Chemotactic activity of extracellular nucleotideson human immune cells.

Purinergic P2 receptors are a class of plasma membrane receptors that are express in many tissues and are ligated by extracellular nucleotides [such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), uridine 5–triphosphate (UTP) and uridine 5–diphosphate (UDP)], which are released as a consequence of cell damage, cell stress, bacterial infection or other noxious stimuli. According to the molecular structure, P2 receptors are divided into two subfamilies: P2X and P2Y receptors. The P2X receptors are ligand-gated channels, whereas P2Y receptors are G-protein-coupled seven-membrane-spanning receptors. Several studies indicate that nucleotides play an important role in immune response modulation through their action on multiple cell types, including monocytes, mast cells, dendritic cells, neutrophils, and eosinophils. Recent work by our group and others identified extracellular nucleotides as chemotaxins for various human immune cells, including eosinophils, neutrophils and dendritic cells. In this review, we summarise recent findings in this field and put forward a hypothesis on the role of P2 receptors in the early recruitment of human immune cells to the site of inflammation

VAMP3/Syb and YKT6 are required for the fusion of constitutive secretory carriers with the plasma membrane

The cellular machinery required for the fusion of constitutive secretory vesicles with the plasma membrane in metazoans remains poorly defined. To address this problem we have developed a powerful, quantitative assay for measuring secretion and used it in combination with combinatorial gene depletion studies in Drosophila cells. This has allowed us to identify at least three SNARE complexes mediating Golgi to PM transport (STX1, SNAP24/29 and Syb; STX1, SNAP24/29 and YKT6; STX4, SNAP24 and Syb). RNAi mediated depletion of YKT6 and VAMP3 in mammalian cells also blocks constitutive secretion suggesting that YKT6 has an evolutionarily conserved role in this process. The unexpected role of YKT6 in plasma membrane fusion may in part explain why RNAi and gene disruption studies have failed to produce the expected phenotypes in higher eukaryotes

The binding of Varp to VAMP7 traps VAMP7 in a closed, fusogenically inactive conformation.

SNAREs provide energy and specificity to membrane fusion events. Fusogenic trans-SNARE complexes are assembled from glutamine-contributing SNAREs (Q-SNAREs) embedded in one membrane and an arginine-contributing SNARE (R-SNARE) embedded in the other. Regulation of membrane fusion events is crucial for intracellular trafficking. We identify the endosomal protein Varp as an R-SNARE-binding regulator of SNARE complex formation. Varp colocalizes with and binds to VAMP7, an R-SNARE that is involved in both endocytic and secretory pathways. We present the structure of the second ankyrin repeat domain of mammalian Varp in complex with the cytosolic portion of VAMP7. The VAMP7-SNARE motif is trapped between Varp and the VAMP7 longin domain, and hence Varp kinetically inhibits the ability of VAMP7 to form SNARE complexes. This inhibition will be increased when Varp can also bind to other proteins present on the same membrane as VAMP7, such as Rab32-GTP

Multimodal population brain imaging in the UK Biobank prospective epidemiological study

Medical imaging has enormous potential for early disease prediction, but is impeded by the difficulty and expense of acquiring data sets before symptom onset. UK Biobank aims to address this problem directly by acquiring high-quality, consistently acquired imaging data from 100,000 predominantly healthy participants, with health outcomes being tracked over the coming decades. The brain imaging includes structural, diffusion and functional modalities. Along with body and cardiac imaging, genetics, lifestyle measures, biological phenotyping and health records, this imaging is expected to enable discovery of imaging markers of a broad range of diseases at their earliest stages, as well as provide unique insight into disease mechanisms. We describe UK Biobank brain imaging and present results derived from the first 5,000 participants' data release. Although this covers just 5% of the ultimate cohort, it has already yielded a rich range of associations between brain imaging and other measures collected by UK Biobank

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty: a longitudinal voxel-based morphometric study.

OBJECTIVE: Voxel-based morphometry (VBM) is a method of assessing brain gray matter volume that has previously been applied to various chronic pain conditions. From this previous work, it appears that chronic pain is associated with altered brain morphology. The present study was undertaken to assess these potential alterations in patients with painful hip osteoarthritis (OA). METHODS: We studied 16 patients with unilateral right-sided hip pain, before and 9 months after hip arthroplasty. This enabled comparison of gray matter volume in patients with chronic musculoskeletal pain versus healthy controls, as well as identification of any changes in volume following alleviation of pain (after surgery). Assessment involved self-completion questionnaires to assess pain, function, and psychosocial variables, and magnetic resonance imaging scanning of the brain for VBM analysis. RESULTS: Significant differences in brain gray matter volume between healthy controls and patients with painful hip arthritis were seen. Specifically, areas of the thalamus in patients with chronic OA pain exhibited decreased gray matter volume. Furthermore, when these preoperative changes were compared with the brain morphology of the patients 9 months after surgery, the areas of reduced thalamic gray matter volume were found to have "reversed" to levels seen in healthy controls. CONCLUSION: Our findings confirm that gray matter volume decreases within the left thalamus in the presence of chronic pain and disability in patients with hip OA. The results also show that these thalamic volume changes reverse after hip arthroplasty and are associated with decreased pain and increased function. These findings have potential implications with regard to optimizing the timing of orthopedic interventions such as arthroplasty