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%。     

Time synchronization module for automatic identification system

This paper proposed a design and implementation procedure of the Time Synchronization Module (TSM) for the Automatic Identification System (AIS). The proposed TSM module uses a Temperature Compensated Crystal Oscillator (TCXO) as a local reference clock, and consists of a Digitally Controlled Oscillator (DCO), a divider, a phase discriminator, and register blocks. The TSM measures time difference between the 1 PPS from the Global Navigation Satellite System (GNSS) receiver and the generated transmitter clock. The measured time difference is compensated by controlling the DCO and the transmit clock is synchronized to the Universal Time Coordinated (UTC). The designed TSM can also be synchronized to the reference time derived from the received message. The proposed module is tested using the experimental AIS transponder set. The experimental results show that the proposed module satisfies the functional and timing specification of the AIS technical standard, ITU-R M.1371.     

Production of insulin-like growth factor I (IGF-I) and IGF-binding proteins by rat intestinal stromal cells in vitro

To determine if intestinal stromal cells secrete diffusible factors such as insulin-like growth factors (IGFs) capable of regulating epithelial cell growth in vitro, stromal cells were isolated by enzymatic digestion of rat intestine. Incorporation of [³H]thymidine into DNA and [¹⁴C]leucine into protein of IEC-6 cells, a model intestinal epithelial cell line, was significantly increased (two- to threefold) when the IEC-6 cells were co-cultured with stromal cells, relative to IEC-6 cells grown alone. Medium conditioned by stromal cells stimulated DNA synthesis of IEC-6 cells in a dose-dependent manner. Analysis of the conditioned medium revealed that intestinal stromal cells secreted IGF-I, but little IGF-II, in addition to an M _r 32,000 IGF-binding protein (IGFBP-2) and an IGFBP having M _r∼ 24,000. We conclude that rat intestinal stromal cells secrete one or more diffusible factors, which may include IGF-I and IGFBPs, capable of stimulating proliferation of IEC-6 cells in vitro. Received 25 August 1997; received after revision 7 November 1997; accepted 20 November 1997