Ligand Discrimination in Myoglobin from Linear-Scaling DFT+U

Myoglobin modulates the binding of diatomic molecules to its heme group via hydrogen-bonding and steric interactions with neighboring residues, and is an important benchmark for computational studies of biomolecules. We have performed calculations on the heme binding site and a significant proportion of the protein environment (more than 1000 atoms) using linear-scaling density functional theory and the DFT+U method to correct for self-interaction errors associated with localized 3d states. We confirm both the hydrogen-bonding nature of the discrimination effect (3.6 kcal/mol) and assumptions that the relative strain energy stored in the protein is low (less than 1 kcal/mol). Our calculations significantly widen the scope for tackling problems in drug design and enzymology, especially in cases where electron localization, allostery or long-ranged polarization influence ligand binding and reaction.Comment: 15 pages, 3 figures. Supplementary material 8 pages, 3 figures. This version matches that accepted for J. Phys. Chem. Lett. on 10th May 201

Renormalization of myoglobin-ligand binding energetics by quantum many-body effects

We carry out a first-principles atomistic study of the electronic mechanisms of ligand binding and discrimination in the myoglobin protein. Electronic correlation effects are taken into account using one of the most advanced methods currently available, namely a linear-scaling density functional theory (DFT) approach wherein the treatment of localized iron 3d electrons is further refined using dynamical mean-field theory (DMFT). This combination of methods explicitly accounts for dynamical and multi-reference quantum physics, such as valence and spin fluctuations, of the 3d electrons, whilst treating a significant proportion of the protein (more than 1000 atoms) with density functional theory. The computed electronic structure of the myoglobin complexes and the nature of the Fe-O2 bonding are validated against experimental spectroscopic observables. We elucidate and solve a long standing problem related to the quantum-mechanical description of the respiration process, namely that DFT calculations predict a strong imbalance between O2 and CO binding, favoring the latter to an unphysically large extent. We show that the explicit inclusion of many body-effects induced by the Hund's coupling mechanism results in the correct prediction of similar binding energies for oxy- and carbonmonoxymyoglobin.Comment: 7 pages, 5 figures. Accepted for publication in the Proceedings of the National Academy of Sciences of the United States of America (2014). For the published article see http://www.pnas.org/content/early/2014/04/09/1322966111.abstrac

Prenatal dexamethasone ‘programmes’ hypotension, but stress-induced hypertension in adult offspring

Low birth weight in humans is predictive of hypertension in adult life. Although the mechanisms underlying this link remain unknown, fetal overexposure to glucocorticoids has been implicated. We previously showed that prenatal dexamethasone (DEX) exposure in the rat lowers birth weight and programmes adult hypertension. The current study aimed to further investigate the nature of this hypertension and to elucidate its origins. Unlike previous studies, we assessed offspring blood pressure (BP) with radiotelemetry, which is unaffected by stress artefacts of measurement. We show that prenatal DEX during the last week of pregnancy results in offspring of low birth weight (14% reduction) that have lower basal BP in adulthood (∼4–8 mmHg lower); with the commonly expected hypertensive phenotype only being noted when these offspring are subjected to even mild disturbance or a more severe stressor (up to 30 mmHg higher than controls). Moreover, DEX-treated offspring sustain their stress-induced hypertension for longer. Promotion of systemic catecholamine release (amphetamine) induced a significantly greater rise of BP in the DEX animals (77% increase) over that observed in the vehicle controls. Additionally, we demonstrate that the isolated mesenteric vasculature of DEX-treated offspring display greater sensitivity to noradrenaline and other vasoconstrictors. We therefore conclude that altered sympathetic responses mediate the stress-induced hypertension associated with prenatal DEX programming

Scrubbing up: multi-scale investigation of woody encroachment in a southern African savannah

