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.

     

Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma

The NLRP3 inflammasome is a critical innate immune pathway responsible for producing active interleukin (IL)-1β, which is associated with tumor development and immunity. However, the mechanisms regulating the inflammatory microenvironment, tumorigenesis and tumor immunity are unclear. Herein, we show that the NLRP3 inflammasome was over-expressed in human HNSCC tissues and that the IL-1β concentration was increased in the peripheral blood of HNSCC patients. Additionally, elevated NLRP3 inflammasome levels were detected in tumor tissues of Tgfbr1/Pten 2cKO HNSCC mice, and elevated IL-1β levels were detected in the peripheral blood serum, spleen, draining lymph nodes and tumor tissues. Blocking NLRP3 inflammasome activation using MCC950 remarkably reduced IL-1β production in an HNSCC mouse model and reduced the numbers of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Moreover, inhibiting NLRP3 inflammasome activation increased the numbers of CD4⁺ and CD8⁺ T cells in HNSCC mice. Notably, the numbers of exhausted PD-1⁺ and Tim3⁺ T cells were significantly reduced. A human HNSCC tissue microarray showed that NLRP3 inflammasome expression was correlated with the expression of CD8 and CD4, the Treg marker Foxp3, the MDSC markers CD11b and CD33, and the TAM markers CD68 and CD163, PD-1 and Tim3. Overall, our results demonstrate that the NLRP3 inflammasome/IL-1β pathway promotes tumorigenesis in HNSCC and inactivation of this pathway delays tumor growth, accompanied by decreased immunosuppressive cell accumulation and an increased number of effector T cells. Thus, inhibition of the tumor microenvironment through the NLRP3 inflammasome/IL-1β pathway may provide a novel approach for HNSCC therapy.     

A Simulation Method for Analyzing and Evaluating Rail System Performance Based on Speed Profile

This paper presents and discusses a simulation method for analyzing and evaluating system performance on a rail line from the perspective of speed profile. Dynamic analysis for train motions is introduced, and a discrete time-operation graph is proposed to represent the relation between speed profile and energy consumption. Based on them, an analytical model is formulated to provide a quick insight into the system performance. The discrete-time simulation (DTS) method is then implemented to study the system in detail. Compared to the existing simulations, two innovations are included in the DTS: (1) the analytical lookup tables that can simplify the dynamic computation and, (2) the speed profile adjustment process that forecasts and avoids future conflicts based on practical constraints. The numerical results show that the DTS speed profile has advantages over existing methods. Finally, the DTS method is used to analyze and evaluate the system performance of the current timetable on Beijing Yizhuang Metro Line. The results suggest that the current timetable is not robust enough, and thus possible improvements are discussed at both scheduling and operating stages. The proposed method is verified to be effective and reliable for practical uses.     

Quantitative Analysis of Multi-Recovery-Based Intrusion Tolerance Model

Quantitative analysis has always been a difficult problem in security analysis of intrusion tolerance systems. An intrusion tolerance model based on multiple recovery mechanisms is introduced in this paper and how to quantify the security attributes of the model is proposed. A state transition model with recovery states more accurately describes the dynamic behavior of the system. Considering that recovery mechanisms have a great impact on the security performance of the system, we set up the cost models corresponding to different recovery mechanisms. We propose a feasible security measure based on mean cost to security failure in order to evaluate the system cost during the recovery phase. The experimental results confirmed the feasibility of the proposed methods.     

Mechanical and corrosion properties of low-carbon steel prepared by friction stir processing

Low-carbon steel plates were successfully subjected to normal friction stir processing(NFSP) in air and submerged friction stir processing(SFSP) under water, and the microstructure, mechanical properties, and corrosion behavior of the NFSP and SFSP samples were investigated. Phase transformation and dynamic recrystallization resulted in fine-grained ferrite and martensite in the processed zone. The SFSP samples had smaller ferrites(5.1 μm), finer martensite laths(557 nm), and more uniform distribution of martensite compared to the NFSP samples. Compared to the base material(BM), the microhardness of the NFSP and SFSP samples increased by 19.8% and 27.1%, respectively because of the combined strengthening effects of grain refinement, phase transformation, and dislocation. The ultimate tensile strengths(UTSs) of the NFSP and SFSP samples increased by 27.1% and 38.7%, respectively. Grain refinement and martensite transformation also improved the electrochemical corrosion properties of the low-carbon steel. Overall, the SFSP samples had better mechanical properties and electrochemical corrosion resistance than the NFSP samples.     

