Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

The E3 ligase parkin ubiquitinates outer mitochondrial membrane proteins during oxidative stress and is linked to early-onset Parkinson’s disease. Parkin is autoinhibited but is activated by the kinase PINK1 that phosphorylates ubiquitin leading to parkin recruitment, and stimulates phosphorylation of parkin’s N-terminal ubiquitin-like (pUbl) domain. How these events alter the structure of parkin to allow recruitment of an E2~Ub conjugate and enhanced ubiquitination is an unresolved question. We present a model of an E2~Ub conjugate bound to the phosphoubiquitin-loaded C-terminus of parkin, derived from NMR chemical shift perturbation experiments. We show the UbcH7~Ub conjugate binds in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR and mass spectrometry experiments indicate the RING0/RING2 interface is re-modelled, remote from the E2 binding site, and this alters the reactivity of the RING2(Rcat) catalytic cysteine, needed for ubiquitin transfer. Our experiments provide evidence that parkin phosphorylation and E2~Ub recruitment act synergistically to enhance a weak interaction of the pUbl domain with the RING0 domain and rearrange the location of the RING2(Rcat) domain to drive parkin activity

The Ajnala Massacre of 1857 and the Politics of Colonial Violence and Commemoration in Contemporary India

In February 2014, an amateur archaeological team unearthed thousands of bones and other remains from an old well in the town of Ajnala, located in the Indian state of Punjab. These remains are believed to belong to 282 Indian sepoys who were summarily executed en masse on 1 August 1857 under the orders of Deputy Commissioner Frederic Cooper, during the height of the Indian Uprising of 1857. The discovery of the bodies has not only reignited fierce debates about the violent history of the British Empire in India, but also offers an interesting glimpse into some of the ways that Indian history and national identity are currently being remade and negotiated in relation to the colonial past. This article is about the contested historical narrations, memories, and ongoing efforts to commemorate the Ajnala Massacre. It reveals how the history and public memory of colonial violence remain poorly understood, and the ways that calls for the recognition of previously forgotten, absent, or erased memories can prompt difficult and highly politicized discussions about the meaning of history, identity, and politics.</p

COERCION AND CONCILIATION AT THE EDGE OF EMPIRE: STATE-BUILDING AND ITS LIMITS IN WAZIRISTAN, 1849–1914

Since 2001, the geo-strategic priorities of the ‘War on Terror’ have prompted renewed attention to the historically significant region of Waziristan. Ironically, given the apparent failure of British attempts to pacify the region in the century after 1849, Waziristan’s colonial history has been picked over by policy-makers, commentators, and scholars for lessons which might be applied to current projects of state-building and counter-insurgency. Unabashedly instrumentalist, these works have reproduced the reductive stereotypes of the colonial sources and helped to entrench partial understandings of the frontier which obscure the dynamic and contingent nature of imperial state-building. This article offers an alternate frame for writing the history of the colonial frontier by re-examining how British officials attempted to constitute colonial authority through their engagements with one of the region’s most powerful groups: the Mahsud Wazirs. Challenging historiographical emphases on oscillating metropolitan strategies, this article maps crucial and largely overlooked continuities in British attempts to pacify the Mahsuds, providing new insights into state-building at the edge of empire and a more nuanced account of how imperial power was engaged, resisted, and deflected by those it sought to control

Optimisation of Wearable Thermoelectric Generators

This meta-study explores some factors that can potentially affect the efficiency of a wearable thermoelectric generator. These include, but are not limited to; doping percentage, manufacturing technology, thermocouple length, area, use of heat spreaders, material, airflow and specific position on the human body. These specific designs and materials have been reviewed in this paper and specific variables have been proposed to ensure greater efficiency. In this meta- study, Bi0.5Sb1.5Te3 and Ag2Se are found to be the most effective materials, with PVD as the most effective manufacturing method. A broad temperature differential generates greater power output. Practically, a condition where there is a difference in temperature of more than 40K between the body and its environment in the application of wearable thermoelectric devices is unlikely. Despite this, a temperature difference below 40K, although small, is extremely feasible and would be able to enough power to keep intended wearable thermoelectric devices running at a constant. Keywords: Thermoelectric; Seebeck Effect; Peltier; TEG; ZT; Wearabl

A Bayesian approach to assist in the diagnosis of coronary heart disease

The objectives of this thesis were to design a method for evaluation of the diagnostic potential of available indicators of coronary heart disease (CHD) and to present a systematics, quantitative procedure to aiding in its diagnosis. A sample space of patients was divided into two mutually exclusive groups, those with angiographic evidence of CHD, and those with no CHD. Active duty or retired military men between the ages of 30 and 67 years constituted the sample space. Tests and risk factors were available in the medical literature that a doctor could view as an indicator or contraindicator of CHD. A vector of these possible indicators was established and the diseased group was compared to the non-diseased group in an effort to evaluate the diagnostic potential of the indicators. This was done by discriminant analysis in conjunction with a Bayesian method of weighting the importance of tests results. The important indicators were then used to formulate a model for diagnosing CHD based on a Bayes' decision technique.http://archive.org/details/abayesianpproach1094516502Captain, United States ArmyApproved for public release; distribution is unlimited