Enhancing governance of energy and water interdependencies

Policy note based on 3 policy and industry workshops in 2014 and 2015

Co-crystalization and in vitro biological characterization of 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors

A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp9

Unified Chew-Mandelstam SAID analysis of pion photoproduction data

A unified description of single-pion photoproduction data, together with pion- and eta-hadroproduction data, has been achieved in a Chew-Mandelstam parametrization which is consistent with unitarity at the two-body level. Energy-dependent and single-energy partial wave analyses of pion photoproduction data have been performed and compared to previous SAID fits and multipoles from the Mainz and Bonn-Gatchina groups.Comment: 11 pages, 9 figures, and 2 table

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p < 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Toward a unified description of hadro- and photoproduction: S-wave pi- and eta-photoproduction amplitudes

The Chew-Mandelstam parameterization, which has been used extensively in the two-body hadronic sector, is generalized in this exploratory study to the electromagnetic sector by simultaneous fits to the pion- and eta-photoproduction S-wave multipole amplitudes for center-of-mass energies from the pion threshold through 1.61 GeV. We review the Chew-Mandelstam parameterization in detail to clarify the theoretical content of the SAID hadronic amplitude analysis and to place the proposed, generalized SAID electromagnetic amplitudes in the context of earlier employed parameterized forms. The parameterization is unitary at the two-body level, employing four hadronic channels and the gamma-N electromagnetic channel. We compare the resulting fit to the MAID parameterization and find qualitative agreement though, numerically, the solution is somewhat different. Applications of the extended parameterization to global fits of the photoproduction data and to global fits of the combined hadronic and photoproduction data are discussed.Comment: 9 pages, 9 figures; added figures and tex

Dramaturgical Aspects of Professional Wrestling Matches

Paper

Risk-Based Decision Model for Determining the Applicability of an Earned Value Management System in Construction

New policy mandated by the Undersecretary of Defense for Acquisition, Technology and Logistics has lowered the dollar thresholds of contracts requiring earned value management (EVM). This policy directed that a risk-based decision be made to determine if EVM should be used on firm-fixed price contracts under $20 million. Although not previously applicable to Military Construction (MILCON) building projects or other Air Force Civil Engineer (CE) managed contracts, the new threshold requires that CE projects be evaluated for risk. Therefore, the focus of this research was to analyze the risk factors associated with construction contracts in an attempt to build a decision model to determine if EVM is warranted on the project. Due to the cost of implementing EVM, this model should probably be used only on Air Force construction projects with cost estimates over$5 million. If the cost growth predicted by the model is greater than 5%, the use of EVM is recommended to monitor the risk factors. However, this recommendation should be tempered with the overall risk associated with a given project. In other words, if the calculated cost growth is high but the probability of occurrence is low, the decision-maker may want to forego the use of EVM and the associated costs. The questions addressed by this research are as follows: (1) What risk factors affect the cost or schedule of Air Force construction projects?; (2) What is the probability of occurrence of the identified risk factors?; (3) What is the subsequent cost growth due to the occurrence of the risk factors?; and (4) How many Air Force construction projects accomplished in the last 5 years and those programmed through FY12 exceed the $20M threshold or fall into a range that must be evaluated

Unveiling the security concerns of low carbon development:climate security analysis of the undesirable and unintended effects of mitigation and adaptation

In debates of climate action, low carbon development has been widely advocated as an opportunity arising from climate change. This paper problematizes low carbon development, arguing that there are undesirable, unintended or perverse effects that give rise to distinct and serious security concerns. The literature on climate security has addressed the effects of climate threats on conflict but there is a notable paucity of research analysing the security implications of responses to climate change in the form of low carbon development. The paper presents critical analysis of the ways low carbon development yields new security concerns as well as entrenching existing ones. Five dimensions of security are examined: spatially uneven effects of low carbon development; violent imaginaries of the global south and the production of ‘ungoverned spaces’; non-violent yet harmful instances of conflict; marginalization and dispossession; depoliticized, techno-managerial effects of resilience. The paper shows that climate (in)security manifests in variegated ways between different populations and spatial scales. Consequently, how, when for whom low carbon development becomes a threat or opportunity is socially constructed and deeply political

Strategic narratives in climate change: Towards a unifying narrative to address the action gap on climate change

There is a significant ‘action gap’ between what scientists argue is necessary to prevent potentially dangerous climate change and what the government, industry and public are doing. This paper argues that a coherent strategic narrative is key to making meaningful progress. It does this by first analysing a number of narratives which have been used to try and create audience buy-in on the need for action on climate change, and those that argue that no action needs to be taken. A framework is then proposed for how compelling and unifying strategic narratives on climate change might be constructed. It is suggested that the unifying strategic narrative could address the complex range of actors who need to be engaged, provide a coherent explanation for government strategy, and harness the drivers of behavioural change needed to meet the challenge. Research into climate change strategic narratives is nascent, but the authors believe that there is much to be gained from pursuing and intensifying this research

Game theory and corporate governance: conditions for effective stewardship of companies exposed to climate change risks

Engagement between investors and corporate boards has been suggested as a pathway to mitigate stranded asset and climate change risks. Debate is ongoing as to whether divestment or active ownership strategies are more appropriate to deliver longterm value and environmental sustainability. The paper tests the effectiveness of owner engagement strategies by studying the conditions for cooperation between investors and their companies. Characteristics of investors and companies are modelled in game theoretic frameworks, informed by semistructured interviews with professionals from the energy and finance industries, and academia, NGO, and regulatory sectors. Conditions for mutual cooperation between investors and companies are characterized as prisoners’ dilemmas. A number of parameters are examined for their impact on the development of sustained cooperative equilibria, including: the benefits and costs of cooperation; the degree of strategic foresight; individual discount factors; and mutual history. Challenges in the formation of investor coalitions are characterized and solutions are proposed