Structural and dynamic changes associated with beneficial engineered single-amino-acid deletion mutations in enhanced green fluorescent protein.

Single-amino-acid deletions are a common part of the natural evolutionary landscape but are rarely sampled during protein engineering owing to limited and prejudiced molecular understanding of mutations that shorten the protein backbone. Single-amino-acid deletion variants of enhanced green fluorescent protein (EGFP) have been identified by directed evolution with the beneficial effect of imparting increased cellular fluorescence. Biophysical characterization revealed that increased functional protein production and not changes to the fluorescence parameters was the mechanism that was likely to be responsible. The structure EGFP(D190Δ) containing a deletion within a loop revealed propagated changes only after the deleted residue. The structure of EGFP(A227Δ) revealed that a `flipping mechanism was used to adjust for residue deletion at the end of a β-strand, with amino acids C-terminal to the deletion site repositioning to take the place of the deleted amino acid. In both variants new networks of short-range and long-range interactions are generated while maintaining the integrity of the hydrophobic core. Both deletion variants also displayed significant local and long-range changes in dynamics, as evident by changes in B factors compared with EGFP. Rather than being detrimental, deletion mutations can introduce beneficial structural effects through altering core protein properties, folding and dynamics, as well as function

Geometric quantum computation with NMR

The experimental realisation of the basic constituents of quantum information processing devices, namely fault-tolerant quantum logic gates, requires conditional quantum dynamics, in which one subsystem undergoes a coherent evolution that depends on the quantum state of another subsystem. In particular, the subsystem may acquire a conditional phase shift. Here we consider a novel scenario in which this phase is of geometric rather than dynamical origin. As the conditional geometric (Berry) phase depends only on the geometry of the path executed it is resilient to certain types of errors, and offers the potential of an intrinsically fault-tolerant way of performing quantum gates. Nuclear Magnetic Resonance (NMR) has already been used to demonstrate both simple quantum information processing and Berry's phase. Here we report an NMR experiment which implements a conditional Berry phase, and thus a controlled phase shift gate. This constitutes the first elementary geometric quantum computation.Comment: Minor additions at request of referees. 4 pages revtex including 2 figures (1 eps). Nature in pres

Adiposity is associated with blunted cardiovascular, neuroendocrine and cognitive responses to acute mental stress

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited - Copyright @ 2012 Jones et al.Obesity and mental stress are potent risk factors for cardiovascular disease but their relationship with each other is unclear. Resilience to stress may differ according to adiposity. Early studies that addressed this are difficult to interpret due to conflicting findings and limited methods. Recent advances in assessment of cardiovascular stress responses and of fat distribution allow accurate assessment of associations between adiposity and stress responsiveness. We measured responses to the Montreal Imaging Stress Task in healthy men (N=43) and women (N=45) with a wide range of BMIs. Heart rate (HR) and blood pressure (BP) measures were used with novel magnetic resonance measures of stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and arterial compliance to assess cardiovascular responses. Salivary cortisol and the number and speed of answers to mathematics problems in the task were used to assess neuroendocrine and cognitive responses, respectively. Visceral and subcutaneous fat was measured using T2*-IDEAL. Greater BMI was associated with generalised blunting of cardiovascular (HR:β=−0.50 bpm.unit−1, P=0.009; SV:β=−0.33 mL.unit−1, P=0.01; CO:β=−61 mL.min−1.unit−1, P=0.002; systolic BP:β=−0.41 mmHg.unit−1, P=0.01; TPR:β=0.11 WU.unit−1, P=0.02), cognitive (correct answers: r=−0.28, P=0.01; time to answer: r=0.26, P=0.02) and endocrine responses (cortisol: r=−0.25, P=0.04) to stress. These associations were largely determined by visceral adiposity except for those related to cognitive performance, which were determined by both visceral and subcutaneous adiposity. Our findings suggest that adiposity is associated with centrally reduced stress responsiveness. Although this may mitigate some long-term health risks of stress responsiveness, reduced performance under stress may be a more immediate negative consequence.This work is funded by the UK National Institute of Health Research (NIHR), Siemens Medical Systems, British Heart Foundation (BHF), NIHR Senior Research Fellowship & The Fondation Leducq, BHF Intermediate Fellowship

