Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ～ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.     

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.     

Swiprosin-1 modulates actin dynamics by regulating the F-actin accessibility to cofilin

Membrane protrusions, like lamellipodia, and cell movement are dependent on actin dynamics, which are regulated by a variety of actin-binding proteins acting cooperatively to reorganize actin filaments. Here, we provide evidence that Swiprosin-1, a newly identified actin-binding protein, modulates lamellipodial dynamics by regulating the accessibility of F-actin to cofilin. Overexpression of Swiprosin-1 increased lamellipodia formation in B16F10 melanoma cells, whereas knockdown of Swiprosin-1 inhibited EGF-induced lamellipodia formation, and led to a loss of actin stress fibers at the leading edges of cells but not in the cell cortex. Swiprosin-1 strongly facilitated the formation of entangled or clustered F-actin, which remodeled the structural organization of actin filaments making them inaccessible to cofilin. EGF-induced phosphorylation of Swiprosin-1 at Ser183, a phosphorylation site newly identified using mass spectrometry, effectively inhibited clustering of actin filaments and permitted cofilin access to F-actin, resulting in actin depolymerization. Cells overexpressing a Swiprosin-1 phosphorylation-mimicking mutant or a phosphorylation-deficient mutant exhibited irregular membrane dynamics during the protrusion and retraction cycles of lamellipodia. Taken together, these findings suggest that dynamic exchange of Swiprosin-1 phosphorylation and dephosphorylation is a novel mechanism that regulates actin dynamics by modulating the pattern of cofilin activity at the leading edges of cells.     

Large protein complexes retained in the ER are dislocated by non-COPII vesicles and degraded by selective autophagy

Multisubunit protein complexes are assembled in the endoplasmic reticulum (ER). Existing pools of single subunits and assembly intermediates ensure the efficient and rapid formation of complete complexes. While being kinetically beneficial, surplus components must be eliminated to prevent potentially harmful accumulation in the ER. Surplus single chains are cleared by the ubiquitin–proteasome system. However, the fate of not secreted assembly intermediates of multisubunit proteins remains elusive. Here we show by high-resolution double-label confocal immunofluorescence and immunogold electron microscopy that naturally occurring surplus fibrinogen Aα–γ assembly intermediates in HepG2 cells are dislocated together with EDEM1 from the ER to the cytoplasm in ER-derived vesicles not corresponding to COPII-coated vesicles originating from the transitional ER. This route corresponds to the novel ER exit path we have previously identified for EDEM1 (Zuber et al. Proc Natl Acad Sci USA 104:4407–4412, 2007). In the cytoplasm, detergent-insoluble aggregates of fibrinogen Aα–γ dimers develop that are targeted by the selective autophagy cargo receptors p62/SQSTM1 and NBR1. These aggregates are degraded by selective autophagy as directly demonstrated by high-resolution microscopy as well as biochemical analysis and inhibition of autophagy by siRNA and kinase inhibitors. Our findings demonstrate that different pathways exist in parallel for ER-to-cytoplasm dislocation and subsequent proteolytic degradation of large luminal protein complexes and of surplus luminal single-chain proteins. This implies that ER-associated protein degradation (ERAD) has a broader function in ER proteostasis and is not limited to the elimination of misfolded glycoproteins.     

Coherent quantum state storage and transfer between two phase qubits via a resonant cavity

As with classical information processing, a quantum information processor requires bits (qubits) that can be independently addressed and read out, long-term memory elements to store arbitrary quantum states, and the ability to transfer quantum information through a coherent communication bus accessible to a large number of qubits. Superconducting qubits made with scalable microfabrication techniques are a promising candidate for the realization of a large-scale quantum information processor. Although these systems have successfully passed tests of coherent coupling for up to four qubits, communication of individual quantum states between superconducting qubits via a quantum bus has not yet been realized. Here, we perform an experiment demonstrating the ability to coherently transfer quantum states between two superconducting Josephson phase qubits through a quantum bus. This quantum bus is a resonant cavity formed by an open-ended superconducting transmission line of length 7 mm. After preparing an initial quantum state with the first qubit, this quantum information is transferred and stored as a nonclassical photon state of the resonant cavity, then retrieved later by the second qubit connected to the opposite end of the cavity. Beyond simple state transfer, these results suggest that a high-quality-factor superconducting cavity could also function as a useful short-term memory element. The basic architecture presented here can be expanded, offering the possibility for the coherent interaction of a large number of superconducting qubits.     

