Legitimacy in conflict: concepts, practices, challenges

The study of legitimacy in situations of conflict and peacebuilding has increased in recent years. However, current work on the topic adopts many assumptions, definitions, and understandings from classical legitimacy theory, which centers on the relationship between the nation-state and its citizens. In this introduction, we provide a detailed critical overview of current theories of legitimacy and legitimation and demonstrate why they have only limited applicability in conflict and post-conflict contexts, focusing on the three main areas that the articles included in this special issue examine: audiences for legitimacy, sources of legitimacy, and legitimation. In particular, we show how conflict and post-conflict contexts are marked by the fragmentation and personalization of power; the proliferation and fragmentation of legitimacy audiences; and ambiguity surrounding legitimation strategies

Increasing adhesion of 3D printing on textile fabrics by polymer coating

3D printing is a technology which has recently found its way into the fi eld of textile fabrics, from fashion design to technical textiles. By combining both technologies with their advantages, new composites with novel physical properties can be created. Increasing adhesion between both components, however, still remains challenging. This paper suggests a new method to improve the adhesion of a 3D printed object on a textile fabric by previously coating the latter with a polymer layer. In this way, adhesion can be substantially enhanced without signifi cantly changing the bending stiffness and haptic properties of a fabric. In this study, this procedure worked especially well for printing PLA (poly(lactic acid)) on PMMA (poly(methyl methacrylate)) or PLA coatings, while for printing ABS (acrylonitrile butadiene styrene), the best textile coatings were ABS and PLA

Germline TERT promoter mutations are rare in familial melanoma.

Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.The authors would like to thank the families for their willingness to participate; and Rajiv Kumar for the provision of mutation positive samples. The collection of samples in the UK population-ascertained sample set was funded by Cancer Research UK (awards C588/A19167 and C8216/A6129) and by the NIH (CA83115). The work of N.A.G. and R.v.D was supported by the Dutch Cancer Society (UL 2012-5489). D.J.A and C.D.R.E are supported by Cancer Research UK, ERC Combat Cancer and the Wellcome Trust. N.K.H is supported by a fellowship from the National Health and Medical Research Council of Australia. A.M.D. and K.A.P. were supported by CRUK grant (C8197/A16565) and The Isaac Newton Trust. K.M.B. is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10689-015-9841-

The cost of changing physical activity behaviour: Evidence from a "physical activity pathway" in the primary care setting

Copyright @ 2011 Boehler et al.BACKGROUND: The ‘Physical Activity Care Pathway’ (a Pilot for the ‘Let’s Get Moving’ policy) is a systematic approach to integrating physical activity promotion into the primary care setting. It combines several methods reported to support behavioural change, including brief interventions, motivational interviewing, goal setting, providing written resources, and follow-up support. This paper compares costs falling on the UK National Health Service (NHS) of implementing the care pathway using two different recruitment strategies and provides initial insights into the cost of changing physical activity behaviour. METHODS: A combination of a time driven variant of activity based costing, audit data through EMIS and a survey of practice managers provided patient-level cost data for 411 screened individuals. Self reported physical activity data of 70 people completing the care pathway at three month was compared with baseline using a regression based ‘difference in differences’ approach. Deterministic and probabilistic sensitivity analyses in combination with hypothesis testing were used to judge how robust findings are to key assumptions and to assess the uncertainty around estimates of the cost of changing physical activity behaviour. RESULTS: It cost £53 (SD 7.8) per patient completing the PACP in opportunistic centres and £191 (SD 39) at disease register sites. The completer rate was higher in disease register centres (27.3% vs. 16.2%) and the difference in differences in time spent on physical activity was 81.32 (SE 17.16) minutes/week in patients completing the PACP; so that the incremental cost of converting one sedentary adult to an ‘active state’ of 150 minutes of moderate intensity physical activity per week amounts to £ 886.50 in disease register practices, compared to opportunistic screening. CONCLUSIONS: Disease register screening is more costly than opportunistic patient recruitment. However, additional costs come with a higher completion rate and better outcomes in terms of behavioural change in patients completing the care pathway. Further research is needed to rigorously evaluate intervention efficiency and to assess the link between behavioural change and changes in quality adjusted life years (QALYs).This article is available through the Brunel Open Access Publishing Fund

Vitamin D-VDR signaling inhibits Wnt/beta-catenin-mediated melanoma progression and promotes anti-tumor immunity

