Expression and function of ZEBRA: the Epstein-Barr viral replication activator

Epstein-Barr virus (EBV) encodes a protein, ZEBRA, which enables the virus to switch from a latent to a lytic life cycle. ZEBRA expression was studied in lymphoid cells harboring either standard virus or a mixture of standard and defective viruses. ZEBRA protein could not be detected in cells latently infected with standard EBV but was constitutively expressed in cells containing both defective and standard EBV genomes. Experiments indicated that regulation of transcription of the ZEBRA gene (BZLF1) is a pivotal event in the control of EBV replication. ZEBRA specific BZLF1 transcripts were spontaneously expressed in cells harboring defective virus but were only synthesized by the latent virus after chemical induction. BZLF1 transcription was sensitive to inhibition of protein synthesis but not to inhibition of lytic viral DNA synthesis. This suggests that ZEBRA is an early replicative protein whose expression is dependent on the synthesis of a viral or cellular factor.The basis domain of the ZEBRA protein is homologous to the Fos/Jun oncogene family and shares their ability to bind the canonical AP-1 site (TGAGTCA). However, ZEBRA does not contain a leucine zipper domain; a motif necessary for DNA binding of Fos/Jun proteins. Additionally, ZEBRA binds to sites which deviate from the AP-1 consensus sequence. Thus, it was of interest to study the DNA binding properties of the ZEBRA protein.Deletional mutagenesis of the BZLF1 cDNA indicated that amino acids 172-227, representing the basic and putative dimerization domains, were required for specific binding to AP-1 and divergent sites. Mutagenesis of three basic amino acids, which are conserved in Fos, abrogated ZEBRA binding to all target sequences. Additionally, ZEBRA was determined to bind DNA as a homodimer.DNA binding studies of ZEBRA and a Fos-GCN4 chimera indicated that although these proteins have homology in their basic DNA binding domains, they have different cognate binding specificities. The autoregulated BZLF1 promoter contains three divergent AP-1 sequences; Fos-GCN4 uniquely recognized one of the sites while ZEBRA bound only the other two sequences. Additionally, ZEBRA, but not Fos, was found to be phosphorylated by casein kinase II in-vitro. This phosphorylation abrogated ZEBRA binding to all of its target DNA sequences. Regulation of ZEBRA\u27s DNA binding activity may be required for the progression of the EBV replicative cycle

Exploring How Faculty Members in Higher Education Respond to an Assessment of their Intercultural Competency

This study addressed the response of faculty members in higher education completing the Intercultural Development Inventory (IDI) to measure their developmental level of intercultural competency. In addition, this study described how faculty members implemented their intercultural development plans (IDPs) and also identified the supports or barriers to their future development of intercultural competency. The literature review examined research on both K-12 and higher education to highlight the problems related to diversity and culturally relevant pedagogy that are consistent at all levels of education. Three case studies and one partial case study were cross-examined to capture the similarities and differences between faculty members’ experiences and interpretations. Results indicated the participants are in agreement regarding their role in creating safe spaces for students and striving towards equity and social justice in higher education. The participants also expressed a desire to model for students and colleagues the handling of cultural conflict and differences. Culturally relevant teaching and professional learning communities were identified as two areas of faculty development that institutions of higher education should support. Results from this study indicated that participants had both positive and negative responses to completing the IDI survey. After participating in the study, faculty members demonstrated a deeper understanding of their developmental level of intercultural competency

Organising care around patients

Healthcare aims to be patient-centred but a large gap remains between the fine words and the reality. Care often feels designed for the convenience of the organisations that deliver it, and not enough around patients and their families, or even around the frontline staff who provide it. Why does this happen? What does it feel like? What can be done about it? This book stimulates reflection on these questions by listening closely to those at the frontline. It provides accounts from patients, carers and healthcare professionals who are patients about what it’s like when services get it right, and wrong, from birth up to the end of life. Quite simply, we want to draw upon the power of storytelling – which is increasingly valued as a tool for learning – to help policymakers and practitioners to understand how to deliver better care. We also hope to enlighten the general reader about how they might go about navigating “the system” while it remains imperfect. There is a growing literature of first-person accounts from patients and from healthcare professionals. This book differs by providing a collection of narratives of experiences of the NHS in England to paint a rich and varied picture. Alongside these narratives we provide some international context, and an overview of the history of moves towards a more patient-centred approach to care. We present the theory and practice of storytelling in the context of healthcare. We also seek to help the reader to draw out the practical learning from the individual accounts

Ganesha: A Study of Personal Worship to a Personal God

Hindu devotees worship Ganesha when they are beginning a new phase or faces obstacles in their lives. In investigating the personal devotion of Hindu gods in India, we have found that there is a difference between the ways a Hindu worships the god Ganesha at a public shrine than in their own home. The main difference in worship style is that in the home, the worshiper acts as his or her own priest. There is room for greater interpretation in worship style and offerings made to the deity. Since our topic is personal devotion, we were drawn to the private aspect of the Hindu devotee. We wish to highlight the differences between the private and public worship of Ganesha. Although scholars have addressed public shrine worship and private worship separately, there has not been much scholarly comparison of the two. By looking at Bridegroom’s Wedding Crown (19th Century), Dancing Ganesha, Lord of obstacles (11-12th Century), and Ganesha, Lord of obstacles (10-11th Century), we hope to demonstrate that although both public and private are forms of personal devotion, home worship is less elaborate than public worship. This suggests that worship is not only for the individual’s religious interests but also for their social standing

