Excavations at the Jewry Wall Site, Leicester

This is an account of the excavations at the Jewry Wall site in Leicester, Leicestershire, England, undertaken between 1936 and 1939. Included are descriptions of human remains and artefacts such as pottery, coins, buildings and metalwork, together with an account of the methodology used to unearth these

A performance edition of thirty instructive and melodic exercises for French horn by Vincenz Ranieri

"The primary purpose of this study was to edit and publish a performance edition of Thirty Instructive and Melodic Exercises for French Horn by Vincenz Ranieri. Corrections were made of typographical note errors and rhythms, unification of parallel stylistic markings, and modernization in the appearance and notation of the etude book. Each etude was compared to a list of inconsistencies found throughout the etude book and corrected to unify compositional style. Range of the rudimental exercises preceding each etude was corrected to encompass the corresponding etude range. Phrases markings, slurs, articulation markings, dynamic markings, and ornamentations were standardized. Typographical errors including notes, rhythms, and stylistic markings were corrected. Aesthetic changes and additions were made to note beaming, courtesy accidentals, excessive articulation markings, and overall layout and format. The secondary purpose was to discover biographical information about the composer and historical information about the etude book. Biographical information about the composer and history about the etude book was researched through general literature survey and inquiries made to horn historians, performers, and teachers. Specific information about Vincenz Ranieri including birth and death dates, life, and profession were sought, as well as purpose, inspiration, and date of composition for his etude book. The outcome of this project is to publish the performance edition in the United States in hopes that the etude book will become an accessible, reputable, and valuable addition to horn literature."--Abstract from author supplied metadata

Report of the Link Resolver Implementation Team

The Link Resolver Implementation Team was charged in March 2016 with carrying out the recommendations of the Link Resolver Investigation Team (http://hdl.handle.net/2027.42/117361), which were to re-launch the MGet It link resolver service as a locally-hosted application using the existing 360 Link knowledge base and the Umlaut open-source software. Specifically, the Implementation Team was asked to: 1) Design a user interface using Umlaut and the 360 Link API; 2) Select and prioritize added services in the link resolver menu interface; 3) Determine what, if anything, should be part of a report-a-problem link and implement corresponding workflows; and 4) Determine in which circumstances the link resolver menu page should appear for which kinds of users. This report outlines our decisions on these three points, details user studies to design the interface, and describes the roll-out process. The new MGet It service was released as a limited beta for library staff on September 14, 2016. After a period of review and feedback from library staff, and subsequent adjustments to the interface, the new interface replaced the native 360 Link interface on Monday, October 17, 2016.http://deepblue.lib.umich.edu/bitstream/2027.42/135723/1/link resolver implementation team final report.pdfDescription of link resolver implementation team final report.pdf : Final Repor

Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Modelling the molecular mechanisms of ageing

This document is the Accepted Manuscript version of a published work that appeared in final form in Bioscience reports. To access the final edited and published work see http://www.bioscirep.org/content/37/1/BSR20160177.The ageing process is driven at the cellular level by random molecular damage which slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the ageing process. The complexity of the ageing process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards, and discusses many specific examples of models which have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p