Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn2+ sensing G-protein coupled receptor (ZnR) that activates Ca2+ signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn2+, by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca2+ release and Zn2+-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na+/H+ exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na+/H+ exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn2+-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn2+, acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes

A new approach to assessing the health benefit from obesity interventions in children and adolescents: the assessing cost-effectiveness in obesity project

OBJECTIVE: To report on a new modelling approach developed for the assessing cost-effectiveness in obesity (ACE-Obesity) project and the likely population health benefit and strength of evidence for 13 potential obesity prevention interventions in children and adolescents in Australia. METHODS: We used the best available evidence, including evidence from non-traditional epidemiological study designs, to determine the health benefits as body mass index (BMI) units saved and disability-adjusted life years (DALYs) saved. We developed new methods to model the impact of behaviours on BMI post-intervention where this was not measured and the impacts on DALYs over the child\u27s lifetime (on the assumption that changes in BMI were maintained into adulthood). A working group of stakeholders provided input into decisions on the selection of interventions, the assumptions for modelling and the strength of the evidence. RESULTS: The likely health benefit varied considerably, as did the strength of the evidence from which that health benefit was calculated. The greatest health benefit is likely to be achieved by the \u27Reduction of TV advertising of high fat and/or high sugar foods and drinks to children\u27, \u27Laparoscopic adjustable gastric banding\u27 and the \u27multi-faceted school-based programme with an active physical education component\u27 interventions. CONCLUSIONS: The use of consistent methods and common health outcome measures enables valid comparison of the potential impact of interventions, but comparisons must take into account the strength of the evidence used. Other considerations, including cost-effectiveness and acceptability to stakeholders, will be presented in future ACE-Obesity papers. Information gaps identified include the need for new and more effective initiatives for the prevention of overweight and obesity and for better evaluations of public health interventions

Planning in Turbulent Times: Exploring Planners' Agency in Jerusalem

This article explores the role of planning in the deeply divided and politically polarized context of Jerusalem. The overall argument developed throughout the article is that the relation between planning and politics is a non-hierarchical set of interactions, negotiated within specific historical, geographical, legal and cultural contexts in other words, orders don't come down from the politicians to be slavishly followed by planners. In this respect our findings, based on in-depth interviews with Israeli planners, suggest that the case of Jerusalem represents a particularly dramatic illustration of the fact that the function of planning expertise can only be understood in relation to the surrounding socio-political environment. Furthermore, contrary to conventional wisdom, planners in Jerusalem are not destined to either complicity or irrelevance in the face of political imperatives; planners' agency, however, does not simply reflect their mastery of specific professional knowledge and tools, but also their ability to act strategically in relation to the context in which they operate. © 2016 Urban Research Publications Limite

Chapter III. Foreign Intelligence in an Inter-Networked World: Time for a Re-Evaluation

The recent and dramatic expansion of foreign intelligence surveillance activities, revealed definitively in a trove of documents made public by former NSA analyst Edward Snowden, can be traced to a few drivers. First and foremost, technical changes have made an immense amount of data practically accessible and analyzable in ways that have no precedent in human history. Most of our activities have migrated to digital networks, raising distinct implications in the foreign intelligence-gathering..

Government’s Defence of Proposed CSE Act Falls Short

In this post, we evaluate the Government’s explanation of some of the more problematic elements of Bill C-59 in its briefing notes. We ultimately conclude that while the government’s briefing material provides insight into some of the ways that the CSE might act following the passage of the CSE Act, the material itself does not resolve our concerns with the CSE Act

Shining a Light on the Encryption Debate: A Canadian Field Guide

Critical analysis and insight that navigates the complex implications of ongoing encryption debates.John D. and Catherine T. MacArthur Foundation, Ford Foundatio

A Reconstruction Method for the Estimation of Temperatures of Multiple Sources Applied for Nanoparticle-Mediated Hyperthermia

Solid malignant tumors are one of the leading causes of death worldwide. Many times complete removal is not possible and alternative methods such as focused hyperthermia are used. Precise control of the hyperthermia process is imperative for the successful application of such treatment. To that end, this research presents a fast method that enables the estimation of deep tissue heat distribution by capturing and processing the transient temperature at the boundary based on a bio-heat transfer model. The theoretical model is rigorously developed and thoroughly validated by a series of experiments. A 10-fold improvement is demonstrated in resolution and visibility on tissue mimicking phantoms. The inverse problem is demonstrated as well with a successful application of the model for imaging deep-tissue embedded heat sources. Thereby, allowing the physician then ability to dynamically evaluate the hyperthermia treatment efficiency in real time

USING VIRTUALIZATION TO VALIDATE FA ULT-TOLERANT DISTRIBUTED SYSTEMS

Asynchronous events and complex system state distributed across independent nodes make exposure and diagnosis of flaws in distributed systems a challenge. The difficulties are exacerbated when the goal is to validate fault tolerance mechanisms that are activated only by the occurrence of errors, which are, by nature, rare. Validation of fault tolerance mechanisms is often done by injecting faults that emulate the actual faults and ‘‘stress’ ’ the functionality of the resilience mechanisms. Validation campaigns lasting days and involving thousands of fault injections are often necessary. We present an infrastructure that combines virtualization and software-implemented fault injection to automate validation campaigns and support the analysis of the behavior of a distributed system under test. Virtualization enables: 1) aflexible fault injector capable of emulating a wide variety of faults, and 2) amechanism for autonomously recovering faulty nodes so that the campaign can continue running on a target system that is fully functional. As acase study we use this infrastructure to validate a Byzantine-fault-tolerant cluster manager. Over 1280 hours of fault injections yielded the exposure of 11 unique flaws in the cluster manager