THE PRINCIPLE OF REPARATION APPLIED TO RATE REGULATION

Those instruments of service, commonly called Public Utilities , have become an essential part of our every day life, if not of our civilization. It is not until we enumerate their uses that we fully appreciate our constant dependence upon them

Everybody Knows: Engaged Research and the Changing Role of the Academic

The rise of the impact and engagement agendas has challenged the role of the academic, and particularly the relationship between the academic, knowledge and the wider public. In this article, we propose that, alongside the existing models of ‘knowledge transfer’ and ‘knowledge exchange’, academic engagement with external audiences can also be conceptualised as a multidimensional ‘knowledge network’. We adopt a case study approach to explore and illustrate what such a knowledge network looks like in practice, and we consider the implications of thinking about university engagement activities in these terms, with particular emphasis on what it means for the shifting role of the academic

Expression profiling of skeletal muscle following acute and chronic β2-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm

Background Systemic administration of β-adrenoceptor (β-AR) agonists has been found to induce skeletal muscle hypertrophy and significant metabolic changes. In the context of energy homeostasis, the importance of β-AR signaling has been highlighted by the inability of β1-3-AR-deficient mice to regulate energy expenditure and susceptibility to diet induced obesity. However, the molecular pathways and gene expression changes that initiate and maintain these phenotypic modulations are poorly understood. Therefore, the aim of this study was to identify differential changes in gene expression in murine skeletal muscle associated with systemic (acute and chronic) administration of the β2-AR agonist formoterol. Results Skeletal muscle gene expression (from murine tibialis anterior) was profiled at both 1 and 4 hours following systemic administration of the β2-AR agonist formoterol, using Illumina 46K mouse BeadArrays. Illumina expression profiling revealed significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress. Differentially expressed genes relevant to the regulation of muscle mass and metabolism (in the context of the hypertrophic phenotype) were further validated by quantitative RT-PCR to examine gene expression in response to both acute (1-24 h) and chronic administration (1-28 days) of formoterol at multiple timepoints. In terms of skeletal muscle hypertrophy, attenuation of myostatin signaling (including differential expression of myostatin, activin receptor IIB, phospho-Smad3 etc) was observed following acute and chronic administration of formoterol. Acute (but not chronic) administration of formoterol also significantly induced the expression of genes involved in oxidative metabolism, including hexokinase 2, sorbin and SH3 domain containing 1, and uncoupling protein 3. Interestingly, formoterol administration also appeared to influence some genes associated with the peripheral regulation of circadian rhythm (including nuclear factor interleukin 3 regulated, D site albumin promoter binding protein, and cryptochrome 2). Conclusion This is the first study to utilize gene expression profiling to examine global gene expression in response to acute β2-AR agonist treatment of skeletal muscle. In summary, systemic administration of a β2-AR agonist had a profound effect on global gene expression in skeletal muscle. In terms of hypertrophy, β2-AR agonist treatment altered the expression of several genes associated with myostatin signaling, a previously unreported effect of β-AR signaling in skeletal muscle. This study also demonstrates a β2-AR agonist regulation of circadian rhythm genes, indicating crosstalk between β-AR signaling and circadian cycling in skeletal muscle. Gene expression alterations discovered in this study provides insight into many of the underlying changes in gene expression that mediate β-AR induced skeletal muscle hypertrophy and altered metabolism

The role of science in physical natural hazard assessment : report to the UK Government by the Natural Hazard Working Group

Following the tragic Asian tsunami on 26 December 2004, the Prime Minister asked the Government’s Chief Scientific Adviser, Sir David King, to convene a group of experts (the Natural Hazard Working Group) to advise on the mechanisms that could and should be established for the detection and early warning of global physical natural hazards. 2. The Group was asked to examine physical hazards which have high global or regional impact and for which an appropriate early warning system could be put in place. It was also asked to consider the global natural hazard frameworks currently in place and under development and their effectiveness in using scientific evidence; to consider whether there is an existing appropriate international body to pull together the international science community to advise governments on the systems that need to be put in place, and to advise on research needed to fill current gaps in knowledge. The Group was asked to make recommendations on whether a new body was needed, or whether other arrangements would be more effective

