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With a global economy dependent on marine traffic there has been little study or recognition of the risk posed to this industry by volcanism. Most major shipping lanes pass close to active volcanoes, or through straits and channels which can be impacted by volcanic debris. In this paper we set out the main hazards presented by volcanoes to shipping, and reflect on the magnitude of risk that these pose. There is a demonstrated track record of losses and damages caused by volcanic events in the past, and as shipping volumes increase, the exposure to similar events in the future also increases. As remote sensing techniques and observation of active volcanism improves, the occurrence of marine volcanic events has clearly been under-reported. We suggest there is a dangerous lack of recognition of the scale of the risk posed to the marine transport industry, and to the supply chains it feeds.

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKaand high affinity for α4β2-type nicotinic receptors (α4β2Rs) are trapped in intracellular acidic vesicles containing α4β2Rsin vitro. Nicotine, with lower pKaand α4β2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligandsin vivoin male and female mouse brain and identifying the trapping brain organellein vitroas Golgi satellites (GSats). Two PET18F-labeled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKaand affinity and [18F]Nifene with nicotine-like pKaand affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4β2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4β2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in β2 subunit knock-out (KO) mice or by acute nicotine (AN) injections demonstrating binding to sites on β2-containing receptors. Chloroquine (CQ), which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributionsin vivoconsistent with only [18F]2-FA trapping in GSats. These results are further supported byin vitrofindings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combiningin vitroandin vivoimaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in α4β2R-containing GSats, which results in very slow release long after nicotine is gone after smoking.SIGNIFICANCE STATEMENTMechanisms of nicotine addiction remain poorly understood. An earlier study usingin vitromethods found that the anti-smoking nicotinic ligand, varenicline (Chantix) was trapped in α4β2R-containing acidic vesicles. Using a fluorescent-labeled high-affinity nicotinic ligand, this study provided evidence that these intracellular acidic vesicles were α4β2R-containing Golgi satellites (GSats).In vivoPET imaging with F-18-labeled nicotinic ligands provided additional evidence that differences in PET ligand trapping in acidic vesicles were the cause of differences in PET ligand kinetics and subcellular distributions. These findings combiningin vitroandin vivoimaging revealed new mechanistic insights into the kinetics of weak base PET imaging ligands and the subcellular mechanisms underlying nicotine addiction.

Development of positron emission tomography (PET) radiotracers that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allows for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. One challenge associated with preclinical PET imaging involves the lack of true tissue reference regions free of specific tracer binding in the rodent brain, impeding accurate quantification of the tracer binding potential. Here, we investigate the use of an image-derived arterial input function for kinetic analysis of radiotracer binding in male and female mice. Two radiotracers were explored in this study: 2-[18F]FA85380 (2-FA), which displays similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [18F]Nifene, which displays similar pKa and binding affinity to nicotine. For both radiotracers, time-activity curves of the left ventricle of the heart displayed similar standardized uptake values (SUVs) across wild type mice, mice lacking the β2 subunit for tracer binding, and acute nicotine-treated mice, whereas typical reference tissue SUVs displayed high variation between groups. Binding potential values estimated from a two-tissue compartment model (2TCM) fit of the data with the image-derived input function were significantly higher than estimates from reference tissue-based estimations. Rate constants of radiotracer dissociation were very slow for 2-FA and very fast for Nifene, similar to the in vitro dissociation rates reported for varenicline and nicotine, respectively. We conclude that use of an image-derived input function for kinetic modeling of nicotinic PET ligands improves quantification compared to reference tissue-based methods, and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.

BackgroundCardiac arrest (CA) patients who survived by cardiopulmonary resuscitation (CPR) can present different levels of neurological deficits ranging from minor cognitive impairments to persistent vegetative state and brain death. The pathophysiology of the resulting brain injury is poorly understood and whether changes in post-CA brain metabolism contribute to the injury are unknown. Here we utilized [18F]FDG-PET to study in vivo cerebral glucose metabolism 72 hours following CA in a murine cardiac arrest model.MethodsAnesthetized and ventilated adult C57BL/6 mice underwent 12-minute KCl-induced CA followed by CPR. Seventy-two hours following cardiac arrest, surviving mice were intraperitoneally injected with [18F]FDG (~186 μCi/200 μL) and imaged on Molecubes preclinical micro PET/CT imaging systems after a 30-minute awake uptake period. Brain [18F]FDG uptake was determined by the VivoQuant software on fused PET/CT images with the 3D brain atlas. Upon completion of PET imaging, remaining [18F]FDG radioactivity in the brain, heart, and liver was determined using a gamma counter.ResultsGlobal increases in brain [18F]FDG uptake in post-CA mice were observed compared to shams and controls. The median standardized uptake value (SUV) of [18F]FDG for CA animals was 1.79 vs. sham 1.25 (p18F]FDG uptake for brain were 7.04%ID/g tissue for CA mice vs 5.537%ID/g tissue for sham animals, pConclusionsThis study has successfully applied [18F]FDG-PET/CT to measure changes in brain metabolism in a murine model of asystolic CA. Our results demonstrate increased [18F]FDG uptake in the brain 72 hours following CA, suggesting increased metabolic demand in the case of severe neurological injury. Further study is warranted to determine the etiology of these changes.

