16 research outputs found
Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia
This is the final version of the article. Available from the publisher via the DOI in this record.Deletion of exon 9 from Cullinâ3 (CUL3, residues 403â459: CUL3Î403â459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form CullinâRINGâubiquitinâligase complexes. Bound to KLHL3, CUL3âRBX1 ubiquitylates WNK kinases, promoting their ubiquitinâmediated proteasomal degradation. Since WNK kinases activate Na/Cl coâtransporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting CullinâRINGâligase formation. We report here that the PHA2E mutant, CUL3Î403â459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Î403â459 autoâubiquitylates and loses interaction with two important Cullin regulators: the COP9âsignalosome and CAND1. A novel knockâin mouse model of CUL3WT/Î403â459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases.This work was supported by the British Heart Foundation (a PhD studentship
to KS and PG 13 89 30577), Medical Research Council, and an ERC Starting
Investigator Grant (to TK), as well as the pharmaceutical companies supporting
the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer
Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica and Pfizer). The
Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical
Research Centre
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APMS SVD methodology and implementation
One of the main tasks within the Aviation Performance Measurement System (APMS) program uses statistical methodologies to find atypical flights. With thousands of flights a day and hundreds of parameters being recorded every second for each flight, the amount of data escalates and the ability to find atypical flights becomes more difficult. The purpose of this paper is to explain the method known as single value decomposition (SVD) employed to search for the atypical flights and display useful graphics that facilitate understanding the causes of atypicality for these flights. Other methods could also perform this search and some are planned for future implementation
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Methodology for uncertainty estimation of Hanford tank chemical and radionuclide inventories and concentrations
The exact physical and chemical nature of 55 million gallons of toxic waste held in 177 underground waste tanks at the Hanford Site is not known with sufficient detail to support the safety, retrieval, and immobilization missions presented to Hanford. The Hanford Best Basis team has made point estimates of the inventories in each tank. The purpose of this study is to estimate probability distributions for each of the 71 analytes and 177 tanks that the Hanford Best Basis team has made point estimates for. This will enable uncertainty intervals to be calculated for the Best Basis inventories and should facilitate the safety, retrieval, and immobilization missions. Section 2 of this document describes the overall approach used to estimate tank inventory uncertainties. Three major components are considered in this approach: chemical concentration, density, and waste volume. Section 2 also describes the two different methods used to evaluate the tank wastes in terms of sludges and in terms of supernatant or saltcakes. Sections 3 and 4 describe in detail the methodology to assess the probability distributions for each of the three components, as well as the data sources for implementation. The conclusions are given in Section 5
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T-200 series tank concentration predictions
Of the 177 tanks containing nuclear waste at the Hanford site, 68 have not been characterized based on sampling information. It may be possible to characterize 34 of the 68 unsampled tanks by using information from other sources, such as the Tank Characterization Database (TCD) and the Historical Tank Content Estimates (HTCE). This report lists predicted concentrations of 17 analytes along with the associated estimates of uncertainty for the T-200 series tanks (T-201, T-202, T-203, T-204), based on historical data and sample results from tanks other than the T-200 tanks. The main benefits of reduced sampling are reduced cost, reduced time to achieve acceptable characterization, and reduced exposure of sampling personnel. However, in order to characterize a tank on the basis of reducing sampling, the predicted tank averages and the associated uncertainties must be technically credible and useful. The objective of this report is to describe the approach to predict (without a sample) or estimate (from a single sample) the concentrations of the 17 analytes for the T-200 tanks. Sampling of these tanks and laboratory analysis of the samples is currently under way (sampling is scheduled for 03/27/97 through 04/21/97). This report briefly describes the statistical prediction techniques
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Robust real-time tracking for visual surveillance
This paper describes a real-time multi-camera surveillance system that can be applied to a range of application domains. This integrated system is designed to observe crowded scenes and has mechanisms to improve tracking of objects that are in close proximity. The four component modules described in this paper are (i) motion detection using a layered background model, (ii) object tracking based on local appearance, (iii) hierarchical object recognition, and (iv) fused multisensor object tracking using multiple features and geometric constraints. This integrated approach to complex scene tracking is validated against a number of representative real-world scenarios to show that robust, real-time analysis can be performed. Copyright (C) 2007 Hindawi Publishing Corporation. All rights reserved
For a critical appraisal of artificial intelligence in healthcare: The problem of bias in mHealth
International audienc
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The future of video analytics for surveillance and its ethical implications
The current state of the art and direction of research in computer vision aimed at automating the analysis of CCTV images is presented. This includes low level identification of objects within the field of view of cameras, following those objects over time and between cameras, and the interpretation of those objectsâ appearance and movements with respect to models of behaviour (and therefore intentions inferred). The potential ethical problems (and some potential opportunities) such developments may pose if and when deployed in the real world are presented, and suggestions made as to the necessary new regulations which will be needed if such systems are not to further enhance the power of the surveillers against the surveilled