1α,25-dihydroxyvitamin D3 signals via the Vitamin D Receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As melanoma patients commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signalling and replicated the findings in TCGA metastases. VDR expression was independently protective for melanoma death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating anti-tumor immunity and correspondingly with higher imputed immune cell scores and histologically detected tumor infiltrating lymphocytes (TILs). High VDR expressing tumors had downregulation of proliferative pathways, notably Wnt/beta-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (< 25 nmol/l ~ 10 ng/ml) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/beta-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail vein metastasis assays. In summary, vitamin D-VDR signaling contributes to controlling pro-proliferative/immunosuppresive Wnt/beta-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of the causal relationship between vitamin D-VDR signaling and melanoma survival which should be explored as a therapeutic target in primary resistance to checkpoint blockade

Towards an Economy of Higher Education

This paper draws a distinction between ways thinking and acting, and hence of policy and practice in higher education, in terms of different kinds of economy: economies of exchange and economies of excess. Crucial features of economies of exchange are outlined and their presence in prevailing conceptions of teaching and learning is illustrated. These are contrasted with other possible forms of practice, which in turn bring to light the nature of an economy of excess. In more philosophical terms, and to expand on the picture, economies of excess are elaborated with reference, first, to the understanding of alterity in the work of Emmanuel Levinas and, second, to the idea of Dionysian intensity that is to be found in Nietzsche. In the light of critical comment on some current directions in policy and practice, the implications of these ways of thinking for the administrator, the teacher and the student in higher education are explored

The Translational Medicine Ontology and Knowledge Base: driving personalized medicine by bridging the gap between bench and bedside

Background: Translational medicine requires the integration of knowledge using heterogeneous data from health care to the life sciences. Here, we describe a collaborative effort to produce a prototype Translational Medicine Knowledge Base (TMKB) capable of answering questions relating to clinical practice and pharmaceutical drug discovery. Results: We developed the Translational Medicine Ontology (TMO) as a unifying ontology to integrate chemical, genomic and proteomic data with disease, treatment, and electronic health records. We demonstrate the use of Semantic Web technologies in the integration of patient and biomedical data, and reveal how such a knowledge base can aid physicians in providing tailored patient care and facilitate the recruitment of patients into active clinical trials. Thus, patients, physicians and researchers may explore the knowledge base to better understand therapeutic options, efficacy, and mechanisms of action. Conclusions: This work takes an important step in using Semantic Web technologies to facilitate integration of relevant, distributed, external sources and progress towards a computational platform to support personalized medicine. Availability: TMO can be downloaded from http://code.google.com/p/translationalmedicineontology and TMKB can be accessed at http://tm.semanticscience.org/sparql

PTPN11 mosaicism causes a spectrum of pigmentary and vascular neurocutaneous disorders and predisposes to melanoma

Phakomatosis pigmentovascularis (PPV) is a diagnosis which denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement including central nervous system disease, asymmetrical growth and a predisposition to malignancy. Using a tightly phenotyped group and high depth next generation sequencing of affected tissues we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of PPV type III or spilorosea. Within an individual the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to demonstrate that the same variants can cause either the specific pigmentary or vascular phenotypes alone, as well as driving melanoma development within the pigmentary lesion. Protein conformational modelling highlights that while variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modelling of the missense variants confirms downstream MAPK pathway overactivation, and widespread disruption of human endothelial cell angiogenesis. Importantly, PTPN11-mosaic patients theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of naevus spilus and capillary malformation syndromes, paving the way for better clinical management

POT1 mutations predispose to familial melanoma

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.D.J.A., C.D.R.-E., Z.D., J.Z.L., J.C.T., M.P. and T.M.K. were supported by Cancer Research UK and the Wellcome Trust (WT098051). C.D.R.-E. was also supported by the Consejo Nacional de Ciencia y Tecnología of Mexico. K.A.P. and A.M.D. were supported by Cancer Research UK (grants C1287/A9540 and C8197/A10123) and by the Isaac Newton Trust. N.K.H. was supported by a fellowship from the National Health and Medical Research Council of Australia (NHMRC). L.G.A. was supported by an Australia and New Zealand Banking Group Limited Trustees PhD scholarship. A.L.P. is supported by Cure Cancer Australia. The work was funded in part by the NHMRC and Cancer Council Queensland. The work of N.A.G. was in part supported by the Dutch Cancer Society (UL 2012-5489). M.H., J.A.N.-B. and D.T.B. were supported by Cancer Research UK (programme awards C588/A4994 and C588/A10589 and the Genomics Initiative). C.L.-O., A.J.R. and V.Q. are funded by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII), the Red Temática de Investigación del Cáncer (RTICC) del ISCIII and the Consolider-Ingenio RNAREG Consortium. C.L.-O. is an investigator with the Botín Foundation.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.294

Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series

Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation. The aim is to assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT ) commonly exhibit spitzoid morphology.Medicin