954 resultados para Alice in Wonderland


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Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent efflux pump that can confer resistance to multiple anticancer drugs and transport conjugated organic anions. Unusually, transport of several MRP1 substrates requires glutathione (GSH). For example, estrone sulfate transport by MRP1 is stimulated by GSH, vincristine is co-transported with GSH, or GSH can be transported alone. In the present study, radioligand binding assays were developed to investigate the mechanistic details of GSH-stimulated transport of estrone sulfate by MRP1. We have established that estrone sulfate binding to MRP1 requires GSH, or its non-reducing analogue S-methyl GSH (S-mGSH), and further that the affinity (Kd) of MRP1 for estrone sulfate is 2.5-fold higher in the presence of S-mGSH than GSH itself. Association kinetics show that GSH binds to MRP1 first, and we propose that GSH binding induces a conformational change, which makes the estrone sulfate binding site accessible. Binding of non-hydrolyzable ATP analogues to MRP1 decreases the affinity for estrone sulfate. However, GSH (or S-mGSH) is still required for estrone sulfate binding, and the affinity for GSH is unchanged. Estrone sulfate affinity remains low following hydrolysis of ATP. The affinity for GSH also appears to decrease in the post-hydrolytic state. Our results indicate ATP binding is sufficient for reconfiguration of the estrone sulfate binding site to lower affinity and argue for the presence of a modulatory GSH binding site not associated with transport of this tripeptide. A model for the mechanism of GSH-stimulated estrone sulfate transport is proposed.

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The transmembrane (TM) domains in P-glycoprotein (P-gp) contain the drug binding sites and undergo conformational changes driven by nucleotide catalysis to effect translocation. However, our understanding of exactly which regions are involved in such events remains unclear. A site-directed labelling approach was used to attach thiol-reactive probes to cysteines introduced into transmembrane segment 6 (TM6) in order to perturb function and infer involvement of specific residues in drug binding and/or interdomain communication. Covalent attachment of coumarin-maleimide at residue 339C within TM6 resulted in impaired ATP hydrolysis by P-gp. The nature of the effect was to reduce the characteristic modulation of basal activity caused by transported substrates, modulators and the potent inhibitor XR9576. Photoaffinity labelling of P-gp with [(3)H]-azidopine indicated that residue 339C does not alter drug binding per se. However, covalent modification of this residue appears to prevent conformational changes that lead to drug stimulation of ATP hydrolysis.

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Aim: To explore current risk assessment processes in general practice and Improving Access to Psychological Therapies (IAPT) services, and to consider whether the Galatean Risk and Safety Tool (GRiST) can help support improved patient care. Background: Much has been written about risk assessment practice in secondary mental health care, but little is known about how it is undertaken at the beginning of patients' care pathways, within general practice and IAPT services. Methods: Interviews with eight general practice and eight IAPT clinicians from two primary care trusts in the West Midlands, UK, and eight service users from the same region. Interviews explored current practice and participants' views and experiences of mental health risk assessment. Two focus groups were also carried out, one with general practice and one with IAPT clinicians, to review interview findings and to elicit views about GRiST from a demonstration of its functionality. Data were analysed using thematic analysis. Findings Variable approaches to mental health risk assessment were observed. Clinicians were anxious that important risk information was being missed, and risk communication was undermined. Patients felt uninvolved in the process, and both clinicians and patients expressed anxiety about risk assessment skills. Clinicians were positive about the potential for GRiST to provide solutions to these problems. Conclusions: A more structured and systematic approach to risk assessment in general practice and IAPT services is needed, to ensure important risk information is captured and communicated across the care pathway. GRiST has the functionality to support this aspect of practice.

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We propose a new approach to the generation of an alphabet for secret key exchange relying on small variations in the cavity length of an ultra-long fiber laser. This new concept is supported by experimental results showing how the radio-frequency spectrum of the laser can be exploited as a carrier to exchange information. The test bench for our proof of principle is a 50 km-long fiber laser linking two users, Alice and Bob, where each user can randomly add an extra 1 km-long segment of fiber. The choice of laser length is driven by two independent random binary values, which makes such length become itself a random variable. The security of key exchange is ensured whenever the two independent random choices lead to the same laser length and, hence, to the same free spectral range.

