Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation

Phagocytosis and autophagy are two important and related arms of the host's first-line defense against microbial invasion. Rubicon is a RUN domain containing cysteine-rich protein that functions as part of a Beclin-1-Vps34-containing autophagy complex. We report that Rubicon is also an essential, positive regulator of the NADPH oxidase complex. Upon microbial infection or Toll-like-receptor 2 (TLR2) activation, Rubicon interacts with the p22phox subunit of the NADPH oxidase complex, facilitating its phagosomal trafficking to induce a burst of reactive oxygen species (ROS) and inflammatory cytokines. Consequently, ectopic expression or depletion of Rubicon profoundly affected ROS, inflammatory cytokine production, and subsequent antimicrobial activity. Rubicon's actions in autophagy and in the NADPH oxidase complex are functionally and genetically separable, indicating that Rubicon functions in two ancient innate immune machineries, autophagy and phagocytosis, depending on the environmental stimulus. Rubicon may thus be pivotal to generating an optimal intracellular immune response against microbial infection.     

A Novel Role of Protein Tyrosine Kinase2 in Mediating Chloride Secretion in Human Airway Epithelial Cells

Ca²⁺ activated Cl⁻ channels (CaCC) are up-regulated in cystic fibrosis (CF) airway surface epithelia. The presence and functional properties of CaCC make it a possible therapeutic target to compensate for the deficiency of Cl⁻ secretion in CF epithelia. CaCC is activated by an increase in cytosolic Ca²⁺, which not only activates epithelial CaCCs, but also inhibits epithelial Na⁺ hyperabsorption, which may also be beneficial in CF. Our previous study has shown that spiperone, a known antipsychotic drug, activates CaCCs and stimulates Cl⁻ secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro, and in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) knockout mice in vivo. Spiperone activates CaCC not by acting in its well-known role as an antagonist of either 5-HT2 or D2 receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Moreover, spiperone independently activates CFTR through a novel mechanism. Herein, we performed a mass spectrometry analysis and identified the signaling molecule that mediates the spiperone effect in activating chloride secretion through CaCC and CFTR. Proline-rich tyrosine kinase 2 (PYK2) is a non-receptor protein tyrosine kinase, which belongs to the focal adhesion kinase family. The inhibition of PYK2 notably reduced the ability of spiperone to increase intracellular Ca²⁺ and Cl⁻ secretion. In conclusion, we have identified the tyrosine kinase, PYK2, as the modulator, which plays a crucial role in the activation of CaCC and CFTR by spiperone. The identification of this novel role of PYK2 reveals a new signaling pathway in human airway epithelial cells.     

基于Argo数据的热带大西洋大眼金枪鱼时空分布

为了解热带大西洋延绳钓大眼金枪鱼适宜渔获水温的等温线时空分布,分析大眼金枪鱼适宜的垂直和水平空间分布范围,采用Argo浮标剖面温度数据,运用Kriging方法重构热带大西洋9、12、13和15℃月平均等温线场,网格化计算了12、13℃等温线深度值和温跃层下界深度差,并结合大西洋金枪鱼国际养护委员会(ICCAT)大眼金枪鱼延绳钓渔业数据,绘制了12、13℃等温线深度与月平均单位捕捞努力渔获量(CPUE)的空间叠加图,用于分析大眼金枪鱼中心渔场CPUE时空分布和高渔获率的水温等值线时空分布的关系.结果表明:热带大西洋大眼金枪鱼中心渔场延绳钓高渔获率的水层垂直分布在温跃层下界以下区域,在表层以下150~450 m深度.在水平空间上,12℃等温线高值CPUE出现的深度值大多小于300m,集中分布在190~260 m,深度值超过400 m几乎没有CPUE值.大眼金枪鱼水平空间分布受12℃等温线影响.13℃等温线高值CPUE出现的深度值大多小于250 m,集中分布在150~230 m,深度值超过300 m几乎没有渔获.采用频次分析和经验累积分布函数计算其适宜次表层环境因子分布:12℃等温线190~260 m;13℃等温线160~240 m;12℃深度差-10~100m;13℃深度差-40~60 m.文章初步得出热带大西洋大眼金枪鱼中心渔场适宜的水平、垂直深度值分布区间,结果可以辅助寻找中心渔场位置,同时指导投钩深度,为大西洋大眼金枪鱼实际生产作业和资源管理提供理论支持.     

Tortuosity of the superficial femoral artery and its influence on blood flow patterns and risk of atherosclerosis

Biomechanics and Modeling in Mechanobiology - The superficial femoral artery (SFA) is a typical atherosclerosis-prone site. We aimed to explore whether the tortuosity of the SFA associates with the...