Safety Grand Challenge: Safe Ship Boarding and Thames Safest River 2030

This report describes the first Lloyd’s Register Foundation Safety Grand Challenge and details how a collaborative, cross disciplinary design research and teaching methodology can provide a platform for a broad variety of participants to develop projects in a complex design safety environment, encourage collaboration and industrial involvement in design education and contribute to a balance between technological developments and the needs of people in the future. The Royal College of Art, generously supported by the Lloyd’s Register Foundation and working with a group of industry stakeholders, investigated two major areas of risk within the maritime context: Sea Safe transfers from ship to ship, and making the Thames the safest city river by the year 2030. In a four month project, thirty two post graduate participants from eleven disciplines and six researcher-tutors at the Royal College of Art worked together and tackle these complex and wicked design challenges using a number of novel design methods. With a focus on finding cutting edge innovative design solution that would reduce risk on the ship to ship transfer and on increasing safety on the River Thames, the research project explored a wide range of approaches that encouraged collaboration, innovation and risk taking in design research practice. The different cultures, practices and knowledge bases led to an array of eight pioneering design solutions, ranging from product-focused innovations through to systemic solutions, material innovations and educational strategies. This report makes a case for the culture of design engaging with risk on water in the context of the wicked problems (Rittel & Webber, 1973; Buchanan, 1992) we identified, the methods and techniques used to tackle these challenges, how cross disciplinary projects can lead to novel insights, and how design education can be used to engage with industry and users to bridge the gap between technological innovation and user needs. Our conclusions support the view that this approach can develop implementable new design for safety solutions, incorporate the social, cultural and psychological human factors into safety design and balances users’ needs by engagement through an appropriate use of technology. Furthermore, we uncover insights into training designers for safety critical environments and the implications this has in terms of projects, cross disciplinarity and practices in the role of design thinking in general and relating to the context of risk and safety at sea and on rivers

Collaborating Design Risk

The “Safety Grand Challenge” is a collaborative research project between the Royal College of Art (RCA) School of Design, and the Lloyd's Register Foundation (LRF). The maritime industry is dominated by “grandfathering” leading to a slow-pace of adopting innovations that can reduce risk and save lives at sea. We describe how impact was achieved through collaboration and design innovations that bridged the risk gap between technologies and human behaviours. Starting from the project brief we designed a collaborative platform that supported a constructive dialogue between academia and partner organisations that aimed to foster innovative design approaches to risk and safety. The project generated an engaged community with diverse expertise that influenced the outcomes which included seven prototypes designed by a group of thirty postgraduates from across the RCA. Throughout the course of the project the network extended to other partners beyond the initial ones that included the RCA, LRF and Royal National Lifeboat Institution. The “Safety Grand Challenge” demonstrates how research can be an explorative platform that offers opportunities to analyse and design solutions to real life safety problems in mature industries through the prototypes that reflect the sophistication of the project’s collaborations. Our conclusions support how design research helped identify the value of design for safety in tackling complex issues that intertwine human, environmental and commercial views and can shape new forms of collaborative research between academia and industrial partners

Viral oncolysis that targets raf-1 signaling control of nuclear transport

The central role of Raf protein kinase isoforms in human cancer demands specific anti-Raf therapeutic inhibitors. Parvoviruses are currently used in experimental cancer therapy due to their natural oncotropism and lytic life cycle. In searching for mechanisms underlying parvovirus oncolysis, we found that trimers of the major structural protein (VP) of the parvovirus minute virus of mice (MVM), which have to be imported into the nucleus for capsid assembly, undergo phosphorylation by the Raf-1 kinase. Purified Raf-1 phosphorylated the capsid subunits in vitro to the two-dimensional pattern found in natural MVM infections. VP trimers isolated from mammalian cells translocated into the nucleus of digitonin-permeabilized human cells. In contrast, VP trimers isolated from insect cells, which are devoid of Raf-1, were neither phosphorylated nor imported into the mammalian nucleus. However, the coexpression of a constitutively active Raf-1 kinase in insect cells restored VP trimer phosphorylation and nuclear transport competence. In MVM-infected normal and transformed cells, Raf-1 inhibition resulted in cytoplasmic retention of capsid proteins, preventing their nuclear assembly and progeny virus maturation. The level of Raf-1 activity in cancer cells was consistent with the extent of VP specific phosphorylation and with the permissiveness to MVM infection. Thus, Raf-1 control of nuclear translocation of MVM capsid assembly intermediates provides a novel target for viral oncolysis. MVM may reinforce specific therapies against frequent human cancers with deregulated Raf signaling. © 2010, American Society for Microbiology. All Rights Reserved.This study was supported by grants from the Spanish Ministerio de Ciencia e Innovación (SAF2008-03238) and Comunidad de Madrid (S-SAL/0185/2006) to the laboratory of J.M.A. and by an institutional grant from Fundación Ramón Areces to the Centro de Biología Molecular “Severo Ochoa.” L.R. was supported in part by a short-term EMBO fellowship.Peer Reviewe