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membranepermeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high-affinity for α4β2-type nicotinic receptors (α4β2Rs) are trapped in intracellular acidic vesicles containing α4β2Rs in vitro. Nicotine, with lower pKa and α4β2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labelled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4β2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4β2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in β2 subunit knockout mice or by acute nicotine injections demonstrating binding to sites on β2-containing receptors. Chloroquine, which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributions in vivo consistent with only [18F]2-FA trapping in GSats. These results are further supported by in vitro findings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combining in vitro and in vivo imaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in α4β2R-containing GSats, which results in very slow release long after nicotine is gone after smoking.SignificanceMechanisms of nicotine addiction remain poorly understood. An earlier study using in vitro methods found that the anti-smoking nicotinic ligand, varenicline (Chantix) was trapped in α4β2R-containing acidic vesicles. Using a fluorescent labeled high-affinity nicotinic ligand, this study provided evidence that these intracellular acidic vesicles were α4β2R-containing Golgi satellites. In vivo PET imaging with F-18 labeled nicotinic ligands provided additional evidence that differences in PET ligand trapping in acidic vesicles were the cause of differences in PET ligand kinetics and subcellular distributions. These findings combining in vitro and in vivo imaging revealed new mechanistic insights into the kinetics of weak base PET imaging ligands and the subcellular mechanisms underlying nicotine addiction.

A lift-driven vertical axis wind turbine (VAWT) generates peak power when it is rotating at high tip-speed ratios (TSR), at which time the blades encounter angles of attack (AOA) over a small range from zero to 30 degrees. However, its ability to self-start is dependent upon its performance at low TSRs, at which time the blades encounter a range of AOAs from zero to 180 degrees. A novel vented aerofoil is presented with the intention of improving the performance of a lift-driven VAWT at low TSRs without hampering the performance of the wind turbine at high TSRs. Computational fluid dynamics (CFD) simulation is used to predict the aerodynamic characteristics of a new vented aerofoil based on the well documented NACA0012 profile. Simulations are performed using the SST turbulence model. The results obtained show a reduction in the coefficient of tangential force (the force that generates torque on the wind turbine) at low AOAs (less than 90 degrees) of no more than 30%, while at high AOAs (more than 90 degrees) an improvement in the tangential force of over 100% is observed. Using a simple momentum based performance prediction model, these results suggest that this would lead to an increase in torque generation by a theoretical three-bladed VAWT of up to 20% at low TSRs and a minor reduction in coefficient of performance of up to 9% at TSR of 2 and closer to 1% at higher TSRs.

BACKGROUND: Cardiac arrest (CA) patients who survived by cardiopulmonary resuscitation (CPR) can present different levels of neurological deficits ranging from minor cognitive impairments to persistent vegetative state and brain death. The pathophysiology of the resulting brain injury is poorly understood and whether changes in post-CA brain metabolism contribute to the injury are unknown. Here we utilized [(18)F]FDG-PET to study in vivo cerebral glucose metabolism 72 hours following CA in a murine cardiac arrest model. METHODS: Anesthetized and ventilated adult C57BL/6 mice underwent 12-minute KCl-induced CA followed by CPR. Seventy-two hours following cardiac arrest, surviving mice were intraperitoneally injected with [(18)F]FDG (~186 μCi/200 μL) and imaged on Molecubes preclinical micro PET/CT imaging systems after a 30-minute awake uptake period. Brain [(18)F]FDG uptake was determined by the VivoQuant software on fused PET/CT images with the 3D brain atlas. Upon completion of PET imaging, remaining [(18)F]FDG radioactivity in the brain, heart, and liver was determined using a gamma counter. RESULTS: Global increases in brain [(18)F]FDG uptake in post-CA mice were observed compared to shams and controls. The median standardized uptake value (SUV) of [(18)F]FDG for CA animals was 1.79 vs. sham 1.25 (p