Super-Bridges Suspended Over Carbon Nanotube Cables

In this paper the new concept of super-bridges, i.e. kilometre-long bridges suspended over carbon nanotube cables, is introduced. The analysis shows that the use of realistic (thus defective) carbon nanotube bundles as suspension cables can enlarge the current limit main span by a factor of 3.Comment: 17 pages, 6 figures, 2 table

Nitric oxide availability is increased in contracting skeletal muscle from aged mice, but does not differentially decrease muscle superoxide

Reactive oxygen and nitrogen species have been implicated in the loss of skeletal muscle mass and function that occurs during aging. Nitric oxide (NO) and superoxide are generated by skeletal muscle and where these are generated in proximity their chemical reaction to form peroxynitrite can compete with the superoxide dismutation to hydrogen peroxide. Changes in NO availability may therefore theoretically modify superoxide and peroxynitrite activities in tissues, but published data are contradictory regarding aging effects on muscle NO availability. We hypothesised that an age-related increase in NO generation might increase peroxynitrite generation in muscles from old mice, leading to an increased nitration of muscle proteins and decreased superoxide availability. This was examined using fluorescent probes and an isolated fiber preparation to examine NO content and superoxide in the cytosol and mitochondria of muscle fibers from adult and old mice both at rest and following contractile activity. We also examined the 3-nitrotyrosine (3-NT) and peroxiredoxin 5 (Prx5) content of muscles from mice as markers of peroxynitrite activity. Data indicate that a substantial age-related increase in NO levels occurred in muscle fibers during contractile activity and this was associated with an increase in muscle eNOS. Muscle proteins from old mice also showed an increased 3-NT content. Inhibition of NOS indicated that NO decreased superoxide bioavailability in muscle mitochondria, although this effect was not age related. Thus increased NO in muscles of old mice was associated with an increased 3-NT content that may potentially contribute to age-related degenerative changes in skeletal muscle

Working Title Films and Universal : The Integration of a British Production Company into a Hollywood Studio

Working Title Films is arguably the most successful and well-known production company in Britain today. For over 30 years, it has produced a diverse range of critically and commercially successful British films including romantic comedies such as Four Weddings and a Funeral (1994) and Bridget Jones’s Diary (2001), family films like Bean (1997) and Nanny McPhee (2005) and dramas including Atonement (2007) and The Theory of Everything (2014). For the majority of its history, however, Working Title has been defined in business terms by its status as a subsidiary of one of two multinational media conglomerates, PolyGram (1992–8) and Universal (1998–present). The transition between the two began when PolyGram, and its film studio, PolyGram Filmed Entertainment (PFE), was sold to Seagram, the parent company of Universal. This article examines Working Title’s integration into Universal and the evolving media ecology which shaped the processes of development, green-lighting, production, marketing and distribution at play within and between both companies between 1998 and 2006. In these respects, Working Title’s transition between parent companies is a narrative of both continuity and change. Significantly, three key stages of gatekeeping remained common to both the PFE and Universal eras: development, green-lighting and distribution. The institutional perimeters within which these points of decision-making occurred, however, changed considerably. The article concludes by considering the impact of such structures and processes on the films which Working Title produced, particularly their various representations of Britain and ‘Britishness’

Systematic analysis of tumour cell-extracellular matrix adhesion identifies independent prognostic factors in breast cancer.

Tumour cell-extracellular matrix (ECM) interactions are fundamental for discrete steps in breast cancer progression. In particular, cancer cell adhesion to ECM proteins present in the microenvironment is critical for accelerating tumour growth and facilitating metastatic spread. To assess the utility of tumour cell-ECM adhesion as a means for discovering prognostic factors in breast cancer survival, here we perform a systematic phenotypic screen and characterise the adhesion properties of a panel of human HER2 amplified breast cancer cell lines across six ECM proteins commonly deregulated in breast cancer. We determine a gene expression signature that defines a subset of cell lines displaying impaired adhesion to laminin. Cells with impaired laminin adhesion showed an enrichment in genes associated with cell motility and molecular pathways linked to cytokine signalling and inflammation. Evaluation of this gene set in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort of 1,964 patients identifies the F12 and STC2 genes as independent prognostic factors for overall survival in breast cancer. Our study demonstrates the potential of in vitro cell adhesion screens as a novel approach for identifying prognostic factors for disease outcome

Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors

© 2016 The Author(s) Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies