Eastnor Castle, Herefordshire

In der europäischen Baukultur stehen Schlösser, Burgen und Country Houses für politische und soziale Macht. Die Gestaltung sowie Funktion dieser Bauten und deren Umgestaltung lassen Schlüsse über die jeweiligen Bauherren und Architekten zu, so dass spezifische und allgemeine Ansprüche der Gesellschaft für die jeweiligen Zeitschichten verdeutlicht werden. Heute ist das Sichern des Fortbestehens dieser meist denkmalgeschützten Bauten in Zeiten von staatlichen Mittelkürzungen und des Klimawandels schwierig. Für diese Ausgangssituation ist ein autarkes Denkmal, das sein Bestehen aus sich selbst heraus sichert, ohne seiner Substanz zu schaden, der wertvollste Lösungsansatz. Ein solches Beispiel wird in der Dissertation in seiner Gesamtheit analysiert. Anhand der Auswertung verschiedener Quellen wird betrachtet, in welchen Schritten die Eigenständigkeit von Eastnor Castle, Herefordshire, entstand. Die Basis für die Analyse beschreibt der Denkmalwert des Country House, der sich aus einer baugeschichtlichen Untersuchung und architekturhistorischen Einordnung ergibt. Den historischen Wert erhält das von Historic England als Grade I eingestufte Baudenkmal aus den mannigfaltigen Zeugnissen der Familien Cocks, Somers und Somers-Cocks, die diesen Bau über mehrere Jahrhunderte prägen. Darüber hinaus stellt Eastnor Castle ein frühes Werk des Architekten Robert Smirke dar, der im Verlauf seiner Karriere viele architektonisch einflussreiche Bauten entwirft. Ferner besitzt Eastnor Castle einen künstlerischen Wert, da es als kompletter Neubau der Regency Ära durchgängig im Norman Style entworfen und aus Bauten wie Lowther Castle, Cumbria, und Warwick Castle, Warwickshire, entwickelt wird. Ähnliche Country Houses als reine Ausprägung dieser Baustilrichtung existieren nur wenige wie beispielsweise Penrhyn Castle, Gwynedd. Eastnor Castle besitzt ferner Raum- und Mobiliargestaltungen im Norman Style sowie das sehr gut erhaltene Interieur des Gothic Drawing Room, welches A.W.N. Pugin am Ende seiner Architekturkarriere entwirft. Diese Raumgestaltung ist eines seiner am besten erhaltenen Interieurs, das gestalterisch für die internationale Architekturbewegung des Puginism steht. Darüber hinaus besitzt Eastnor Castle eine technikgeschichtliche Bedeutung, da Robert Smirke einerseits neue Baumaterialen wie Eisenträger verwendet und es andererseits in einem neuen Bauablauf errichtet. Außerdem prägen Eastnor Castle und sein Vorgängerbau Castle Ditch die Region der Malvern Hills nachhaltig. In einem zweiten Schritt untersucht die Arbeit die heutige Nutzung des Denkmals und wertet sie aus. Eine wichtige Rolle hierbei spielt das bestehende Funktionsdreieck aus Wohnhaus, Denkmal und Event-Stätte. Das Ausbalancieren dieses Dreiecks hat oberste Priorität und bildet die Grundlage für das autarke Fortbestehen des Denkmals. Einzelne Erkenntnisse dieser Untersuchung können schließlich als Resultate der Arbeit verallgemeinert und übertragen werden.Castles and country houses represent political and social power in European building culture. Their design, function and transformation enable conclusions about the owners as well as their architects, leading to conclusions about specific and general expectations of society during a time period. Today the continued existence of these mostly listed buildings in times of funding cuts and climate change is difficult. For this initial situation a self-supporting monument, which secures its survival on its own, is the most valuable solution approach. Such an example is analysed as a whole in the dissertation. The evaluation of different sources shows, how the independence of Eastnor Castle, Herefordshire, developed. The basis of this analysis are the different monumental values of the country house, which arise out of the study of the building’s history and its architectural classification. The grade I listed monument gains its historical value from diverse testimonials of the Cocks, Somers and Somers-Cocks families, who have shaped the building during several centuries. Further Eastnor Castle is an early work of the architect Robert Smirke, who designed several architectonically influential buildings during his career. In addition, the country house has an artistical value, since it was designed as a new building during the regency era in a consistent Norman style and was developed from Lowther Castle, Cumbria, as well as Warwick Castle, Warwickshire. Only a few country houses exist as pure display of this building style as for example Penrhyn Castle, Gwynedd. Additionally, Eastnor Castle has interior decorations and furniture in the Norman style along with the very well retained interior of the gothic drawing room, which was designed by A.W.N. Pugin near the end of his career. This room is one of his best obtained interiors, which represents the international architectural movement of puginism. Further Eastnor Castle has a value of technological history, since Smirke firstly used materials like iron girders and secondly builds the country house in a new construction procedure. Next to these values Eastnor Castle and its predecessor Castle Ditch influence the region of the Malvern Hills in a sustainable manner by visual axes and pathways. In a second step the dissertation continues to analyse the country houses utilization. An important aspect is described by a triangle created by its functions of residence, monument and venue. The equilibration of this triangle has first priority and provides the basis for the self-supporting and substance sustaining existence of the monument. Lastly individual aspects of this study are generalized and conveyed to other historic monuments

