Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24.

Familial combined hyperlipidaemia (FCHL) is a common inherited disorder of lipid metabolism with a prevalence of 0.5-2.0% (refs 1, 2). It is estimated to cause 10% of premature coronary heart disease. The underlying metabolic and genetic defects in FCHL have not been identified, but a population study has suggested an association between FCHL and an XmnI restriction fragment length polymorphism (RFLP) within the apolipoprotein AI-CIII-AIV gene cluster. Here we confirm this association and show that it results from linkage disequilibrium between FCHL and the 6.6-kilobase (kb) allele of the XmnI RFLP. Subsequent analysis in seven FCHL families, ascertained through a proband carrying the 6.6 kb XmnI allele, demonstrated linkage to the AI-CIII-AIV cluster on 11q23-q24, zeta = 6.86 with no recombinants. This assignment will facilitate the identification of the mutation that causes hyperlipidaemia in these families.     

Selection of single-stranded DNA molecules that bind and inhibit human thrombin.

Aptamers are double-stranded DNA or single-stranded RNA molecules that bind specific molecular targets. Large randomly generated populations can be enriched in aptamers by in vitro selection and polymerase chain reaction. But so far single-stranded DNA has not been investigated for aptamer properties, nor has a target protein been considered that does not interact physiologically with nucleic acid. Here we describe the isolation of single-stranded DNA aptamers to the protease thrombin of the blood coagulation cascade and report binding affinities in the range 25-200 nM. Sequence data from 32 thrombin aptamers, selected from a pool of DNA containing 60 nucleotides of random sequence, displayed a highly conserved 14-17-base region. Several of these aptamers at nanomolar concentrations inhibited thrombin-catalysed fibrin-clot formation in vitro using either purified fibrinogen or human plasma.     

Celiac disease patient IgA antibodies induce endothelial adhesion and cell polarization defects via extracellular transglutaminase 2

We have recently found that celiac disease patient serum-derived autoantibodies targeted against transglutaminase 2 interfere with several steps of angiogenesis, including endothelial sprouting and migration, though the mechanism involved remained to be fully characterized. This study now investigated the processes underlying the antiangiogenic effects exerted by celiac disease patient antibodies on endothelial cells, with particular regard to the adhesion, migration, and polarization signaling pathway. We observed that celiac IgA reduced endothelial cell numbers by affecting adhesion without increasing apoptosis. Endothelial cells in the presence of celiac IgA showed weak attachment, a high susceptibility to detach from fibronectin, and a disorganized extracellular matrix due to a reduction of protein cross-links. Furthermore, celiac patient IgA led to secretion of active transglutaminase 2 from endothelial cells into the culture supernatants. Additionally, cell surface transglutaminase 2 mediated integrin clustering in the presence of celiac IgA was coupled to augmented expression of β1-integrin. We also observed that celiac patient IgA-treated endothelial cells had migratory defects and a less polarized phenotype when compared to control groups, and this was associated with the RhoA signaling pathway. These biological effects mediated by celiac IgA on endothelial cells were partially influenced but not completely abolished by R281, an irreversible extracellular transglutaminase 2 enzymatic activity inhibitor. Taken together, our results imply that celiac patient IgA antibodies disturb the extracellular protein cross-linking function of transglutaminase 2, thus altering cell-extracellular matrix interactions and thereby affecting endothelial cell adhesion, polarization, and motility.     

Zircon U-Pb and Hf isotopes of volcanic rocks from the Batamayineishan Formation in the eastern Junggar Basin

An internal structural study was conducted to investigate U-Pb age, trace elements and Hf isotopes of basaltic zircons from the Batamayineishan Formation. The basalt was obtained from drill well San-Can 1 on the eastern Luliang uplift within the Junggar Basin. Trace element data of zircons show that all samples are magmatic, with similar REE patterns, including positive Ce (δCe=5.06–134), but negative Eu (δEu=0.06⦒0.55) anomalies and enrichment in heavy rare earth elements. Among 25 grains, the concordant ages were subdivided into three groups; ages of 300.4±1.3 Ma (n=11), 339.2±2.7 Ma (n=3) and 392.0±1.7 Ma (n=8). Three remaining grains were nearly concordant, with ²⁰⁶Pb/²³⁸U ages of 510±7, 488±6 and 453±6 Ma, respectively. The youngest concordant age (i.e., 300.4±1.3 Ma) could be interpreted as the formation age of the studied basaltic rock; this is consistent with the sampling position at the upper part of the Batamayineishan Formation. On the other hand, ages such as Ordovician and early Devonian are consistent with the ages of island-arc volcanic rocks (enrichment in Pb) or ophiolites around the basin. Moreover, the positive ɛ _Hf(t) values of the early and middle Paleozoic zircons (+3.6–+10.5) may suggest that the basement traversed by the studied volcanic rocks may be Paleozoic in age, formed from the residual oceanic crust and island-arc complex. The ɛ _Hf(t) values (+4.2–+17.1) of the late Paleozoic (∼300.4 Ma) zircons suggest that the basaltic magmas were derived from partial melting of the asthenospheric mantle or depleted lithospheric mantle. These magmas were slightly contaminated by the existence of early-middle Paleozoic materials. The late Carboniferous basalts represent direct eruption of mantle-derived magmas at the upper crustal level during a post-collisional tectonic setting. We therefore consider that extensive vertical growth of the continental crust to have occurred before the late Carboniferous.     

U-Pb dating of zircons from quartz diorite and its enclaves at Tongguanshan in Anhui and its petrogenetic implication

The Tongling area, Anhui Province lies in the centralpart of the Cu-Fe-Au mineralization belt of the Mid-dle-Lower Yangtze River region, and hosts the highestincidence of this mineralization belt. Geotectonically, theTongling area is located at the middle of the Lower Yang-tze fold belt in the Yangtze block. Silurian to Triassicshallow marine carbonatite and a few semi-abyssal sili-ceous rocks, continental-ocean arenites are the dominantoutcropping strata. A series of NE trending fold s…     

Toward interoperable bioscience data

To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open 'data commoning' culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared 'Investigation-Study-Assay' framework to support that vision.     

A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.     

The binary Kuiper-belt object 1998 WW31

The recent discovery of a binary asteroid during a spacecraft fly-by generated keen interest, because the orbital parameters of binaries can provide measures of the masses, and mutual eclipses could allow us to determine individual sizes and bulk densities. Several binary near-Earth, main-belt and Trojan asteroids have subsequently been discovered. The Kuiper belt-the region of space extending from Neptune (at 30 astronomical units) to well over 100 AU and believed to be the source of new short-period comets-has become a fascinating new window onto the formation of our Solar System since the first member object, not counting Pluto, was discovered in 1992 (ref. 13). Here we report that the Kuiper-belt object 1998 WW31 is binary with a highly eccentric orbit (eccentricity e approximately 0.8) and a long period (about 570 days), very different from the Pluto/Charon system, which was hitherto the only previously known binary in the Kuiper belt. Assuming a density in the range of 1 to 2 g cm-3, the albedo of the binary components is between 0.05 and 0.08, close to the value of 0.04 generally assumed for Kuiper-belt objects.