The role of small RNAs in Paget's associated osteosarcoma

Small RNAs (sRNAs) are a class of non-coding RNA molecules that arekey regulators of gene expression. SRNAs are also specific biomarkersdue to their dysregulation in disease. Next generation sequencing is thegold standard for sRNA discovery, profiling and expression analysis.Bias has been found in different platforms of sequencing due to RNAligase preference for sequence complementarity between sRNA andadapters. We developed high definition (HD) adapters to overcome thebias. We applied the use of HD adapters and sequencing to our studiesof bone cancer. One of these studies investigated sRNA expression inPaget’s associated osteosarcoma, a rare complication of Paget’s diseaseof bone that carries a poor prognosis. We found that expression of amicroRNA, miR-16, was highly expressed in Paget’s associated osteo-sarcoma tissue when compared to controls and Paget’s disease of bone.Bioinformatics analysis revealed miR-16 directly targets the sequesto-some 1 (SQSTM1) messenger RNA. SQSTM1 protein has long been as-sociated with Paget’s disease of bone development. SQSTM1 was hy-pothesised to be involved with transformation to osteosarcoma asSQSTM1 variants are positively associated with disease severity. Wespeculated that negative regulation of SQSTM1 by miR-16 incapacitatesSQSTM1’s role in the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-like 2 (NFE2L2) pathway, a major cellulardefence mechanism against oxidative stress and cancer development.Molecular testing may help provide a robust diagnosis and is particu-larly useful in rare cancers such as Paget’s associated osteosarcomawhere transformation is often missed until late stage. We are now in-vestigating this biological data further, using single cell simultaneousgenome and transcriptome sequencing

Paget's disease of bone-associated osteosarcoma: molecular basis, signs and symptoms, treatment and research

Darrell Green is a Big C-funded molecular biologist at the University of East Anglia, performing research towards a PhD. He works with Professor Tamas Dalmay, Head of Biological Sciences and Chair of RNA Biology at the University of East Anglia and Professor Bill Fraser who is a Trustee of The Paget’s Association, Director of The Norfolk Bone and Joint Centre, the Bioanalytical Facility and Head of Department of Medicine at Norwich Medical School and Consultant Metabolic Physician at the Norfolk and Norwich University Hospital. Here they discuss the molecular basis of Paget’s associated osteosarcoma, identifi cation of patients at risk, signs and symptoms, treatment and current research

The role of small RNAs in Paget's associated osteosarcoma

Small RNAs (sRNAs) are a class of non-coding RNA molecules that arekey regulators of gene expression. SRNAs are also specific biomarkersdue to their dysregulation in disease. Next generation sequencing is thegold standard for sRNA discovery, profiling and expression analysis.Bias has been found in different platforms of sequencing due to RNAligase preference for sequence complementarity between sRNA andadapters. We developed high definition (HD) adapters to overcome thebias. We applied the use of HD adapters and sequencing to our studiesof bone cancer. One of these studies investigated sRNA expression inPaget’s associated osteosarcoma, a rare complication of Paget’s diseaseof bone that carries a poor prognosis. We found that expression of amicroRNA, miR-16, was highly expressed in Paget’s associated osteo-sarcoma tissue when compared to controls and Paget’s disease of bone.Bioinformatics analysis revealed miR-16 directly targets the sequesto-some 1 (SQSTM1) messenger RNA. SQSTM1 protein has long been as-sociated with Paget’s disease of bone development. SQSTM1 was hy-pothesised to be involved with transformation to osteosarcoma asSQSTM1 variants are positively associated with disease severity. Wespeculated that negative regulation of SQSTM1 by miR-16 incapacitatesSQSTM1’s role in the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-like 2 (NFE2L2) pathway, a major cellulardefence mechanism against oxidative stress and cancer development.Molecular testing may help provide a robust diagnosis and is particu-larly useful in rare cancers such as Paget’s associated osteosarcomawhere transformation is often missed until late stage. We are now in-vestigating this biological data further, using single cell simultaneousgenome and transcriptome sequencing