The design of wind turbines requires a deep insight into their complex aerodynamics, such as dynamic stall of a single airfoil and flow vortices. The calculation of the aerodynamic forces on the wind turbine blade at different angles of attack (AOAs) is a fundamental task in the design of the blades. The accurate and efficient calculation of aerodynamic forces (lift and drag) and the prediction of stall of an airfoil are challenging tasks. Computational fluid dynamics (CFD) is able to provide a better understanding of complex flows induced by the rotation of wind turbine blades. A numerical simulation is carried out to determine the aerodynamic characteristics of a single airfoil in a wide range of conditions. Reynolds-averaged Navier–Stokes (RANS) equations and large-eddy simulation (LES) results of flow over a single NACA0012 airfoil are presented in a wide range of AOAs from low lift through stall. Due to the symmetrical nature of airfoils, and also to reduce computational cost, the RANS simulation is performed in the 2D domain. However, the 3D domain is used for the LES calculations with periodical boundary conditions in the spanwise direction. The results obtained are verified and validated against experimental and computational data from previous works. The comparisons of LES and RANS results demonstrate that the RANS model considerably overpredicts the lift and drag of the airfoil at post-stall AOAs because the RANS model is not able to reproduce vorticity diffusion and the formation of the vortex. LES calculations offer good agreement with the experimental measurements.

Learning and memory are critical functions for all animals, giving individuals the ability to respond to changes in their environment. Within populations, individuals vary, however the mechanisms underlying this variation in performance are largely unknown. Thus, it remains to be determined what genetic factors cause an individual to have high learning ability and what factors determine how well an individual will remember what they have learned. To genetically dissect learning and memory performance, we used the Drosophila synthetic population resource (DSPR), a multiparent mapping resource in the model system Drosophila melanogaster, consisting of a large set of recombinant inbred lines (RILs) that naturally vary in these and other traits. Fruit flies can be trained in a "heat box" to learn to remain on one side of a chamber (place learning) and can remember this (place memory) over short timescales. Using this paradigm, we measured place learning and memory for ~49 000 individual flies from over 700 DSPR RILs. We identified 16 different loci across the genome that significantly affect place learning and/or memory performance, with 5 of these loci affecting both traits. To identify transcriptomic differences associated with performance, we performed RNA-Seq on pooled samples of seven high performing and seven low performing RILs for both learning and memory and identified hundreds of genes with differences in expression in the two sets. Integrating our transcriptomic results with the mapping results allowed us to identify nine promising candidate genes, advancing our understanding of the genetic basis underlying natural variation in learning and memory performance.

Learning and memory are critical functions for all animals, giving individuals the ability to respond effectively to changes in their environment. Within populations, individuals vary in performance, however the mechanisms underlying this variation in performance are largely unknown. To uncover the genetic basis for variation in learning and memory performance, we used the DSPR, a multiparent mapping resource in the model system Drosophila melanogaster, consisting of a large set of recombinant inbred lines (RILs) that naturally vary in these and other traits. Fruit flies can be trained in a “heat box” to learn to remain on one side of a chamber (place learning), and can remember this (place memory) over short timescales. Using this paradigm, we measured place learning and memory for ~49,000 individual flies from over 700 DSPR RILs. We identified 16 different loci across the genome that significantly affect place learning and/or memory performance, with 5 of these loci affecting both traits. To identify transcriptomic differences associated with performance, we performed RNA-Seq on pooled samples of 7 high performing and 7 low performing RILs for both learning and memory and identified hundreds of genes with differences in expression in the two sets. Integrating our transcriptomic results with the mapping results allowed us to identify several promising candidate genes, advancing our understanding of the genetic basis underlying natural variation in learning and memory performance. Significance What genetic factors cause an individual to have high learning ability, and what factors determine how well an individual will remember what they have learned? Traditionally, genes involved in learning and memory have been discovered via loss of function mutants or other large perturbations. However, these studies have not been able to inform how genetic variants currently segregating in a population affect learning and memory performance. Our study identifies multiple such variants that influence place learning and memory performance in the Drosophila melanogaster model system and characterizes the differences in gene expression in low versus high performers. These results are a critical first step towards characterizing the genetic differences that determine an individual’s learning and memory abilities.