科氏力对高速旋转汽轮机叶片动态特性的影响

采用解析的方法，建立了高速旋转汽轮机叶片中科氏力和科氏动应力的计算模型。该模型克服了以往在叶片动态特性分析时难以考虑科氏力影响的问题，导出了科氏动应力和非稳态气流动应力比值的计算公式以及科氏力和离心力比值的计算公式，并进行了实例分析．计算结果表明，科氏力对叶片轴向振动和扭转振动的固有频率没有影响，对切向振动的影响很小，可以忽略不计；科氏力所产生的动应力不到非稳态气流动应力的1%。     

DNA-programmable nanoparticle crystallization

It was first shown more than ten years ago that DNA oligonucleotides can be attached to gold nanoparticles rationally to direct the formation of larger assemblies. Since then, oligonucleotide-functionalized nanoparticles have been developed into powerful diagnostic tools for nucleic acids and proteins, and into intracellular probes and gene regulators. In contrast, the conceptually simple yet powerful idea that functionalized nanoparticles might serve as basic building blocks that can be rationally assembled through programmable base-pairing interactions into highly ordered macroscopic materials remains poorly developed. So far, the approach has mainly resulted in polymerization, with modest control over the placement of, the periodicity in, and the distance between particles within the assembled material. That is, most of the materials obtained thus far are best classified as amorphous polymers, although a few examples of colloidal crystal formation exist. Here, we demonstrate that DNA can be used to control the crystallization of nanoparticle-oligonucleotide conjugates to the extent that different DNA sequences guide the assembly of the same type of inorganic nanoparticle into different crystalline states. We show that the choice of DNA sequences attached to the nanoparticle building blocks, the DNA linking molecules and the absence or presence of a non-bonding single-base flexor can be adjusted so that gold nanoparticles assemble into micrometre-sized face-centred-cubic or body-centred-cubic crystal structures. Our findings thus clearly demonstrate that synthetically programmable colloidal crystallization is possible, and that a single-component system can be directed to form different structures.     

Crystal structure of opsin in its G-protein-interacting conformation

Opsin, the ligand-free form of the G-protein-coupled receptor rhodopsin, at low pH adopts a conformationally distinct, active G-protein-binding state known as Ops*. A synthetic peptide derived from the main binding site of the heterotrimeric G protein-the carboxy terminus of the alpha-subunit (GalphaCT)-stabilizes Ops*. Here we present the 3.2 A crystal structure of the bovine Ops*-GalphaCT peptide complex. GalphaCT binds to a site in opsin that is opened by an outward tilt of transmembrane helix (TM) 6, a pairing of TM5 and TM6, and a restructured TM7-helix 8 kink. Contacts along the inner surface of TM5 and TM6 induce an alpha-helical conformation in GalphaCT with a C-terminal reverse turn. Main-chain carbonyl groups in the reverse turn constitute the centre of a hydrogen-bonded network, which links the two receptor regions containing the conserved E(D)RY and NPxxY(x)(5,6)F motifs. On the basis of the Ops*-GalphaCT structure and known conformational changes in Galpha, we discuss signal transfer from the receptor to the G protein nucleotide-binding site.     

Boosting charge collection efficiency via large-area free-standing Ag/ZnO core-shell nanowire array electrodes

Hybrid nanostructures, comprising of a metal core and a semiconductor shell layer, show great potential for a new generation of low-cost solar cells due to their unique electronic and optical properties. However, experimental results have fallen far short of the ultra-high efficiency(i.e. beyond Shockley-Queisser limit) predicted by theoretical simulations. This limits the commercial application of these materials. Here, a non-transparent organic solar cell with an array of Ag/ZnO nanowires has been experimentally fabricated to increase the internal quantum efficiency(IQE) by a factor of 2.5 compared to a planar counterpart. This result indicates a significant enhancement of charge collection efficiency due to the ultrafast Ag nanowire channels. This hybrid nanostructure can also serve as a perfect back reflector for semi-transparent solar cells, which can result in enhanced light absorption by a factor of 1.8 compared to the reference samples. The enhanced charge collection and light absorption can make these Ag/ZnO nanostructures available for the application of modern optoelectronic devices.     

Compressive deformation behavior of an indirect-extruded Mg-8Sn-1Al-1Zn alloy

The medium and warm deformation behaviors of an indirect-extruded Mg-8Sn-1Al-1Zn alloy were investigated by compression tests at temperatures between 298 and 523 K and strain rates of 0.001–10 s?1. It was found that the twinning-slip transition temperature was strain rate dependent, and all the true stress-true strain curves could be divided into two groups: concave and convex curves. Associated microstructural investigations indicated that the dynamic recrystallization (DRX) behavior of the alloy varied with deformation conditions. At high strain rate and low temperature, dynamically recrystallized grains preferentially nucleated and developed in the twinned regions, indicating that twinning-induced DRX was dominant. While, at low strain rate, DRX developed extensively at grain boundaries and twins, and the process of twinning contributed to both oriented nucleation and selective growth. For the studied alloy, cracks mainly initiated from the shear band and twinning lamellar over the ranges of temperature and strain rate currently applied.