Allosteric Analysis of Glucocorticoid Receptor-DNA Interface Induced by Cyclic Py-Im Polyamide: A Molecular Dynamics Simulation Study

Background: It has been extensively developed in recent years that cell-permeable small molecules, such as polyamide, can be programmed to disrupt transcription factor-DNA interfaces and can silence aberrant gene expression. For example, cyclic pyrrole-imidazole polyamide that competes with glucocorticoid receptor (GR) for binding to glucocorticoid response elements could be expected to affect the DNA dependent binding by interfering with the protein-DNA interface. However, how such small molecules affect the transcription factor-DNA interfaces and gene regulatory pathways through DNA structure distortion is not fully understood so far. Methodology/Principal Findings: In the present work, we have constructed some models, especially the ternary model of polyamides+DNA+GR DNA-binding domain (GRDBD) dimer, and carried out molecular dynamics simulations and free energy calculations for them to address how polyamide molecules disrupt the GRDBD and DNA interface when polyamide and protein bind at the same sites on opposite grooves of DNA. Conclusions/Significance: We found that the cyclic polyamide binding in minor groove of DNA can induce a large structural perturbation of DNA, i.e. a.4 A ˚ widening of the DNA minor groove and a compression of the major groove by more than 4A ˚ as compared with the DNA molecule in the GRDBD dimer+DNA complex. Further investigations for the ternary system of polyamides+DNA+GRDBD dimer and the binary system of allosteric DNA+GRDBD dimer revealed that the compression o

Transcatheter Aortic Valve Replacement Using a Self-Expanding Bioprosthesis in Patients With Severe Aortic Stenosis at Extreme Risk for Surgery

Objectives This study sought to evaluate the safety and efficacy of the CoreValve transcatheter heart valve (THV) for the treatment of severe aortic stenosis in patients at extreme risk for surgery. Background Untreated severe aortic stenosis is a progressive disease with a poor prognosis. Transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis is a potentially effective therapy. Methods We performed a prospective, multicenter, nonrandomized investigation evaluating the safety and efficacy of self-expanding TAVR in patients with symptomatic severe aortic stenosis with prohibitive risks for surgery. The primary endpoint was a composite of all-cause mortality or major stroke at 12 months, which was compared with a pre-specified objective performance goal (OPG). Results A total of 41 sites in the United States recruited 506 patients, of whom 489 underwent attempted treatment with the CoreValve THV. The rate of all-cause mortality or major stroke at 12 months was 26.0% (upper 2-sided 95% confidence bound: 29.9%) versus 43.0% with the OPG (p < 0.0001). Individual 30-day and 12-month events included all-cause mortality (8.4% and 24.3%, respectively) and major stroke (2.3% and 4.3%, respectively). Procedural events at 30 days included life-threatening/disabling bleeding (12.7%), major vascular complications (8.2%), and need for permanent pacemaker placement (21.6%). The frequency of moderate or severe paravalvular aortic regurgitation was lower 12 months after self-expanding TAVR (4.2%) than at discharge (10.7%; p = 0.004 for paired analysis). Conclusions TAVR with a self-expanding bioprosthesis was safe and effective in patients with symptomatic severe aortic stenosis at prohibitive risk for surgical valve replacement. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902) (C) 2014 by the American College of Cardiology Foundatio

Rethinking the experiences and entitlements of people with dementia: Taking vision into account

A large proportion of people with dementia will have some kind of problem with their vision. Such problems may be the result of disturbances to low-level visual functions such as contrast sensitivity, colour vision, or visual acuity, for example. In addition, dementia can have detrimental effects on higher cognitive aspects of visual function such as visual attention, spatial localization, object recognition, facial recognition, and visual memory. The underlying cause of these visual problems is likely to be a result of a combination of a number of different factors (it is recognized that medication can also affect vision, but this will not be discussed here): (1) the direct patho-physiological effects of dementia on the brain and visual system, (2) the losses in visual function that occur as part and parcel of the normal ageing process, and (3) the losses in visual function that are a consequence of ocular diseases, such as age-related macular degeneration, glaucoma, or cataracts, which are more common in older people.In this article, the likely prevalence of visual problems among people with dementia is highlighted and the ways in which dementia, ageing, and common eye conditions affect a person's vision are briefly described. The main aim of this article is to increase knowledge of visual issues and, in particular, eye health, and to argue that people with dementia are entitled to have their visual experiences and sight problems fully recognized and eye sight routinely tested.A second aim of this article is to report on the findings of a small-scale scoping study commissioned by Thomas Pocklington Trust - a charity for people with sight loss. Drawing on work completed for this study, the article explores the extent to which existing models of dementia care, such as Kitwood's enriched model, and best practice guidelines take account of the visual experiences and problems that people with dementia have. Some of the shortcomings of these models are identified and the general lack of awareness in the best practice literature is highlighted. Reporting on this study provides further context for arguing that vision must be taken into account when working with people with dementia. Finally, the article concludes with some recommendations for practice development, including a call for the development of an online practice development network. <br/