The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression

Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas(G12D)-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier.     

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.     

杭州科技成果转移转化政策体系研究

本文以我国10个科技创新指数排名前列的城市最新科技成果转化相关政策文本为样本,采用ROST-CM6分析工具,运用“政策工具-政策目标”二维分析法以及可视化的社会和语义网络分析图进行分析研究,提出了对杭州出台科技成果转化政策体系的思考和建议。     

未来的计算机的体系结构

自从1981年10月在东京的国际会议上日本发表第五代计算机规划以来,在计算机科学界渐渐承认冯·诺依曼式计算机的地位将变得愈来愈不重要。计算从顺序而集中转向并行而分布,此时大量的系统必须在一起工作,这将要求有新一代的通用计算机。     

青藏高原古里雅冰芯中NO3-浓度与太阳活动

恢复了古里雅冰芯中NO- 3浓度近 10 0 0多年来的时间变化序列 ,并对其进行了谱分析 ,发现在该冰芯NO- 3浓度的变化中存在与太阳活动的多种周期相一致的周期 .该冰芯中NO- 3浓度的长期变化趋势与太阳活动强弱的各种指标的对比表明 ,其长期变化趋势与太阳活动呈现正相关关系 .古里雅冰帽地区降水中NO- 3浓度的变化滞后于太阳活动约 1 5a .     

现有防疫通风措施及基于先进气流组织的源头控制技术应用

新冠疫情暴发后,如何应对呼吸道传染病的传播这一难题再次摆在了人们面前.通风是最重要的工程防疫措施,ASHRAE、REHVA、SHASE以及中国的相关机构、学会就如何利用暖通空调系统有效防控COVID-19的传播相继出台了指导性文件.总结和分析系列指导性文件中有关通风量和气流组织方面的内容,发现现有工程防疫措施尚存在诸多...     

Nanostructured TiO2（B）:the effect of size and shape on anode properties for Li-ion batteries

Reducing the dimensions of electrode materials from the micron to the nanoscale can have a profound influence on their properties and hence on the performance of electrochemical devices,e.g.Li-ion batteries,that employ such electrodes.TiO2(B) has received growing interest as a possible anode for Li-ion batteries in recent years.It offers the possibility of higher energy storage compared with the commercialized Li4Ti5O12.Bulk,nanowire,nanotube,and nanoparticle morphologies have been prepared and studied.However,to date these materials have not be compared in one article.In the current review we first summarize the different synthesis methods for the preparation of nanostructured TiO2(B);then present the effects of size and shape on the electrochemical properties.Finally TiO2(B) with nanometer dimensions exhibit a higher capacity to store Li,regardless of rate,due to structural distortions inherent at the nanoscale.     

Transforming growth factor-β-inducible early response gene 1 is a novel substrate for atypical protein kinase Cs

The protein kinase C (PKC) family of serine/threonine kinases consists of ten different isoforms grouped into three subfamilies, denoted classical, novel and atypical PKCs (aPKCs). The aPKCs, PKCι/λ and PKCζ serve important roles during development and in processes subverted in cancer such as cell and tissue polarity, cell proliferation, differentiation and apoptosis. In an effort to identify novel interaction partners for aPKCs, we performed a yeast two-hybrid screen with the regulatory domain of PKCι/λ as bait and identified the Krüppel-like factors family protein TIEG1 as a putative interaction partner for PKCι/λ. We confirmed the interaction of both aPKCs with TIEG1 in vitro and in cells, and found that both aPKCs phosphorylate the DNA-binding domain of TIEG1 on two critical residues. Interestingly, the aPKC-mediated phosphorylation of TIEG1 affected its DNA-binding activity, subnuclear localization and transactivation potential.     

Novel macrophage polarization model: from gene expression to identification of new anti-inflammatory molecules

Plasticity is a well-known property of macrophages that is controlled by different changes in environmental signals. Macrophage polarization is regarded as a spectrum of activation phenotypes adjusted from one activation extreme, the classic (M1), to the other, the alternative (M2) activation. Here we show, in vitro and in vivo, that both M1 and M2 macrophage phenotypes are tightly coupled to specific patterns of gene expression. Novel M2-associated markers were characterized and identified as genes controlling the extracellular metabolism of ATP to generate pyrophosphates (PPi). Stimulation of M1 macrophages with PPi dampens both NLR and TLR signaling and thus mediates cytokine production. In this context extracellular PPi enhanced the resolution phase of a murine peritonitis model via a decrease in pro-inflammatory cytokine production. Therefore, our study reveals an additional level of plasticity modulating the resolution of inflammation.     

Nitric oxide stimulates human neural progenitor cell migration via cGMP-mediated signal transduction

Neuronal migration is one of the most critical processes during early brain development. The gaseous messenger nitric oxide (NO) has been shown to modulate neuronal and glial migration in various experimental models. Here, we analyze a potential role for NO signaling in the migration of fetal human neural progenitor cells. Cells migrate out of cultured neurospheres and differentiate into both neuronal and glial cells. The neurosphere cultures express neuronal nitric oxide synthase and soluble guanylyl cyclase that produces cGMP upon activation with NO. By employing small bioactive enzyme activators and inhibitors in both gain and loss of function experiments, we show NO/cGMP signaling as a positive regulator of migration in neurosphere cultures of early developing human brain cells. Since NO signaling regulates cell movements from developing insects to mammalian nervous systems, this transduction pathway may have evolutionary conserved functions.