Splicing mutation analysis reveals previously unrecognized pathways in lymph node-invasive breast cancer.

Somatic mutations reported in large-scale breast cancer (BC) sequencing studies primarily consist of protein coding mutations. mRNA splicing mutation analyses have been limited in scope, despite their prevalence in Mendelian genetic disorders. We predicted splicing mutations in 442 BC tumour and matched normal exomes from The Cancer Genome Atlas Consortium (TCGA). These splicing defects were validated by abnormal expression changes in these tumours. Of the 5,206 putative mutations identified, exon skipping, leaky or cryptic splicing was confirmed for 988 variants. Pathway enrichment analysis of the mutated genes revealed mutations in 9 NCAM1-related pathways, which were significantly increased in samples with evidence of lymph node metastasis, but not in lymph node-negative tumours. We suggest that comprehensive reporting of DNA sequencing data should include non-trivial splicing analyses to avoid missing clinically-significant deleterious splicing mutations, which may reveal novel mutated pathways present in genetic disorders

Risk and protective factors for meningococcal disease in adolescents: matched cohort study

Objective: To examine biological and social risk factors for meningococcal disease in adolescents. Design: Prospective, population based, matched cohort study with controls matched for age and sex in 1:1 matching. Controls were sought from the general practitioner. Setting: Six contiguous regions of England, which represent some 65% of the country’s population. Participants: 15-19 year olds with meningococcal disease recruited at hospital admission in six regions (representing 65% of the population of England) from January 1999 to June 2000, and their matched controls. Methods: Blood samples and pernasal and throat swabs were taken from case patients at admission to hospital and from cases and matched controls at interview. Data on potential risk factors were gathered by confidential interview. Data were analysed by using univariate and multivariate conditional logistic regression. Results: 144 case control pairs were recruited (74 male (51%); median age 17.6). 114 cases (79%) were confirmed microbiologically. Significant independent risk factors for meningococcal disease were history of preceding illness (matched odds ratio 2.9, 95% confidence interval 1.4 to 5.9), intimate kissing with multiple partners (3.7, 1.7 to 8.1), being a university student (3.4, 1.2 to 10) and preterm birth (3.7, 1.0 to 13.5). Religious observance (0.09, 0.02 to 0.6) and meningococcal vaccination (0.12, 0.04 to 0.4) were associated with protection. Conclusions: Activities and events increasing risk for meningococcal disease in adolescence are different from in childhood. Students are at higher risk. Altering personal behaviours could moderate the risk. However, the development of further effective meningococcal vaccines remains a key public health priority

Childhood risk factors for lifetime bulimic or compulsive eating by age 30 years in a British national birth cohort.

OBJECTIVE: To examine whether previously identified childhood risk factors for bulimia or compulsive eating (BCE) predict self-reported lifetime BCE by age 30 years in a prospective birth cohort. METHOD: Using data from the 1970 British Cohort Study at birth, 5, and 10 years, associations between 22 putative childhood risk factors and self-reported lifetime BCE at 30 years were examined, adjusting for sex and socioeconomic status. RESULTS: Only female sex (odds ratio (OR): 9.2; 95% confidence interval (CI): 1.9-43.7; p = 0.005), low self-esteem (OR:2.9; 95%CI: 1.1-7.5; p = 0.03) and high maternal education (OR:5.4; 95%CI: 2.0-14.8; p = 0.001) were significantly associated with higher risk of BCE, whereas high SES at 10 years was significantly protective (OR:0.2; 95%CI: 0.1-0.8; p = 0.022) of BCE in fully adjusted multivariable logistic regression analysis. DISCUSSION: Our findings do not support a strong role for childhood weight status and eating behaviours in the development of bulimia and compulsive eating pathology, rather suggesting a focus on self esteem may have greater relative importance. Findings in relation to maternal education and SES need further exploration

Effects of screentime on the health and well-being of children and adolescents: a systematic review of reviews

OBJECTIVES: To systematically examine the evidence of harms and benefits relating to time spent on screens for children and young people’s (CYP) health and well-being, to inform policy. // METHODS: Systematic review of reviews undertaken to answer the question ‘What is the evidence for health and well-being effects of screentime in children and adolescents (CYP)?’ Electronic databases were searched for systematic reviews in February 2018. Eligible reviews reported associations between time on screens (screentime; any type) and any health/well-being outcome in CYP. Quality of reviews was assessed and strength of evidence across reviews evaluated. // RESULTS: 13 reviews were identified (1 high quality, 9 medium and 3 low quality). 6 addressed body composition; 3 diet/energy intake; 7 mental health; 4 cardiovascular risk; 4 for fitness; 3 for sleep; 1 pain; 1 asthma. We found moderately strong evidence for associations between screentime and greater obesity/adiposity and higher depressive symptoms; moderate evidence for an association between screentime and higher energy intake, less healthy diet quality and poorer quality of life. There was weak evidence for associations of screentime with behaviour problems, anxiety, hyperactivity and inattention, poorer self-esteem, poorer well-being and poorer psychosocial health, metabolic syndrome, poorer cardiorespiratory fitness, poorer cognitive development and lower educational attainments and poor sleep outcomes. There was no or insufficient evidence for an association of screentime with eating disorders or suicidal ideation, individual cardiovascular risk factors, asthma prevalence or pain. Evidence for threshold effects was weak. We found weak evidence that small amounts of daily screen use is not harmful and may have some benefits. // CONCLUSIONS: There is evidence that higher levels of screentime is associated with a variety of health harms for CYP, with evidence strongest for adiposity, unhealthy diet, depressive symptoms and quality of life. Evidence to guide policy on safe CYP screentime exposure is limited