Review of Gender and the Victorian Periodical

\u27We are dominated by Journalism\u27 \u27a really remarkable power\u27, Oscar Wilde observed, not entirely neutrally, in \u27The Soul of Man under Socialism\u27 published in the Fortnightly Review in 1891. Like many of his contemporaries, Wilde recognized not only the power of the press, but also its modernity. In this wide ranging and important study Hilary Fraser, Stephanie Green and Judith Johnston argue that precisely because of its power the periodical press occupied a central position in the construction of gender in Victorian cultural history. Journalism was gendered masculine by those who accorded it a lofty status within the profession of letters, they suggest. It was just as insistently gendered feminine by those who denigrated writing for the press. Hence Matthew Arnold\u27s description of the so-called \u27New Journalism\u27 in 1887 as \u27full of ability, novelty, variety, sensation, sympathy, generous instincts; its one great fault is that it is featherbrained\u27, - all attributes conventionally associated with women. Ironically the increasing number of women who joined the ranks of journalists as the century progressed served to downgrade the periodical press still further, by emphasizing its femininity. But for emerging writers like Marian Evans, Harriet Martineau, Margaret Oliphant and Eliza Lynn Linton earlier in the century the press provided a platform from which their careers were launched. Just as anonymity permitted men \u27never meant for authors\u27 to enter the writing profession, it gave women with literary ambitions an opportunity to write for publication. Fraser and Johnston quote Daniel Brown\u27s comment that the periodical essay became \u27the Trojan horse that allowed women writers to enter the male preserve of professional writing\u27. And their male counterparts were aware of their arrival. G. H. Lewes\u27s article \u27The Condition of Authors in England, Germany and France\u27 (1847) despite its jocular tone, reveals anxiety about the infiltration of the masculine writing profession by \u27speculators\u27 - \u27women, children, and ill-trained troops\u27. A subsequent article in The Leader, \u27A Gentle Hint to Writing Women\u27 (1850), continued the military metaphor, claiming that \u27women have made an invasion of our legitimate domain\u27 - \u27they are ruining our profession\u27 - \u27My idea of a perfect woman\u27, the article concludes, \u27is of one who can write but won\u27t\u27 , an unexpected comment, as the authors observe, by the man who was to become George Eliot\u27s consort

Three-Pronged Strings and 1/4 BPS States in N=4 Super-Yang-Mills Theory

We provide an explicit construction of 1/4 BPS states in four-dimensional N=4 Super-Yang-Mills theory with a gauge group SU(3). These states correspond to three-pronged strings connecting three D3-branes. We also find curves of marginal stability in the moduli space of the theory, at which the above states can decay into two 1/2 BPS states.Comment: LaTex file, 15 pages, 5 postscript figures; misprints corrected, references added, comment on spin>1 added at the end of section 4.

Media and Information Education in the UK - A Report for the EU / COST: Transforming Audiences Project

This is a position paper on the capacity for media and information education in the UK in 2014 to facilitate media, digital and information literacy as defined by the European Commission (EC) and on the relationship between UK media/information education, regulation and law. Because the UK has a long tradition of media education within the formal curriculum (schools and colleges), the premise of this report is that the most tangible evidence of media literacy education is to be found in the teaching of Media Studies at GCSE and A-level and in higher education. Therefore the most substantive section of the report is analysis of the extent to which achievement in Media Studies can be mapped against the EC objectives for media literacy. For this purpose, media education in the mainstream curriculum is measured for its capacity to develop media literacy against a pragmatic working model derived from publications from the EC, COST/ANR, UNESCO and the UK regulator, Ofcom. Information education is currently a distinct category from media education in the UK, with a mandate for entitlement (in the case of e-safety) but without formal qualifications or assessment. The report demonstrates that the composite model of media literacy is too broad in scope and ambition for mainstream education to ‘deliver’. The model derived for this analysis, from EC, COST and Ofcom documents and reports, covers public sphere engagement and empowerment outcomes, a broad range of stakeholders, an equally broad range of media/information content/contexts and a pedagogic intention to combine cultural, critical and creative learning. This analysis of formal media education concludes that the performance criteria and assessment objectives of teaching specifications and awarding body marking materials, combined with the achievement rates in the A and A* grade boundaries, indicate that only a small percentage of people studying media in the curriculum can be said to acquire all the cultural, critical and creative learning. Furthermore, specifications, combined with teacher choices, cover a relatively narrow range of the media/information contexts included in the COST definition. Finally, topic choice means that public sphere engagement and citizen empowerment is difficult to relate to achievement in Media Studies. Therefore the great success of the UK in providing media education in the mainstream curriculum (currently threatened by curriculum reforms for 2016) is balanced by the lack of a coherent match between curriculum content, assessment modes and media literacy policy objectives. There is therefore a fundamental mismatch between the objectives of media literacy as articulated in policy and the capacity of education as the agent for its development in society. Related to this, media literacy/education is mistakenly burdened with responsibility for fixing access and engagement barriers that are media producer/design/regulation issues. The data and analysis in this report supports that view. The UK is currently very well placed to provide media literacy through media education, given the status of Media Studies as an established curriculum subject. However, to coherently match Media Studies to the policy objectives for media literacy expressed in EC, COST and Ofcom statements, funding (for teacher training), and government support and endorsement for Media Studies is essential. Given the uncertainty over the continuation of Media Studies in the formal curriculum in secondary and further education, this is unlikely to be supported within the UK. This report on the state of UK Media Education in 2014 is one of 28 reports mapping the state of Media Education in each of the EC member states. All reports can be found at www.translit.f

