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1.
This article explores the importance of power and dissymmetry in promoting participative knowledge and change in action research. Based on the analysis of two action research cases, the paper builds its argument by analyzing two key aspects: the construction of the action research setting and its maintenance during the process. It does so by highlighting the decisions assumed with respect to the relationship between researchers and participants and with respect to power issues. The findings indicate that promoting a functional dissymmetry in internal relationships allows distribution of the necessary types of power that make the participants use their authority and knowledge to invest in change. Thus, the distributed leadership is essential every time an organization needs to create a realistic and workable change of roles and responsibilities inside its boundaries. The article discusses some key factors in employing dissymmetry for sustained learning and knowledge-sharing. 相似文献
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Oxysterols direct immune cell migration via EBI2 总被引:1,自引:0,他引:1
Hannedouche S Zhang J Yi T Shen W Nguyen D Pereira JP Guerini D Baumgarten BU Roggo S Wen B Knochenmuss R Noël S Gessier F Kelly LM Vanek M Laurent S Preuss I Miault C Christen I Karuna R Li W Koo DI Suply T Schmedt C Peters EC Falchetto R Katopodis A Spanka C Roy MO Detheux M Chen YA Schultz PG Cho CY Seuwen K Cyster JG Sailer AW 《Nature》2011,475(7357):524-527
Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response. 相似文献
3.
Prox J Willenbrock M Weber S Lehmann T Schmidt-Arras D Schwanbeck R Saftig P Schwake M 《Cellular and molecular life sciences : CMLS》2012,69(17):2919-2932
A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well-documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10-TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10. 相似文献
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Silvio Maracchia 《Archive for History of Exact Sciences》1980,21(3):201-228
Riassunto
Aristotele accenna a due diverse dimostrazioni della incommensurabilità tra lato e diagonale di uno stesso quadrato, una esatta e l'altra, avverte, errata. Nel presente lavoro viene presa in esame quest'ultima proponendone una ricostruzione in connessione, come é accennato da Aristotele, con le argomentazioni di Zenone.Nel corso del lavoro vengono esaminati due altri brani di Aristotele attraverso i quali é possibile osservare un momento dello sviluppo matematico dell'algoritmo euclideo e il cosiddetto postulato di Eudosso-Archimede nel più vasto ambito dei primi contatti con problemi di analisi infinitesimale.Nell'Appendice, poi, vengono elencati tutti i brani di Aristotele raccolti dall'autore sulla detta incommensurabilità.
Memoria presentata da C. Truesdell 相似文献
Summary Aristotle mentions two different demonstrations of the incommensurability of side with diagonal of the same square, one of which is correct, and the other, as he points out, incorrect. This work examines the latter suggesting a reconstruction of it in connection, as Aristotle mentioned, with Zeno's argumentations.In the course of this work, two other passages by Aristotle are examined, by which it is possible to observe a moment of the mathematical development of the Euclidean algorithm and the so called Axiom of Eudoxus-Archimedes in the broader ambit of early contacts with problems of infinitesimal analysis.In the Appendix, secondly, all the passages by Aristotle regarding incommensurability gathered by the author are listed.
Résumé Aristote parle de deux différentes démonstrations de l'incommensurabilité entre le côté et la diagonale d'un même carré, une exacte et l'autre, nous prévient-il, inexacte. Dans ce travail on examine cette dernière démonstration en connexion, comme Aristote lui-même le suggère, avec les argumentations de Zénon.Au cours du travail l'auteur examine deux autres morceaux d'Aristote, à travers lesquels il est possible d'observer un moment du développement mathématique de l'algorithme euclidien et ce qu'on appelle le postulat d'Eudoxe-Archimède dans le domaine bien plus vaste des premiers contacts avec des problèmes d'analyse infinitésimale.Dans l'appendice on peut trouver la liste de tous les morceaux d'Aristote que l'auteur a rassemblés sur la susdite incommensurabilité.
Memoria presentata da C. Truesdell 相似文献
6.
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer 总被引:1,自引:0,他引:1
Misale S Yaeger R Hobor S Scala E Janakiraman M Liska D Valtorta E Schiavo R Buscarino M Siravegna G Bencardino K Cercek A Chen CT Veronese S Zanon C Sartore-Bianchi A Gambacorta M Gallicchio M Vakiani E Boscaro V Medico E Weiser M Siena S Di Nicolantonio F Solit D Bardelli A 《Nature》2012,486(7404):532-536
A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. 相似文献
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Role of YAP/TAZ in mechanotransduction 总被引:3,自引:0,他引:3
Dupont S Morsut L Aragona M Enzo E Giulitti S Cordenonsi M Zanconato F Le Digabel J Forcato M Bicciato S Elvassore N Piccolo S 《Nature》2011,474(7350):179-183
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M Montagner E Enzo M Forcato F Zanconato A Parenti E Rampazzo G Basso G Leo A Rosato S Bicciato M Cordenonsi S Piccolo 《Nature》2012,487(7407):380-384
The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity. 相似文献
10.
STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis 总被引:1,自引:0,他引:1
Synaptic transmission is mediated by neurotransmitters that are stored in synaptic vesicles and released by exocytosis upon activation. The vesicle membrane is then retrieved by endocytosis, and synaptic vesicles are regenerated and re-filled with neurotransmitter. Although many aspects of vesicle recycling are understood, the fate of the vesicles after fusion is still unclear. Do their components diffuse on the plasma membrane, or do they remain together? This question has been difficult to answer because synaptic vesicles are too small (approximately 40 nm in diameter) and too densely packed to be resolved by available fluorescence microscopes. Here we use stimulated emission depletion (STED) to reduce the focal spot area by about an order of magnitude below the diffraction limit, thereby resolving individual vesicles in the synapse. We show that synaptotagmin I, a protein resident in the vesicle membrane, remains clustered in isolated patches on the presynaptic membrane regardless of whether the nerve terminals are mildly active or intensely stimulated. This suggests that at least some vesicle constituents remain together during recycling. Our study also demonstrates that questions involving cellular structures with dimensions of a few tens of nanometres can be resolved with conventional far-field optics and visible light. 相似文献