Arabidopsis DOF Transcription Factors Act Redundantly to Reduce CONSTANS Expression and Are Essential for a Photoperiodic Flowering Response

SummaryFlowering of Arabidopsis is induced by long summer days (LDs). The transcriptional regulator CONSTANS (CO) promotes flowering, and its transcription is increased under LDs. We systematically misexpressed transcription factors in companion cells and identified several DOF proteins that delay flowering by repressing CO transcription. Combining mutations in four of these, including CYCLING DOF FACTOR 2 (CDF2), caused photoperiod-insensitive early flowering by increasing CO mRNA levels. CO transcription is promoted to differing extents by GIGANTEA (GI) and the F-box protein FKF1. We show that GI stabilizes FKF1, thereby reducing CDF2 abundance and allowing transcription of CO. Despite the crucial function of GI in wild-type plants, introducing mutations in the four DOF-encoding genes into gi mutants restored the diurnal rhythm and light inducibility of CO. Thus, antagonism between GI and DOF transcription factors contributes to photoperiodic flowering by modulating an underlying diurnal rhythm in CO transcript levels

Adaptive-mutation compact genetic algorithm for dynamic environments

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow‐up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1‐positiveM3 UMs were associated with prolonged survival compared to nBAP1‐negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing ‘predominantly diffuse’ in most nBAP1‐negative UM, a distinct ‘focal perinuclear’ expression pattern – localized immediately adjacent to the cis Golgi – was seen in 31% (18/59). These tumours tended to carry loss‐of‐function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non‐genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1‐negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation

Uveal melanoma UK national guidelines

The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website

Keeping children safe at home: protocol for a case-control study of modifiable risk factors for scalds

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. BACKGROUND: Scalds are one of the most common forms of thermal injury in young children worldwide. Childhood scald injuries, which mostly occur in the home, result in substantial health service use and considerable morbidity and mortality. There is little research on effective interventions to prevent scald injuries in young children.OBJECTIVES: To determine the relationship between a range of modifiable risk factors for medically attended scalds in children under the age of 5 years.DESIGN: A multicentre case-control study in UK hospitals and minor injury units with parallel home observation to validate parental reported exposures. Cases will be 0-4 years old with a medically attended scald injury which occurred in their home or garden, matched on gender and age with community controls. An additional control group will comprise unmatched hospital controls drawn from children aged 0-4 years attending the same hospitals and minor injury units for other types of injury. Conditional logistic regression will be used for the analysis of cases and matched controls, and unconditional logistic regression for the analysis of cases and unmatched controls to estimate ORs and 95% CI, adjusted and unadjusted for confounding variables.MAIN EXPOSURE MEASURES: Use of safety equipment and safety practices for scald prevention and scald hazards.DISCUSSION: This large case-control study will investigate modifiable risk factors for scalds injuries, adjust for potential confounders and validate measures of exposure. Its findings will enhance the evidence base for prevention of scalds injuries in young children

Living risk prediction algorithm (QCOVID) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study.

OBJECTIVE: To derive and validate a risk prediction algorithm to estimate hospital admission and mortality outcomes from coronavirus disease 2019 (covid-19) in adults. DESIGN: Population based cohort study. SETTING AND PARTICIPANTS: QResearch database, comprising 1205 general practices in England with linkage to covid-19 test results, Hospital Episode Statistics, and death registry data. 6.08 million adults aged 19-100 years were included in the derivation dataset and 2.17 million in the validation dataset. The derivation and first validation cohort period was 24 January 2020 to 30 April 2020. The second temporal validation cohort covered the period 1 May 2020 to 30 June 2020. MAIN OUTCOME MEASURES: The primary outcome was time to death from covid-19, defined as death due to confirmed or suspected covid-19 as per the death certification or death occurring in a person with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the period 24 January to 30 April 2020. The secondary outcome was time to hospital admission with confirmed SARS-CoV-2 infection. Models were fitted in the derivation cohort to derive risk equations using a range of predictor variables. Performance, including measures of discrimination and calibration, was evaluated in each validation time period. RESULTS: 4384 deaths from covid-19 occurred in the derivation cohort during follow-up and 1722 in the first validation cohort period and 621 in the second validation cohort period. The final risk algorithms included age, ethnicity, deprivation, body mass index, and a range of comorbidities. The algorithm had good calibration in the first validation cohort. For deaths from covid-19 in men, it explained 73.1% (95% confidence interval 71.9% to 74.3%) of the variation in time to death (R2); the D statistic was 3.37 (95% confidence interval 3.27 to 3.47), and Harrell's C was 0.928 (0.919 to 0.938). Similar results were obtained for women, for both outcomes, and in both time periods. In the top 5% of patients with the highest predicted risks of death, the sensitivity for identifying deaths within 97 days was 75.7%. People in the top 20% of predicted risk of death accounted for 94% of all deaths from covid-19. CONCLUSION: The QCOVID population based risk algorithm performed well, showing very high levels of discrimination for deaths and hospital admissions due to covid-19. The absolute risks presented, however, will change over time in line with the prevailing SARS-C0V-2 infection rate and the extent of social distancing measures in place, so they should be interpreted with caution. The model can be recalibrated for different time periods, however, and has the potential to be dynamically updated as the pandemic evolves

Welshness in British Wales: Negotiating national identity at the margins

Popular interpretations of national identity often focus on the unifying qualities of nationhood. However, societies frequently draw hierarchical distinctions between the people and places who are ‘most national’, and those who are ‘least national’. Little attention is paid to these marginal places within the nation and the experiences of their inhabitants. This article helps to address this by analysing the ‘less Welsh’ British Wales region of Wales, a country that has traditionally possessed a hierarchical, regionally constituted nationhood. The article studies the British Wales region both ‘from above’ – considering how some areas develop as ‘less national’ – and ‘from below’, introducing empirical ethnographic work into ‘everyday Welshness’ in this area. Whilst previous work on hierarchical nationhood focuses on how hierarchies are institutionalized by the state, this article demonstrates how people at the margins of the nation actively negotiate their place in the nation. Whilst people in this area expressed a strong Welshness, they also struggled to place themselves in the nation because they had internalized their lowly place within the national hierarchy. The article demonstrates the importance of place and social class for national identity construction and draws attention to the role of power in the discursive construction of hierarchical nationhood

Short-term breast cancer survival in relation to ethnicity, stage, grade and receptor status: national cohort study in England.

In the re-organisation of cancer registration in England in 2012, a high priority was given to the recording of cancer stage and other prognostic clinical data items. We extracted 86 852 breast cancer records for women resident in England and diagnosed during 2012-2013. Information on age, ethnicity, socio-economic status, comorbidity, tumour stage, grade, morphology and oestrogen, progesterone and HER2 receptor status was included. The two-year cumulative risk of death from any cause was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regressions were used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI). The follow-up ended on 31 December 2014. The completeness of registration for prognostic variables was generally high (around 80% or higher), but it was low for progesterone receptor status (41%). Women with negative receptor status for each of the oestrogen, progesterone and HER2 receptors (triple-negative cancers) had an adjusted HR for death of 2.00 (95%CI 1.84-2.17). Black women had an age-adjusted HR of 1.77 (1.48-2.13) compared with White women. The excess mortality of Black women with breast cancer has contributions from socio-economic factors, stage distribution and tumour biology. The study illustrates the richness of detail in the national cancer registration data. This allows for analysis of cancer outcomes at a high level of resolution, and may form the basis for risk stratification.British Journal of Cancer advance online publication, 25 October 2016; doi:10.1038/bjc.2016.335 www.bjcancer.com