411 research outputs found

    Rethingking the orality-literacy paradigm in musicology

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    This paper poses questions regarding the implications of mainstream orality-literacy research on musicological perspectives, and the relevance of musicological research for orality-literacy studies. First, why has musical scholarship been ignored in the mainstream of orality-literacy studies? The two major schools of thought in orality studies offer two different springboards for discussion where musicology might have both contributed to and benefited from interdisciplinary exchanges. Second, what have been the casualties of lost connections with the academic mainstream discussions on orality and literacy? Finally, what are the possible unique contributions of musicological research to the overarching questions of the orality-literacy problematic, particularly in the electronic world? Issues raised in Birkerts' book, The Gutenberg Elegies: The Fate of Reading in the Electronic Age (2006), exemplify the kinds of questions musicologists could be discussing with mainstream academia about the challenges we face regarding our multiple literacies--musical as well as literary.Not

    ASC filament formation serves as a signal amplification mechanism for inflammasomes

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    A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASC(PYD) into filaments and cross-linking of these filaments by ASC(CARD). ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASC(PYD) is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1β, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production

    TARJETA POSTAL NAVIDEÑA. VIRGEN CON NIÑO. FRA. FILIPPO LIPPI [Material gráfico]

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    ITALIACopia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

    TARJETA POSTAL NAVIDEÑA [Material gráfico]

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    ITALIACopia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

    Revisiting the NMR Structure of the Ultrafast Downhill Folding Protein gpW from Bacteriophage λ

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    GpW is a 68-residue protein from bacteriophage λ that participates in virus head morphogenesis. Previous NMR studies revealed a novel α+β fold for this protein. Recent experiments have shown that gpW folds in microseconds by crossing a marginal free energy barrier (i.e., downhill folding). These features make gpW a highly desirable target for further experimental and computational folding studies. As a step in that direction, we have re-determined the high-resolution structure of gpW by multidimensional NMR on a construct that eliminates the purification tags and unstructured C-terminal tail present in the prior study. In contrast to the previous work, we have obtained a full manual assignment and calculated the structure using only unambiguous distance restraints. This new structure confirms the α+β topology, but reveals important differences in tertiary packing. Namely, the two α-helices are rotated along their main axis to form a leucine zipper. The β-hairpin is orthogonal to the helical interface rather than parallel, displaying most tertiary contacts through strand 1. There also are differences in secondary structure: longer and less curved helices and a hairpin that now shows the typical right-hand twist. Molecular dynamics simulations starting from both gpW structures, and calculations with CS-Rosetta, all converge to our gpW structure. This confirms that the original structure has strange tertiary packing and strained secondary structure. A comparison of NMR datasets suggests that the problems were mainly caused by incomplete chemical shift assignments, mistakes in NOE assignment and the inclusion of ambiguous distance restraints during the automated procedure used in the original study. The new gpW corrects these problems, providing the appropriate structural reference for future work. Furthermore, our results are a cautionary tale against the inclusion of ambiguous experimental information in the determination of protein structures

    In Conversation with Iain Sinclair

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    In Conversation with Iain Sinclair (1st February 2018

    GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

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    Pyroptosis is a lytic type of cell death that is initiated by inflammatory caspases. These caspases are activated within multi-protein inflammasome complexes that assemble in response to pathogens and endogenous danger signals. Pyroptotic cell death has been proposed to proceed via the formation of a plasma membrane pore, but the underlying molecular mechanism has remained unclear. Recently, gasdermin D (GSDMD), a member of the ill-characterized gasdermin protein family, was identified as a caspase substrate and an essential mediator of pyroptosis. GSDMD is thus a candidate for pyroptotic pore formation. Here, we characterize GSDMD function in live cells and in vitro We show that the N-terminal fragment of caspase-1-cleaved GSDMD rapidly targets the membrane fraction of macrophages and that it induces the formation of a plasma membrane pore. In vitro, the N-terminal fragment of caspase-1-cleaved recombinant GSDMD tightly binds liposomes and forms large permeability pores. Visualization of liposome-inserted GSDMD at nanometer resolution by cryo-electron and atomic force microscopy shows circular pores with variable ring diameters around 20 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death

    Editorial/Editoriale/Éditorial/Editorial

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    Editorial/Editoriale/Éditorial/Editoria
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