Changes in the extent of woody vegetation represent a major conservation question in many savannah systems around the globe. To address the problem of the current lack of broad-scale cost-effective tools for land cover monitoring in complex savannah environments, we use a multi-scale approach to quantifying vegetation change in Kruger National Park (KNP), South Africa. We test whether medium spatial resolution satellite data (Landsat, existing back to the 1970s), which have pixel sizes larger than typical vegetation patches, can nevertheless capture the thematic detail required to detect woody encroachment in savannahs. We quantify vegetation change over a 13-year period in KNP, examine the changes that have occurred, assess the drivers of these changes, and compare appropriate remote sensing data sources for monitoring change. We generate land cover maps for three areas of southern KNP using very high resolution (VHR) and medium resolution satellite sensor imagery from February 2001 to 2014. Considerable land cover change has occurred, with large increases in shrubs replacing both trees and grassland. Examination of exclosure areas and potential environmental driver data suggests two mechanisms: elephant herbivory removing trees and at least one separate mechanism responsible for conversion of grassland to shrubs, theorised to be increasing atmospheric CO2. Thus, the combination of these mechanisms causes the novel two-directional shrub encroachment that we observe (tree loss and grassland conversion). Multi-scale comparison of classifications indicates that although spatial detail is lost when using medium resolution rather than VHR imagery for land cover classification (e.g., Landsat imagery cannot readily distinguish between tree and shrub classes, while VHR imagery can), the thematic detail contained within both VHR and medium resolution classifications is remarkably congruent. This suggests that medium resolution imagery contains sufficient thematic information for most broad-scale land cover monitoring requirements in heterogeneous savannahs, while having the benefits of being cost-free and providing a longer historical archive of data than VHR sources. We conclude that monitoring of broad-scale land cover change using remote sensing has considerable potential as a cost-effective tool for both better informing land management practitioners, and for monitoring the future landscape-scale impacts of management policies in savannahs

Patterns of psychotropic prescribing and polypharmacy in older hospitalized patients in Ireland: the influence of dementia on prescribing

Neuropsychiatric Symptoms (NPS) are ubiquitous in dementia and are often treated pharmacologically. The objectives of this study were to describe the use of psychotropic, anti-cholinergic, and deliriogenic medications and to identify the prevalence of polypharmacy and psychotropic polypharmacy, among older hospitalized patients in Ireland, with and without dementia. All older patients (≥ 70 years old) that had elective or emergency admissions to six Irish study hospitals were eligible for inclusion in a longitudinal observational study. Of 676 eligible patients, 598 patients were recruited and diagnosed as having dementia, or not, by medical experts. These 598 patients were assessed for delirium, medication use, co-morbidity, functional ability, and nutritional status. We conducted a retrospective cross-sectional analysis of medication data on admission for 583/598 patients with complete medication data, and controlled for age, sex, and co-morbidity. Of 149 patients diagnosed with dementia, only 53 had a previous diagnosis. At hospital admission, 458/583 patients experienced polypharmacy (≥ 5 medications). People with dementia (PwD) were significantly more likely to be prescribed at least one psychotropic medication than patients without dementia (99/147 vs. 182/436; p < 0.001). PwD were also more likely to experience psychotropic polypharmacy (≥ two psychotropics) than those without dementia (54/147 vs. 61/436; p < 0.001). There were no significant differences in the prescribing patterns of anti-cholinergics (23/147 vs. 42/436; p = 0.18) or deliriogenics (79/147 vs. 235/436; p = 0.62). Polypharmacy and psychotropic drug use is highly prevalent in older Irish hospitalized patients, especially in PwD. Hospital admission presents an ideal time for medication reviews in PwD

Carbon nanocage supported synthesis of V2O5 nanorods and V2O5/TiO2 nanocomposites for Li-ion batteries