Predicting the Impact of Climate Change on Threatened Species in UK Waters

Global climate change is affecting the distribution of marine species and is thought to represent a threat to biodiversity. Previous studies project expansion of species range for some species and local extinction elsewhere under climate change. Such range shifts raise concern for species whose long-term persistence is already threatened by other human disturbances such as fishing. However, few studies have attempted to assess the effects of future climate change on threatened vertebrate marine species using a multi-model approach. There has also been a recent surge of interest in climate change impacts on protected areas. This study applies three species distribution models and two sets of climate model projections to explore the potential impacts of climate change on marine species by 2050. A set of species in the North Sea, including seven threatened and ten major commercial species were used as a case study. Changes in habitat suitability in selected candidate protected areas around the UK under future climatic scenarios were assessed for these species. Moreover, change in the degree of overlap between commercial and threatened species ranges was calculated as a proxy of the potential threat posed by overfishing through bycatch. The ensemble projections suggest northward shifts in species at an average rate of 27 km per decade, resulting in small average changes in range overlap between threatened and commercially exploited species. Furthermore, the adverse consequences of climate change on the habitat suitability of protected areas were projected to be small. Although the models show large variation in the predicted consequences of climate change, the multi-model approach helps identify the potential risk of increased exposure to human stressors of critically endangered species such as common skate (Dipturus batis) and angelshark (Squatina squatina)

Beyond the 'post-industrial' city: valuing and planning for industry in London

This paper examines the challenges that planners face if industry is to survive and thrive in a growing ‘post-industrial’ city. It examines London, where the difference between the value of land for residential and industrial use, and the pressure to address the housing crisis, is leading to the rapid loss of industrial land and premises. The paper first explores the role of industry in a high-value city such as London, arguing that trends in manufacturing in advanced economies are increasing the benefit for firms of an urban location, whilst at the same time, cities continue to need industry if they are to be economically and socially resilient, sustainable and vibrant. The paper then explores current approaches to planning for industry in London, identifying impacts of a policy framework that anticipates and plans for its decline. Finally, it focuses on the question of how to plan for a productive and inclusive city: we explore the arguments in favour of integrating industry into the urban fabric as well as the benefits of separating land uses and retaining employment land designations, and reveal how urbanists are divided. We argue that if London is to continue to prosper, and meet the needs of all Londoners, then we need to strategically and proactively plan for industry in the city, to experiment with innovative ways of integrating it with other city uses, whilst protecting land for industry, where required. We put forward a critical research agenda to effectively meet this challenge in the future

Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD

Objective We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy. Methods Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57–75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St George’s Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. Results For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. Discussion Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations

Maxillary brown tumour: unusual presentation of parathyroid carcinoma

This is a report of a maxillary brown tumour caused by primary hyperparathyroidism (HPT) secondary to parathyroid carcinoma. A 62-year-old man presented with a large swelling in the right maxilla, which caused right-sided nasal obstruction, intermittent bleeding and diplopia. A computed tomography scan demonstrated an expansible, destructive soft tissue mass centred on the right ethmoid sinus, extending from the maxilla to the orbital floor. Histology showed a central giant cell granuloma of bone, thought to be a brown tumour of HPT and this was supported by serum calcium of 3.0 mmol/l and serum parathyroid hormone of 880 ng/l (normal 7 to 40 ng/l). Parathyroid imaging was consistent with a left lower parathyroid adenoma. The patient underwent removal of the parathyroid gland, left hemithyroidectomy and central node dissection. Histology confirmed parathyroid carcinoma. Surgical removal of the brown tumour was offered but declined. The symptoms improved and the maxillary swelling gradually reduced in size. The management of brown tumours is controversial, but a pragmatic approach is essential to a successful outcome. The general consensus seems to be adequate treatment of the HPT and surgical excision of the brown tumour only if the mass effect of the lesion is troublesome.Keywords: parathyroid carcinoma, brown tumour, primary hyperparathyroidis

Cladding strategies for building-integrated photovoltaics

Photovoltaic cladding on the surfaces of commercial buildings has the potential for considerable reductions in carbon emissions due to embedded renewable power generation displacing conventional power utilization. In this paper, a model is described for the optimization of photovoltaic cladding densities on commercial building surfaces. The model uses a modified form of the ‘fill factor’ method for photovoltaic power supply coupled to new regression-based procedures for power demand estimation. An optimization is included based on a defined ‘mean index of satisfaction’ for matched power supply and demand (i.e., zero power exportation to the grid). The mean index of satisfaction directly translates to the reduction in carbon emission that might be expected over conventional power use. On clear days throughout the year, reductions of conventional power use of at least 60% can be achieved with an optimum cladding pattern targeted to lighting and small power load demands