Safety Grand Challenge: Safe Ship Boarding & Thames Safest River 2030

This report describes the first Lloyd’s Register Foundation Safety Grand Challenge and details how a collaborative, cross disciplinary design research and teaching approach can provide a platform for a broad variety of participants to develop projects in a complex design safety environment, encourage collaboration and industrial involvement in design education and contribute to a balance between technological developments and the needs of people in the future. The Royal College of Art, generously supported by the Lloyd’s Register Foundation and working with a group of industry stakeholders, investigated two major areas of risk within the maritime context: Sea Safe transfers from ship to ship, and making the Thames the safest city river by the year 2030. In a four month project, thirty-two postgraduate participants from eleven disciplines and six researcher-tutors at the Royal College of Art worked together to tackle these complex and wicked design challenges using a number of novel design methods. With a focus on finding cutting-edge innovative design solutions that would reduce risk on the ship to ship transfer and on increasing safety on the River Thames, the research project explored a wide range of approaches that encouraged collaboration, innovation and risk taking in design research practice. The different cultures, practices and knowledge bases led to an array of eight pioneering design solutions, ranging from product-focused innovations through to systemic solutions, material innovations and educational strategies. This report makes a case for the culture of design engaging with risk on water in the context of the wicked problems (Rittel & Webber, 1973; Buchanan, 1992) we identified, the methods and techniques used to tackle these challenges, how cross disciplinary projects can lead to novel insights, and how design education can be used to engage with industry and users to bridge the gap between technological innovation and user needs. Our conclusions support the view that this approach can develop implementable new design for safety solutions, incorporate social, cultural and psychological human factors into safety design and balance users’ needs by engagement through an appropriate use of technology. Furthermore, we uncover insights into training designers for safety critical environments and the implications this has in terms of projects, cross disciplinarity and practices in the role of design thinking in general

Content validity of the Recap of atopic eczema (RECAP) instrument in Dutch, English and German to measure eczema control in young people with atopic eczema: a cognitive interview study

