Heterodimers and family-B GPCRs:RAMPs, CGRP and adrenomedullin

RAMPs (receptor activity-modifying proteins) are single-pass transmembrane proteins that associate with certain family-B GPCRs (G-protein-coupled receptors). Specifically for the CT (calcitonin) receptor-like receptor and the CT receptor, this results in profound changes in ligand binding and receptor pharmacology, allowing the generation of six distinct receptors with preferences for CGRP (CT gene-related peptide) adrenomedullin, amylin and CT. There are three RAMPs: RAMP1-RAMP3. The N-terminus appears to be the main determinant of receptor pharmacology whereas the transmembrane domain contributes to association of the RAMP with the GPCR. The N-terminus of all members of the RAMP family probably contains two disulphide bonds; a potential third disulphide is found in RAMP1 and RAMP3. The N-terminus appears to be in close proximity to the ligand and plays a key role in its binding, either directly or indirectly. BIBN4096BS, a CGRP antagonist, targets RAMP1 and this gives the compound very high selectivity for the human CGRP(1) receptor.

Structural properties of a family of hydrogen-bonded co-crystals formed between gemfibrozil and hydroxy derivatives of t-butylamine, determined directly from powder X-ray diffraction data

We report the formation and structural properties of co-crystals containing gemfibrozil and hydroxy derivatives of t-butylamine H2NC(CH3)3-n(CH2OH)n, with n=0, 1, 2 and 3. In each case, a 1:1 co-crystal is formed, with transfer of a proton from the carboxylic acid group of gemfibrozil to the amino group of the t-butylamine derivative. All of the co-crystal materials prepared are polycrystalline powders, and do not contain single crystals of suitable size and/or quality for single crystal X-ray diffraction studies. Structure determination of these materials has been carried out directly from powder X-ray diffraction data, using the direct-space Genetic Algorithm technique for structure solution followed by Rietveld refinement. The structural chemistry of this series of co-crystal materials reveals well-defined structural trends within the first three members of the family (n=0, 1, 2), but significantly contrasting structural properties for the member with n=3. © 2007 Elsevier Inc. All rights reserved.

Family relocation: worse or just different?

Organisational relocation directly affects the family. It is thus often assumed that relocation is more difficult for individuals with families; however, few studies actually examine this premise. This paper investigates whether family status plays a role in relocation by comparing single individuals to married individuals. The paper uses qualitative and quantitative indicators to uncover subtle nuances between the groups and, on the basis of these, develops proposition for future research to test. Quantitative indicators highlight several important differences: Individuals with families report a greater number of moving tasks and difficulties; family relocation is viewed as more complex because of the impact of non-relocation related factors; and employees with families experience more negative and positive consequences of relocation. Qualitative techniques help to uncover subtle differences between groups and suggest that although relocation for families is different from individual relocation, it is not necessarily worse. RP0721.

Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries

Background: Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution. Methods: The localisation of VEGFs A–C and their receptors (VEGFRs 1–3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting. Results: Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominately localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens. Conclusion: This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A–C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications.

Encoding order and developmental dyslexia:a family of skills predicting different orthographic components

We investigated order encoding in developmental dyslexia using a task that presented nonalphanumeric visual characters either simultaneously or sequentially—to tap spatial and temporal order encoding, respectively—and asked participants to reproduce their order. Dyslexic participants performed poorly in the sequential condition, but normally in the simultaneous condition, except for positions most susceptible to interference. These results are novel in demonstrating a selective difficulty with temporal order encoding in a dyslexic group. We also tested the associations between our order reconstruction tasks and: (a) lexical learning and phonological tasks; and (b) different reading and spelling tasks. Correlations were extensive when the whole group of participants was considered together. When dyslexics and controls were considered separately, different patterns of association emerged between orthographic tasks on the one side and tasks tapping order encoding, phonological processing, and written learning on the other. These results indicate that different skills support different aspects of orthographic processing and are impaired to different degrees in individuals with dyslexia. Therefore, developmental dyslexia is not caused by a single impairment, but by a family of deficits loosely related to difficulties with order. Understanding the contribution of these different deficits will be crucial to deepen our understanding of this disorder.