Dissertation, In this dissertation, we study algorithmic problems motivated by the optimization of networks under uncertainty.We summarize our contributions:\begin{itemize}\item \textbf{Subset $k$-server:} We propose and give algorithms for the \emph{all-or-one $k$-server}, a generalization of classical $k$-server problem. $k$-server is an example of a problem in an \emph{online setting}: the algorithm must make irrevocable decisions without knowledge of future inputs. In the all-or-one $k$-server generalization, clients can make a request for a particular server, or they can submit a general request that may be served by any server. We give an $O(\log k)$-competitive randomized algorithm for this problem on a uniform metric. We additionally study other, similar generalizations of $k$-server.\item \textbf{Retraction:} Motivated by the problem of deploying distributed applications in the cloud, we initiate the algorithmic study of \emph{graph retraction} to a cycle, which seeks a mapping of a graph to a cycle in the graph so as to minimize the maximum stretch of any edge, subject to the constraint that each vertex in the cycle is mapped to itself. Our main results are an $O(\min\{k, \sqrt{n}\})$-approximation for retracting any graph on $n$ nodes to a cycle with $k$ nodes, and an optimal algorithm when the graph is planar.\item \textbf{Symmetric Interdiction:} We study the symmetric matching interdiction problem. This problem can be simply stated as follows: find a matching whose removal minimizes the size of the maximum matching in the remaining graph. We show that this problem is APX-hard, and obtain a $3/2$-approximation algorithm. We additionally introduce symmetric interdiction as a general model. We give a general framework that relates optimization to symmetric interdiction for a broad class of optimization problems. We are motivated by applications in traffic engineering, where a network operator wishes to route traffic in a datacenter, but cannot distinguish between malicious and legitimate traffic.\item \textbf{Multicast Games:} We study the effect of strategic behavior on network design. In \emph{multicast} and \emph{broadcast} games, agents in a graph attempt to connect to a \emph{root node} at minimum cost to themselves, sharing the cost of each edge along their path to the root equally with the other agents using the edge. Such games can have many Nash equilibria, and networks formed dynamically by these agents could end up in any one of these equilibria, and may be very expensive. The main open problem in this field has been to bound the ratio of least expensive Nash equilibrium to the least expensive network, called the price of stability (PoS). We make progress towards a better price of stability bound for multicast games.In particular, we show a constant upper bound on the PoS of multicast games for quasi-bipartite graphs. These are graphs where all edges are between two terminals (as in broadcast games) or between a terminal and a nonterminal, but there is no edge between nonterminals. This represents a natural class of intermediate generality between broadcast and multicast games. \end{itemize}

International audience; The increasing availability and use of sports supplements is of concern as highlighted by a number of studies reporting endocrine disruptor contamination in such products. The health food supplement market, including sport supplements, is growing across the Developed World. Therefore, the need to ensure the quality and safety of sport supplements for the consumer is essential. The development and validation of two reporter gene assays coupled with solid phase sample preparation enabling the detection of estrogenic and androgenic constituents in sport supplements is reported. Both assays were shown to be of high sensitivity with the estrogen and androgen reporter gene assays having an EC(50) of 0.01 ng mL(-1) and 0.16 ng mL(-1) respectively. The developed assays were applied in a survey of 63 sport supplements samples obtained across the Island of Ireland with an additional seven reference samples previously investigated using LC-MS/MS. Androgen and estrogen bio-activity was found in 71% of the investigated samples. Bio-activity profiling was further broken down into agonists, partial agonists and antagonists. Supplements (13) with the strongest estrogenic bio-activity were chosen for further investigation. LC-MS/MS analysis of these samples determined the presence of phytoestrogens in seven of them. Supplements (38) with androgen bio-activity were also selected for further investigation. Androgen agonist bio-activity was detected in 12 supplements, antagonistic bio-activity was detected in 16 and partial antagonistic bio-activity was detected in 10. A further group of supplements (7) did not present androgenic bio-activity when tested alone but enhanced the androgenic agonist bio-activity of dihydrotestosterone when combined. The developed assays offer advantages in detection of known, unknown and low-level mixtures of endocrine disruptors over existing analytical screening techniques. For the detection and identification of constituent hormonally active compounds the combination of biological and physio-chemical techniques is optimal. (C) 2010 Elsevier B.V. All rights reserved.

In this work, the views of thinkers in education who have been concerned with expertise are scanned. In the introduction, the importance of the subject is established. The point is made that the ratio of administrators has gone from one supervisor to 32 teachers in 1920 to one administrator for everey 12 teachers in 1985. As well, specialists in teaching have increased 1, 000 percent in the sixteen years before 1980. In their plans for career stages the current reform efforts of the Holmes group and the Carnegie Forum have emphasized an increase in both steps of the hierarchy of education and the type of specialization that might occur. It is crusial to consider “our most prominent educations thinkers” for their “insights about the effects of educations expertise”.

This paper draws on European views of partnerships that stress policy implications for change rather than financial contributions to an existing system. In North America, critics rant against business influences, but partnerships can transform an inner-directed system. Charter schools need to be related to partnerships. In Canada, unlike the United States, charter schools are strongly resisted by education professionals. Cultural traditions account for the drastic differences between Canadians’ and Americans’ reaction to charter schools and the varying perceptions of partnerships between Europeans and North Americans.

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