Human CC chemokines macrophage inflammatory protein (MIP)-1␣, MIP-1␤, and RANTES (regulated on activation normal T cell expressed) self-associate to form high-molecular mass aggregates. To explore the biological significance of chemokine aggregation, nonaggregating variants were sought. The phenotypes of 105 hMIP-1␣ variants generated by systematic mutagenesis and expression in yeast were determined. hMIP-1␣ residues Asp 26 and Glu 66 were critical to the self-association process. Substitution at either residue resulted in the formation of essentially homogenous tetramers at 0.5 mg/ml. Substitution of identical or analogous residues in homologous positions in both hMIP-1␤ and RAN-TES demonstrated that they were also critical to aggregation. Our analysis suggests that a single charged residue at either position 26 or 66 is insufficient to support extensive aggregation and that two charged residues must be present. Solution of the three-dimensional NMR structure of hMIP-1␣ has enabled comparison of these residues in hMIP-1␤ and RANTES. Aggregated and disaggregated forms of hMIP-1␣, hMIP-1␤, and RANTES generally have equivalent G-protein-coupled receptormediated biological potencies. We have therefore generated novel reagents to evaluate the role of hMIP-1␣, hMIP-1␤, and RANTES aggregation in vitro and in vivo. The disaggregated chemokines retained their human immunodeficiency virus (HIV) inhibitory activities. Surprisingly, high concentrations of RANTES, but not disaggregated RANTES variants, enhanced infection of cells by both M-and T-tropic HIV isolates/strains. This observation has important implications for potential therapeutic uses of chemokines implying that disaggregated forms may be necessary for safe clinical investigation.

The relationship between deoxynivalenol (DON) intake and first morning urinary DON was examined in UK adults to validate the latter as a biomarker of human exposure. DON was assessed in first morning samples collected during a period of normal diet, a wheat-restriction intervention diet, and partial wheat-restriction intervention in which bread was allowed. During the partial intervention duplicate bread portions were collected for DON analysis. During the normal diet, partial intervention and full intervention, urinary DON was detected in 198/210 (geometric mean 10.1 ng DON mg(-1) creatinine, 95% confidence interval (CI) 8.6-11.6 ng mg(-1); range nd-70.7 ng mg(-1)), in 94/98 (5.9 ng mg(-1), 95% CI 4.8-7.0 ng mg(-1); range nd-28.4 ng mg(-1)), and 17/40 (0.5 ng mg(-1), 95% CI 0.3-0.7 ng mg(-1); range nd-3.3 ng mg(-1)) volunteers, respectively. A strong correlation between DON intake and the urinary biomarker was observed (p <0.001, adjusted r(2) = 0.83) in models adjusting for age, sex and body mass index. These data demonstrate a quantitative correlation between DON exposure and urinary DON, and serve to validate the use of urinary DON as an exposure biomarker.

No abstract

Summary Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant‐derived cholesterol‐like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC‐MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.

Dietary exposure to deoxynivalenol (DON) from contaminated cereal crops is frequent in Europe, and farm workers who handle grain or silage may be at additional risk. In this study we refined a urinary assay for DON and present a novel assay for the DON metabolite de-epoxy-deoxynivalenol (DOM-1). These were applied to a pilot survey of male French farmers (n = 76, aged 23-74). DON was detected in 75/76 samples (range 0.5-28.8 ng/mL) and DOM-1 in 26/76 samples (range 0.2-2.8 ng/mL). In multivariate analysis including creatinine as a covariate, bread consumption, other cereal consumption, and maize acreage contributed to the model, explaining the variation in urinary "DON and DOM-1" concentration combined (R(2) = 0.33). This is the first exposure biomarker survey for DON in a French population, and the first demonstration of urinary DOM-1 in humans. Further investigations into occupational activity, handling, or airborne exposures would be informative.

An oligoamide helix mimicking foldamer with well-defined conformation is shown to recognize its target protein hDM2 in a manner that depends upon the composition, spatial projection and stereochemistry of functional groups appended to the scaffold.

Metallosupramolecular chemistry relies on self-assembly processes in which complicated species form through labile dative-covalent interactions. Two remarkable areas of this chemistry are the synthesis of topologically complicated threaded assemblies and of three-dimensional (3D) polyhedral assemblies. Very few polyhedral 3D metallosupramolecular assemblies show threaded motifs within them. Here we report an example of a new type of threaded 3D metallosupramolecular assembly built from four organic ligands and four palladium ions, a Pd(4)L(4) so-called 'Solomon's cube' in which interweaving and twisting of the ligands form both Solomon's links and figure-of-eight ring motifs. In the solid state, six of these Pd(4)L(4) tetramers assemble into a hollow spheroid that closely resembles a stellated truncated hexahedron.

The synthesis of the three isomeric tris(pyridylmethylamino)cyclotriguaiacylene cavitands is reported, along with the crystal structures of the 2- and 4-pyridyl derivatives. The generality of a previously described [Ag(2){tris(3-pyridylmethylamino)cyclotriguaiacylene}(2)](2+) dimeric capsule motif and the [Ag(4){tris(4-pyridylmethylamino)cyclotriguaiacylene}(4)](4+) tetrahedron with several silver salts was confirmed in the solid state and the corresponding solution species were investigated by NMR spectroscopy. Host-guest interactions in these systems have been probed and these interactions are demonstrated to alter and influence the self-assembly outcome of the reaction. Notably, introduction of larger glutaronitrile guest molecules to the [Ag(4)L(4)](4+) tetrahedron system prevents formation of the tetrahedral structure, resulting instead in the formation of a 4.8(2) coordination network in the solid state. In the absence of templating acetonitrile guests in the [Ag(2)(3)(2)](2+) capsule system, formation of a cage-based one-dimensional coordination polymer is observed.