Student- and school-level belonging and commitment and student smoking, drinking and misbehaviour

Objectives: It has been suggested that students are healthier in schools where more students are committed to school. Previous research has examined this only using a proxy measure of value-added education (a measure of whether school-level attendance and attainment are higher than predicted by students’ social profile), finding associations with smoking tobacco, use of alcohol and illicit drugs, and violence. These findings do not provide direct insights into the associations between school-level aggregate student commitment and health behaviours, and may simply reflect the proxy measure being residually confounded by unmeasured student characteristics. We examined the previously used proxy measure of value-added education, as well as direct measures at the level of the school and the student of lack of student commitment to school to see whether these were associated with students’ self-reported smoking tobacco, alcohol use and school misbehaviour. Design: Cross-sectional survey. Setting: A total of 40 schools in south-east England. Methods: Multi-level analyses. Results: There were associations between school- and student-level measures of lack of commitment to school and tobacco smoking, alcohol use and school misbehaviour outcomes, but the proxy measure of school-level commitment, value-added education, was not associated with these outcomes. A sensitivity analysis focused only on violent aspects of school misbehaviour found a pattern of associations identical to that found for the measure of misbehaviour. Conclusion: Our study provides the first direct evidence in support of the Theory of Human Functioning and School Organisation

T Cell Recognition of the Dominant I-Ak–Restricted Hen Egg Lysozyme Epitope: Critical Role for Asparagine Deamidation

Type-B T cells raised against the immunodominant peptide in hen egg lysozyme (HEL48–62) do not respond to whole lysozyme, and this has been thought to indicate that peptide can bind to l-Ak in different conformations. Here we demonstrate that such T cells recognize a deamidated form of the HEL peptide and not the native peptide. The sequence of the HEL epitope facilitates rapid and spontaneous deamidation when present as a free peptide or within a flexible domain. However, this deamidated epitope is not created within intact lysozyme, most likely because it resides in a highly structured part of the protein. These findings argue against the existence of multiple conformations of the same peptide–MHC complex and have important implications for the design of peptide-based vaccines. Furthermore, as the type-B T cells are known to selectively evade induction of tolerance when HEL is expressed as a transgene, these results suggest that recognition of posttranslationally modified self-antigen may play a role in autoimmunity

Understanding hydrogen recombination line observations with ALMA and EVLA

Hydrogen recombination lines are one of the major diagnostics of H II region physical properties and kinematics. In the near future, the Expanded Very Large Array (EVLA) and the Atacama Large Millimeter Array (ALMA) will allow observers to study recombination lines in the radio and sub-mm regime in unprecedented detail. In this paper, we study the properties of recombination lines, in particular at ALMA wavelengths. We find that such lines will lie in almost every wideband ALMA setup and that the line emission will be equally detectable in all bands. Furthermore, we present our implementation of hydrogen recombination lines in the adaptive-mesh radiative transfer code RADMC-3D. We particularly emphasize the importance of non-LTE (local thermodynamical equilibrium) modeling since non-LTE effects can drastically affect the line shapes and produce asymmetric line profiles from radially symmetric H II regions. We demonstrate how these non-LTE effects can be used as a probe of systematic motions (infall & outflow) in the gas. We use RADMC-3D to produce synthetic observations of model H II regions and study the necessary conditions for observing such asymmetric line profiles with ALMA and EVLA.Comment: MNRAS in pres

Tawney and the third way

From the 1920s to the 1950s R. H. Tawney was the most influential socialist thinker in Britain. He articulated an ethical socialism at odds with powerful statist and mechanistic traditions in British socialist thinking. Tawney's work is thus an important antecedent to third way thinking. Tawney's religiously-based critique of the morality of capitalism was combined with a concern for detailed institutional reform, challenging simple dichotomies between public and private ownership. He began a debate about democratizing the enterprise and corporate governance though his efforts fell on stony ground. Conversely, Tawney's moralism informed a whole-hearted condemnation of market forces in tension with both his concern with institutional reform and modern third way thought. Unfortunately, he refused to engage seriously with emergent welfare economics which for many social democrats promised a more nuanced understanding of the limits of market forces. Tawney's legacy is a complex one, whose various elements form a vital part of the intellectual background to current third way thinking

Olive phenology as a sensitive indicator of future climatic warming in the Mediterranean

Experimental and modelling work suggests a strong dependence of olive flowering date on spring temperatures. Since airborne pollen concentrations reflect the flowering phenology of olive populations within a radius of 50 km, they may be a sensitive regional indicator of climatic warming. We assessed this potential sensitivity with phenology models fitted to flowering dates inferred from maximum airborne pollen data. Of four models tested, a thermal time model gave the best fit for Montpellier, France, and was the most effective at the regional scale, providing reasonable predictions for 10 sites in the western Mediterranean. This model was forced with replicated future temperature simulations for the western Mediterranean from a coupled ocean-atmosphere general circulation model (GCM). The GCM temperatures rose by 4·5 °C between 1990 and 2099 with a 1% per year increase in greenhouse gases, and modelled flowering date advanced at a rate of 6·2 d per °C. The results indicated that this long-term regional trend in phenology might be statistically significant as early as 2030, but with marked spatial variation in magnitude, with the calculated flowering date between the 1990s and 2030s advancing by 3–23 d. Future monitoring of airborne olive pollen may therefore provide an early biological indicator of climatic warming in the Mediterranean