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排序方式: 共有238条查询结果,搜索用时 15 毫秒
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Serena Stadler Chi Huu Nguyen Helga Schachner Daniela Milovanovic Silvio Holzner Stefan Brenner Julia Eichsteininger Mira Stadler Daniel Senfter Liselotte Krenn Wolfgang M. Schmidt Nicole Huttary Sigurd Krieger Oskar Koperek Zsuzsanna Bago-Horvath Konstantin Alexander Brendel Brigitte Marian Oliver de Wever Robert M. Mader Benedikt Giessrigl Walter Jäger Helmut Dolznig Georg Krupitza 《Cellular and molecular life sciences : CMLS》2017,74(10):1907-1921
Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca2+-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour–stroma interaction. 相似文献
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Ludwig Heesen Michael Peitz Laura Torres-Benito Irmgard Hölker Kristina Hupperich Kristina Dobrindt Johannes Jungverdorben Swetlana Ritzenhofen Beatrice Weykopf Daniela Eckert Seyyed Mohsen Hosseini-Barkooie Markus Storbeck Noemi Fusaki Renata Lonigro Raoul Heller Min Jeong Kye Oliver Brüstle Brunhilde Wirth 《Cellular and molecular life sciences : CMLS》2016,73(10):2089-2104
107.
Oliver Stoll 《Studies in history and philosophy of science》2012,43(2):250-257
Xenophon’s Peri hippikes <technees>, “On Horsemanship,” and the Hipparchikos <logos>, “the Cavalry Commander”, writings which can be regarded as technical works with a didactic purpose, are almost unknown. Xenophon was interested in problems of leadership and the exercise of power (For the titles of the both writings and the analogous supplementary terms “technees” and “logos” compare Breitenbach, 1966, 1761. Angled brackets are used by modern editors of ancient texts as text-critical signs and are inserted here because “peri hippikes” and “hipparchikos” are adjectives and cannot stand alone; “technees” and “logos” are supplied as absent, but implied, substantives. The conventional signs “<>” clarify this supplementary act for the modern reader.). The “Cavalry Commander” (ca. 365 B.C.) intended for the instruction of potential hipparchs (calvary commanders) is simultaneously political and didactic and technical; in this text, categories of leadership that had been developed in earlier works are combined in a powerful manner. Xenophon constructed “leaders” as exempla (“examples”) of correct behaviour; military and political theory are synthesised. The Hipparchikos logos, as a didactic work, aims to produce specialists who master their techné (“art” or “skill”), to develop their ideal qualities. Both texts are directed at an Athenian society, in which the cavalry had lost their significance and pride as a result of recent political turbulence. Xenophon hoped to reform the cavalry for the benefit of Athens. The basic question of the didactic work is: how can I become the best hipparch, how can I go beyond simply filling the office, and instead develop it for the well-being of the polis and thus serve the city? The art of leadership consists in dealing with subordinates in such a manner that they obey and follow voluntarily—still an innovative and modern approach today. 相似文献
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Submillimetre galaxies reside in dark matter haloes with masses greater than 3 × 10(11) solar masses
Amblard A Cooray A Serra P Altieri B Arumugam V Aussel H Blain A Bock J Boselli A Buat V Castro-Rodríguez N Cava A Chanial P Chapin E Clements DL Conley A Conversi L Dowell CD Dwek E Eales S Elbaz D Farrah D Franceschini A Gear W Glenn J Griffin M Halpern M Hatziminaoglou E Ibar E Isaak K Ivison RJ Khostovan AA Lagache G Levenson L Lu N Madden S Maffei B Mainetti G Marchetti L Marsden G Mitchell-Wynne K Nguyen HT O'Halloran B Oliver SJ Omont A Page MJ Panuzzo P Papageorgiou A Pearson CP 《Nature》2011,470(7335):510-512
The extragalactic background light at far-infrared wavelengths comes from optically faint, dusty, star-forming galaxies in the Universe with star formation rates of a few hundred solar masses per year. These faint, submillimetre galaxies are challenging to study individually because of the relatively poor spatial resolution of far-infrared telescopes. Instead, their average properties can be studied using statistics such as the angular power spectrum of the background intensity variations. A previous attempt at measuring this power spectrum resulted in the suggestion that the clustering amplitude is below the level computed with a simple ansatz based on a halo model. Here we report excess clustering over the linear prediction at arcminute angular scales in the power spectrum of brightness fluctuations at 250, 350 and 500?μm. From this excess, we find that submillimetre galaxies are located in dark matter haloes with a minimum mass, M(min), such that log(10)[M(min)/M(⊙)] = 11.5(+0.7)(-0.2) at 350?μm, where M(⊙) is the solar mass. This minimum dark matter halo mass corresponds to the most efficient mass scale for star formation in the Universe, and is lower than that predicted by semi-analytical models for galaxy formation. 相似文献
109.
Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease 总被引:1,自引:0,他引:1
Koch P Breuer P Peitz M Jungverdorben J Kesavan J Poppe D Doerr J Ladewig J Mertens J Tüting T Hoffmann P Klockgether T Evert BO Wüllner U Brüstle O 《Nature》2011,480(7378):543-546
Machado-Joseph disease (MJD; also called spinocerebellar ataxia type 3) is a dominantly inherited late-onset neurodegenerative disorder caused by expansion of polyglutamine (polyQ)-encoding CAG repeats in the MJD1 gene (also known as ATXN3). Proteolytic liberation of highly aggregation-prone polyQ fragments from the protective sequence of the MJD1 gene product ataxin 3 (ATXN3) has been proposed to trigger the formation of ATXN3-containing aggregates, the neuropathological hallmark of MJD. ATXN3 fragments are detected in brain tissue of MJD patients and transgenic mice expressing mutant human ATXN3(Q71), and their amount increases with disease severity, supporting a relationship between ATXN3 processing and disease progression. The formation of early aggregation intermediates is thought to have a critical role in disease initiation, but the precise pathogenic mechanism operating in MJD has remained elusive. Here we show that L-glutamate-induced excitation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons initiates Ca(2+)-dependent proteolysis of ATXN3 followed by the formation of SDS-insoluble aggregates. This phenotype could be abolished by calpain inhibition, confirming a key role of this protease in ATXN3 aggregation. Aggregate formation was further dependent on functional Na(+) and K(+) channels as well as ionotropic and voltage-gated Ca(2+) channels, and was not observed in iPSCs, fibroblasts or glia, thereby providing an explanation for the neuron-specific phenotype of this disease. Our data illustrate that iPSCs enable the study of aberrant protein processing associated with late-onset neurodegenerative disorders in patient-specific neurons. 相似文献
110.
Fritsch J Scheerer P Frielingsdorf S Kroschinsky S Friedrich B Lenz O Spahn CM 《Nature》2011,479(7372):249-252
Hydrogenases are abundant enzymes that catalyse the reversible interconversion of H(2) into protons and electrons at high rates. Those hydrogenases maintaining their activity in the presence of O(2) are considered to be central to H(2)-based technologies, such as enzymatic fuel cells and for light-driven H(2) production. Despite comprehensive genetic, biochemical, electrochemical and spectroscopic investigations, the molecular background allowing a structural interpretation of how the catalytic centre is protected from irreversible inactivation by O(2) has remained unclear. Here we present the crystal structure of an O(2)-tolerant [NiFe]-hydrogenase from the aerobic H(2) oxidizer Ralstonia eutropha H16 at 1.5?? resolution. The heterodimeric enzyme consists of a large subunit harbouring the catalytic centre in the H(2)-reduced state and a small subunit containing an electron relay consisting of three different iron-sulphur clusters. The cluster proximal to the active site displays an unprecedented [4Fe-3S] structure and is coordinated by six cysteines. According to the current model, this cofactor operates as an electronic switch depending on the nature of the gas molecule approaching the active site. It serves as an electron acceptor in the course of H(2) oxidation and as an electron-delivering device upon O(2) attack at the active site. This dual function is supported by the capability of the novel iron-sulphur cluster to adopt three redox states at physiological redox potentials. The second structural feature is a network of extended water cavities that may act as a channel facilitating the removal of water produced at the [NiFe] active site. These discoveries will have an impact on the design of biological and chemical H(2)-converting catalysts that are capable of cycling H(2) in air. 相似文献