Background: Recap of atopic eczema (RECAP) is a patient-reported outcome measure assessing eczema control. This instrument has been developed and validated in the UK. There are self-reported and proxy-reported versions in English, Dutch and German. However, it is unclear whether the self-reported version shows adequate content validity when completed by young people (8–16 years) in these languages. Objectives: To assess the content validity (comprehensibility, relevance and comprehensiveness) of the English, German and Dutch versions of the self-reported RECAP in young people with atopic eczema and to identify the most appropriate age cutoff for self-completion. Methods: We conducted 23 semistructured cognitive interviews with young people aged 8–16 years, using the ‘think-aloud’ method. In Germany and the Netherlands, participants were recruited in dermatology clinics and in the UK through social media and existing mailing lists. Interviews were audio recorded, transcribed verbatim and analysed in the three languages, using a problem-focused coding manual. Transcripts were coded by two independent reviewers in each country. Themes were translated into English and compared across the three countries. Results: Significant age-related comprehensibility issues with the last three items of the questionnaire occurred with young people aged 8–11 years, causing difficulties completing RECAP without help. However, older children had only minor problems and were able to complete the questionnaire by themselves. The self-reported version of RECAP has sufficient content validity for self-completion in young people aged 12 years and above. However, the German version with some translational adaptations may be appropriate for children from the age of 8 years. There may be some situations where the proxy version is needed for older children too. Conclusions: The self-reported version of RECAP is appropriate for use from the age of 12 years. The proxy version can be used in children younger than 12 years. Other measurement properties should be further investigated. What is already known about this topic? Recap of atopic eczema (RECAP) is an instrument recommended by the Harmonising Outcome Measures for Eczema initiative for the core outcome domain of long-term control of atopic eczema. Content validity of RECAP for self-completion by adults and of the proxy version has been assessed. What does this study add? In this study, content validity (comprehensibility, relevance and comprehensiveness) of the self-reported version of RECAP among young people (aged 8–16 years) with atopic eczema across the UK, Germany and the Netherlands is assessed. Based on these findings, key recommendations on how to measure eczema control in young people with atopic eczema are formulated. What are the clinical implications of this work? The Dutch, English and German self-completion versions of RECAP are recommended for use in adolescents from the age of 12 years. The proxy version could be used in children younger than 12 years or where children are cognitively or physically incapable of reporting their experience of eczema control. Caregivers should be encouraged to complete RECAP together with their child where possible

Foreign rule?: transnational, national, and local perspectives on Venice and Venetia within the “multinational” empire

The history of the Habsburg Empire in the post-Napoleonic era is frequently approached from the perspective of its various component nationalities. These were traditionally portrayed in the historiography as engaged in more-or-less open struggle with control from Vienna. This article argues that the over-privileging of such national categories can distort the picture. By looking at a number of case studies – the naming of Lombardy-Venetia, the Biblioteca italiana, the Panteon veneto – the relationship between Venice (and its Terraferma) and Habsburg rule during the second Austrian domination is examined. It will be argued that it is more profitable to see Venetian identities (municipal, local, Italian, and as part of a wider transnational European culture) as capable of working for as well as against the empire, and that Habsburg policy was as often concerned with managing potential local rivalries (notably between Lombards and Venetians) as with controlling a perceived Italian threat. It is also suggested that, while cultivation of local identity was often used to reinforce the national, the Austrian authorities were also happy to annex both to further imperial interests

Secretion of Genome-Free Hepatitis B Virus – Single Strand Blocking Model for Virion Morphogenesis of Para-retrovirus

As a para-retrovirus, hepatitis B virus (HBV) is an enveloped virus with a double-stranded (DS) DNA genome that is replicated by reverse transcription of an RNA intermediate, the pregenomic RNA or pgRNA. HBV assembly begins with the formation of an “immature” nucleocapsid (NC) incorporating pgRNA, which is converted via reverse transcription within the maturing NC to the DS DNA genome. Only the mature, DS DNA-containing NCs are enveloped and secreted as virions whereas immature NCs containing RNA or single-stranded (SS) DNA are not enveloped. The current model for selective virion morphogenesis postulates that accumulation of DS DNA within the NC induces a “maturation signal” that, in turn, triggers its envelopment and secretion. However, we have found, by careful quantification of viral DNA and NCs in HBV virions secreted in vitro and in vivo, that the vast majority of HBV virions (over 90%) contained no DNA at all, indicating that NCs with no genome were enveloped and secreted as empty virions (i.e., enveloped NCs with no DNA). Furthermore, viral mutants bearing mutations precluding any DNA synthesis secreted exclusively empty virions. Thus, viral DNA synthesis is not required for HBV virion morphogenesis. On the other hand, NCs containing RNA or SS DNA were excluded from virion formation. The secretion of DS DNA-containing as well as empty virions on one hand, and the lack of secretion of virions containing single-stranded (SS) DNA or RNA on the other, prompted us to propose an alternative, “Single Strand Blocking” model to explain selective HBV morphogenesis whereby SS nucleic acid within the NC negatively regulates NC envelopment, which is relieved upon second strand DNA synthesis

Gene-Disease Network Analysis Reveals Functional Modules in Mendelian, Complex and Environmental Diseases

Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download