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Increased global uptake of entertainment gaming has the potential to lead to high expectations of engagement and interactivity from users of technology-enhanced learning environments. Blended approaches to implementing game-based learning as part of distance or technology-enhanced education have led to demonstrations of the benefits they might bring, allowing learners to interact with immersive technologies as part of a broader, structured learning experience. In this article, we explore how the integration of a serious game can be extended to a learning content management system (LCMS) to support a blended and holistic approach, described as an 'intuitive-guided' method. Through a case study within the EU-Funded Adaptive Learning via Intuitive/Interactive, Collaborative and Emotional Systems (ALICE) project, a technical integration of a gaming engine with a proprietary LCMS is demonstrated, building upon earlier work and demonstrating how this approach might be realized. In particular, how this method can support an intuitive-guided approach to learning is considered, whereby the learner is given the potential to explore a non-linear environment whilst scaffolding and blending provide guidance ensuring targeted learning objectives are met. Through an evaluation of the developed prototype with 32 students aged 14-16 across two Italian schools, a varied response from learners is observed, coupled with a positive reception from tutors. The study demonstrates that challenges remain in providing high-fidelity content in a classroom environment, particularly as an increasing gap in technology availability between leisure and school times emerges.

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Historically, recombinant membrane protein production has been a major challenge meaning that many fewer membrane protein structures have been published than those of soluble proteins. However, there has been a recent, almost exponential increase in the number of membrane protein structures being deposited in the Protein Data Bank. This suggests that empirical methods are now available that can ensure the required protein supply for these difficult targets. This review focuses on methods that are available for protein production in yeast, which is an important source of recombinant eukaryotic membrane proteins. We provide an overview of approaches to optimize the expression plasmid, host cell and culture conditions, as well as the extraction and purification of functional protein for crystallization trials in preparation for structural studies.

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troduct I on . An observational longitudinal study. P ur P ose . Assess the relationship between obstructive sleep apnoea (OSA) and DR cross-sectionally and longitudinally. M ethods . Adults with Type 2 diabetes mellitus (T2DM), who were re - cruited from a hospital-based diabetes clinic in the UK. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopa - thy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory study (Alice PDX, Philips Respironics, USA). DR was assessed us - ing retinal images between 2007 and 2012. Sight threatening diabetic retinopathy (STDR) was defined as presence of pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. r esults . 199 patients were included (57.3% (n=114) men, 47.7% (n=95) White Europeans). STDR and OSA prevalence were 38.7% (n=77) and 62.8% respectively. A t b A sel I ne . STR prevalence was higher in patients with OSA (OSA+) compared to those without OSA (OSA-) [48.8% n=61 vs. 21.6% n=16, p<0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95% CI 1.6-8.9, p=0.006), maculopathy (OR 4.5, 95% CI 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 95% CI 1.02-15.3, p=0.047). Mild and moderate to severe OSA were independently associated with STR and maculopathy and only moderate to severe OSA was associated with advanced DR following adjustment for con - founders. l ong I tud I n A lly . Over the follow-up period of (4.4±1 years), more OSA+ patients progressed from no or background DR to advanced DR (15.3% (n=17) vs. 3% (n=2), p=0.01). OSA was an independent pre - dictor of advanced DR development after adjustment for confounders (OR 6.6, 95% CI 1.2-35.1, p=0.03). OSA did not predict the develop - ment of maculopathy. c onclus I ons . OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Intervention - al studies are needed to assess the impact of OSA treatment on DR.

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Background and aims: Diabetic Retinopathy (DR) is a leading cause of blindness. OSA is associated with increased oxidative and nitrosative stress and endothelial dysfunction in patients with type 2 diabetes (T2DM). Hence, it is plausible that OSA can promote the development and progression of DR. Materials and methods: An observational longitudinal study in adults with T2DM. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopathy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory monitoring (Alice PDX, etc.). DR was assesses using retinal images between 2007 and 2012. Sight threatening retinopathy (STR) was defined as pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. Results: 199 patients were included (57.3% men, 47.7% White Europeans). STR and OSA prevalence were 38.7 % and 62.8% respectively. STR preva-lence was higher in patients with OSA (OSA+) compared to those with-out (OSA-) [48.8% vs. 21.6%, p <0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95%CI 1.6-8.9, p=0.006, maculopathy (OR 4.5, 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 1.02-15.3, p=0.047). Over 4.4±1 years, more OSA+ patients progressed from no or background DR to advanced DR (15.3% vs. 3%, p=0.01). OSA was an independent predictor of advanced DR development after adjustment (OR 6.6, 95%CI 1.2-35.1, p=0.03). OSA did not predict the development of maculopathy. Patients received continuous positive airway pressure treatment were less likely to develop advanced DR. Conclusion: OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on DR.Supported by: NIHR (UK) and The UK Novo Nordisk Research Foundation.

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Membrane proteins account for a third of the eukaryotic proteome, but are greatly under-represented in the Protein Data Bank. Unfortunately, recent technological advances in X-ray crystallography and EM cannot account for the poor solubility and stability of membrane protein samples. A limitation of conventional detergent-based methods is that detergent molecules destabilize membrane proteins, leading to their aggregation. The use of orthologues, mutants and fusion tags has helped improve protein stability, but at the expense of not working with the sequence of interest. Novel detergents such as glucose neopentyl glycol (GNG), maltose neopentyl glycol (MNG) and calixarene-based detergents can improve protein stability without compromising their solubilizing properties. Styrene maleic acid lipid particles (SMALPs) focus on retaining the native lipid bilayer of a membrane protein during purification and biophysical analysis. Overcoming bottlenecks in the membrane protein structural biology pipeline, primarily by maintaining protein stability, will facilitate the elucidation of many more membrane protein structures in the near future.

