Using Covalent Modifications to Distinguish Protein Electrospray Mechanisms: Charged Residue Model (CRM) vs. Chain Ejection Model (CEM)

Different mechanisms have been proposed for the formation of gaseous protein ions during electrospray ionization (ESI). In the charged residue model (CRM) ions are produced upon nanodroplet evaporation to dryness. This mechanism is thought to dominate in native ESI, where proteins retain compact conformations, with charge states close to the Rayleigh charge of protein-sized aqueous droplets. Much higher charge states are generated from proteins that are unfolded in solution. The chain ejection model (CEM) has been proposed for ESI under such denaturing conditions. In the CEM proteins are gradually expelled, while mobile H+ equilibrate between the droplet and its protruding tail. Providing clear-cut evidence for these scenarios remains difficult, because electrosprayed ions do not usually retain any features that reveal their formation mechanism. In this work we propose that the stepwise elimination of basic sites can serve to distinguish between the CRM and CEM. Using cytochrome c as a model system, we studied proteins that had between zero and 19 Lys blocked by acetylation. In native ESI (pH 7) the same low charge states were observed regardless of acetylation. This behavior is consistent with the CRM, where charge states are governed by protein size, rather than protein surface chemistry. Denaturing (pH 2) conditions resulted in much higher ESI charge states. Intriguingly, spectra acquired under these pH 2 conditions gradually shifted to lower charge states when the number of acetylated Lys was increased. This charge reduction is attributed to the fact that lowering the number of basic sites compromises the ability of the protein to compete with the droplet for mobile H+ during the CEM. In conclusion, we illustrate that simple covalent modifications can help distinguish between protein ion formation via the CRM or the CEM

Positron detection in silica monoliths for miniaturised quality control of PET radiotracers

We demonstrate the use of the miniaturised Medipix positron sensor for detection of the clinical PET radiotracer, [⁶⁸Ga]gallium-citrate, on a silica-based monolith, towards microfluidic quality control. The system achieved a far superior signal-to-noise ratio compared to conventional sodium iodide-based radio-HPLC detection and allowed real-time visualisation of positrons in the monolith

A novel 18F-labelled high affinity agent for PET imaging of the translocator protein

The translocator protein (TSPO) is an important target for imaging focal neuroinflammation in diseases such as brain cancer, stroke and neurodegeneration, but current tracers for non-invasive imaging of TSPO have important limitations. We present the synthesis and evaluation of a novel 3-fluoromethylquinoline-2-carboxamide, AB5186, which was prepared in eight steps using a one-pot two component indium(III)-catalysed reaction for the rapid and efficient assembly of the 4-phenylquinoline core. Biological assessment and the implementation of a physicochemical study showed AB5186 to have low nanomolar affinity for TSPO, as well as optimal plasma protein binding and membrane permeability properties. Generation of [18F]-AB5186 through 18F incorporation was achieved in good radiochemical yield and subsequent in vitro and ex vivo autoradiography revealed the ability of this compound to bind with specificity to TSPO in mouse glioblastoma xenografts. Initial positron emission tomography imaging of a glioma bearing mouse and a healthy baboon support the potential for [18F]-AB5186 use as a radiotracer for non-invasive TSPO imaging in vivo

Social trajectories or disrupted identities? : Changing and competing models of teacher professionalism under New Labour

Since the 1988 Education Reform Act, the teacher’s role in England has changed in many ways, a process which intensified under New Labour after 1997. Conceptions of teacher professionalism have become more structured and formalized, often heavily influenced by government policy objectives. Career paths have become more diverse and specialised. In this article, three post-1997 professional roles are given consideration as examples of these new specialised career paths: Higher Level Teaching Assistants, Teach First trainees and Advanced Skills Teachers. The article goes on to examine such developments within teaching, using Bourdieu’s concept of habitus to inform the analysis, as well as Bernstein’s theories of knowledge and identity. The article concludes that there has been considerable specialization and subsequent fragmentation of roles within the teaching profession, as part of workforce remodelling initiatives. However, there is still further scope for developing a greater sense of professional cohesion through social activism initiatives, such as the children's agenda. This may produce more stable professional identities in the future as the role of teachers within the wider children’s workforce is clarified

Family Medicine needs assessment: Studying the clinical work of general practitioners in Ethiopia

Background and Objective: Some universities in sub-Saharan Africa have initiated Family Medicine (FM) residency programs. This study was conducted by FM colleagues at Addis Ababa University (AAU) in Ethiopia and the University of Toronto, Canada to inform the FM residency curriculum at AAU. It was designed to determine the clinical problems that family physicians in Ethiopia may encounter.Methods: We used a mixed methods approach: Modified time-motion study and brief interviews. We observed 46 general practitioners (GPs) across ten sites in Ethiopia. Trained observers recorded time-motion data while GPs conducted their daily work. This data was supplemented by brief interviews with the GPs.Findings: Clinical encounters occupied 82% of GP work. The common symptoms were digestive-abdominal pain (21% visits), respiratory-cough (16%), and general-fever and chills (16%). The common diagnoses were infectious (22% visits), genitourinary (12%), circulatory (10%), and endocrine (10%). Challenges identified were lack of clinical resources (57% of GPs), difficulties in communication (48%) and excessive workload (33%). Most common requests were for information technology (78%) and HIV (46%) training.Conclusion: The profile of common symptoms and diagnoses indicated the competencies family physicians in the regions should have. This information will be used to develop an appropriate FM curriculum at AAU

