London 2012 and Climate Change. Examining the potential impact of the current economic crisis in the environmental legacy of the Games

The International Olympic Committee (IOC) declares environmental protection to be the third dimension of the Olympic movement. That, in effect, means that nations wishing to host the Games have to present themselves as reliable practitioners of environmental sustainability (ES) in their applications. The greening of sports mega-events, and the hosting of Olympic Games in particular, is now reasonably well established. Yet evidence from the first decade of environmentally-conscious Olympics points to diverging patterns of achievement in the operationalisation of the IOC’s ‘third pillar’. As is now common knowledge, for example, Sydney 2000 was the first ‘Green Olympics’ in the history of the Games; yet four years later, Athens provided a stark contrast, and was the subject of highly critical assessment reports by environmental organisations. Yet Athens has not stopped the Bid Committee for the Beijing 2008 Games claiming that it would ‘leave the greatest Olympic Games environmental legacy ever’ (UNEP 2007: 26), while the London 2012 promotes the concept of the ‘One Planet Olympics’.

In this context and in light of the current global economic crisis, can we claim that London 2012 has the capacity to fulfil its environmental ambitions? This question is adopted in continuity with similar framed questions that have been posed in relation to the most recent Olympics and it is tackled by adopting an investigative model that is placed within discourses of ‘reflexive modernisation’.

Vision and Virtuality:The Construction of Narrative Space in Film and Computer Games

This paper seeks to explore the construction of narrative space in 3D PC computer games. With reference to Stephen Heath’s theory of filmic narrative space, the paper will examine how computer games, based on the rendition of a continuous 3D, real-time interactive environment, construct a distinct mode of narrativisation. The dynamic imbrication of the manipulation of 3D objects in a virtual world and the (re)presentation of this virtual mise-en-scene constitute an interaction that affects the concept of narrative in computer games. This leads to several questions that the paper seeks to investigate: How does the construction of space in PC games contribute to the meaning-making process or the gamer’s experience of narrative? How then is this experience of narrative game-space different from that of film?

TRP channels in vascular disorders

In recent years, research on the roles of TRP channels in vascular function and disease has undergone a rapid expansion from tens of reports published in the early 2000s to several hundreds of papers published to date. Multiple TRP subtypes are expressed in vascular smooth muscle cells and endothelial cells, where they form diverse non-selective cation channels permeable to Ca2+. These channels mediate Ca2+ entry following receptor stimulation, Ca2+ store depletion and mechanical stimulation of vascular myocytes and endothelial cells. The complex molecular composition and signalling pathways leading to the activation of various vascular TRP channels and the growing evidence for their involvement in various vascular disorders, including dysregulation of vascular tone and hypertension, impaired endothelium-dependent vasodilatation, increased endothelial permeability, occlusive vascular disease, vascular injury and oxidative stress, are summarised and discussed in this review.

ND3, ND1 and 39 kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I

An intriguing feature of mitochondrial complex I from several species is the so-called A/D transition, whereby the idle enzyme spontaneously converts from the active (A) form to the de-active (D) form. The A/D transition plays an important role in tissue response to the lack of oxygen and hypoxic deactivation of the enzyme is one of the key regulatory events that occur in mitochondria during ischaemia. We demonstrate for the first time that the A/D conformational change of complex I does not affect the macromolecular organisation of supercomplexes in vitro as revealed by two types of native electrophoresis. Cysteine 39 of the mitochondrially-encoded ND3 subunit is known to become exposed upon de-activation. Here we show that even if complex I is a constituent of the I + III + IV (S) supercomplex, cysteine 39 is accessible for chemical modification in only the D-form. Using lysine-specific fluorescent labelling and a DIGE-like approach we further identified two new subunits involved in structural rearrangements during the A/D transition: ND1 (MT-ND1) and 39 kDa (NDUFA9). These results clearly show that structural rearrangements during de-activation of complex I include several subunits located at the junction between hydrophilic and hydrophobic domains, in the region of the quinone binding site. De-activation of mitochondrial complex I results in concerted structural rearrangement of membrane subunits which leads to the disruption of the sealed quinone chamber required for catalytic turnover.

Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation

Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged (∼2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders (Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima–media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO₂^–) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3–4 (acute high altitude) and 12–14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders’ FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2vs. 6.6 ± 0.3 m s⁻¹; P = 0.001). These changes persisted at days 12–14, and after allometrically scaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio (∼19%, P ≤ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO₂^– increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r = −0.53) and chronic (n = 7, r = −0.69; P ≤ 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (n = 11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspired O₂ fraction () = 0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure when compared to normoxic baseline (5.7 ± 1.6 vs. 8.0 ±1.3%; P < 0.01); this decline in FMD was largely reversed following α₁-adrenoreceptor blockade. In conclusion, high-altitude exposure in lowlanders caused persistent impairment in vascular function, which was mediated partially via oxidative stress and sympathoexcitation. Although a lifetime of high-altitude exposure neither intensifies nor attenuates the impairments seen with short-term exposure, chronic high-altitude exposure appears to be associated with arterial remodelling.

Endothelial function, antioxidant status and vascular compliance in newly diagnosed HFE C282Y homozygotes

Purpose: This pilot study was aimed to establish techniques for assessing and observing trends in endothelial function, antioxidant status and vascular compliance in newly diagnosed HFE haemochromatosis during the first year of venesection.

Patients/methods: Untreated newly diagnosed HFE haemochromatosis patients were tested for baseline liver function, iron indices, lipid profile, markers of endothelial function, anti-oxidant status and vascular compliance. Following baseline assessment, subjects attended at 6-weeks and at 3, 6, 9 and 12-months for follow-up studies.

Results: Ten patients were recruited (M = 8, F = 2, mean age = 51 years). Venesection significantly increased high density lipoproteins at 12-months (1.25 mmol/L vs. 1.37 mmol/L, p = 0.01). However, venesection did not significantly affect lipid hydroperoxides, intracellular and vascular cell adhesion molecules or high sensitivity C-reactive protein (0.57 mu mol/L vs. 0.51 mu mol/L, p = 0.45, 427.4 ng/ml vs. 307.22 ng/ml, p = 0.54, 517.70 ng/ml vs. 377.50 ng/ml, p = 0.51 and 290.75 mu g/dL vs. 224.26 mu g/dL, p = 0.25). There was also no significant effect of venesection on anti-oxidant status or pulse wave velocity (9.65 m/s vs. 8.74 m/s, p = 0.34).

Conclusions: Venesection significantly reduced high density lipoproteins but was not associated with significant changes in endothelial function, anti-oxidant status or vascular compliance. Larger studies using this established methodology are required to clarify this relationship further. 

Use of Inhaled Tobramycin in Cystic Fibrosis

Chronic infection with Pseudomonas aeruginosa is associated with poor outcomes in patients with cystic fibrosis (CF). It leads to a reduced quality of life, acceleration of the decline in lung function, and increased frequency and severity of pulmonary exacerbations. Tobramycin, administered by inhalation as a long-term therapy, decreases bacterial density in airways, reduces exacerbation frequency, and improves quality of life and lung function in patients with chronic P. aeruginosa infection. In the last decade, tobramycin inhalation has become an important contributor to CF treatment as a means to control chronic infection and as a first-line treatment for the eradication of early acquisition of P. aeruginosa. Recently, a dry powder inhalation (DPI) form of tobramycin has become available, which is more convenient for administration and has comparable efficacy to the tobramycin solution. This DPI, the Podhaler™ (Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA), requires less time for treatment delivery and is more portable than a nebulizer, and so is a welcome additional therapeutic option for many patients.

Importance of surface carbide formation on the activity and selectivity of Pd surfaces in the selective hydrogenation of acetylene

A recent experimental investigation (Kim et al. J. Catal. 306 (2013) 146-154) on the selective hydrogenation of acetylene over Pd nanoparticles with different shapes concluded that Pd(100) showed higher activity and selectivity than Pd(111) for acetylene hydrogenation. However, our recent density functional calculations (Yang et al. J. Catal. 305 (2013) 264-276) observed that the clean Pd(111) surface should result in higher activity and ethylene selectivity compared with the clean Pd(100) surface for acetylene hydrogenation. In the current work, using density functional theory calculations, we find that Pd(100) in the carbide form gives rise to higher activity and selectivity than Pd(111) carbide. These results indicate that the catalyst surface is most likely in the carbide form under the experimental reaction conditions. Furthermore, the adsorption energies of hydrogen atoms as a function of the hydrogen coverage at the surface and subsurface sites over Pd(100) are compared with those over Pd(111), and it is found that the adsorption of hydrogen atoms is always less favoured on Pd(100) over the whole coverage range. This suggests that the Pd(100) hydride surface will be less stable than the Pd(111) hydride surface, which is also in accordance with the experimental results reported.

