Direct evidence that reverse cholesterol transport is mediated by high-density lipoprotein in rabbit

Mammalian cells obtain cholesterol for membrane synthesis mostly via the receptor-mediated endocytosis of low-density lipoprotein (LDL). Macrophages and vascular endothelium additionally have receptors that recognize certain modified forms of LDL (for example, acetyl-LDL). The process by which cholesterol returns from peripheral cells to hepatocytes (reverse cholesterol transport) has not been established; although tissue culture studies have favoured high-density lipoprotein (HDL) as the principal vehicle, the in vivo evidence for this is meagre. When cholesterol-loaded macrophages are incubated in medium containing plasma, cholesterol moves from the cells to HDL and is then esterified by lecithin/cholesterol acyltransferase. The accumulation of cholesteryl esters in the particles increases their size and decreases their density; enrichment with apoprotein E (apo E) also occurs, producing a decrease in electrophoretic mobility. We now report that similar changes occur in the circulating HDL of rabbits, when their peripheral tissues are loaded with cholesterol by intravenous (i.v.) injection of acetylated or native human LDL. This result suggests that HDL is involved in reverse cholesterol transport in vivo.     

Stable sulphate clusters as a source of new atmospheric particles

The formation of new atmospheric particles with diameters of 3-10 nm has been observed at a variety of altitudes and locations. Such aerosol particles have the potential to grow into cloud condensation nuclei, thus affecting cloud formation as well as the global radiation budget. In some cases, the observed formation rates of new particles have been adequately explained by binary nucleation, involving water and sulphuric acid, but in certain locations--particularly those within the marine boundary layer and at continental sites--observed ambient nucleation rates exceed those predicted by the binary scheme. In these locations, ambient sulphuric acid (H2SO4) levels are typically lower than required for binary nucleation, but are sufficient for ternary nucleation (sulphuric acid-ammonia-water). Here we present results from an aerosol dynamics model with a ternary nucleation scheme which indicate that nucleation in the troposphere should be ubiquitous, and yield a reservoir of thermodynamically stable clusters 1-3 nm in size. We suggest that the growth of these clusters to a detectable size (> 3 nm particle diameter) is restricted by the availability of condensable vapour. Observations of atmospheric particle formation and growth from a continental and a coastal site support this hypothesis, indicating that a growth process including ternary nucleation is likely to be responsible for the formation of cloud condensation nuclei.     

Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.     

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.     

Genome-wide association analysis identifies susceptibility loci for migraine without aura

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.