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The roles digital media-technologies play in raising public issues relating to emerging technologies and their potential for engaging publics with science and policy assessments is a lively field of inquiry in Science and Technology Studies (STS). This paper presents an analysis of controversies over proposals for the large-scale removal of atmospheric carbon dioxide (CDR). The study combines a digital method (web-querying) with document analysis to map debates about two CDR approaches: bioenergy with carbon capture and storage (BECCS) and afforestation. In the first step, we locate actors using the web to engage with BECCS and afforestation and map their alignments in relation to competing framings of CDR. In a second step, we examine the devices deployed by UK-based actors to evidence and contest the feasibility of BECCS and afforestation. Our analysis shows that policy distinctions between "natural" and "engineered" CDR are used flexibly in practice and do not map neatly onto actor engagement with BECCS and afforestation. We highlight the predominance of cross-cutting techno-economic expertise and argue that framings of CDR as a solution to governing climate change may contribute to public disengagement from climate policy processes. The paper reflects on methods for studying controversies, publics, and issues emerging around processes of technoscientific assessment. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • High burden of stochastic point mutations in carcinogen-induced murine tumours. • Distinct mutational imprint in tumours arising after diethylnitrosamine exposure. • Mutations in Ras/MAPK pathway genes drive DEN-initiated liver tumorigenesis. • Apc mutations associated with progression of DEN-initiated tumours to carcinoma. Background & Aims Carcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and are critical for validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the genomic alterations driving these mouse tumour genomes are comparable to those found in human tumours. Herein, we provide a detailed genomic characterisation of tumours from a commonly used mouse model of hepatocellular carcinoma (HCC). Methods We analysed whole exome sequences of liver tumours arising in mice exposed to diethylnitrosamine (DEN). Mutational signatures were compared between liver tumours from DEN-treated and untreated mice, and human HCCs. Results DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras , in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/β-catenin signalling in cancer progression. Conclusions Our study provides detailed insight into the mutational landscape of tumours arising in a commonly used carcinogen model of HCC, facilitating the future use of this model to better understand the human disease. Lay summary Mouse models are widely used to study the biology of cancer and to test potential therapies. Herein, we have described the mutational landscape of tumours arising in a carcinogen-induced mouse model of liver cancer. Since cancer is a disease caused by genomic alterations, information about the patterns and types of mutations in the tumours in this mouse model should facilitate its use to study human liver cancer. [ABSTRACT FROM AUTHOR]

DNA methylation is an important mechanism by which gene transcription and hence cellular function are regulated. Here, we provide detailed functional genome-wide methylome maps of 5 primary peripheral blood leukocyte subsets including T cells, B cells, monocytes/macrophages, and neutrophils obtained from healthy individuals. A comparison of these methylomes revealed highly specific cell-lineage and cell-subset methylation profiles. DNA hypomethylation is known to be permissive for gene expression and we identified cell-subset-specific hypomethylated regions (HMRs) that strongly correlate with gene transcription levels suggesting these HMRs may regulate corresponding cell functions. Single-nucleotide polymorphisms associated with immune-mediated disease in genome-wide association studies preferentially localized to these cell-specific regulatory HMRs, offering insight into pathogenesis by highlighting cell subsets in which specific epigenetic changes may drive disease. Our data provide a valuable reference tool for researchers aiming to investigate the role of DNA methylation in regulating primary leukocyte function in health and immune-mediated disease. [ABSTRACT FROM AUTHOR]

Since the mid-1990s, the aim of keeping climate change within 2 °C has become firmly entrenched in policy discourses. In the past few years, the likelihood of achieving it has been increasingly called into question. The debate around what to do with a target that seems less and less achievable is, however, only just beginning. As the UN commences a two-year review of the 2 °C target, this article moves beyond the somewhat binary debates about whether or not it should or will be met, in order to analyse more fully some of the alternative options that have been identified but not fully explored in the existing literature. For the first time, uncertainties, risks, and opportunities associated with four such options are identified and synthesized from the literature. The analysis finds that the significant risks and uncertainties associated with some options may encourage decision makers to recommit to the 2 °C target as the least unattractive course of action. [ABSTRACT FROM AUTHOR]