Estimated Dissemination Ratio -a practical alternative to the Reproduction Number for infectious diseases

Peer reviewedPublisher PD

The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial

Background: Despite improving evidence-based practice following clinical guidelines to optimise drug therapy, Type 2 diabetes (T2DM) still exerts a devastating toll from vascular complications and premature death. Biochemical remission of T2DM has been demonstrated with weight loss around 15kg following bariatric surgery and in several small studies of non-surgical energy-restriction treatments. The non-surgical Counterweight-Plus programme, running in Primary Care where obesity and T2DM are routinely managed, produces >15 kg weight loss in 33 % of all enrolled patients. The Diabetes UK-funded Counterpoint study suggested that this should be sufficient to reverse T2DM by removing ectopic fat in liver and pancreas, restoring first-phase insulin secretion. The Diabetes Remission Clinical Trial (DiRECT) was designed to determine whether a structured, intensive, weight management programme, delivered in a routine Primary Care setting, is a viable treatment for achieving durable normoglycaemia. Other aims are to understand the mechanistic basis of remission and to identify psychological predictors of response. Methods/Design: Cluster-randomised design with GP practice as the unit of randomisation: 280 participants from around 30 practices in Scotland and England will be allocated either to continue usual guideline-based care or to add the Counterweight-Plus weight management programme, which includes primary care nurse or dietitian delivery of 12-20weeks low calorie diet replacement, food reintroduction, and long-term weight loss maintenance. Main inclusion criteria: men and women aged 20-65years, all ethnicities, T2DM 0-6years duration, BMI 27-45 kg/m2. Tyneside participants will undergo Magnetic Resonance (MR) studies of pancreatic and hepatic fat, and metabolic studies to determine mechanisms underlying T2DM remission. Co-primary endpoints: weight reduction ≥ 15 kg and HbA1c <48 mmol/mol at one year. Further follow-up at 2 years. Discussion: This study will establish whether a structured weight management programme, delivered in Primary Care by practice nurses or dietitians, is a viable treatment to achieve T2DM remission. Results, available from 2018 onwards, will inform future service strategy

Using Big Data in Policy Evaluations: the Troubled Families Programme

Background The Ministry for Housing, Communities and Local Government have carried out one of the biggest data linkage exercises in government in order to evaluate the impact of the Troubled Families Programme. Linking individual and family level data across multiple administrative datasets has proven to be both innovative and cost-effective, enabling us to place children in the broader context of their family and household circumstances for our analysis. Objectives To use administrative datasets to measure children’s service use outcomes, for both programme and comparison individuals and families, to assess the impact of the Troubled Families Programme on outcomes for ‘children needing help’. Methods The comparison group provide a counterfactual, used to derive a robust assessment of the programme’s impact on children’s outcomes: in this case child safeguarding. Linked datasets means we can control for both individual and family level characteristics, such as parental employment, benefits, school attendance, children and adult offending and the circumstances of siblings. We have used propensity score matching to control for all covariates impacting on both treatment and outcome status. Findings Preliminary findings show a statistically significant reduction in the number of ‘children in need’ in the 6-12 month period after intervention start compared to the matched comparison group, and a reduction in the number of ‘looked after children’. There was an increase in the number of children with a ‘child protection plan’, but this was not statistically significantly different to the comparison group. Conclusions While access to such a wide range of individual and family characteristics is a key methodological advantage to evaluation, challenges include: missing data, time lags in the datasets and complex variable definitions. We have worked and continue to work with other government departments to overcome these. Whilst still in its earliest stages preliminary results for the programme’s impact are encouraging

The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936

Background: The DNA methylation-based 'epigenetic clock' correlates strongly with chronological age, but it is currently unclear what drives individual differences. We examine cross-sectional and longitudinal associations between the epigenetic clock and four mortality-linked markers of physical and mental fitness: lung function, walking speed, grip strength and cognitive ability. Methods: DNA methylation-based age acceleration (residuals of the epigenetic clock estimate regressed on chronological age) were estimated in the Lothian Birth Cohort 1936 at ages 70 (n=920), 73 (n=299) and 76 (n=273) years. General cognitive ability, walking speed, lung function and grip strength were measured concurrently. Cross-sectional correlations between age acceleration and the fitness variables were calculated. Longitudinal change in the epigenetic clock estimates and the fitness variables were assessed via linear mixed models and latent growth curves. Epigenetic age acceleration at age 70 was used as a predictor of longitudinal change in fitness. Epigenome-wide association studies (EWASs) were conducted on the four fitness measures. Results: Cross-sectional correlations were significant between greater age acceleration and poorer performance on the lung function, cognition and grip strength measures (r range: -0.07 to -0.05, P range: 9.7 x 10 to 0.024). All of the fitness variables declined over time but age acceleration did not correlate with subsequent change over 6 years. There were no EWAS hits for the fitness traits. Conclusions: Markers of physical and mental fitness are associated with the epigenetic clock (lower abilities associated with age acceleration). However, age acceleration does not associate with decline in these measures, at least over a relatively short follow-up