Discovering functional modules by identifying recurrent and mutually exclusive mutational patterns in tumors

<p>Abstract</p> <p>Background</p> <p>Assays of multiple tumor samples frequently reveal recurrent genomic aberrations, including point mutations and copy-number alterations, that affect individual genes. Analyses that extend beyond single genes are often restricted to examining pathways, interactions and functional modules that are already known.</p> <p>Methods</p> <p>We present a method that identifies functional modules without any information other than patterns of recurrent and mutually exclusive aberrations (RME patterns) that arise due to positive selection for key cancer phenotypes. Our algorithm efficiently constructs and searches networks of potential interactions and identifies significant modules (RME modules) by using the algorithmic significance test.</p> <p>Results</p> <p>We apply the method to the TCGA collection of 145 glioblastoma samples, resulting in extension of known pathways and discovery of new functional modules. The method predicts a role for <it>EP300 </it>that was previously unknown in glioblastoma. We demonstrate the clinical relevance of these results by validating that expression of <it>EP300 </it>is prognostic, predicting survival independent of age at diagnosis and tumor grade.</p> <p>Conclusions</p> <p>We have developed a sensitive, simple, and fast method for automatically detecting functional modules in tumors based solely on patterns of recurrent genomic aberration. Due to its ability to analyze very large amounts of diverse data, we expect it to be increasingly useful when applied to the many tumor panels scheduled to be assayed in the near future.</p

Structural determinants of Sleeping Beauty transposase activity

Transposases are important tools in genome engineering, and there is considerable interest in engineering more efficient ones. Here, we seek to understand the factors determining their activity using the Sleeping Beauty transposase. Recent work suggests that protein coevolutionary information can be used to classify groups of physically connected, coevolving residues into elements called "sectors", which have proven useful for understanding the folding, allosteric interactions, and enzymatic activity of proteins. Using extensive mutagenesis data, protein modeling and analysis of folding energies, we show that (i) The Sleeping Beauty transposase contains two sectors, which span across conserved domains, and are enriched in DNA-binding residues, indicating that the DNA binding and endonuclease functions of the transposase coevolve; (ii) Sector residues are highly sensitive to mutations, and most mutations of these residues strongly reduce transposition rate; (iii) Mutations with a strong effect on free energy of folding in the DDE domain of the transposase significantly reduce transposition rate. (iv) Mutations that influence DNA and protein-protein interactions generally reduce transposition rate, although most hyperactive mutants are also located on the protein surface, including residues with protein-protein interactions. This suggests that hyperactivity results from the modification of protein interactions, rather than the stabilization of protein fold.Molecular Therapy (2016); doi:10.1038/mt.2016.110

Irish and Scottish poetry in the Romantic era

Ireland and Scotland witnessed a huge explosion in the publication of printed verse in the Romantic era as a plethora of poets ventured into print in the wake of Robert Burn’s Kilmarnock edition. They produced an interesting and diverse, yet largely neglected, body of verse which is characterised by aesthetic, stylistic and linguistic variety. A re-evaluation of this body of literature casts new light on the interconnections between Scottish and Irish literary traditions. The links between Irish and Scottish poets and contemporise and predecessors from other parts of the archipelago, and their involvement in wider literary trends, also suggests that Romanticism could be re-configured as an archipelagic phenomenon. There were certainly potent Hiberno-Scottish links during this period as is demonstrated by the work of Thomas Dermody and James Orr, who were profoundly influenced by Burns. This thesis identifies and studies a series of inter-connected genres that achieved a particular resonance in Ireland and Scotland during the Romantic era. The New Year poem, the apparition poem, the valediction, the self-elegy, the graveyard meditation, the Habbie elegy and dying words all draw on the motif of loss and all become conspicuous features of the literary terrain. The use of genre as an organising paradigm means that a wide range of texts can be discussed and a sense of the variety of aesthetic and stylistic approaches adopted by Irish and Scottish poets of the period can be conveyed. By employing comparative paradigms and organising the study by genre, national barriers can be transcended and Ireland and Scotland’s interwoven literary histories are thrown into sharp focus. These genres demonstrate the agreements and divergences that characterise Irish and Scottish literature of the Romantic era. Several of them demonstrate the traditionally overlooked influence of Scottish literature, and in particular the poetry of Burns on Irish poets. Other genres, meanwhile, demonstrate that contrasting historical, political and cultural contexts could manifest themselves in divergences in the way the genres were manipulated in Ireland and Scotland.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Labour mobility: the ten billion dollar prize

Pacific Island countries face unique development challenges. Given their youth bulge, unemployment is a pressing problem. Where these countries are unable to bring jobs to the people, the alternative is to bring the people to where the jobs are. Expanding labour mobility is vital for the future of the Pacific region. And advanced economies around the Pacific Rim will need migrants in the coming years to fill gaps in their domestic labour markets. This is especially likely in sectors that often struggle to attract domestic workers, such as aged care. Australia and New Zealand both have deep interests in a stable and prosperous Pacific, interests that would be advanced by increased Pacific labour mobility. Taking a long-term view, the report shows what is possible through overseas employment for Pacific Islanders.This report was commisioned by Pacific Possibl

Fetal umbilical artery Doppler pulsatility index and childhood neurocognitive outcome at 12 years