Despite the fact that mainstreaming of climate change into existing EU sectoral policies is a key aim, empirical knowledge of how it works in practice remains scarce. With this paper we explore the degree to which climate considerations are taken into account in the implementation of one of the most influential pieces of European water legislation, the Water Framework Directive and, more importantly, we assess possible explanations for the geographical variability in levels of mainstreaming observed. Our empirical research is based on an analysis of both EU and local policy documents, as well as more than forty in-depth interviews, and shows that, for various reasons, the degree of mainstreaming that has taken place differs widely. We conclude that timely incentives and clear guidance will be necessary to ensure progress is made by all, but that a residual fear that the adaptation agenda is open to abuse by those seeking to rationalise failures to fully implement the Water Framework Directive has put a brake on the mainstreaming agenda. [ABSTRACT FROM AUTHOR]

Background: Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. Methods: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. Results: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti–proteinase 3 ANCA was associated with HLA-DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10−89, P=5.6×10−12, and P=2.6×10−7, respectively). Anti–myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10−8). Conclusions: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA–associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.) [ABSTRACT FROM PUBLISHER]

Climate change is widely recognised as a ‘wicked’ policy problem. Agreeing and implementing governance responses is proving extremely difficult. Policy makers in many jurisdictions now emphasise their ambition to govern using the best available evidence. One obvious source of such evidence is the evaluations of the performance of existing policies. But to what extent do these evaluations provide insights into the difficult dilemmas that governors typically encounter? We address this question by reviewing the content of 262 evaluation studies of European climate policies in the light of six kinds of dilemma found in the governance literature. We are interested in what these studies say about the performance of European climate policies and in their capacity to inform evidence-based policy-making. We find that the evaluations do arrive at common findings: that climate change is framed as a problem of market and/or state failure; that voluntary measures tend to be ineffective; that market-based instruments tend to be regressive; that EU-level policies have driven climate policies in the latecomer EU Member States; and that lack of monitoring and weak enforcement are major obstacles to effective policy implementation. However, we also conclude that the evidence base these studies represent is surprisingly weak for such a high profile area. There is too little systematic climate policy evaluation work in the EU to support systematic evidence-based policy making. This reduces the scope for sound policy making in the short run and is a constraint to policy learning in the longer term. [ABSTRACT FROM AUTHOR]

Background: Sharing of microarray data within the research community has been greatly facilitated by the development of the disclosure and communication standards MIAME and MAGEML by the MGED Society. However, the complexity of the MAGE-ML format has made its use impractical for laboratories lacking dedicated bioinformatics support. Results: We propose a simple tab-delimited, spreadsheet-based format, MAGE-TAB, which will become a part of the MAGE microarray data standard and can be used for annotating and communicating microarray data in a MIAME compliant fashion. Conclusion: MAGE-TAB will enable laboratories without bioinformatics experience or support to manage, exchange and submit well-annotated microarray data in a standard format using a spreadsheet. The MAGE-TAB format is self-contained, and does not require an understanding of MAGE-ML or XML. [ABSTRACT FROM AUTHOR]

Appraisal—defined here to include a variety of ex ante techniques and procedures that seek to predict and evaluate the consequences of certain human actions—has been afforded an increas- ingly important role in environmental policy. We argue in this paper, however, that both the nature of appraisal and its role in the political process have been inadequately conceptualised. Exploring a literature that has tended to polarise ‘technical’ and ‘deliberative’ models, we identify a need for sensitive selection and combination of approaches, taking account of both the object and the objective of appraisal in particular contexts. We suggest that an important role for appraisal (by design or by default) may be that of providing spaces for dialogue and learning in the making of policies and decisions. A better understanding of such processes requires further research, particularly well- designed longitudinal work involving retrospective and ‘real time’ studies of appraisal in practice. [ABSTRACT FROM AUTHOR]

In this paper, we seek to contribute to the debate concerning the emergence of a 'new realism' in transport planning in the UK, through an examination of the development of Local Transport Plans. After describing the background to these policy changes, we consider how one central tenet of the new realism—the need to manage demand—is taking shape within the local transport planning process in Cambridgeshire and Leicester. We argue that although a 'climate of desperation' exists in each case over levels of traffic growth and their associated impacts, policy learning and change have been confined to a 'weak' interpretation of new realism where transport planning remains effectively subservient to prevailing local notions of how economic competitiveness ought to be promoted. In conclusion, we argue that this poses fundamental challenges for national government's transport and sustainable development policies. [ABSTRACT FROM AUTHOR]

Researchers expect under-reaction in climate policy. However, this might differ depending on the access of different interest groups to a political system. To explore the relationship between entrenched patterns of domestic politics and proportionality of climate policy, we compare two renewables policies which financially support new renewable electricity in the UK. Drawing on the literature on policy styles and related opportunity structures, this article shows that UK political parties have responded to growing public concern and NGO pressure by, at times, trying to out-green one another to win votes. However, powerful industry actors have been influential in shaping UK renewables policies, in particular when political competition about the individual policies has been low. The findings suggest that an over-reaction in terms of exceeding the marginal costs of renewable electricity production is equally likely under conditions of high or low political competition. [ABSTRACT FROM AUTHOR]

A key dimension of the debate about policy innovation is the extent to which new policies achieve significant and lasting effects on the problems they purport to address. However, little is known about such effects. We break new ground by investigating how far current evaluation practices in a policy system with relatively ambitious climate policies – the European Union – identify the most effective (carbon-reducing) policies. We find that a small number of policy instruments are projected to deliver the lion’s share of emission reductions. Setting aside the special case of emissions trading, these instruments are not particularly innovative. If significant practical and political obstacles can be addressed, more (detailed) evaluations could enhance the evidence base and also the political prospects for delivering deeper emissions cuts through to 2050. An evaluation perspective could also offer a very different way to consider policy innovation dynamics. [ABSTRACT FROM AUTHOR]

The relationship between evidence, governance and institutions in the pursuit of sustainable development is notoriously complicated. Studying organisations whose roles include managing boundaries between evidence and policy is one way to better understand this relationship. But in spite of the complexity, such organisations often appear - officially at least - to have rather limited remits, with very sharply drawn boundaries. This paper investigates this puzzle through study of the United Kingdom Parliamentary Environmental Audit Committee (EAC), established in 1997 to scrutinise government departments' efforts to integrate environment and sustainable development into policymaking. Gathering and deployment of evidence are critical to its work, and it is able to call as witnesses both members of the executive and experts from outside government. Drawing on Jasanoff's work on issue framing and boundaries, and Owens and Rayner's work on Royal Commissions, this paper employs a broad definition of boundary work to allow potential identification of multiple boundaries shaped by different sorts of boundary work. It investigates what boundaries are drawn, how, why and by whom. Through analysis of EAC reports, and elite interviews, the paper examines the context, consultation processes, roles played and influence of the EAC. The committee is found to play many roles, including analyst, forum for debate and political lever, all of which provide potential for influence on specific policies, and on the nature and space of political debate. The EAC shapes many boundaries using various mechanisms, both informal and institutionally-sanctioned. The rich and subtle variety of these boundaries, and different work carried out around them, confirms that a simple reading of the EAC's remit of government scrutiny falls short of understanding how it works in practice. The results vividly illustrate the politicised nature of sustainable development policy, and informs prospects for 'filling' any gap between evidence and policy. [ABSTRACT FROM AUTHOR]

With this paper we explore the potential of committees in parliamentary systems of government to influence environmental public policy making. We draw on delegation theory to argue that parliamentary committees are crucial ex post mechanisms used by the legislature (the principal) to monitor the activities of the executive (its agent). To examine this relationship in depth, we focus on the United Kingdom's Environmental Audit (select) Committee (EAC), which is an innovation as the world's first cross-cutting environmental parliamentary committee. We find that delegation theory provides fresh insights into the relationship between the EAC, the legislature, the executive, and the wider public. We find that an incomplete system of delegation in the United Kingdom has left an accountability deficit, meaning that the EAC's ability to exert influence on the executive's environmental policy is limited. [ABSTRACT FROM AUTHOR]