Phylogenetic distribution and membrane topology of the LytR-CpsA-Psr protein family

BACKGROUND: The bacterial cell wall is the target of many antibiotics and cell envelope constituents are critical to host-pathogen interactions. To combat resistance development and virulence, a detailed knowledge of the individual factors involved is essential. Members of the LytR-CpsA-Psr family of cell envelope-associated attenuators are relevant for beta-lactam resistance, biofilm formation, and stress tolerance, and they are suggested to play a role in cell wall maintenance. However, their precise function is still unknown. This study addresses the occurrence as well as sequence-based characteristics of the LytR-CpsA-Psr proteins. RESULTS: A comprehensive list of LytR-CpsA-Psr proteins was established, and their phylogenetic distribution and clustering into subgroups was determined. LytR-CpsA-Psr proteins were present in all Gram-positive organisms, except for the cell wall-deficient Mollicutes and one strain of the Clostridiales. In contrast, the majority of Gram-negatives did not contain LytR-CpsA-Psr family members. Despite high sequence divergence, the LytR-CpsA-Psr domains of different subclusters shared a highly similar, predicted mixed alpha/beta-structure, and conserved charged residues. PhoA fusion experiments, using MsrR of Staphylococcus aureus, confirmed membrane topology predictions and extracellular location of its LytR-CpsA-Psr domain. CONCLUSIONS: The LytR-CpsA-Psr domain is unique to bacteria. The presence of diverse subgroups within the LytR-CpsA-Psr family might indicate functional differences, and could explain variations in phenotypes of respective mutants reported. The identified conserved structural elements and amino acids are likely to be important for the function of the domain and will help to guide future studies of the LytR-CpsA-Psr proteins

MRSA Causing Infections in Hospitals in Greater Metropolitan New York: Major Shift in the Dominant Clonal Type Between 1996 and 2014

A surveillance study in 1996 identified the USA100 clone (ST5/SCCmecII)-also known as the New York/Japan clone-as the most prevalent MRSA causing infections in 12 New York City hospitals. Here we update the epidemiology of MRSA in seven of the same hospitals eighteen years later in 2013/14. Most of the current MRSA isolates (78 of 121) belonged to the MRSA clone USA300 (CC8/SCCmecIV) but the USA100 clone-dominant in the 1996 survey-still remained the second most frequent MRSA (25 of the 121 isolates) causing 32% of blood stream infections. The USA300 clone was most common in skin and soft tissue infections (SSTIs) and was associated with 84.5% of SSTIs compared to 5% caused by the USA100 clone. Our data indicate that by 2013/14, the USA300 clone replaced the New York/Japan clone as the most frequent cause of MRSA infections in hospitals in Metropolitan New York. In parallel with this shift in the clonal type of MRSA, there was also a striking change in the types of MRSA infections from 1996 to 2014

Effect of Succimer on Growth of Preschool Children with Moderate Blood Lead Levels.

Growth deficits associated with lead exposure might be ameliorated by chelation. We examined the effect of succimer on growth in 780 children 12-33 months old who had blood lead levels of 20-44 microg/dL and were randomized to receive up to three 26-day courses of succimer or placebo in a multicenter, double-blind trial. The difference in changes in weight and height between succimer and placebo groups at 1-34 months was calculated by fitting cubic splines. The difference in height change in children on succimer compared with placebo was -0.27 cm [95% confidence interval (95% CI), -0.42 to -0.11] from baseline to 9 months, when 99% of children had completed treatment, and -0.43 cm (95% CI, -0.77 to -0.09) during 34 months of follow-up. Similar differences in weight gain were not statistically significant. Although succimer lowers blood lead in moderately lead-poisoned children, it does not have a beneficial effect on growth and may have an adverse effect.Other Research Uni

Developing a clinical prediction rule for repeated consultations with functional somatic symptoms in primary care:A cohort study