We present the facile synthesis of crystalline V2O5 nanorods and V2O5/TiO2 nanocomposites structures by a carbon nanocage (CNC)-assisted growth process, using vanadium triisopropoxide oxide and titanium isopropoxide precursors in air at 500 [degree]C. The diameters of the resultant V2O5 nanorods ranged between [similar]10 and 70 nm, while the crystalline V2O5/TiO2 nanocomposite structures adopted a unique morphology, due to both crystallisation and templating processes, with V2O5 adopting small-diameter nanowire and nanorod morphologies surrounded by sub-30 nm TiO2 nanoparticles. The V2O5 nanorods and V2O5/TiO2 nanocomposites were characterised by electron microscopy and X-ray diffraction techniques and subsequently reviewed as positive Li-ion electrodes. The phase-pure V2O5 nanorod structures exhibited appreciable Li+ storage properties over the potential range of 2.0-4.0 V vs. Li/Li+, displaying capacities of up to 288 mA h g-1 with appreciable cyclic behaviour at test rates of up to [similar]1 C. The crystalline V2O5/TiO2 nanocomposite structures displayed similar Li+ storage properties, however, increasing molar fractions of TiO2 led to a decline in the overall capacity versus the single-phase V2O5 counterparts. Interestingly, the Li+ insertion behaviour of the V2O5/TiO2 nanocomposite displayed character more-typical of amorphous V2O5, which was ascribed to a structural buffering effect of the inactive TiO2 phase

‘Why so high?’ Examining discrepancies between the Sr biosphere map and archaeological tooth data from the Peak District, England

The analysis of 87Sr/86Sr isotope ratios in human and nonhuman tooth enamel is used worldwide for archaeological and forensic purposes to establish if an individual is likely to have grown up in the area from which their remains were excavated. The English Peak District has produced an unusually high proportion of archaeological humans who, based on Sr isotope ratios, appear to have come from elsewhere. We have used modern plant samples from the Peak to show that the current understanding of Sr isotope ratios for this area is incomplete – we found many plant samples growing on gritstone sediments had higher Sr values than would be expected based on the current literature. In addition we demonstrated that the taxonomy of the plant does not appear to affect the Sr isotope values (we also found that mycorrhizal type did not determine Sr isotope values in these plants), rather it is the substrate on which it is growing that is important. In terms of human movement, our work suggests it is likely that many archaeological individuals found in the Peak District are indeed local, rather than migrants. It is also possible that the expansion of blanket peat in the Peak has over time reduced the amount of Sr entering the food chain from mineral soils, reducing the radiogenic Sr isotope values in more recent teeth. While our case study is the Peak District, our findings have implications for anomalously high archaeological 87Sr/86Sr isotope values in other upland regions with similar geologies and blanket peats

A European training system in cardiothoracic surgery: is it time?

OBJECTIVE Training in cardiothoracic surgery across Europe remains diverse and variable despite the ever closer integration of European countries at all levels and in all areas of life. Coupled with the increasing ease of movement across Europe, the need for uniform training programmes has arisen to allow for equivalent accreditation and certification. METHODS We review the current training paradigms within the specialty across the world and in Europe and also explore the concept of competence. RESULTS There are diverse training systems across the world and in Europe in particular. Competence-based training is the new model of training; however, competence remains difficult to define and measure. We propose a European Training Programme in Cardiothoracic Surgery that aims to standardize training across the European countries. CONCLUSIONS The difficulties in unifying training across Europe are numerous, but it is time to implement a European Training System in Cardiothoracic Surgery that will deliver a competence-based curriculu

Double valve replacement for acute spontaneous left chordal rupture secondary to chronic aortic incompetence

A 54 years old male with undiagnosed chronic calcific degenerative aortic valve incompetence presented with acute left anterior chordae tendinae rupture resulting in severe left heart failure and cardiogenic shock. He was successfully treated with emergency double valve replacement using mechanical valves. The pathogenesis of acute rupture of the anterior chordae tendinae, without any evidence of infective endocarditis or ischemic heart disease seems to have been attrition of the subvalvular mitral apparatus by the chronic regurgitant jet of aortic incompetence with chronic volume overload. We review the literature with specific focus on the occurrence of this unusual event