Summary The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution. [ABSTRACT FROM AUTHOR]

MicroRNAs (MiRs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we show that MiR-210 is induced by Oct-2, a key transcriptional mediator of B cell activation. Germline deletion of MiR-210 results in the development of autoantibodies from 5 mo of age. Overexpression of MiR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice overexpressing MiR-210 exhibited impaired class-switched Ab responses, a finding confirmed in wild-type B cells transfected with a MiR-210 mimic. In vitro studies demonstrated defects in cellular proliferation and cell cycle entry, which were consistent with the transcriptomic analysis demonstrating downregulation of genes involved in cellular proliferation and B cell activation. These findings indicate that Oct-2 induction of MiR-210 provides a novel inhibitory mechanism for the control of B cells and autoantibody production. [ABSTRACT FROM AUTHOR]

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy. [ABSTRACT FROM AUTHOR]

Follicular helper (TFH) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of TFH numbers maintains self tolerance. We describe a population of Foxp3+Blimp-1+CD4+ T cells constituting 10-25% of the CXCR5highPD-1highCD4+ T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (TFR) cells share phenotypic characteristics with TFH and conventional Foxp3+ regulatory T (Treg) cells yet are distinct from both. Similar to TFH cells, TFR cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, TFR cells originate from thymic-derived Foxp3+ precursors, not naive or TFH cells. TFR cells are suppressive in vitro and limit TFH cell and germinal center B cell numbers in vivo. In the absence of TFR cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the TFH differentiation pathway is co-opted by Treg cells to control the germinal center response. [ABSTRACT FROM AUTHOR]

Climate policy is a relatively young and dynamic area of public policy making. However, its development has attracted far more attention than the results it delivers in practice, which of course are the concern of policy evaluators. This article attempts to provide the first systematic cataloging of the emerging patterns of policy evaluation undertaken in different parts of the European Union. Theories of policy evaluation suggest that these evaluation practices should acknowledge the inherent complexity of climate policy making, be reflexive by questioning official policy goals, and be participatory. A meta-analysis of 259 climate policy evaluations suggests that current practice engages with some but not all of these issues. This article concludes by analyzing the implications of this finding for those in the academic and practitioner community who are keen to understand the extent to which climate policy evaluation is delivering on its promises. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a muttisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcγRllb is an inhibitory Fc receptor .with a critical role in immune regulation. Mouse data suggest that FcγRllb deficiency increases susceptibility to autoimmune disease but protects against infection. We show that a SNP in human FCGR2B that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians. The minor allele of this SNP is more common in Southeast Asians and Africans. populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56; P = 7.1 x 10-5). This protective effect against malaria may contribute to the higher frequency of this SNP and hence, SLE in Africans and Southeast Asians. [ABSTRACT FROM AUTHOR]

ArrayExpress is a public microarray repository founded on the Minimum Information About a Microarray Experiment (MIAME) principles that stores MIAME-compliant gene expression data. Plant-based data sets represent approximately one-quarter of the experiments in ArrayExpress. The majority are based on Arabidopsis (Arabidopsis thaliana); however, there are other data sets based on Triticum aestivum, Hordeum vulgare, and Populus subsp. AtMIAMExpress is an open-source Web-based software application for the submission of Arabidopsis-based microarray data to ArrayExpress. AtMIAMExpress exports data in MAGE-ML format for upload to any MAGE-ML-compliant application, such as J-Express and ArrayExpress. It was designed as a tool for users with minimal bioinformatics expertise, has comprehensive help and user support, and represents a simple solution to meeting the MIAME guidelines for the Arabidopsis community. Plant data are queryable both in ArrayExpress and in the Data Warehouse databases, which support queries based on gene-centric and sample-centric annotation. The AtMIAMExpress submission tool is available at http://www.ebi.ac.uk/at-miamexpress/. The software is open source and is available from http://sourceforge.net/projects/miamexpress/. For information, contact miamexpress@ebi.ac.uk. [ABSTRACT FROM AUTHOR]