ImpacT2 project: preliminary study 1: establishing the relationship between networked technology and attainment

This report explored teaching practices, beliefs and teaching styles and their influences on ICT use and implementation by pupils. Additional factors explored included the value of school and LEA policies and teacher competence in the use of ICT in classroom settings. ImpaCT2 was a major longitudinal study (1999-2002) involving 60 schools in England, its aims were to: identify the impact of networked technologies on the school and out-of-school environment; determine whether or not this impact affected the educational attainment of pupils aged 816 years (at Key Stages 2, 3, and 4); and provide information that would assist in the formation of national, local and school policies on the deployment of IC

The SUMO Ligase Protein Inhibitor of Activated STAT 1 (PIAS1) is a constituent PML-NB protein that contributes to the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1)

Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukaemia (PML)-nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signalling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase Protein Inhibitor of Activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well characterized PML-NB proteins. In contrast to Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation

ImpaCT2: pupils' and teachers' perceptions of ICT in the home, school and community

The Strand 2 report of the ImpaCT 2 research describes the results of applying a range of research methods to explore, how pupils use ICT, in particular out of school and what had been gained from this use. ImpaCT2 was a major longitudinal study (1999-2002) involving 60 schools in England, its aims were to: identify the impact of networked technologies on the school and out-of-school environment; determine whether or not this impact affected the educational attainment of pupils aged 8 - 16 years (at Key Stages 2, 3, and 4); and provide information that would assist in the formation of national, local and school policies on the deployment of ICT

ImpaCT2: the impact of information and communication technologies on pupil learning and attainment

The report explores the impact of networked technologies on patterns of use of ICT in English, Mathematics and Science at Key Stages 2, 3 and 4 and the relative gain for high ICT users versus low ICT users in each of these subjects. This publication reports primarily on the outcomes of Strand 1, but draws on some material from the other strands of the study. ImpaCT2 was a major longitudinal study (1999-2002) involving 60 schools in England, its aims were to: identify the impact of networked technologies on the school and out-of-school environment; determine whether or not this impact affected the educational attainment of pupils aged 8 - 16 years (at Key Stages 2, 3, and 4); and provide information that would assist in the formation of national, local and school policies on the deployment of ICT

Resolution studies and performance evaluation of the LHCb VELO upgrade

The LHCb detector at CERN is scheduled to undergo an upgrade during the second long shutdown of the LHC. As part of this upgrade, the vertex detector (VELO) will be replaced with a new hybrid pixel detector, based on an evolution of the Timepix ASIC. The performance of this detector should improve upon that achieved by the current VELO, in addition to facilitating the complete detector readout at 40 MHz. As part of the preparation for this upgrade, this thesis presents the results of studies carried out on the single hit resolution of silicon hybrid pixel detectors. The development of a particle beam telescope has been carried out to allow these studies, shown to operate with track rates in excess of 45 kHz and with a pointing resolution at the device under test of less than 2 μm. A wide range of sensor types, thicknesses and resistivities have then been tested under different operating conditions and the results presented, with single hit resolutions varying between 4 μm and 12 μm depending on the conditions and incident angle. The resistivity of the devices is observed to have a significant effect on the single hit resolution, with high resistivity substrates allowing operation at lower bias voltages. This facilitates increased charge sharing, and the corresponding improvement in resolution. At sufficiently large incident angles however, the resolution becomes independent of the electric field, being instead dominated by the sensor geometry and variations in the charge deposited along the track length. No significant differences were found between the various detector technologies (n-on-n, n-on-p and p-on-n) though a difference in performance is expected for low-voltage operation of higher resistivity samples. A simplified model of the physical processes contributing to the detector resolution has been constructed, shown to reasonably reproduce the observed resolution as a function of angle and bias voltage. This model is extrapolated to potential future directions in the design of pixel sensors, highlighting the differences between various technology choices. The integration of the ATLAS FE-I4 ASIC into the telescope has been carried out, and the performance of an unirradiated planar silicon sensor was shown in order to verify this. Efficiency measurements show that the device is fully efficient in the angular range measured. The tracking performance of two irradiated sensors mounted on FE-I4 ASICs has been investigated, in addition to the mapping of collected charge over the pixel unit cell under various biasing conditions and at varying incident angles with respect to the incoming particles. For the sample irradiated to 2e15 1 MeV neq /cm2 the single hit resolution was 12.5 μm at perpendicular incidence, dropping to 8 μm at 22 degrees. The sample irradiated to 4e15 1 MeV neq /cm2 was found to have a resolution of around 13.5 μm, which remained relatively insensitive to the incident track angle. The conclusions drawn suggest that the upgraded VELO detector will be able to overcome the difficult radiation environment if it is able to reach the high voltage operation required. The implementation of these observations in the LHCb simulation environment has allowed some initial studies on the likely degradation of the detector performance to take place, showing that the high tracking efficiency (99.4 % for Long tracks) is likely to be maintained throughout the full lifetime of the upgrade. The impact parameter resolution was not observed to vary significantly. These studies have been carried out alongside simulations to gauge the expected compression that can be achieved in the data transmission of the VELOPix ASIC. Different designs of the front-end have been implemented, leading to the adoption of binary readout for the upgraded VELO. The uniformity of the pixel pitch across the detector has additionally been used to show the sensitivity of the system to multiple scattering, shown to be a credible tool with which to control the event reconstruction in the online LHCb trigger. A reduction of the number of VELO tracks passed to the forward reconstruction of almost 50 % has been shown, for the loss of only 5 % of tracks with momentum above 20 GeV/c. This could potentially replace the lifetime biasing cuts currently envisaged in the trigger

