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VanA-type resistance to glycopeptide antibiotics in clinical enterococci is regulated by the VanS A R A two-component signal transduction system. The nature of the molecular ligand that is recognised by the VanS A sensory component has not hitherto been identified. Here we employ purified, intact and active VanS A membrane protein (henceforth referred to as VanS) in analytical ultracentrifugation experiments to study VanS oligomeric state and conformation in the absence and presence of vancomycin. A combination of sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge (SEDFIT, SEDFIT-MSTAR and MULTISIG analysis) showed that VanS in the absence of the ligand is almost entirely monomeric (molar mass M  = 45.7 kDa) in dilute aqueous solution with a trace amount of high molar mass material ( M  ~ 200 kDa). The sedimentation coefficient s suggests the monomer adopts an extended conformation in aqueous solution with an equivalent aspect ratio of ~(12 ± 2). In the presence of vancomycin over a 33% increase in the sedimentation coefficient is observed with the appearance of additional higher s components, demonstrating an interaction, an observation consistent with our circular dichroism measurements. The two possible causes of this increase in s – either a ligand induced dimerization and/or compaction of the monomer are considered.

The novel vertical sample chamber, developed at the B23 beamline for synchrotron radiation circular dichroism (SRCD), has enabled the Diamond User community to conduct different types of experiments from high throughput CD of protein and DNA folding using 96-well multiplates to CD imaging at high spatial resolution. Here, we present the application of CD imaging to large areas of achiral polymer PVA films doped with D-dopa to assess the chiral homogeneity of the film preparation with potential antimicrobial property. Synopsis: CDi application of Diamond B23 SRCD beamline.

Kinetochores in the parasite Leishmania and related kinetoplastids appear to be unique amongst eukaryotes and contain protein kinases as core components. Using the kinetochore kinases KKT2, KKT3 and CLK2 as baits, we developed a BirA* proximity biotinylation methodology optimised for sensitivity, XL-BioID, to investigate the composition and function of the Leishmania kinetochore. We could detect many of the predicted components and also discovered two novel kinetochore proteins, KKT24 and KKT26. Using KKT3 tagged with a fast-acting promiscuous biotin ligase variant, we took proximity biotinylation snapshots of the kinetochore in synchronised parasites. To quantify proximal phosphosites at the kinetochore as the parasite progressed through the cell cycle, we further developed a spatially referenced proximity phosphoproteomics approach. This revealed a group of phosphosites at the kinetochore that were highly dynamic during kinetochore assembly. We show that the kinase inhibitor AB1 targets CLK1/CLK2 (KKT10/KKT19) in Leishmania leading to defective cytokinesis. Using AB1 to uncover CLK1/CLK2 driven signalling pathways important for kinetochore function at G2/M, we found a set of 16 inhibitor responsive kinetochore-proximal phosphosites. Our results exploit new proximity labelling approaches to provide a direct analysis of the Leishmania kinetochore, which is emerging as a promising drug target. Combination of proximity biotinylation and protein cross-linking allows proximity phosphoproteomics of the kinetochore in Leishmania parasites during the cell cycle and captures perturbations at the kinetochore after treatment with a protein kinase inhibitor.

Social media can lead to rejection, cyber-bullying victimisation, and cyber-aggression, and these experiences are not fully understood as experienced by autistic adults. To investigate this, 78 autistic adults completed self-report measures of social media use, cyber-bullying victimisation, cyber-aggression, and self-esteem. High levels of social media use were found to be associated with an increased risk of cyber-victimisation; whereas self-esteem was positively correlated with feelings of belonging to an online community and negatively correlated with feelings of being ignored on social network sites and chat rooms. Future studies are needed to further investigate the experience of cyber-bullying victimisation of autistic adults.

An encompassing, comparative study of all major cases of ethnic cleansing in modern Europe and contains case studies from global history. Not only covers Eastern Europe, but also the motivation of western countries and statesmen and their involvement in large scale population removals. The book is based on literature and sources collected from all the countries that were affected by ethnic cleansing. Explains the motivation of the major agents and perpetrators of ethnic cleansing.

Background and Objective N , N -dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects. Methods The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability. Results In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9–21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9–12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight. Conclusion This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD. Clinical Trial Registration Registered on ClinicalTrials.gov (NCT04673383).