OBJECTIVES: Patients who present in primary care with chronic functional somatic symptoms (FSS) have reduced quality of life and increased health care costs. Recognising these early is a challenge. The aim is to develop and internally validate a clinical prediction rule for repeated consultations with FSS. DESIGN AND SETTING: Records from the longitudinal population-based ('Lifelines') cohort study were linked to electronic health records from general practitioners (GPs). PARTICIPANTS: We included patients consulting a GP with FSS within 1 year after baseline assessment in the Lifelines cohort. OUTCOME MEASURES: The outcome is repeated consultations with FSS, defined as ≥3 extra consultations for FSS within 1 year after the first consultation. Multivariable logistic regression, with bootstrapping for internal validation, was used to develop a risk prediction model from 14 literature-based predictors. Model discrimination, calibration and diagnostic accuracy were assessed. RESULTS: 18 810 participants were identified by database linkage, of whom 2650 consulted a GP with FSS and 297 (11%) had ≥3 extra consultations. In the final multivariable model, older age, female sex, lack of healthy activity, presence of generalised anxiety disorder and higher number of GP consultations in the last year predicted repeated consultations. Discrimination after internal validation was 0.64 with a calibration slope of 0.95. The positive predictive value of patients with high scores on the model was 0.37 (0.29-0.47). CONCLUSIONS: Several theoretically suggested predisposing and precipitating predictors, including neuroticism and stressful life events, surprisingly failed to contribute to our final model. Moreover, this model mostly included general predictors of increased risk of repeated consultations among patients with FSS. The model discrimination and positive predictive values were insufficient and preclude clinical implementation

MsrR contributes to cell surface characteristics and virulence in Staphylococcus aureus

MsrR, a factor contributing to methicillin resistance in Staphylococcus aureus, belongs to the LytR-CpsA-Psr family of cell envelope-associated proteins. Deletion of msrR increased cell size and aggregation, and altered envelope properties, leading to a temporary reduction in cell surface hydrophobicity, diminished colony-spreading ability, and an increased susceptibility to Congo red. The reduced phosphorus content of purified cell walls of the msrR mutant suggested a reduction in wall teichoic acids, which may explain some of the observed phenotypes. Microarray analysis of the msrR deletion mutant revealed only minor changes in the global transcriptome, suggesting that MsrR has structural rather than regulatory functions. Importantly, virulence of the msrR mutant was decreased in a nematode-killing assay as well as in rat experimental endocarditis. MsrR is therefore likely to play a role in cell envelope maintenance, cell separation, and pathogenicity of S. aureu

Living with an imperfect cell wall: compensation of femAB inactivation in Staphylococcus aureus

Background: Synthesis of the Staphylococcus aureus peptidoglycan pentaglycine interpeptide bridge is catalyzed by the nonribosomal peptidyl transferases FemX, FemA and FemB. Inactivation of the femAB operon reduces the interpeptide to a monoglycine, leading to a poorly crosslinked peptidoglycan. femAB mutants show a reduced growth rate and are hypersusceptible to virtually all antibiotics, including methicillin, making FemAB a potential target to restore β-lactam susceptibility in methicillin-resistant S. aureus (MRSA). Cis-complementation with wild type femAB only restores synthesis of the pentaglycine interpeptide and methicillin resistance, but the growth rate remains low. This study characterizes the adaptations that ensured survival of the cells after femAB inactivation. Results: In addition to slow growth, the cis-complemented femAB mutant showed temperature sensitivity and a higher methicillin resistance than the wild type. Transcriptional profiling paired with reporter metabolite analysis revealed multiple changes in the global transcriptome. A number of transporters for sugars, glycerol, and glycine betaine, some of which could serve as osmoprotectants, were upregulated. Striking differences were found in the transcription of several genes involved in nitrogen metabolism and the arginine-deiminase pathway, an alternative for ATP production. In addition, microarray data indicated enhanced expression of virulence factors that correlated with premature expression of the global regulators sae, sarA, and agr. Conclusion: Survival under conditions preventing normal cell wall formation triggered complex adaptations that incurred a fitness cost, showing the remarkable flexibility of S. aureus to circumvent cell wall damage. Potential FemAB inhibitors would have to be used in combination with other antibiotics to prevent selection of resistant survivors

Curating gene sets: challenges and opportunities for integrative analysis.

Genomic data interpretation often requires analyses that move from a gene-by-gene focus to a focus on sets of genes that are associated with biological phenomena such as molecular processes, phenotypes, diseases, drug interactions or environmental conditions. Unique challenges exist in the curation of gene sets beyond the challenges in curation of individual genes. Here we highlight a literature curation workflow whereby gene sets are curated from peer-reviewed published data into GeneWeaver (GW), a data repository and analysis platform. We describe the system features that allow for a flexible yet precise curation procedure. We illustrate the value of curation by gene sets through analysis of independently curated sets that relate to the integrated stress response, showing that sets curated from independent sources all share significant Jaccard similarity. A suite of reproducible analysis tools is provided in GW as services to carry out interactive functional investigation of user-submitted gene sets within the context of over 150 000 gene sets constructed from publicly available resources and published gene lists. A curation interface supports the ability of users to design and maintain curation workflows of gene sets, including assigning, reviewing and releasing gene sets within a curation project context