Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene

The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability. Here we identify the mouse Fbxw7 gene as a p53-dependent tumour suppressor gene by using a mammalian genetic screen for p53-dependent genes involved in tumorigenesis. Radiation-induced lymphomas from p53+/- mice, but not those from p53-/- mice, show frequent loss of heterozygosity and a 10% mutation rate of the Fbxw7 gene. Fbxw7+/- mice have greater susceptibility to radiation-induced tumorigenesis, but most tumours retain and express the wild-type allele, indicating that Fbxw7 is a haploinsufficient tumour suppressor gene. Loss of Fbxw7 alters the spectrum of tumours that develop in p53 deficient mice to include a range of tumours in epithelial tissues such as the lung, liver and ovary. Mouse embryo fibroblasts from Fbxw7-deficient mice, or wild-type mouse cells expressing Fbxw7 small interfering RNA, have higher levels of Aurora-A kinase, c-Jun and Notch4, but not of cyclin E. We propose that p53-dependent loss of Fbxw7 leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers.     

Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells

In this study, we examined agonist-induced internalization, recycling and signalling (measure of cAMP levels) of the cloned human nociceptin receptor (hNOP) expressed in CHO-K1 cells. Internalization was proven by a receptor-binding assay on viable cells. The agonist nociceptin/orphanin FQ (NC) promoted rapid internalization of the hNOP receptor (approximately 78% of cell surface receptors were lost after 2 min exposure to 1 microM NC) in a clathrin- and ATP-dependent manner. Internalization was more rapid and marked in CHO-K1 cells than, as we previously reported, in SK-N-BE cells. This difference may be related to higher levels of beta-arrestin isoforms detected in CHO-K1 than in SK-N-BE cells. hNOP receptor internalization was partially reversible and recycling occurred in the presence of the agonist; receptor recycling was dependent on okadaic acid-sensitive phosphatases and was blocked by monensin. Confocal microscopy analysis confirmed the internalization and the recycling back to the plasma membrane of an epitope-tagged hNOP receptor expressed in CHO-K1 cells. These receptors underwent rapid desensitization upon agonist challenge: NC efficacy in inhibiting forskolin-stimulated cAMP production was significantly reduced 10 min after exposure and correlated with the rate of receptor internalization. Moreover, we observed that blockade of hNOP receptor recycling by monensin would cause a more prolonged and relevant desensitization of this receptor. Thus, the dynamic cycle between hNOP receptor activation, internalization and recycling determines the activity of this receptor on the cell surface.     

Increasing dominance of large lianas in Amazonian forests

Ecological orthodoxy suggests that old-growth forests should be close to dynamic equilibrium, but this view has been challenged by recent findings that neotropical forests are accumulating carbon and biomass, possibly in response to the increasing atmospheric concentrations of carbon dioxide. However, it is unclear whether the recent increase in tree biomass has been accompanied by a shift in community composition. Such changes could reduce or enhance the carbon storage potential of old-growth forests in the long term. Here we show that non-fragmented Amazon forests are experiencing a concerted increase in the density, basal area and mean size of woody climbing plants (lianas). Over the last two decades of the twentieth century the dominance of large lianas relative to trees has increased by 1.7-4.6% a year. Lianas enhance tree mortality and suppress tree growth, so their rapid increase implies that the tropical terrestrial carbon sink may shut down sooner than current models suggest. Predictions of future tropical carbon fluxes will need to account for the changing composition and dynamics of supposedly undisturbed forests.     

