximal surface changes in monolayers of DOPG (7.5 mN m⁻¹) and DOPE monolayers (6 mN m⁻¹) suggesting that the membrane interactions of Aurein 2.5 were driven by amphiphilicity rather than electrostatic interaction. Based on these data, it was suggested that the differing ability of Aurein 2.5 to insert into membranes of B. subtilis and E. coli was probably related to membrane-based factors such as differences in lipid packing characteristics. The peptide was active against both sessile E. coli and Staphylococcus aureus with an MIC of 125 μM. The broad-spectrum antibacterial activity and non-specific modes of membrane action used by Aurein 2.5 suggested use as an anti-biofilm agent such as in the decontamination of medical devices.     

Volume-based thermoelasticity: consequences of the (near) proportionality of isothermal compressibility to formula-unit volume

Groups of structurally related materials, including the alkali halides, exhibit a proportionality of isothermal compressibility to formula-unit volume. The relationship has recently been explored by Glasser and by Recio et al. In this paper, we present the consequences of such proportionality on the relationships of Born-Lande? and Born-Mayer parameters to the formula-unit volume. These relationships have then been tested separately on (i) alkali (excluding cesium) halides and (ii) cesium halides. We conclude that the equations fit the NaCl-type materials satisfactorily, but less well for the CsCl-type materials, and that the Born-Mayer equation is more applicable. These results confirm the conclusion that volume is intimately linked to thermodynamic quantities, as already demonstrated by our development of volume-based thermodynamics (VBT).     

Lateralization produced by envelope-based interaural temporal disparities of high-frequency, raised-sine stimuli: empirical data and modeling

An acoustic pointing task was used to measure extents of laterality produced by ongoing interaural temporal disparities (ITDs) conveyed by the envelopes of 4-kHz-centered raised-sine stimuli while varying, parametrically, their peakedness, depth of modulation, and frequency of modulation. One purpose of the study was to determine whether such manipulations would produce changes in laterality logically consistent with those found for ITD-discrimination thresholds reported by Bernstein and Trahiotis [J. Acoust. Soc. Am. 125, 3234-3242 (2009)]. The data obtained revealed that they did in that (1) increasing depth of modulation, peakedness, or frequency of modulation between 32 and 128 Hz produced smaller threshold ITDs and greater laterality and (2) increasing frequency of modulation to 256 Hz produced modest increases in threshold ITDs and modest decreases in laterality. The extents of laterality measured were successfully accounted for via an augmentation of the cross-correlation-based "position-variable" modeling approach developed by Stern and Shear [J. Acoust. Soc. Am. 100, 2278-2288 (1996)] to account for ITD-based extents of laterality obtained at low spectral frequencies.     

Spinach--a software library for simulation of spin dynamics in large spin systems

We introduce a software library incorporating our recent research into efficient simulation algorithms for large spin systems. Liouville space simulations (including symmetry, relaxation and chemical kinetics) of most liquid-state NMR experiments on 40+ spin systems can now be performed without effort on a desktop workstation. Much progress has also been made with improving the efficiency of ESR, solid state NMR and Spin Chemistry simulations. Spinach is available for download at http://spindynamics.org.     

A new criterion for weak subintegrality 1

In a previous paper the authors, together with Balwant Singh, introduced an elementwisc char­acterization of weak subintegrality for an extension A?B of commutative rings. In the present paper we improve our methods for working with this characterization. This leads us to propose two new types of “elementary weakly subintegral extension”.