Using Answer Set Programming for Solving Boolean Games

Boolean games are a framework for reasoning about the rational behaviour of agents, whose goals are formalized using propositional formulas. They offer an attractive alternative to normal-form games, because they allow for a more intuitive and more compact encoding. Unfortunately, however, there is currently no general, tailor-made method available to compute the equilibria of Boolean games. In this paper, we introduce a method for finding the pure Nash equilibria based on disjunctive answer set programming. Our method is furthermore capable of finding the core elements and the Pareto optimal equilibria, and can easily be modified to support other forms of optimality, thanks to the declarative nature of disjunctive answer set programming. Experimental results clearly demonstrate the effectiveness of the proposed method.

Ischemic A/D transition of mitochondrial complex I and its role in ROS generation

Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a key enzyme in cellular energy metabolism and provides approximately 40% of the proton-motive force that is utilized during mitochondrial ATP production. The dysregulation of complex I function – either genetically, pharmacologically, or metabolically induced – has severe pathophysiological consequences that often involve an imbalance in the production of reactive oxygen species (ROS). Slow transition of the active (A) enzyme to the deactive, dormant (D) form takes place during ischemia in metabolically active organs such as the heart and brain. The reactivation of complex I occurs upon reoxygenation of ischemic tissue, a process that is usually accompanied by an increase in cellular ROS production. Complex I in the D-form serves as a protective mechanism preventing the oxidative burst upon reperfusion. Conversely, however, the D-form is more vulnerable to oxidative/nitrosative damage. Understanding the so-called active/deactive (A/D) transition may contribute to the development of new therapeutic interventions for conditions like stroke, cardiac infarction, and other ischemia-associated pathologies. In this review, we summarize current knowledge on the mechanism of A/D transition of mitochondrial complex I considering recently available structural data and site-specific labeling experiments. In addition, this review discusses in detail the impact of the A/D transition on ROS production by complex I and the S-nitrosation of a critical cysteine residue of subunit ND3 as a strategy to prevent oxidative damage and tissue damage during ischemia–reperfusion injury.

INFLUENCE OF NOX4 NADPH OXIDASE ON GENERATION AND ANGIOGENIC FUNCTION OF INDUCED PLURIPOTENT STEM CELL-DERIVED ENDOTHELIAL CELLS

Human induced pluripotent stem (iPS) cell-derived endothelial cells (ECs) hold clear potential for therapeutic angiogenesis as a novel strategy for ischaemic disease. Recently, we have developed a novel method for direct reprogramming of partial iPS (PiPS) cells, which unlike iPS cells, are generated before pluripotency so do not form tumours, and may be differentiated into ECs with characteristic morphology and pro-angiogenic actions. Our previous work showed that PiPS-derived ECs are capable of forming vascular-like tubes both in vitro and in vivo and promoting re-endothelialisation of ischemic tissue, with greater effectiveness versus mature ECs.

Interestingly, our preliminary data demonstrate that Nox NADPH oxidases, which are reported to influence stem cell function, are progressively induced during PiPs/PiPS-EC differentiation and in response to hypoxia, with Nox4 demonstrating highest expression. As this isoform is an established regulator of angiogenesis, we hypothesize that Nox4 plays a key role in modulating PiPS-EC generation and angiogenic function.

The aim of this project is therefore to investigate: (1) the specific role of Nox4 in direct reprogramming of PiPS cells and differentiation to PiPS-ECs; (2) whether genetic manipulation of Nox4 influences in vitro function of PiPs-ECs and their ability to promote in vivo angiogenesis. This will be achieved by employing established in vitro functional assays and an experimental model of hindlimb ischaemia with assessment of relevant end-points. Identification of a key role for Nox4 in regulating PiPS-EC generation/function may inform selective targeting of this isoform to enhance the efficiency of PiPS-EC differentiation and their capacity to treat ischemic disease.

Franz Liszt’s Piano Sonata in B Minor: Precedents for an Analytical Evolution

Franz Liszt has all too often been discarded as the virtuosic showman, despite the fact that his several of works have often gained great praise and attracted scholarly engagement. However, one also finds striking development of formal design and tonal harmony in many of the works for his principal composition medium, the piano. This paper seeks to explore the practical application of James A. Hepokoski and Warren Darcy’s 'Sonata Theory' upon Liszt’s magnum opus for the instrument, the Sonata in B Minor.