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The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society.

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Lepidocaryum tenue Mart. (Arecaceae) is a small, understory palm of terra firme forests of the western and central Amazon basin. Known as irapai, it is used for roof thatch by Amazonian peoples who collect its leaves from the wild and generate income from its fronds and articles fabricated from them. Increasing demand has caused local concern that populations are declining. Cultivation attempts have been unsuccessful. The purpose of this study was to investigate market conditions and quantify population dynamics and demographic responses of harvested and unharvested irapai growing near Iquitos, Peru. ^ Ethnobotanical research included participant surveys to determine movement of thatch tiles, called crisnejas, through Moronacocha Port. I also conducted a seed germination trial, and for four years studied five populations growing in communities with similar topography and soils but different land tenure and management strategies. Stage, survival, leaf production, and reproductive transitions were used to calculate ramet demographic rates and develop population projection matrices. ^ Weavers made an average of 20–30 crisnejas per day (90–130 leaves each), and earned US$0.09 to 0.70 each (US$1.80 to 21.00 per day). Average crisnejas per month sold per vendor was 2,955 with a profit range of US$0.05 to 0.32 per crisneja. Wholesalers worked with capital outlay from US$100 to 400, and an estimated ten to twenty vendors could be found at a given time. Consumers paid between US$0.23 to 1.20 per crisneja. Although differences in demographic rates by location existed, most were not significant enough to attribute to management. ^ After 60 months, mean seed germination rate was 19.5% in all media (37.9% in peat). Seedling survival was less than two percent after twelve months. Annual palm mortality was three percent, and occurred disproportionately in small (<50 cm) palms. Small palms grew more in height. Unharvested palms grew less than harvested palms. Large palms (≥50 cm) produced more leaves, were more likely to reproduce, and collectors harvested them more frequently. Reproductive potentials (sexual and asexual) were low. Population growth rates were greater than or not significantly different from 1.0, indicating populations maintained or increased in size. Current levels of irapai harvest appear sustainable. DNA analysis of stems and recruits is recommended to understand population composition and stage-specific asexual fecundity. ^

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In the framework of the global energy balance, the radiative energy exchanges between Sun, Earth and space are now accurately quantified from new satellite missions. Much less is known about the magnitude of the energy flows within the climate system and at the Earth surface, which cannot be directly measured by satellites. In addition to satellite observations, here we make extensive use of the growing number of surface observations to constrain the global energy balance not only from space, but also from the surface. We combine these observations with the latest modeling efforts performed for the 5th IPCC assessment report to infer best estimates for the global mean surface radiative components. Our analyses favor global mean downward surface solar and thermal radiation values near 185 and 342 Wm**-2, respectively, which are most compatible with surface observations. Combined with an estimated surface absorbed solar radiation and thermal emission of 161 Wm**-2 and 397 Wm**-2, respectively, this leaves 106 Wm**-2 of surface net radiation available for distribution amongst the non-radiative surface energy balance components. The climate models overestimate the downward solar and underestimate the downward thermal radiation, thereby simulating nevertheless an adequate global mean surface net radiation by error compensation. This also suggests that, globally, the simulated surface sensible and latent heat fluxes, around 20 and 85 Wm**-2 on average, state realistic values. The findings of this study are compiled into a new global energy balance diagram, which may be able to reconcile currently disputed inconsistencies between energy and water cycle estimates.

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Acknowledgements We thank Ruth B Murray for reviewing and editing this manuscript. We thank Joan B Soriano for his critical review and constructive comments. We thank Helga Mikkelsen and Alessandra Cifra for their assistance with manuscript editing and revision. Finally, we thank the Journal blind peer reviewers, whose suggestions and critical appraisal significantly improved our original submission. FUNDING This study was funded by Meda, Solna, Sweden. Data acquisition and analyses were funded by Meda. The study was conducted by Research in Real Life as an independent research organisation; Meda had no role in the conduct or reporting of the study.

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ACKNOWLEDGEMENTS This research is based upon work supported in part by the U.S. ARL and U.K. Ministry of Defense under Agreement Number W911NF-06-3-0001, and by the NSF under award CNS-1213140. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views or represent the official policies of the NSF, the U.S. ARL, the U.S. Government, the U.K. Ministry of Defense or the U.K. Government. The U.S. and U.K. Governments are authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation hereon.