Perspectives on Depression: A synthesis of biological and behavioural findings

Introduction: Depression is a complex and widespread phenomenon, with few effective treatments that may be universally applied. Although a great deal of research has been reported on various aspects of depression from the perspectives of the different disciplines of general psychiatry, genetics, neuroscience, endocrinology, immunology, pharmacology, psychology, behaviour analysis and evolutionary theory, there is no extant synthesis of those data that is recent or comprehensive in its coverage. This thesis therefore reviewed the literatures from these nine areas, focussing principally from a neurobiological perspective, and drew the findings from that review into a comprehensive model of the way in which depression develops and why it occurs. Method: Working from a selection of authoritative texts, plus cross-referencing and weekly checks of over 20 major journals that reported data on depression during the period 2000 to 2010, plus online electronic searches via four search engines, more than 100 review chapters and over 3,500 journal articles on depression were found across the disciplines mentioned above. From these, a subset of 768 sources was identified as holding information directly pertinent to the focus of this thesis. These sources were then reviewed and summarised in discrete sections of this thesis. From these summaries, a new model of depression was developed which encompassed the wider literature. Results & Conclusion: Commencing with genetic bases for depression (gender, predisposition to melancholic depression) and two major indicators of the organism's exaggerated responsivity to environmental threat (the 5-HTTLPR polymorphism, methylation of several key genes involved in the HPA axis function) which cause increases in the activity of the Hypothalamus-Pituitary-Adrenal (HPA) axis, the model developed in this thesis considers the effects of that HPA axis hyperactivation and resultant elevated circulating cortisol

The SUMOylation pathway suppresses arbovirus replication in <i>Aedes aegypti</i> cells

Mosquitoes are responsible for the transmission of many clinically important arboviruses that cause significant levels of annual mortality and socioeconomic health burden worldwide. Deciphering the mechanisms by which mosquitoes modulate arbovirus infection is crucial to understand how viral-host interactions promote vector transmission and human disease. SUMOylation is a post-translational modification that leads to the covalent attachment of the Small Ubiquitin-like MOdifier (SUMO) protein to host factors, which in turn can modulate their stability, interaction networks, sub-cellular localisation, and biochemical function. While the SUMOylation pathway is known to play a key role in the regulation of host immune defences to virus infection in humans, the importance of this pathway during arbovirus infection in mosquito vectors, such as Aedes aegypti (Ae. aegypti), remains unknown. Here we characterise the sequence, structure, biochemical properties, and tissue-specific expression profiles of component proteins of the Ae. aegypti SUMOylation pathway. We demonstrate significant biochemical differences between Ae. aegypti and Homo sapiens SUMOylation pathways and identify cell-type specific patterns of SUMO expression in Ae. aegypti tissues known to support arbovirus replication. Importantly, depletion of core SUMOylation effector proteins (SUMO, Ubc9 and PIAS) in Ae. aegypti cells led to enhanced levels of arbovirus replication from three different families; Zika (Flaviviridae), Semliki Forest (Togaviridae), and Bunyamwera (Bunyaviridae) viruses. Our findings identify an important role for mosquito SUMOylation in the cellular restriction of arboviruses that may directly influence vector competence and transmission of clinically important arboviruses