R型半胱氨酸体系电荷转移百分数的理论计算

采用密度泛函理论中的CAM-B3LYP方法, 在6-31G(d)基组水平上优化气相条件下R型半胱氨酸(R-Cys)分子的几何构型, 理论研究电子激发过程中R-Cys体系片段间的电荷转移特征, 并基于弛豫与非弛豫激发态密度计算片段间的电荷转移百分数. 结果表明: 对于SH片段, S0到S3的电荷转移百分数为57.96%； 对于COOH片段, S0到S1~S5各激发态的电荷转移百分数均为负值, 二者电荷转移的定性结果一致； 对于NH2片段, S0到S1和S4的电荷转移百分数分别为6.98%和31.45%.     

Primality Testing for Numbers of the Form h·2~n± 1

This paper studies the problem of primality testing for numbers of the form h · 2~n± 1,where h 2~n is odd, and n is a positive integer. The authors describe a Lucasian primality test for these numbers in certain cases, which runs in deterministic quasi-quadratic time. In particular, the authors construct a Lucasian primality test for numbers of the form 3 · 5 · 17 · 2~n± 1, where n is a positive integer, in half of the cases among the congruences of n modulo 12, by means of a Lucasian sequence with a suitable seed not depending on n. The methods of Bosma(1993), Berrizbeitia and Berry(2004), Deng and Huang(2016) can not test the primality of these numbers.     

Facile synthesis of flake-like dihydrate zinc oxalate particles

Monodispersed dihydrated zinc oxalate(ZnC_2O_4·2H_2O) particles with characteristic morphology were synthesized by aging a mixed solution of zinc nitrate(Zn(NO_3)_2) and sodium oxalate(Na_2C_2O_4) in the presence of a citrate ligand, with an average flat size of approximately 10–15 μm. The important parameters, including the solution pH values and the concentration of the zinc ions and citrate ligand, were investigated using a series of experiments. It is verified that the citrate ligand significantly affects the morphology of zinc oxalate particles, probably via its multiple roles of chelating, dispersing, and selective absorption. Thermodynamic equilibrium of the distribution of zinc species in an aqueous solution of Zn(Ⅱ)-citrate-oxalate-H_2O was estimated to explain the experimental results and to clarify the size and morphological evolution mechanism of the precipitated particles.     

Estimation of Partially Linear Panel Data Models with Cross-Sectional Dependence

Journal of Systems Science and Complexity - This paper studies the estimation of the partially linear panel data models, allowing for cross-sectional dependence through a common factors structure....     

基于垂直管道内重油-水两相流动型态的持水率和压降预测模型

针对重油井筒举升流动规律认识不清的问题，本文采用高黏（584.24 cp，1.889 g/cm3）重油作为研究对象，研究重油-水在上升管中的流动特性，得到了五种重油-水两相流动型态。结果表明与轻油-水流动不同，重油-水流动过程中未发生相转化，该现象与表面能方程的预测结果相似。通过持水率测量得到重油-水两相的滑移效应随油水混合流速降低或持水率增加而变得更加明显，基于漂移流模型和动量守恒方程推导得到五种流态下重油-水两相流的持水率预测模型，相对误差率在20%以内。总压降梯度在低持水率时以重力压力梯度为主，高混合流速和高持水率时以摩擦压力梯度为主。采用基于Bannwart模型建立的重油-水中心环状流压降预测模型，误差率在30%以内，为进一步提高重油井筒举升流动参数的预测精度提供了理论基础。