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21.
Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors 总被引:1,自引:0,他引:1
BK Koo M Spit I Jordens TY Low DE Stange M van de Wetering JH van Es S Mohammed AJ Heck MM Maurice H Clevers 《Nature》2012,488(7413):665-669
LGR5+ stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5+ stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5+ stem cells. In vitro, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the RNF43-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation. 相似文献
22.
Aoki SK Diner EJ de Roodenbeke CT Burgess BR Poole SJ Braaten BA Jones AM Webb JS Hayes CS Cotter PA Low DA 《Nature》2010,468(7322):439-442
Bacteria have developed mechanisms to communicate and compete with one another in diverse environments. A new form of intercellular communication, contact-dependent growth inhibition (CDI), was discovered recently in Escherichia coli. CDI is mediated by the CdiB/CdiA two-partner secretion (TPS) system. CdiB facilitates secretion of the CdiA 'exoprotein' onto the cell surface. An additional small immunity protein (CdiI) protects CDI(+) cells from autoinhibition. The mechanisms by which CDI blocks cell growth and by which CdiI counteracts this growth arrest are unknown. Moreover, the existence of CDI activity in other bacteria has not been explored. Here we show that the CDI growth inhibitory activity resides within the carboxy-terminal region of CdiA (CdiA-CT), and that CdiI binds and inactivates cognate CdiA-CT, but not heterologous CdiA-CT. Bioinformatic and experimental analyses show that multiple bacterial species encode functional CDI systems with high sequence variability in the CdiA-CT and CdiI coding regions. CdiA-CT heterogeneity implies that a range of toxic activities are used during CDI. Indeed, CdiA-CTs from uropathogenic E.?coli and the plant pathogen Dickeya dadantii have different nuclease activities, each providing a distinct mechanism of growth inhibition. Finally, we show that bacteria lacking the CdiA-CT and CdiI coding regions are unable to compete with isogenic wild-type CDI(+) cells both in laboratory media and on a eukaryotic host. Taken together, these results suggest that CDI systems constitute an intricate immunity network with an important function in bacterial competition. 相似文献
23.
(滚)法推拿形成运动狭窄粘弹性血管血液动力学 总被引:2,自引:0,他引:2
建立具有局部轴向运动狭窄的粘弹性血管中脉动血流模型,模拟研究中医扌衮法推拿的血液动力学机理.血液为牛顿流体,血流遵循线化Navier Stokes方程,血管壁为线性粘弹体,扌衮法推拿作用下血管形成轴向运动狭窄水平外力作用.求解得出血管内血液流速、流量以及管壁切应力.结果表明在扌衮法作用下,血管一个心动周期血液流量有明显变化,且随手法频率的加快以及作用力水平渗透系数增大而增大,随最大狭窄度的增大而减小;同时狭窄段内以及狭窄后部切应力随手法作用也明显变化.手法频率,血管最大狭窄度和作用力水平渗透系数,是中医扌衮法推拿的重要参数. 相似文献
24.
小角度掠射X-Ray Diffraction用于离子注入后金属材料的物相鉴定 总被引:1,自引:1,他引:0
用小角度掠射 X 光法对工业纯铝,45# 钢等材料表面经离子注入改性后的表层物质进行了物相分析,这一方法可以准确确定材料表层厚度为几十 nm 时的物相结构 ,从而为确立材料表层改性的机制提供了较为可靠的依据. 对比实验表明,采用小角度掠射 X 光衍射法比常规衍射仪法更加突出了表层物质对衍射谱的贡献,这为表面物理的研究提供了一种有效的方法. 相似文献
25.
Huiyu Low Chun Song Chua Tiow-Suan Sim 《Cellular and molecular life sciences : CMLS》2009,66(18):3081-3090
A mitogen-activated protein kinase (MAPK), Pfmap2, has been identified in Plasmodium falciparum. However, its bona fide activator remains elusive as no MAPK kinase (MAPKK) homologues have been found so far. Instead, Pfnek3,
a NIMA (never in mitosis, Aspergillus)-related kinase, was earlier reported to display a MAPKK-like activity due to its activating effect on Pfmap2. In this study,
the regulatory mechanism of Pfnek3 was investigated. Pfnek3 was found to possess a SSEQSS motif within its activation loop
that fulfills the consensus SXXXS/T phospho-activating sequence of MAPKKs. Functional analyses of the SSEQSS motif by site-directed
mutagenesis revealed that phosphorylation of residues S221 and S226 is essential for mediating Pfnek3 activity. Moreover,
via tandem mass-spectrometry, residue T82 was uncovered as an additional phosphorylation site involved in Pfnek3 activation.
Collectively, these results provide valuable insights into the potential in vivo regulation of Pfnek3, with residues T82,
S221 and S226 functioning as phospho-activating sites. 相似文献
26.
由于中国学生赴澳大利亚留学人数逐年增加,他们在澳洲生活、学习及心理、生理健康状况已成为国人关心的焦点问题。本文通过对在澳洲新南威尔士州各大学部分中国留学生的访谈分析,报告中国留学生在澳现状和心理感受,并提出参考建议,以期达到出国留学朝着更健康和更理性的道路发展之目的。 相似文献
27.
Gut hormone PYY(3-36) physiologically inhibits food intake 总被引:42,自引:0,他引:42
Batterham RL Cowley MA Small CJ Herzog H Cohen MA Dakin CL Wren AM Brynes AE Low MJ Ghatei MA Cone RD Bloom SR 《Nature》2002,418(6898):650-654
Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY(3-36) inhibits food intake. PYY(3-36) also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway. 相似文献
28.
E. J. Ewaschuk G. Wielgosz M. Low E. V. YoungLai 《Cellular and molecular life sciences : CMLS》1980,36(4):465-466
Summary Ovarian follicles isolated from female rabbits after active immunization against testosterone-3-oxime bovine serum albumin produced more testosterone than similar follicles from controls.This work was supported by the Medical Research Council of Canada MT 4192. 相似文献
29.
Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2 总被引:12,自引:0,他引:12
Coste SC Kesterson RA Heldwein KA Stevens SL Heard AD Hollis JH Murray SE Hill JK Pantely GA Hohimer AR Hatton DC Phillips TJ Finn DA Low MJ Rittenberg MB Stenzel P Stenzel-Poore MP 《Nature genetics》2000,24(4):403-409
The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2. 相似文献
30.
Rapid planetesimal formation in turbulent circumstellar disks 总被引:1,自引:0,他引:1
During the initial stages of planet formation in circumstellar gas disks, dust grains collide and build up larger and larger bodies. How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem: boulders are expected to stick together poorly, and to spiral into the protostar in a few hundred orbits owing to a 'headwind' from the slower rotating gas. Gravitational collapse of the solid component has been suggested to overcome this barrier. But even low levels of turbulence will inhibit sedimentation of solids to a sufficiently dense midplane layer, and turbulence must be present to explain observed gas accretion in protostellar disks. Here we report that boulders can undergo efficient gravitational collapse in locally overdense regions in the midplane of the disk. The boulders concentrate initially in transient high pressure regions in the turbulent gas, and these concentrations are augmented a further order of magnitude by a streaming instability driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar disks. 相似文献