Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.     

A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene

Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.     

Preparation of ultrahigh surface area porous carbons templated using zeolite 13X for enhanced hydrogen storage

In this report,the use of zeolite 13X as a template to generate ultrahigh surface area carbons,via a two-step process combining liquid impregnation and chemical vapour deposition is explored.The first step in the nanocasting process involves impregnation of zeolite 13X with furfuryl alcohol and the second step consists of chemical vapour deposition(CVD) of ethylene at 700 1C.Zeolite-like structural ordering was achieved for zeolite templated carbons(ZTCs) prepared at variable heating ramp rates of 5,10 or 15 1C/min.The textural properties of ZTCs prepared at all heating ramp rates were comparable with small variations in which the lowest ramp rate(5 1C/min) generated ZTC with highest surface area and pore volume of 3332 m 2 /g and 1.66 cm 3 /g respectively.The carbon materials achieved a remarkable hydrogen uptake of 7.3 wt% at 20 bar and 77 K which is the highest ever recorded for carbon materials.This report also explores the mechanical stability of the ZTCs via compaction at up to 10t(equivalent to 740 MPa) in which the compacted samples showed minimal modification and retained high hydrogen storage capacity.     

Preparation of Al-Cu-Fe-(Sn,Si) quasicrystalline bulks by laser multilayer cladding

(Al₆₅Cul₂₀Fe₁₅)_100-x Sn_x (x=0, 12, 20, 30) and Al₅₇Si₁₀Cu₁₈Fe₁₅ powders were cladded on a medium carbon steel (45# steel) substrate by laser multilayer cladding, respectively. The phases and properties of the produced quasicrystalline bulks were investigated. It was found that the main phases in the Al₆₅Cul₂₀Fe₁₅ sample were crystalline λ-Al₁₃Fe₄ and icosahedral quasicrystal together with a small volume fraction of θ-Al₂Cu phase. The volume fraction of icosahedral phase decreased as the Sn content in the (Al₆₅Cul₂₀Fe₁₅)_100-x Sn_x samples increased owing to the formation of β-CuSn phase. The increase of Sn content improved the brittleness of the quasicrystal samples. The morphology of the solidification microstructure in the Al₅₇Si₁₀Cu₁₈Fe₁₅ sample changed from elongated shape to spherical shape due to the addition of Si. The nanohardness of the laser multilayer cladded quasicrystal samples was equal to that of the as-cast sample prepared by vacuum quenching. In terms of hardness, the laser cladded Al₅₇Si₁₀Cu₁₈Fe₁₅ quasicrystalline alloy has the highest value among all the investigated samples.     

Mode of débitage and technical cognition of hominids at the Guanyindong site

Exploring and interpreting the mode of cognition and behavioral patterns of prehistoric hunter-gatherers is always one of the main goals of current Paleolithic research. In the 1940s, French prehistorians proposed the technological method for studying lithic assemblages which opened a brand-new perspective on the prehistoric domain. In the 1960s, French ethnographer and anthropologist Andre Leroi-Gourhan proposed the concept ＂chaine operatoire＂ and established the theory of lithic technological study. After the 1980s, the concept ＂chaine operatoire＂ was substituted for two different but complementary concepts： techno-cognition and techno-economy, which contributed not only to revealing the technical knowledge and know-how applied during lithic production but also to interpreting the technical behavior of prehistoric hunter-gatherers from social and economic viewpoints. The lithic technological study of the Guanyindong site, presented in this paper, was carried out for the first time by applying lithic technological method developed by French prehistorians to the Chinese materials. Our analytical results demonstrated that the debitage system of Guanyindong is quite distinct from the concept Levallois largely used in Europe, Near-East and Africa. The differentiation between these two debitage modes may contribute to exploring and interpreting the relationship in Middle Paleolithic between China and Europe, Near-East and Africa.     

Deep carbon export from a Southern Ocean iron-fertilized diatom bloom

Fertilization of the ocean by adding iron compounds has induced diatom-dominated phytoplankton blooms accompanied by considerable carbon dioxide drawdown in the ocean surface layer. However, because the fate of bloom biomass could not be adequately resolved in these experiments, the timescales of carbon sequestration from the atmosphere are uncertain. Here we report the results of a five-week experiment carried out in the closed core of a vertically coherent, mesoscale eddy of the Antarctic Circumpolar Current, during which we tracked sinking particles from the surface to the deep-sea floor. A large diatom bloom peaked in the fourth week after fertilization. This was followed by mass mortality of several diatom species that formed rapidly sinking, mucilaginous aggregates of entangled cells and chains. Taken together, multiple lines of evidence-although each with important uncertainties-lead us to conclude that at least half the bloom biomass sank far below a depth of 1,000 metres and that a substantial portion is likely to have reached the sea floor. Thus, iron-fertilized diatom blooms may sequester carbon for timescales of centuries in ocean bottom water and for longer in the sediments.     

MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function

The basic unit of skeletal muscle in all metazoans is the multinucleate myofibre, within which individual nuclei are regularly positioned. The molecular machinery responsible for myonuclear positioning is not known. Improperly positioned nuclei are a hallmark of numerous diseases of muscle, including centronuclear myopathies, but it is unclear whether correct nuclear positioning is necessary for muscle function. Here we identify the microtubule-associated protein ensconsin (Ens)/microtubule-associated protein 7 (MAP7) and kinesin heavy chain (Khc)/Kif5b as essential, evolutionarily conserved regulators of myonuclear positioning in Drosophila and cultured mammalian myotubes. We find that these proteins interact physically and that expression of the Kif5b motor domain fused to the MAP7 microtubule-binding domain rescues nuclear positioning defects in MAP7-depleted cells. This suggests that MAP7 links Kif5b to the microtubule cytoskeleton to promote nuclear positioning. Finally, we show that myonuclear positioning is physiologically important. Drosophila ens mutant larvae have decreased locomotion and incorrect myonuclear positioning, and these phenotypes are rescued by muscle-specific expression of Ens. We conclude that improper nuclear positioning contributes to muscle dysfunction in a cell-autonomous fashion.