The role of the RNA binding protein FUS in androgen signalling

The multi-functional RNA binding protein FUS was identified as an androgen down-regulated target in a 2D proteomic screen in the LNCaP cell line. This screen was designed to identify novel markers and therapeutic targets for prostate cancer. Cell cycle analysis and growth assays revealed that increased FUS levels in LNCaP cells resulted in inhibition of the androgen-dependent G1-S cell cycle transition and induced apoptosis. This is brought about, in part, via the FUS-dependent modulation of the expression of G1- S check-point regulatory proteins, including decreased expression of Cyclin D1. Therefore, we have identified FUS as a key link between androgen signalling and cell cycle regulation. FUS also modulates androgen signalling by repressing Androgen Receptor (AR) activity. FUS is known to interact with the DNA binding domain of some nuclear receptors, and a mammalian 2-hybrid interaction assay revealed a ligand-dependent interaction between FUS and the AR that required the FUS RNA recognition motif. Transcription assays demonstrated that FUS is a novel co-repressor of AR activity, and quantitative real time PCR showed that increasing FUS levels down-regulated androgen-regulated gene expression in LNCaP cells, whilst reducing FUS levels resulted in an increase of the androgen-regulated gene TMPRSS2. Investigation into the mechanism(s) by which FUS represses AR activity revealed that FUS contains an NH2-terminal activation domain (amino acids 1-366) that is consistent with the AR transcriptional repression domain. Furthermore, the FUS NH2- terminal interacts with co-activators, including SRC-1, suggesting FUS may repress AR activity by competition with co-activator activity. Recent studies in Dr Charlotte Bevan’s laboratory demonstrated an inverse correlation between FUS expression and Gleason grade in human prostate tumours. This, combined with these findings that FUS is an inhibitor of androgen-dependent growth which is, in part, via repression of the AR, suggests that FUS is a key regulator in AR signalling and prostate cancer progression, and may be a novel tumour suppressor

Profits v. Purpose: Hybrid Companies and the Charitable Dollar

Social entrepreneurship -- a catch-all term meaning harnessing business practices for social good -- has attracted people who want to “do well while doing good” for decades. Advocates of the idea have succeeded in blurring the boundaries among legal ownership types and inspired nonprofit/for-profit joint ventures, public-private partnerships, and the widespread privatization of traditional government functions and activities. The most recent manifestation of this trend is the creation of hybrid non-profit/for-profit firms. In the United States, the Low-Profit Limited Liability Company (L3C) is growing, and there are similar firms in the United Kingdom and Canada. In this paper we address the narrow, legal justifications for L3Cs in the U.S., as well as the broader justifications for hybrid organizations. We then identify four types of problems raised by the L3C and, perhaps to a lesser extent, other models: 1) their internal, legal incoherence; 2) the risk to charitable assets and potential for inappropriate use of tax subsidies; 3) the problematic assumption that for-profits are more efficient than nonprofit or government alternatives; and 4) the potentially inappropriate use of government imprimatur. However, recognizing the increasing and unyielding limits on the ability of nonprofits to raise capital, we concede that L3Cs may well offer a valuable route to capital while avoiding conversions to for-profit ownership

Profits v. Purpose: Hybrid Companies and the Charitable Dollar

Social entrepreneurship -- a catch-all term meaning harnessing business practices for social good -- has attracted people who want to “do well while doing good” for decades. Advocates of the idea have succeeded in blurring the boundaries among legal ownership types and inspired nonprofit/for-profit joint ventures, public-private partnerships, and the widespread privatization of traditional government functions and activities. The most recent manifestation of this trend is the creation of hybrid non-profit/for-profit firms. In the United States, the Low-Profit Limited Liability Company (L3C) is growing, and there are similar firms in the United Kingdom and Canada. In this paper we address the narrow, legal justifications for L3Cs in the U.S., as well as the broader justifications for hybrid organizations. We then identify four types of problems raised by the L3C and, perhaps to a lesser extent, other models: 1) their internal, legal incoherence; 2) the risk to charitable assets and potential for inappropriate use of tax subsidies; 3) the problematic assumption that for-profits are more efficient than nonprofit or government alternatives; and 4) the potentially inappropriate use of government imprimatur. However, recognizing the increasing and unyielding limits on the ability of nonprofits to raise capital, we concede that L3Cs may well offer a valuable route to capital while avoiding conversions to for-profit ownership

Margaret Chase Smith Essay: High School Student Essay Winners

Maine has benefited from the public service of many well-respected and influential national leaders over the last two centuries. One of them, Senator Margaret Chase Smith, offered her reflections on leadership at a time when the United States faced a struggle for civil rights at home and the tensions of the Cold War abroad. With the country currently confronting challenges such as the threat of terrorism, ongoing tensions in the Middle East, and the taint of corporate scandals, the Margaret Chase Smith Library annual essay contest invited Maine high school seniors to reflect on the qualities leaders will need to possess in order to be more effective in the twenty-first century. We feature here the three top prize-winning essays by Emily Parker (first), Rachel Culley (second) and Miles Kirby (third)

Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo:Sulforaphane is protective in the articular Joint

Sulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis

The Workwell trial: protocol for the process evaluation of a randomised controlled trial of job retention vocational rehabilitation for employed people with inflammatory arthritis.