OBJECTIVE: To determine whether an elevated fetal umbilical artery Doppler (UAD) pulsatility index (PI) at 28 weeks’ gestation, in the absence of fetal growth restriction (FGR) and prematurity, is associated with adverse neurocognitive outcome in children aged 12 years. METHODS: Prospective cohort study, comparing children with a normal fetal UAD PI (<90th centile) (n=110) and those with an elevated PI (≥90th centile) (n=40). UAD was performed at 28, 32 and 34 weeks gestation. At 12 years of age, all children were assessed under standardised conditions at Queen's University, Belfast, UK to determine cognitive and behavioural outcomes using the British Ability Score-II and Achenbach Child Behavioural Checklist Parent Rated Version under standardised conditions. Regression analysis was performed, controlling for confounders such as gender, socioeconomic status and age at assessment. RESULTS: The mean age of follow-up was 12.4 years (±0.5 SD) with 44% of children male (n=63). When UAD was assessed at 28 weeks, the elevated fetal UAD group had lower scores in cognitive assessments of information processing and memory. Parameters included (1) recall of objects immediate verbal (p=0.002), (2) delayed verbal (p=0.008) and (3) recall of objects immediate spatial (p=0.0016). There were no significant differences between the Doppler groups at 32 or 34 weeks' gestation. CONCLUSIONS: An elevated UAD PI at 28 weeks' gestation in the absence of FGR or prematurity is associated with lower scores of declarative memory in children aged 12 years. A potential explanation for this is an element of placental insufficiency in the presence of the appropriately grown fetus, which affects the development of the fetal hippocampus and information processing and memory long-term. These findings, however, had no impact on overall academic ability, mental processing and reasoning or overall behavioural function

Early practical experience and the social responsiveness of clinical education: systematic review

Objectives To find how early experience in clinical and community settings (“early experience”) affects medical education, and identify strengths and limitations of the available evidence. Design A systematic review rating, by consensus, the strength and importance of outcomes reported in the decade 1992-2001. Data sources Bibliographical databases and journals were searched for publications on the topic, reviewed under the auspices of the recently formed Best Evidence Medical Education (BEME) collaboration. Selection of studies All empirical studies (verifiable, observational data) were included, whatever their design, method, or language of publication. Results Early experience was most commonly provided in community settings, aiming to recruit primary care practitioners for underserved populations. It increased the popularity of primary care residencies, albeit among self selected students. It fostered self awareness and empathic attitudes towards ill people, boosted students' confidence, motivated them, gave them satisfaction, and helped them develop a professional identity. By helping develop interpersonal skills, it made entering clerkships a less stressful experience. Early experience helped students learn about professional roles and responsibilities, healthcare systems, and health needs of a population. It made biomedical, behavioural, and social sciences more relevant and easier to learn. It motivated and rewarded teachers and patients and enriched curriculums. In some countries, junior students provided preventive health care directly to underserved populations. Conclusion Early experience helps medical students learn, helps them develop appropriate attitudes towards their studies and future practice, and orientates medical curriculums towards society's needs. Experimental evidence of its benefit is unlikely to be forthcoming and yet more medical schools are likely to provide it. Effort could usefully be concentrated on evaluating the methods and outcomes of early experience provided within non-experimental research designs, and using that evaluation to improve the quality of curriculums

How can experience in clinical and community settings contribute to early medical education? A BEME systematic review

Review date: Review period January 1992-December 2001. Final analysis July 2004-January 2005. Background and review context: There has been no rigorous systematic review of the outcomes of early exposure to clinical and community settings in medical education. Objectives of review: (1) Identify published empirical evidence of the effects of early experience in medical education, analyse it, and synthesize conclusions from it. (2) Identify the strengths and limitations of the research effort to date, and identify objectives for future research. Search strategy: Ovid search of. BEI, ERIC, Medline, CIATAHL and EMBASE Additional electronic searches of: Psychinfo, Timelit, EBM reviews, SIGLE, and the Cochrane databases. Hand-searches of: Medical Education, Medical Teacher, Academic Medicine, Teaching and Learning in Medicine, Advances in Health Sciences Education, Journal of Educational Psychology. Criteria: Definitions: Experience: Authentic (real as opposed to simulated) human contact in a social or clinical context that enhances learning of health, illness and/or disease, and the role of the health professional. Early: What would traditionally have been regarded as the preclinical phase, usually the first 2 years. Inclusions: All empirical studies (verifiable, observational data) of early experience in the basic education of health professionals, whatever their design or methodology, including papers not in English. Evidence from other health care professions that could be applied to medicine was included. Exclusions: Not empirical; not early; post-basic; simulated rather than 'authentic' experience. Data collection: Careful validation of selection processes. Coding by two reviewers onto an extensively modified version of the standard BEME coding sheet. Accumulation into an Access database. Secondary coding and synthesis of an interpretation. Headline results: A total of 73 studies met the selection criteria and yielded 277 educational outcomes; 116 of those outcomes (from 38 studies) were rated strong and important enough to include in a narrative synthesis of results; 76% of those outcomes were from descriptive studies and 24% from comparative studies. Early experience motivated and satisfied students of the health professions and helped them acclimatize to clinical environments, develop professionally, interact with patients with more confidence and less stress, develop self-reflection and appraisal skill, and develop a professional identity. It strengthened their learning and made it more real and relevant to clinical practice. It helped students learn about the structure and function of the healthcare system, and about preventive care and the role of health professionals. It supported the learning of both biomedical and behavioural/social sciences and helped students acquire communication and basic clinical skills. There were outcomes for beneficiaries other than students, including teachers, patients, populations, organizations and specialties. Early experience increased recruitment to primary care/rural medical practice, though mainly in US studies which introduced it for that specific purpose as part of a complex intervention. Conclusions: Early experience helps medical students socialize to their chosen profession. It. helps them acquire a range of subject matter and makes their learning more real and relevant. It has potential benefits for other stakeholders, notably teachers and patients. It can influence career choices