Licence to Kill: The Murderous Outrages Act and the rule of law in colonial India, 1867–1925

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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

Conformational Arrangements of UbcH7-Ubiquitin with OspG and Parkin

The E2-ubiquitin conjugate is a key regulator of ubiquitination and is therefore an important component of cellular homeostasis. Disruptions to proper E2-ubiquitin functioning have implications in diseases such as shigellosis and Parkinson’s disease discussed here. E2-ubiquitin conjugates like UbcH7-ubiquitin are extremely dynamic and can adopt multiple conformations in solution or bound to target proteins. However, the conformational arrangements that UbcH7-ubiquitin adopts while free in solution, bound to the shigellosis-associated kinase OspG or to the Parkinson’s disease-related E3 ligase parkin are unknown. Also unknown, is a mechanistic explanation for how UbcH7-ubiquitin interactions with OspG and parkin are associated with disease. Here, we determined the crystal structure of OspG bound to UbcH7-ubiquitin, the crystal structure of autoinhibited full-length human parkin with and without a phosphorylation-mimetic, the crystal and NMR structures of activated full-length human parkin bound to a phosphorylated-ubiquitin molecule, and an NMR structure of activated human parkin bound to both phosphorylated-ubiquitin and UbcH7-ubiquitin. This work determined that UbcH7-ubiquitin predominantly occupies closed states in solution but binds to OspG and parkin in open conformations. Further key findings include showing that UbcH7-ubiquitin is a biological target of OspG and that OspG involvement in shigellosis is to halt host ubiquitination by competitively binding to UbcH7-ubiquitin in a way that mimics host HECT E3 binding. We showed that parkin is autoinhibited through interdomain interactions. Phosphorylation of autoinhibited parkin primes phosphorylated-ubiquitin binding and this binding relieves autoinhibition by inducing allosteric rearrangements in parkin to allow subsequent UbcH7-ubiquitin engagement. Finally, we showed that certain hereditary variants in parkin are likely associated with autosomal recessive juvenile parkinsonism due to a loss in the ability to interact with UbcH7-ubiquitin. Research here has significant implications for understanding the basis of shigellosis and hereditary forms of Parkinson’s disease, and has contributed significant molecular understandings for the use in developing therapeutics

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

Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis

The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N‐terminal ubiquitin‐like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin‐binding interface, provide a model for the phosphoubiquitin–parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin‐binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin

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