Systemic Racism and Health Disparities: A Statement from Editors of Family Medicine Journals

The year 2020 has been marked by historic protests across the United States and the globe sparked by the deaths of George Floyd, Ahmaud Arbery, Breonna Taylor, and so many other Black people. The protests heightened awareness of racism as a public health crisis and triggered an antiracism movement. The editors of several North American family medicine publications have come together to address this call to action and share resources on racism across our readerships.http://deepblue.lib.umich.edu/bitstream/2027.42/163331/1/Final Statement on Systemic Racism- with acknowledgements.pdf-1Description of Final Statement on Systemic Racism- with acknowledgements.pdf : Main ArticleSEL

Investigation of the summer 2018 European ozone air pollution episodes using novel satellite data and modelling

In the summer of 2018, Europe experienced an intense heat wave which coincided with several persistent large-scale ozone (O3) pollution episodes. Novel satellite data of lower tropospheric column O3 from the Global Ozone Monitoring Experiment-2 (GOME-2) and Infrared Atmospheric Sounding Interferometer (IASI) on the MetOp satellite showed substantial enhancements in 2018 relative to other years since 2012. Surface observations also showed ozone enhancements across large regions of continental Europe in summer 2018 compared to 2017. Enhancements to surface temperature and the O3 precursor gases carbon monoxide and methanol in 2018 were co-retrieved from MetOp observations by the same scheme. This analysis was supported by the TOMCAT chemistry transport model (CTM) to investigate processes driving the observed O3 enhancements. Through several targeted sensitivity experiments we show that meteorological processes, and emissions to a secondary order, were important for controlling the elevated O3 concentrations at the surface. However, mid-tropospheric (~500 hPa) O3 enhancements were dominated by meteorological processes. We find that contributions from stratospheric O3 intrusions ranged between 15&ndash;40 %. Analysis of back trajectories indicates that the import of O3-enriched air masses into Europe originated over the North Atlantic substantially increasing O3 in the 500 hPa layer during summer 2018.</p

The geographies of access to enterprise finance: the case of the West Midlands, UK

The geographies of access to enterprise finance: the case of the West Midlands, UK, Regional Studies. Whilst there is a long history of credit rationing to small and medium-sized enterprises (SMEs) in the UK, the financial crisis has seen banks retreat further from lending to viable SMEs due to a reassessment of risk and lack of available capital. In so doing, the credit crunch is thought to be creating new geographies of financial exclusion. This paper explores the financial inclusion of enterprise through community development finance institutions (CDFIs) which provide loan finance to firms at the commercial margins in the West Midlands, UK. The paper concludes that CDFIs could partially address the financial exclusion of enterprise as an additional, alternative source of finance to that of mainstream banks

The politics of aspiration: neo-liberal education policy, 'low' parental aspirations, and primary school Extended Services in disadvantaged communities

Geographical research on education has grown rapidly in both volume and scope during the first decade of the twenty-first century, and one relatively new theme to emerge from this growing literature is that of education and aspiration. Much of the nascent interest in aspiration concerns access to quality schooling and University education. In this paper by contrast we highlight the importance of studying the ways aspirations are (re)produced within the school community. Our empirical focus is on low-income England under New Labour. Here we pursue a two-fold approach: firstly examining how education professionals define parental aspirations for primary-aged children as low; before secondly considering their alternative understandings of appropriate aspirations and the practices through which they seek to promote these, both in school and through the use of Extended Services for parents and children. In conclusion we highlight the importance of inward and outward geographies of education which ‘recouple’ schools with their social context, and discuss the moral and political ambiguities involved in practices designed to raise aspirations

Exploring the role of the connection length of screen-printed electrodes towards the hydrogen and oxygen evolution reactions

Zero-emission hydrogen and oxygen production are critical for the UK to reach net-zero greenhouse gasses by 2050. Electrochemical techniques such as water splitting (electrolysis) coupled with renewables energy can provide a unique approach to achieving zero emissions. Many studies exploring electrocatalysts need to “electrically wire” to their material to measure their performance, which usually involves immobilization upon a solid electrode. We demonstrate that significant differences in the calculated onset potential for both the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) can be observed when using screen-printed electrodes (SPEs) of differing connection lengths which are immobilized with a range of electrocatalysts. This can lead to false improvements in the reported performance of different electrocatalysts and poor comparisons between the literature. Through the use of electrochemical impedance spectroscopy, uncompensated ohmic resistance can be overcome providing more accurate Tafel analysis