The impact of pre-existing hypertension and its treatment on outcomes in patients admitted to hospital with COVID-19

The impact of pre-existing hypertension on outcomes in patients with the novel corona virus (SARS-CoV-2) remains controversial. To address this, we examined the impact of pre-existing hypertension and its treatment on in-hospital mortality in patients admitted to hospital with Covid-19. Using the CAPACITY-COVID patient registry we examined the impact of pre-existing hypertension and guideline-recommended treatments for hypertension on in-hospital mortality in unadjusted and multi-variate-adjusted analyses using logistic regression. Data from 9197 hospitalised patients with Covid-19 (median age 69 [IQR 57-78] years, 60.6% male, n = 5573) was analysed. Of these, 48.3% (n = 4443) had documented pre-existing hypertension. Patients with pre-existing hypertension were older (73 vs. 62 years, p < 0.001) and had twice the occurrence of any cardiac disease (49.3 vs. 21.8%; p < 0.001) when compared to patients without hypertension. The most documented class of anti-hypertensive drugs were angiotensin receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEi) (n = 2499, 27.2%). In-hospital mortality occurred in (n = 2020, 22.0%), with more deaths occurring in those with pre-existing hypertension (26.0 vs. 18.2%, p < 0.001). Pre-existing hypertension was associated with in-hospital mortality in unadjusted analyses (OR 1.57, 95% CI 1.42,1.74), no significant association was found following multivariable adjustment for age and other hypertension-related covariates (OR 0.97, 95% CI 0.87,1.10). Use of ACEi or ARB tended to have a protective effect for in-hospital mortality in fully adjusted models (OR 0.88, 95% CI 0.78,0.99). After appropriate adjustment for confounding, pre-existing hypertension, or treatment for hypertension, does not independently confer an increased risk of in-hospital mortality patients hospitalized with Covid-19

AD|ARC (Administrative Data| Agricultural Research Collection): Linking individual, household and farm business data for agricultural research – The challenges and opportunities of partnership working across ADR UK

Objectives ADARC is a partnership of six government departments and three research institutions across ADR-UK aiming to build four Research Ready Datasets about farming households. A|ARC requires government data linking experts to work closely with agricultural statisticians and academics across traditional boundaries pooling a wide range of data and expertise. Methods The ADARC partnership aims to build a model of collaborative working for administrative data research. ADARC brings together those collecting data with those linking and analysing de-identified data and eventually those using results to develop future policies. The data is from several different sources at individual, household and business levels requiring new methodologies developed by this collaboration. ADARC is also working between all four ADR centres to share learning across the ADR network building relationships for future projects beyond agriculture. The linkage process has been different in all four nations but this has offered new learning for all involved. Results Due to the Covid-19 pandemic, Phase 1 of the project has been slower than hoped. However, ADARC has shown that it is possible to conduct a truly UK-wide four nation project. Data linking is underway in all four nations bringing together data on individuals, households and businesses and analysis has begun in Wales and England. The project to date has faced the usual challenges of data acquisition and data quality issues which the partnership approach has been vital for overcoming. Despite this, we’ve demonstrated that there’s a huge level of enthusiasm for working together across organisational barriers. ADARC has just been funded for Phase 2 to expand the datasets in scope and explore the feasibility of linking in spatial data. Conclusion ADARC has created a model which demonstrates that partnership working is essential for fully achieving the objective of ADR UK of unlocking the potential of administrative data. The lessons of ADARC also provides a powerful case study for future cross-UK projects far beyond agriculture