"Bravest of the brave": the making and re-making of 'the Gurkhas', 1857-2009

This paper explores the history of Gurkha recruiting from the mid-nineteenth century, charting the emergence and subsequent reworkings of a discourse of Nepalese 'martial aptitude.

Transnational Dialogues: Antoinette Burton and the Rewritings of British Imperial History

Book Revie

Decolonising the immortal heritage: Empire, war and history in contemporary Britain

A blog for the Society for the History of War, about empire, war and memory in contemporary Britain. Focussing on the Commonwealth War Graves Commission's 'Non-Commemorated' report, the blog explores the memorialisation of imperial conflict and soldiers and asks questions about the legacies of empire amidst the contemporary 'culture wars'

‘From the Black Mountain to Waziristan’: culture and combat on the North-West frontier

The chapter offers a cultural reading of colonial campaigning, arguing that combat on the frontier was shaped, in important ways, by a cultural exchange: strategic, tactical and logistical calculations reflected ideas and assumptions about the frontier, its population and their relationship to colonial power. By tracing the development of specific rationalities for frontier conflict through a series of deployments, the chapter reveals the intersection of colonial culture and imperial military power, confirming Nicholas Thomas’s assertion that colonial violence was always ‘mediated and enframed by structures of meaning’

Coercion and conciliation at the edge of empire: state-building and its limits in Waziristan, 1849-1914

This paper proposes an alternative history of the colonial frontier. Focussing on Waziristan, the paper challenges prevailing understandings of colonial frontier policy by demonstrating important and widely-overlooked continuities in colonial engagements with the people and territory of the frontier

In Vivo Analysis of the Notch Receptor S1 Cleavage

A ligand-independent cleavage (S1) in the extracellular domain of the mammalian Notch receptor results in what is considered to be the canonical heterodimeric form of Notch on the cell surface. The in vivo consequences and significance of this cleavage on Drosophila Notch signaling remain unclear and contradictory. We determined the cleavage site in Drosophila and examined its in vivo function by a transgenic analysis of receptors that cannot be cleaved. Our results demonstrate a correlation between loss of cleavage and loss of in vivo function of the Notch receptor, supporting the notion that S1 cleavage is an in vivo mechanism of Notch signal control

Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2

Notch receptors are normally cleaved during maturation by a furin-like protease at an extracellular site termed S1, creating a heterodimer of non-covalently associated subunits. The S1 site lies within a key negative regulatory region (NRR) of the receptor, which contains three highly conserved Lin12/Notch repeats and a heterodimerization domain (HD) that interact to prevent premature signaling in the absence of ligands. Because the role of S1 cleavage in Notch signaling remains unresolved, we investigated the effect of S1 cleavage on the structure, surface trafficking and ligand-mediated activation of human Notch1 and Notch2, as well as on ligand-independent activation of Notch1 by mutations found in human leukemia.The X-ray structure of the Notch1 NRR after furin cleavage shows little change when compared with that of an engineered Notch1 NRR lacking the S1-cleavage loop. Likewise, NMR studies of the Notch2 HD domain show that the loop containing the S1 site can be removed or cleaved without causing a substantial change in its structure. However, Notch1 and Notch2 receptors engineered to resist S1 cleavage exhibit unexpected differences in surface delivery and signaling competence: S1-resistant Notch1 receptors exhibit decreased, but detectable, surface expression and ligand-mediated receptor activation, whereas S1-resistant Notch2 receptors are fully competent for cell surface delivery and for activation by ligands. Variable dependence on S1 cleavage also extends to T-ALL-associated NRR mutations, as common class 1 mutations display variable decrements in ligand-independent activation when introduced into furin-resistant receptors, whereas a class 2 mutation exhibits increased signaling activity.S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins. These findings are consistent with models for receptor activation in which ligand-binding or T-ALL-associated mutations lead to conformational changes of the NRR that permit metalloprotease cleavage

Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation

, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival., a direct Notch target that has an important role in Notch-associated T-ALL.We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis

Integrating mass spectrometry of intact protein complexes into structural proteomics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92070/1/pmic7069.pd