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.     

试论古籍数字化背景下专业出版社的地位

信息时代,各类出版社被数字化浪潮推动着不断前进,数字化出版已经成为趋势.在古籍数字化出版的过程中,拥有专业优势的出版社应该是古籍数字化出版的主体,但是目前的状况却和我们的预期不同.在古籍数字化背景下如何实现专业出版社的主体地位,是我们古籍专业出版人的面临的困难与挑战.本文对当前专业出版社在古籍数字化出版中的地位问题以及如何实现其应有的主体地位等方面进行论述,以期对出版从业者提供工作思路.     

关于映射周期性的若干性质及其应用的注记

若f∈PfT(R)∩C(R),则F(x)=∫axf(t)dt,x∈R与周期函数有何关系,具有哪些性质?本文将就这一问题进行研究,获得了一个关于周期函数一个重要的若干性质的定理,应用其便捷的处理了一大批与周期函数有关的问题,进而给出了关于映射周期性的若干性质及其应用的注记,这对经济周期性研究有一定的参考意义。     

完全市场中的Yaari对偶效用最大化问题

效用最大化问题是经济学和金融学中的最重要和最基本的问题之一.经典的von NeumannMorgenstern期望效用模型在实践中都受到诸多挑战.Yaari对偶效用理论是重要的非期望效用模型之一.本文研究完全金融市场中的Yaari对偶效用最大化问题.前人在某种单调性条件下得到了该问题最优解的显式刻画.而在本文中,无需任何单调性条件,我们得到了最优解的显式刻画.     

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.

     

海上电泵结蜡井热循环洗井工艺参数优化设计

为探索海上油田电泵举升结蜡井热循环洗井工艺井筒温度场分布规律，综合考虑潜油电机增温、电缆散热、热流体注入量、注入深度、注入温度、结蜡管段传热和海水空气导热的影响，基于热能守恒原理，建立了电泵井结蜡热循环洗井工艺井筒温度场计算模型，分析了热流体注入温度和注入量对混合产出流体的井筒温度分布的影响。研究结果表明，随着注入量的增加混合产出液沿程井筒温度增加，随着注入温度的增加混合产出液沿程井筒温度增加。该方法可有效指导现场措施工艺的实施，达到延长结蜡井的清蜡周期、延缓产液/产油量下降速度的目的。     

远距离支援干扰下双隐身飞机自卫相参干扰对单脉冲雷达影响

以复杂电磁环境下双隐身飞机自卫相参干扰对抗单脉冲雷达为研究背景,针对单脉冲雷达角欺骗问题,提出了远距离多假目标干扰下双隐身飞机自卫相参干扰模型。首先构建双隐身飞机姿态敏感性模型,提取即时雷达散射截面序列,依据目标回波与干扰信号对应关系,建立复合等效信干比模型。在此基础上,采用脱靶与有效干扰最小即时距离对双机干扰模式下雷达角跟踪误差形成评判指标。仿真表明，该组网干扰模式使雷达角跟踪误差提高696.49倍,比单一干扰模式使单脉冲雷达角跟踪误差平均提高1.07倍,检验了组网复合相参干扰样式的有效性。     

The modernity of Dedekind’s anticipations contained in What are numbers and what are they good for?

Archive for History of Exact Sciences - We show that Dedekind, in his proof of the principle of definition by mathematical recursion, used implicitly both the concept of an inductive cone from an...