排序方式: 共有73条查询结果,搜索用时 750 毫秒
31.
Autophagy in stem and progenitor cells 总被引:1,自引:1,他引:0
32.
The origin and growth of magnetic fields in galaxies is still something of an enigma. It is generally assumed that seed fields are amplified over time through the dynamo effect, but there are few constraints on the timescale. It was recently demonstrated that field strengths as traced by rotation measures of distant (and hence ancient) quasars are comparable to those seen today, but it was unclear whether the high fields were in the unusual environments of the quasars themselves or distributed along the lines of sight. Here we report high-resolution spectra that demonstrate that the quasars with strong Mg II absorption lines are unambiguously associated with larger rotation measures. Because Mg ii absorption occurs in the haloes of normal galaxies along the sightlines to the quasars, this association requires that organized fields of surprisingly high strengths are associated with normal galaxies when the Universe was only about one-third of its present age. 相似文献
33.
Song MS Salmena L Carracedo A Egia A Lo-Coco F Teruya-Feldstein J Pandolfi PP 《Nature》2008,455(7214):813-817
Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML-RARalpha fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARalpha degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization. 相似文献
34.
35.
Extending previous risk model backtesting literature, we construct multiple hypothesis testing (MHT) with the stationary bootstrap. We conduct multiple tests which control for the generalized confidence level and employ the bootstrap MHT to design multiple comparison testing. We consider absolute and relative predictive ability to test a range of competing risk models, focusing on value‐at‐risk and expected shortfall (ExS). In devising the test for the absolute predictive ability, we take the route of recent literature and construct balanced simultaneous confidence sets that control for the generalized family‐wise error rate, which is the joint probability of rejecting true hypotheses. We implement a step‐down method which increases the power of the MHT in isolating false discoveries. In testing for the ExS model predictive ability, we design a new simple test to draw inference about recursive model forecasting capability. In the second suite of statistical testing, we develop a novel device for measuring the relative predictive ability in the bootstrap MHT framework. The device, which we coin multiple comparison mapping, provides a statistically robust instrument designed to answer the question: ‘Which model is the best model?’ Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
36.
Logan CV Lucke B Pottinger C Abdelhamed ZA Parry DA Szymanska K Diggle CP van Riesen A Morgan JE Markham G Ellis I Manzur AY Markham AF Shires M Helliwell T Scoto M Hübner C Bonthron DT Taylor GR Sheridan E Muntoni F Carr IM Schuelke M Johnson CA 《Nature genetics》2011,43(12):1189-1192
Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia. 相似文献
37.
Manuela Ambrosio Francesca Fanelli Silvia Brocchetti Francesco Raimondi Mario Mauri G. Enrico Rovati Valérie Capra 《Cellular and molecular life sciences : CMLS》2010,67(17):2979-2989
In class A GPCRs the E/DRY motif is critical for receptor activation and function. According to experimental and computational
data, R3.50 forms a double salt bridge with the adjacent E/D3.49 and E/D6.30 in helix 6, constraining the receptor in an inactive
state. The disruption of this network of interactions facilitates conformational transitions that generate a signal or constitutive
activity. Here we demonstrate that non-conservative substitution of either E129(3.49) or E240(6.30) of thromboxane prostanoid receptor (TP) resulted in mutants characterized by agonist-induced more efficient signaling properties,
regardless of the G protein coupling. Results of computational modeling suggested a more effective interaction between Gq and the agonist-bound forms of the TP mutants, compared to the wild type. Yet, none of the mutants examined revealed any
increase in basal activity, precluding their classification as constitutively active mutants. Here, we propose that these
alternative active conformations might be identified as superactive mutants or SAM. 相似文献
38.
Architecture of the Mediator head module 总被引:1,自引:0,他引:1
Imasaki T Calero G Cai G Tsai KL Yamada K Cardelli F Erdjument-Bromage H Tempst P Berger I Kornberg GL Asturias FJ Kornberg RD Takagi Y 《Nature》2011,475(7355):240-243
39.
Oxygen sensing in plants is mediated by an N-end rule pathway for protein destabilization 总被引:3,自引:0,他引:3
Licausi F Kosmacz M Weits DA Giuntoli B Giorgi FM Voesenek LA Perata P van Dongen JT 《Nature》2011,479(7373):419-422
40.
Willer T Lee H Lommel M Yoshida-Moriguchi T de Bernabe DB Venzke D Cirak S Schachter H Vajsar J Voit T Muntoni F Loder AS Dobyns WB Winder TL Strahl S Mathews KD Nelson SF Moore SA Campbell KP 《Nature genetics》2012,44(5):575-580
Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology. 相似文献