Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

Introduction

Islets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets.

Materials and methods

GPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches in the PubMed, IUPHAR and Ingenuity databases. Distribution of PYY protein in mouse and human islets was determined by immunohistochemistry. Insulin, glucagon and somatostatin secretion from islets was measured by radioimmunoassay.

Results

We have quantified GPCR peptide ligand mRNA expression in human and mouse islets and created specific signalomes mapping the pathways by which islet peptide ligands regulate human and mouse GPCR signalling. We also identified species-specific islet expression of several GPCR ligands. In particular, PYY mRNA levels were ~ 40,000-fold higher in mouse than human islets, suggesting a more important role of locally secreted Pyy in mouse islets. This was confirmed by IHC and functional experiments measuring insulin, glucagon and somatostatin secretion.

Discussion

The detailed human and mouse islet GPCR peptide ligand atlases will allow accurate translation of mouse islet functional studies for the identification of GPCR/peptide signalling pathways relevant for human physiology, which may lead to novel treatment modalities of diabetes and metabolic disease.

     

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.     

Common variants near MC4R are associated with fat mass, weight and risk of obesity

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.     

关于L-Fuzzy子集层仿紧性的注记

文[2]曾指出L－Fuzzy拓扑学中关于L－Fuzzy子集的几种仿紧性不是一般拓扑学中子集仿紧性的真正推广,即它们不以分明子集仿紧性为特款,进一步修正了几个定义并重新证明了有关的几个定理,在这篇文章中,我们拟对层仿紧性进行修正并重证相关的几个定理。     

Impact of the RMB Joining in the SDR Basket on Its Internationalization from the Perspective of Risk Spillover

For evaluating the influence of the Chinese renminbi(RMB) joining in the special drawing right(SDR) basket on RMB's internationalization, the authors systemically study the risk spillover networks and examine the dynamic relationship of exchange rates among the SDR currencies including the US dollar(USD), European Union euro(EUR), Japanese yen(JPY) and British pound(GBP).The empirical results demonstrate that the USD takes a dominant position and holds the biggest risk spillover to other currencies, and the RMB's inclusion to the SDR basket makes the risk spillover to get average, giving rise to the SDR currency system more stable to a certain degree. The inclusion of the RMB in the SDR not only can reduce the systematic risk of the SDR, but also has a certain impact on the international exchange rate markets. Nowadays, in front of the growing trade friction, more such researches could help to effectively deal with the currency disputes.     

某型重机枪身管的多物理场耦合分析

为了研究具有不同厚度铬涂层的某型重机枪身管在高温、高压、高速火药流体作用下的温度场和应力场,采用基于多物理场耦合程序接口MpCCI联合结构计算软件Abaqus和流体计算软件Fluent进行耦合计算的方法,对涂层厚度分别为0.28mm、0.35mm、0.41mm的身管进行流-固-热多物理场耦合仿真计算。通过计算得到了不同铬涂层厚度下身管应力和温度的分布规律。结果表明,借助MpCCI联合Abaqus和Fluent进行多物理场耦合计算的方法是可行的;随着涂层厚度的增加身管内壁的温度和应力依次降低,但在涂层与身管结合处的集中应力逐渐增大。结论对身管的结构设计和寿命预测有一定的指导意义。     

Genome-wide association studies of 14 agronomic traits in rice landraces

Uncovering the genetic basis of agronomic traits in crop landraces that have adapted to various agro-climatic conditions is important to world food security. Here we have identified ～ 3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data-imputation method. We performed genome-wide association studies (GWAS) for 14 agronomic traits in the population of Oryza sativa indica subspecies. The loci identified through GWAS explained ～ 36% of the phenotypic variance, on average. The peak signals at six loci were tied closely to previously identified genes. This study provides a fundamental resource for rice genetics research and breeding, and demonstrates that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice.     

月地高速再入返回飞行器陀螺在轨自主标定技术研究及实现

针对包含非正交安装陀螺的捷联惯导平台轻量化自主对准问题,建立了非正交陀螺组误差模型,提出一套基于最小二乘法的标定算法和地面试验验证方法,在计算能力受限的情况下完成了高精度在轨标定.地面数学仿真和试验验证结果表明,该方法与扩展卡尔曼滤波法精度相当,计算量却大幅减小.在此基础上,通过对标定算法进行逻辑设计,实现了在轨多组陀螺同步容错和标定.该方法已成功应用于探月工程三期月地高速再入返回飞行器的实际飞行,实现了2套惯性导航平台的高精度初始姿态同步对准.     

Genome-wide association study of flowering time and grain yield traits in a worldwide collection of rice germplasm

A high-density haplotype map recently enabled a genome-wide association study (GWAS) in a population of indica subspecies of Chinese rice landraces. Here we extend this methodology to a larger and more diverse sample of 950 worldwide rice varieties, including the Oryza sativa indica and Oryza sativa japonica subspecies, to perform an additional GWAS. We identified a total of 32 new loci associated with flowering time and with ten grain-related traits, indicating that the larger sample increased the power to detect trait-associated variants using GWAS. To characterize various alleles and complex genetic variation, we developed an analytical framework for haplotype-based de novo assembly of the low-coverage sequencing data in rice. We identified candidate genes for 18 associated loci through detailed annotation. This study shows that the integrated approach of sequence-based GWAS and functional genome annotation has the potential to match complex traits to their causal polymorphisms in rice.