Background: The Workwell trial is a multi-centre randomised controlled trial with the aims of evaluating the effectiveness and cost-effectiveness of job retention vocational rehabilitation for employed people with inflammatory arthritis, who are experiencing work difficulties due to their arthritis. Vocational rehabilitation is delivered by health service occupational therapists, who have received additional training in providing this Workwell intervention. A process evaluation will be undertaken alongside the main trial to: investigate implementation fidelity; understand key stakeholders’ perspectives of the intervention and the social and structural context in which the intervention is provided; and explore issues related to future implementation in clinical practice. This protocol describes the aims, objectives, and methodology of the Workwell trial process evaluation. Methods: This mixed methods process evaluation will follow the Medical Research Council’s Guidance on process evaluations for complex interventions. It will be underpinned by the Conceptual Framework for Implementation Fidelity (CFIF) and Normalisation Process Theory (NPT). We will analyse treatment records, work assessments and treatment notes to ascertain implementation fidelity. Semi-structured interviews with trial participants, their employer/line managers, treating therapists, and their therapy service managers will be undertaken to explore perceptions of the intervention, contextual factors, and potential for future implementation in practice. Interview topic guides will be informed by NPT. Therapists’ views about Workwell training will be explored via questionnaires following training, and interviews and focus groups following treatment delivery to inform future implementation. Quantitative data will be analysed descriptively. Qualitative data will be analysed using Thematic Analysis. NPT will guide data analysis, and interpretation. Findings from the different elements of this embedded design process evaluation will be reported separately and then the elements integrated. The process evaluation data will be analysed independently of the Workwell trial outcome evaluation. The process evaluation data will then be reviewed in the light of the trial findings. Discussion: Few trials of job retention vocational rehabilitation in arthritis have included process evaluations. This process evaluation will assist in understanding factors influencing trial outcomes and identifying potential contextual barriers and facilitators for the potential implementation of Workwell vocational rehabilitation into clinical services

The Marine Viromes of Four Oceanic Regions

Viruses are the most common biological entities in the marine environment. There has not been a global survey of these viruses, and consequently, it is not known what types of viruses are in Earth's oceans or how they are distributed. Metagenomic analyses of 184 viral assemblages collected over a decade and representing 68 sites in four major oceanic regions showed that most of the viral sequences were not similar to those in the current databases. There was a distinct “marine-ness” quality to the viral assemblages. Global diversity was very high, presumably several hundred thousand of species, and regional richness varied on a North-South latitudinal gradient. The marine regions had different assemblages of viruses. Cyanophages and a newly discovered clade of single-stranded DNA phages dominated the Sargasso Sea sample, whereas prophage-like sequences were most common in the Arctic. However most viral species were found to be widespread. With a majority of shared species between oceanic regions, most of the differences between viral assemblages seemed to be explained by variation in the occurrence of the most common viral species and not by exclusion of different viral genomes. These results support the idea that viruses are widely dispersed and that local environmental conditions enrich for certain viral types through selective pressure

Common genetic variation drives molecular heterogeneity in human iPSCs.

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The development and evaluation of a vocational rehabilitation training programme for rheumatology occupational therapists

People with inflammatory arthritis rapidly develop work disability, yet there is limited provision of vocational rehabilitation (VR) in rheumatology departments. As part of a randomized, controlled trial, ten occupational therapists (OTs) were surveyed to identify their current VR provision and training needs. As a result, a VR training course for OTs was developed which included both taught and self-directed learning. The course included: employment and health and safety legislation, work assessment and practical application of ergonomic principles at work. Pre-, immediately post- and two months post-training, the ten OTs completed a questionnaire about their VR knowledge and confidence On completion, they reported a significant increase (p<0.01)in their knowledge and confidence when delivering vocational rehabilitation. They rated the course as very or extremely relevant, although seven recommended more practical sessions. The preference for practical sessions was highlighted, in that the aspects they felt most beneficial were role-playing assessments and sharing ideas through discussion and presentations. In conclusion, the course was considered effective in increasing both knowledge and confidence in using VR as an intervention, but, due to time constraints within the working day, some of the self-directed learning should be incorporated into the training days