Improving the description of interactions between Ca2+ and protein carboxylate groups, including γ-carboxyglutamic acid: revised CHARMM22∗ parameters

A reliable description of ion pair interactions for biological systems, particularly those involving polyatomic ions such as carboxylate and divalent ions such as Ca²⁺, using biomolecular force-fields is essential for making useful predictions for a range of protein functions. In particular, the interaction of divalent ions with the double carboxylate group present in γ-carboxyglutamic acid (Gla), relevant to the function of many proteins, is relatively understudied using biomolecular force-fields. Using force-field based metadynamics simulations to predict the free energy of binding between Ca²⁺ and the carboxylate group in liquid water, we show that a widely-used biomolecular force-field, CHARMM22∗, substantially over-estimates the binding strength between Ca²⁺ and the side-chains of both glutamic acid (Glu) and Gla, compared with experimental data obtained for the analogous systems of aqueous calcium-acetate and calcium-malonate. To correct for this, we propose and test a range of modifications to the σ value of the heteroatomic Lennard-Jones interaction between Ca²⁺ and the oxygen of the carboxylate group. Our revised parameter set can recover the same three association modes of this aqueous ion pair as the standard parameter set, and yields free energies of binding for the carboxylate-Ca²⁺ interaction in good agreement with experimental data. The revised parameter set recovers other structural properties of the ion pair in agreement with the standard CHARMM22∗ parameter set.

Jones -v- Bartlett: landlords` liability to tenants and members of their household in negligence

According to the latest available statistics, in 1997-98, of the total of seven million Australian households, two million were renting their dwelling from a State housing authority or private landlords.Therefore, the decision on the scope of landlords' liability to tenants, members of their households, and guests in the right of the tenant handed down by the High Court of Australia in November 2000 was not only of legal, but also of social and economic significance. This note will discuss the Jones v Bartlett case in the context of the traditional common law approach to landlords' liability and the ground-breaking, if flawed, case of Northern Sandblasting Pty Ltd v Harris.

Microsatellite loci for studies of wild and hatchery Australian Murray cod Maccullochella peelii peelii (Percichthyidae)

Murray cod is a species of conservation concern that is subject both to wild harvest and to aquaculture production. Six polymorphic microsatellite loci have been developed for this species, which will facilitate studies of wild-stock structure, will help the management of hatchery diversity, and will aid genetic improvement programmes. The markers exhibited nonindependence of genotypes between loci and deviations from Hardy–Weinberg expectations, although these most probably reflect practices at the hatchery from which the genotyped individuals were sourced.

Saving psychoanalysts: Ernest Jones and the Isakowers

This article examines the role played by Ernest Jones in saving psychoanalysts from Germany and Austria during the 1930s, and, in particular, in the case of Drs Otto and Salomea Isakower from Vienna. Archives from the Library of Congress and the British Psychoanalytical Society are used to document how Jones navigated the considerable difficulties presented in both Europe and London as well as by colleagues and was able to help the Isakowers emigrate to Liverpool where they worked and began the ‘North of England’ training group with others and emigrated to the USA in 1940. As President of the International Psychoanalytical Association and of the British Psychoanalytical Society, Jones had responsibilities with psychoanalyst refugees, which he performed with care, commitment and political competence. Although Jones did not succeed in saving psychoanalysis in Europe, he played a crucial role in saving psychoanalysts. He helped to spread the world-wide standing and influence of psychoanalysis.

Fabric of a dream: the Fletcher Jones story

This is the story of how a shell-shocked World War I veteran, who left school at 12, ended up building a national icon. An inspiring man with bold and imaginative ideas, Fletcher Jones was influenced by Japanese reformer Toyohiko Kagawa. Jones established his clothing design, retail and manufacturing business with emphasis on quality, service and innovation. But his primary concern was for people both his customers and his workers and they, in turn, were intensely loyal.

Examination of the role of intestinal Fatty acid-binding protein in drug absorption using a parallel artificial membrane permeability assay

Transcellular diffusion across the absorptive epithelial cells (enterocytes) of the small intestine is the main route of absorption for most orally administered drugs. The process by which lipophilic compounds transverse the aqueous environment of the cytoplasm, however, remains poorly defined. In the present study, we have identified a structurally diverse group of lipophilic drugs that display low micromolar binding affinities for a cytosolic lipid-binding protein—intestinal fatty acid-binding protein (I-FABP). Binding to I-FABP significantly enhanced the transport of lipophilic drug molecules across a model membrane, and the degree of transport enhancement was related to both drug lipophilicity and I-FABP binding affinity. These data suggest that intracellular lipid-binding proteins such as I-FABP may enhance the membrane transport of lipophilic xenobiotics and facilitate drug access to the enterocyte cytoplasm and cytoplasmic organelles.

Genome - wide association study identifies novel breast cancer susceptibility loci

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r² > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10^-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Biodegradable Mg-Ca and Mg-Ca-Y alloys for regenerative medicine

In this study, Mg-xCa (x = 0.5, 1.0, 2.0, 5.0, 10.0, 15.0 and 20.0 %, wt.%, hereafter) and Mg-1Ca-1Y alloys were investigated as new biodegradable bone implant materials. The compressive strength, ultimate strength and hardness of the Mg-Ca alloys increased, whilst the corrosion rate and biocompatibility decreased, with the increase of the Ca content in the Mg-Ca alloys; higher Ca content caused the Mg-Ca alloy to become brittle. Solutions of simulated body fluid (SBF) and modified minimum essential media (MMEM) with the immersion of Mg-xCa and Mg-1Ca-1Y alloys showed strong alkalisation. The yttrium addition to the Mg-Ca alloys does not improve the corrosion resistance of the Mg-1Ca-1Y alloy as expected compared to the Mg-1Ca alloy. It is suggested that Mg-Ca alloys with Ca additions less than 1.0 wt.% exhibited good biocompatibility and low corrosion rate.