I shall first consider the historical analyses placed upon the work that deal with structural design, as it pertains to the paradigm of Classical sonata-form. Previous research reveals two main theoretical camps; those in favour of a multi-movement analysis (with conflicting hypotheses therein) and those in favour of a single movement sonata-form. An understanding of these historical conceptions of the piece allows one to then highlight areas of conflict and offer a new solution.

Finally, I shall use Sonata Theory to survey the Sonata in B Minor’s landscape in a new light. The title ‘Sonata’ has clear generic implications, many of which are met by Liszt; 'Sonata Theory' provides a model with which to outline the compositional deformations employed by the composer and the implications of this practice. In particular, I offer new perspectives on the validity of the double-function form, insight into the rhetorical layout of a rotational discourse, and propose a nuanced analysis befitting of this striking work.

Multicenter Randomized Controlled Trial of Withdrawal of Inhaled Corticosteroids in Cystic Fibrosis

Rationale: Lung inflammation and injury is critical in cystic fibrosis. An ideal antiinflammatory agent has not been identified but inhaled corticosteroids are widely used despite lack of evidence.

Objectives: To test the safety of withdrawal of inhaled corticosteroids with the hypothesis this would not be associated with an earlier onset of acute chest exacerbations.

Methods: Multicenter randomized double-blind placebo-controlled trial in 18 pediatric and adult UK centers. Eligibility criteria included age > 6.0 yr, FEV1 ? 40% predicted, and corticosteroid use > 3 mo. During the 2-mo run-in period, all patients received fluticasone; they then took either fluticasone or placebo for 6 mo.

Measurements and Main Results: Fluticasone group: n = 84, median age 14.6 yr, mean (SD) FEV1 76% (18); placebo group: n = 87, median age 15.8 yr, mean (SD) FEV1 76% (18). There was no difference in time to first exacerbation (primary outcome) with hazard ratio (95% confidence interval) of 1.07 (0.68 to 1.70) for fluticasone versus placebo. There was no effect of age, atopy, corticosteroid dose, FEV1, or Pseudomonas aeruginosa status. There was no change in lung function or differences in antibiotic or rescue bronchodilator use. Fewer patients in the fluticasone group withdrew from the study due to lung-related adverse events (9 vs. 15%); with a relative risk (95% confidence interval) of 0.59 (0.23–1.48) fluticasone versus placebo.

Conclusions: In this study population (applicable to 40% of patients with cystic fibrosis in the UK), it appears safe to consider stopping inhaled corticosteroids. Potential advantages will be to reduce the drug burden on patients, reduce adverse effects, and make financial savings.

Nonlinear response of permanent dipoles in a uniaxial potential to alternating fields

It is shown how the existing theory of the dynamic Kerr effect and nonlinear dielectric relaxation based on the noninertial Brownian rotation of noninteracting rigid dipolar particles may be generalized to take into account interparticle interactions using the Maier-Saupe mean field potential. The results (available in simple closed form) suggest that the frequency dependent nonlinear response provides a method of measuring the Kramers escape rate (or in the analogous problem of magnetic relaxation of fine single domain ferromagnetic particles, the superparamagnetic relaxation time).

Differences In Metabolic Profile In the Testes of Streptozotocin Induced Diabetes Mellitus Mice As Detected By 1H NMR

Contrary to the traditional view, recent studies suggest that diabetes mellitus has an adverse influence on male reproductive function. Our aim was to determine the affect of diabetes on the testicular environment by identifying and then assessing perturbations in small molecule metabolites. Testes were obtained from control and streptozotocin induced diabetic C57BL/6 mice, two, four and eight weeks post treatment. Diabetic status was confirmed by HbA1c, non fasting blood glucose, physiological condition and body weight. Protein free, low molecular weight, water soluble extracts were assessed using 1H NMR spectroscopy. Principal Component Analysis of the derived profiles was used to classify any variations and specific metabolites were identified based on their spectral pattern. Characteristic metabolite profiles were identified for control and diabetic animals with the most distinctive being from mice with the greatest physical deterioration and loss of bodyweight. Eight streptozotocin treated animals did not develop diabetes and displayed profiles similar to controls. Diabetic mice had decreases in creatine, choline and carnitine and increases in lactate, alanine and myo-inositol. Betaine levels were found to be increased in the majority of diabetic mice but decreased in two animals with severe loss of body weight and physical condition. The association between perturbations in a number of small molecule metabolites known to be influential in sperm function, with diabetic status and physiological condition, adds further impetus to the proposal that diabetes influences important spermatogenic pathways and mechanisms in a subtle and previously unrecognised manner.