Mathematics Out Of Nothing: Talking About Powerful Mathematical Ideas With Children

Parents and educators have powerful opportunities to introduce children to big mathematical ideas, when those ideas become necessary. Children are capable and curious. They don’t need to be sheltered from big mathematical ideas. Bring out mathematical ideas when kids are ready, or when they are needed. This article describes one such instance, when I helped my six-year-old son move beyond zero in the negative direction when subtracting

"Bedeviled Minds": Reflections on the History of Satanic Thoughts

In his classic account of Christian awakening, Grace Abounding to the Chief of Sinners (1666),John Bunyan described how the Devil planted evil thoughts in his mind. The spiritual enemy assailed him with “whole floods of blasphemies,both against God, Christ and the scriptures”. These shocking ideas came with unbidden and terrible force; suddenly his mind would be “strangely snatched away” by thoughts that he could not control, which assailed him like “a mighty whirlwind”

Molecular and immunological characterisation of two vaccine dominant antigens of Schistosoma mansoni.

Exposure to radiation attenuated cercariae of Schistosoma mansoni induces immunologically mediated protection against a challenge infection. One approach towards the selection of putative vaccine candidate molecules has therefore been the identification of ’vaccine dominant' antigens. Such molecules can be defined as those which are recognised by sera from animals vaccinated with irradiated parasites but not by sera raised in non-immune animals harbouring a single sex infection. This thesis describes the immunological and molecular characterisation of a 16 kDa vaccine dominant schistosomula surface antigen of S.mansoni and a 15 kDa antigen found on all stages of the parasite which also meets this criteria. The 16 kDa antigen extracted from mechanically transformed schistosomula and subsequently purified by immunoaffinity chromatography was shown to be a glycoprotein which incorporates both protein and carbohydrate epitopes. The latter, which include the target of a passively protective monoclonal antibody (Bickle et at., 1986), bind the lectins peanut and ricin agglutinin and are believed to incorporate the monosaccharide N- acetylgalactosamine O-linked to the peptide core. Attempts to determine the amino acid sequence of the antigen by gas phase NH2-terminal amino acid sequencing have also suggested that the protein moiety of the 16 kDa antigen is N-terminally blocked. The immunoaffinity purified 16 kDa antigen was subsequently used to immunise groups of mice in conjunction with a number of different adjuvants. Significant, albeit low, levels of resistance were achieved following immunisation with the 16 kDa molecule plus the nova some adjuvant formulation. Clones encoding the 15 kDa antigen were identified during the screening of a cDNA sporocyst library with sera specific for low molecular weight antigens. Sequence obtained for the antigen showed that it had some homology to members of a calcium binding protein superfamily, although the 15 kDa antigen itself was unable to bind calcium. The cDNA encoding this antigen was subsequently subcloned into a vector suitable for expression and the resulting fusion protein was used to immunise mice. Sera raised in these mice recognised the native 15 kDa antigen by Western blotting. However, the mice were not protected against a challenge infection

Insights into Neuroblastoma Initiation and Disease Progression Through integrative Genomics and Epigenomics

In this dissertation, we use integrative genomics to shed new insights into the molecular lesions and mechanisms that drive neuroblastoma. In Part 1, we use imputation and epigenetic profiling in order to identify the causal germline SNP that drives differential susceptibility to neuroblastoma at the LMO1 oncogene locus. In Part 2, we use whole genome sequencing and Bayesian statistical modeling to understand the clonal evolution that occurs between diagnosis and relapse. Part 1: Neuroblastoma is a pediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumor cells. Here we investigate the causal DNA variant at this locus. We show that SNP rs2168101 G\u3eT is the most highly associated variant and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumor formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele ablates GATA3 binding and enhancer activity, and is associated with decreased total and allele-specific LMO1 expression in neuroblastoma primary tumors. These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis. Part 2: The majority of high-risk neuroblastomas initially respond to chemotherapy, but over half of patients will experience therapy-resistant relapses which are nearly always fatal. The molecular defects driving relapse and drug resistance are unknown. We performed whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas, and corresponding normal lymphocyte DNAs, to define genetic alterations associated with relapse. Unbiased pathway analysis of the somatic mutations detected in the relapse tissues identified a strong enrichment in genes associated with RAS-MAPK signaling (18 of 23 patients). These RAS-MAPK mutations were clonally enriched at relapse and exist within clonal or major subclonal tumor populations. Similar MAPK pathway mutations were detected in 11 of 18 human neuroblastoma-derived cell lines, and these lesions are predicted to be sensitive to small molecule inhibition of MEK in vitro and in vivo. In this study of 23 neuroblastoma cases, MAPK pathway mutations were highly enriched in the relapsed genomes, providing a potential biomarker for new therapeutic approaches to chemotherapy refractory disease. Collectively, these studies provide important insights into the genetic and epigenetic factors driving neuroblastoma, and suggest new opportunities for pathway-targeted therapies