Binary companions of nearby supernova remnants found with Gaia

© ESO, 2017. Aims. We search for runaway former companions of the progenitors of nearby Galactic core-collapse supernova remnants (SNRs) in the Tycho-Gaia astrometric solution (TGAS). Methods. We look for candidates among a sample of ten SNRs with distances 2kpc, taking astrometry and G magnitude from TGAS and B,V magnitudes from the AAVSO Photometric All-Sky Survey (APASS). A simple method of tracking back stars and finding the closest point to the SNR centre is shown to have several failings when ranking candidates. In particular, it neglects our expectation that massive stars preferentially have massive companions. We evolve a grid of binary stars to exploit these covariances in the distribution of runaway star properties in colour - magnitude - ejection velocity space. We construct an analytic model which predicts the properties of a runaway star, in which the model paramet ers are the location in the grid of progenitor binaries and the properties of the SNR. Using nested sampling we calculate the Bayesian evidence for each candidate to be the runaway and simultaneously constrain the properties of that runaway and of the SNR itself. Results. We identify four likely runaway companions of the Cygnus Loop (G074.0-08.5), HB 21 (G089.0+ 04.7), S147 (G180.0+ 01.7) and the Monoceros Loop (G205.5+ 00.5). HD 37424 has previously been suggested as the companion of S147, however the other three stars are new candidates. The favoured companion of HB 21 is the Be star BD+50 3188 whose emission-line features could be explained by pre-supernova mass transfer from the primary. There is a small probability that the 2M candidate runaway TYC 2688-1556-1 associated with the Cygnus Loop is a hypervelocity star. If the Monoceros Loop is related to the on-going star formation in the Mon OB2 association, the progenitor of the Monoceros Loop is required to be more massive than 40M which is in tension with the posterior for our candidate runaway star HD 261393.DPB is grateful to the Science and Technology Facilities Council (STFC) for providing Ph.D. funding. M.F. is supported by a Royal Society – Science Foundation Ireland University Research Fellowship. This work was partly supported by the European Union FP7 programme through ERC grant number 320360. RGI thanks the STFC for funding his Rutherford fellowship under grant ST/L003910/1 and Churchill College, Cambridge for his fellowship

Methods of treatment and diagnosis of tumours

The invention relates to a method of treating a cartilage matrix-forming bone tumour and/or a metastatic cancer originating from a cartilage matrix-forming bone tumour, for example chondrosarcoma, in which one or more of an inhibitor of RUNX2 activity, an inhibitor of RUNX2 expression, an inhibitor of YBX1 activity and an inhibitor of YBX1 expression, is administered to a subject in need thereof. The invention also relates to an in vitro method for detecting the presence of a cartilage matrix-forming bone tumour in a subject or the risk of a subject developing a cartilage matrix-forming bone tumour, for example chondrosarcoma, in which the following steps are performed: (i) measuring the expression level of at least one of RUNX2 and YBX1 in a biological sample obtained from a subject , and (ii) com paring the expression level of RUNX2 and/or YBX1 in the biological sample obtained from the subject with the respective expression level of RUNX2 and/or YBX1 in normal cartilage or other biological material. A higher expression level of RUNX2 and/or YBX1 in the biological sample obtained from the subject compared to the respective expression level of RUNX2 and/or YBX1 in the normal cartilage or other biological material indicates the presence of or an increased risk of developing a cartilage matrix-forming bone tumour