This volume, a revised and extended version of two well-reviewed books published in German and Czech, explores the social and political background to this “opera mania” in nineteenth century Central Europe. After tracing the major trends in the opera history of the period, including the emergence of national genres of opera and its various social functions and cultural meanings, the author contrasts the histories of the major houses in Dresden (a court theater), Lemberg (a theater built and sponsored by aristocrats), and Prague (a civic institution). Beyond the operatic institutions and their key stage productions, composers such as Carl Maria von Weber, Richard Wagner, Bedřich Smetana, Stanisław Moniuszko, Antonín Dvořák, and Richard Strauss are put in their social and political contexts. The concluding chapter, bringing together the different leitmotifs of social and cultural history explored in the rest of the book, explains the specificities of opera life in Central Europe within a wider European and global framework.

ObjectiveThis study describes the baseline clinical characteristics, predictors of successful extubation at referring hospitals and short-term outcomes of children intubated for status epilepticus and referred to United Kingdom (UK) paediatric critical care transport teams (PCCTs).DesignMulticentre audit with case–control analysis, conducted between 1 September 2018 and 1 September 2020.SettingThis study involved 10 UK PCCTs.PatientsChildren over 1 month of age intubated during emergency management for status epilepticus (SE), referred to UK PCCTs. Patients with trauma, requiring time-critical neurosurgical intervention or those with a tracheostomy were excluded.InterventionsNo interventions were implemented.Measurements and main resultsOut of the 1622 referrals for SE, 1136 (70%) were intubated at referral. The median age was 3 years (IQR 1.25–6.54 years). Among the intubated children, 396 (34.8%) were extubated locally by the referring team, with 19 (4.8%) requiring reintubation. Therefore, the overall rate of successful extubation was 33% (377/1136). There was significant variation between PCCTs, with local extubation rates ranging from 2% to 74%. Multivariable analyses showed region/PCCT, contributing diagnosis, acute changes on CT, preceding encephalopathy and type of continuous sedation (midazolam) used postintubation were significantly associated with transfer to a critical care unit.ConclusionThis study highlights wide regional variation in early extubation practices. Regions with high successful extubation rates have established extubation guidelines from PCCTs. Successful extubation represents critical care transports that have been avoided.

IntroductionCONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC).MethodsThe treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic (‘COVID’ cohort, 16/03/2020-10/05/2020), with 12-month follow-up.ResultsAmong 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8–4.1) vs. 4.4 (IQR 3.6–5.2) months, p = 0.093).ConclusionPathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.

My research looks at education in the context of today's 'surveillance society'. It aims to conceptualise flows of surveillance in the independent school context, and to establish their impacts. The positioning of the teacher has undergone a significant shift as a result of the increasing role of surveillance in our liquid-modern and increasingly consumer-driven society; the historically one-way process of the teacher surveilling the pupil has been replaced with a complex web, or assemblage, of surveillance, with the teacher of the centre of it, and surveilled by various stakeholders, such as parents, pupils, management, colleagues, and even intrapersonally. This thesis outlines my case-study of one independent school in the South of England amid a move to a 'glass walls culture', and offers findings from twenty-three interviews undertaken with teachers, Heads of Departments, pupils, parents, and Senior Leadership members regarding their experiences of, and views on, the surveillance of the teacher. Using Page's (2017a) work on teacher surveillance as a valuable starting point, my research outlines more than thirty different ways that teachers are surveilled in schools, as demonstrated by my diagram 'the Surveillant 360', which outlines ways in which knowledge is accessed, generated and shared. The application of Deleuze and Guattari's (1987) theorisation of desire lines shines a light on ways in which teachers are surveilled by different surveillant stakeholders, and how power relations are destabilised. The case is made that the surveillant assemblage is characterised by liquidity, multiplicity and exchangeability, and that there is a shift from surveillance undertaken by external stakeholders to more intrapersonal surveillance. Ultimately, surveillance is shown to be neither positive nor negative in and of itself, yet it is the ways in which the surveillant knowledge is used, and individuals' perceptions of such, that is significant. The surveillance of the teacher can lead to feelings of validation, a sense of care and protection, and have developmental benefits. However, my findings also suggest that the surveillance of the teacher can result in suspicion, frustration, increased workload, and, perhaps, most concerning of all - an ontological insecurity and shift in focus of the teacher whereby they put the ways in which they are seen by others above the needs of their pupils. This study is significant not only in that it treads new ground by being located within the independent sector, but also because it is the most in-depth application of assemblage theory to surveillance in education to date, and it can be of great use to policy-makers.