Collective Digital Innovation: Integrating The Expertise Of Multiple Specialist Stakeholders Including Young Homeless People In The Creation Of Mobile Apps For Social Change

This paper reports on a collaborative action research project which sought to combine the knowledge and expertise of multiple specialist organisations with the understanding and insight of young homeless people in order to find digital ways of supporting them before they became homeless. We discovered that adopting a collective approach to the demands of digital innovation enabled us to develop precise hypotheses and resulted in mobile apps for young people targeted at specific moments of emotional and practical need. The action research project is reflexively analysed in seeking to understand this process of collective digital innovation

The MacNew Heart Disease health-related quality of life instrument: A summary

BACKGROUND: The measurement of health, the effects of disease, and the impact of health care include not only an indication of changes in disease frequency and severity but also an estimate of patients' perception of health status before and after treatment. One of the more important developments in health care in the past decade may be the recognition that the patient's perspective is as legitimate and valid as the clinician's in monitoring health care outcomes. This has lead to the development of instruments to quantify the patients' perception of their health status before and after treatment. METHODS: We review evidence supporting the measurement properties of the MacNew Heart Disease Health-related Quality of Life [MacNew] Questionnaire which was designed to evaluate how daily activities and physical, emotional, and social functioning are affected by coronary heart disease and its treatment. RESULTS: Reliability was demonstrated by using internal consistency and the intraclass correlation coefficients for the three domains in the Dutch, English, Farsi, German, and Spanish versions of the MacNew. With internal consistency and intraclass correlation coefficients =>0.73, reliability is high. Validity of the MacNew was examined with factor analysis and three core underlying factors, physical, emotional, and social, were identified, explaining 63.0 – 66.5% of the observed variance and replicated in the translations with psychometric data. Construct validity of the MacNew was further demonstrated by extensive substantiation of the logical relationships, defined a priori, between items and other comparison tools. The MacNew is responsive and sensitive to changes in HRQL following various interventions for patients with heart disease with 11 of 13 effect size statistics >0.80. Taking an average of 10 minutes or less to complete, the respondent-burden for the MacNew is low and its acceptability is demonstrated by response rates of over 90%. Normative data are available for patients with myocardial infarction, angina, and heart failure in the English version. CONCLUSION: The MacNew may be a valuable tool for assessing and evaluating health related quality of life in patients with heart disease

An examination of the care and career experiences of mid-life women who combine formal employment and informal caring of dependent adults

This thesis is based on the care and career experiences of mid-life (ages 45 – 65) women engaging in paid employment alongside informal caring of dependent adults. It was carried out within the context of a growing ‘social care crisis’ in the wake of depleting social and healthcare resources and government policies encouraging people to ‘care for their own’, alongside policies to boost the employment of older workers. Calendar interviews with 30 mid-life women with experience of caring and paid employment in Leicester and Leicestershire were conducted between June and December 2016. This research took place within the interpretive paradigm, with the aim of hearing from women about their experiences in their own voices. The study draws upon three intersecting areas of literature and theory around concepts of work, careers and caring, to make sense of the women’s experiences. As a result, the study reveals key themes: the negative and positive impacts of caring on formal career trajectories; changing perspectives on concepts of work and the notion of care as ‘work’; understandings of career, and the emergence of care as an ‘unexpected career’, which helps in conceptualising women’s careers. The study contributes empirically by generating further knowledge and understanding of caring and career, particularly as there are limited existing qualitative studies in this area. Through analysis of the careers of participants, a typology of women’s formal careers affected by caring and a typology of informal caring careers were developed, providing frameworks for the study of women’s careers. The thesis identifies the notion of women’s polymorphic careers, demonstrated through the development of a new model of women’s formal and informal caring careers. It also offers recommendations for both policy and practice. This includes greater support from local and national government, provision of information and training to carers. It is also important for workplaces to understand the moral and business case for supporting working carers, having clear policies which are structured, with consistent support but also flexible enough to be personalised to individual circumstances. Furthermore, line managers should be given training, support and time to engage with their employees and to understand all aspects of their development. Finally, the thesis concludes with areas for possible future research incorporating further longitudinal study, different participant groups, and applying the model to different contexts