Dual effect of cannabinoid CB<Subscript>1</Subscript> receptor stimulation on a vanilloid VR1 receptor-mediated response

Cannabinoid CB1 receptors and vanilloid VR1 receptors are co-localized to some extent in sensory neurons of the spinal cord and dorsal root ganglia. In this study, we over-expressed both receptor types in human embryonic kidney (HEK)-293 cells and investigated the effect of the CB1 agonist HU-210 on the VR1-mediated increase in intracellular Ca2+ ([Ca2+]i), a well-known response of the prototypical VR1 agonist capsaicin. After a 5-min pre-treatment, HU-210 (0.1 microM) significantly enhanced the effect of several concentrations of capsaicin on [Ca2+]i in HEK-293 cells over-expressing both rat CB1 and human VR1 (CB1-VR1-HEK cells), but not in cells over-expressing only human VR1 (VR1-HEK cells). This effect was blocked by the CB1 receptor antagonist SR141716A (0.5 microM), and by phosphoinositide-3-kinase and phospholipase C inhibitors. The endogenous agonist of CB1 and VR1 receptors, anandamide, was more efficacious in inducing a VR1-mediated stimulation of [Ca2+]i in CB1-VR1-HEK cells than in VR1-HEK cells, and part of its effect on the former cells was blocked by SR141716A (0.5 microM). Pre-treatment of CB1-VR1-HEK cells with forskolin, an adenylate cyclase activator, enhanced the capsaicin effect on [Ca2+]i. HU-210, which in the same cells inhibits forskolin-induced enhancement of cAMP levels, blocked the stimulatory effect of forskolin on capsaicin. Our data suggest that in cells co-expressing both CB1 and VR1 receptors, pre-treatment with CB1 agonists inhibits or stimulates VR1 gating by capsaicin depending on whether or not cAMP-mediated signalling has been concomitantly activated.     

Children's family change: reports and records of mothers, fathers and children compared

Family change, when adults depart or arrive around children, raises policy issues. Its measurement depends upon the evidence collected and from whom. This paper compares British children's histories obtained from fathers and mothers. The evidence, on one birth cohort of parents, comes from two sources: the National Child Development Study and the ONS Longitudinal Study. The resulting account of family change is not substantially different between parents. There is some under-reporting of children not living with their fathers. This is due to under-reporting by those included in the studies and to under-representation in them of absent fathers and lone parents.     

满足左正则性条件的IC富足半群

一个有限半群是满足左正则性条件的IC富足半群当且仅当它是一个幂等元形成左正则带的纯整超富足半群,但满足左正则性条件的无限IC富足半群不都是幂等元形成左正则带的纯整超富足半群.     

弹性纵波在不同非线性法向变形行为节理处的传播

对正向入射弹性纵波穿越具有不同非线性法向变形本构关系的单一岩石干性节理的特性进行理论研究.在没有剪切波的条件下,探讨了BB双曲线模型和经典指数模型两种不同的节理非线性法向变形行为对弹性纵波传播的影响.依据这两类节理本构关系,建立了不同的非线性位移不连续模式,分别获得了弹性纵波穿越单一节理时的反射、透射系数的解析解及数值差分解.针对节理初始法向刚度(kni)、节理闭合量(dn)与最大允许闭合量(dma)比值(γ)以及入射波频率(f)等参数进行研究,同时将2种模型的计算结果进行比较,得到的结论具有一定理论意义.     

基于小波变换和奇异值分解相结合的加密图像数字水印算法

以一种加密算法和多级小波变换,奇异值分解为基础,提出一种数字水印算法.将原始图像进行多级小波分解,然后对低频部分进行奇异值变换,将加密的水印信息嵌入其中.实验结果表明:该算法不仅具有较好的不可感性,而且对几何变换,如旋转、剪切、镜像,叠加噪声如椒盐、高斯噪声及高斯滤波等均具有很好的鲁棒性.     

创建平安公路构建和谐交通

文章通过分析道路交通事故的原因，提出减少道路交通事故、创建平安公路的对策措施。     

退火温度对25Mn-3Si-3Al-TWIP钢组织和力学性能的影响

研究了不同退火温度对25Mn-3Si-3Al-TWIP钢组织和力学性能的影响.结果表明经1000℃退火后,此钢种可达到640MPa左右的抗拉强度和255MPa左右的屈服强度以及82%以上的延伸率,具有较好的综合力学性能.其室温组织为单相奥氏体基体的退火孪晶,通过TEM观察内部为大量的层错和孪晶共存结构.在随后的拉伸变形过程中产生大量形变孪晶,发生了TWIP效应——孪晶诱发塑性效应,使钢板具有优良的力学性能.