Endothelin-Converting Enzyme-1 (ECE-1) Is Post-Transcriptionally Regulated by Alternative Polyadenylation

Endothelin-converting enzyme-1 (ECE-1) is the enzyme predominantly responsible for producing active endothelin-1 (ET-1), a mitogenic peptide implicated in the aetiology of a number of diseases, including cancer. Elevated levels of ECE-1 have been observed in a range of malignancies, with high expression conferring poor prognosis and aiding the acquisition of androgen independence in prostate cancer. The mechanisms regulating the expression of ECE-1 in cancer cells are poorly understood, hampering the development of novel therapies targeting the endothelin axis. Here we provide evidence that the expression of ECE-1 is markedly inhibited by its 3′UTR, and that alternative polyadenylation (APA) results in the production of ECE-1 transcripts with truncated 3′UTRs which promote elevated protein expression. Abolition of the ECE-1 APA sites reduced protein expression from a reporter vector in prostate cancer cells, suggesting these sites are functional. This is the first study to identify ECE-1 as a target for APA, a regulatory mechanism aberrantly activated in cancer cells, and provides novel information about the mechanisms leading to ECE-1 overexpression in malignant cells

Supporting security-oriented, inter-disciplinary research: crossing the social, clinical and geospatial domains

How many people have had a chronic disease for longer than 5-years in Scotland? How has this impacted upon their choices of employment? Are there any geographical clusters in Scotland where a high-incidence of patients with such long-term illness can be found? How does the life expectancy of such individuals compare with the national averages? Such questions are important to understand the health of nations and the best ways in which health care should be delivered and measured for their impact and success. In tackling such research questions, e-Infrastructures need to provide tailored, secure access to an extensible range of distributed resources including primary and secondary e-Health clinical data; social science data, and geospatial data sets amongst numerous others. In this paper we describe the security models underlying these e-Infrastructures and demonstrate their implementation in supporting secure, federated access to a variety of distributed and heterogeneous data sets exploiting the results of a variety of projects at the National e-Science Centre (NeSC) at the University of Glasgow

The curious nonexistence of Gaussian 2-designs

2-designs -- ensembles of quantum pure states whose 2nd moments equal those of the uniform Haar ensemble -- are optimal solutions for several tasks in quantum information science, especially state and process tomography. We show that Gaussian states cannot form a 2-design for the continuous-variable (quantum optical) Hilbert space L2(R). This is surprising because the affine symplectic group HWSp (the natural symmetry group of Gaussian states) is irreducible on the symmetric subspace of two copies. In finite dimensional Hilbert spaces, irreducibility guarantees that HWSp-covariant ensembles (such as mutually unbiased bases in prime dimensions) are always 2-designs. This property is violated by continuous variables, for a subtle reason: the (well-defined) HWSp-invariant ensemble of Gaussian states does not have an average state because the averaging integral does not converge. In fact, no Gaussian ensemble is even close (in a precise sense) to being a 2-design. This surprising difference between discrete and continuous quantum mechanics has important implications for optical state and process tomography.Comment: 9 pages, no pretty figures (sorry!

Glacial geomorphology of the Great Glen Region of Scotland

This paper presents a detailed glacial Main Map of the Great Glen region of Scotland, UK, covering an area of over 6800 km2 extending from 56°34′7″ to 57°41′1″ N and from 3°44′2″ to 5°33′24″ W. This represents the first extensive mapping of the glacial geomorphology of the Great Glen and builds upon previous studies that conducted localised field mapping or ice-sheet wide mapping using remote sensing. Particular emphasis is placed on deriving medium-scale glacial retreat patterns from these data, and examining differences in landsystem assemblages across the region. Features were typically mapped at a scale of 1:8000 to 1:10,000 and will be used to investigate the pattern and dynamics of the British-Irish Ice Sheet during deglaciation. Mapping was conducted using the NEXTMap digital terrain model. In total, 17,637 glacial landforms were mapped, with 58% identified as moraines, 23% as meltwater channels, 10% as bedrock controlled glacial lineations, 3% as eskers, 2% as cirques or arêtes, 2% as kame topography or kame terraces, and 1% as drumlins. Additionally, 10 palaeo-lake shorelines were identified. Complex landform assemblages in the form of streamlined subglacial bedforms, moraines and glaciofluvial features exist across the region. Extensive subglacial meltwater networks are found over the Monadhliath Mountain Range. Transverse and longitudinal moraine ridges generally arc across valley floors or are located on valley slopes respectively. Hummocky moraines are found almost exclusively across Rannoch Moor. Finally, eskers, meltwater channels and kame landforms form spatial relationships along the axis of Strathspey. These glacial landsystems reveal the dynamics and patterns of retreat of the British-Irish Ice Sheet during the last deglaciation

Spinal plasticity in robot-mediated therapy for the lower limbs.

Robot-mediated therapy can help improve walking ability in patients following injuries to the central nervous system. However, the efficacy of this treatment varies between patients, and evidence for the mechanisms underlying functional improvements in humans is poor, particularly in terms of neural changes in the spinal cord. Here, we review the recent literature on spinal plasticity induced by robotic-based training in humans and propose recommendations for the measurement of spinal plasticity using robotic devices. Evidence for spinal plasticity in humans following robotic training is limited to the lower limbs. Body weight-supported (BWS) robotic-assisted step training of patients with spinal cord injury (SCI) or stroke patients has been shown to lead to changes in the amplitude and phase modulation of spinal reflex pathways elicited by electrical stimulation or joint rotations. Of particular importance is the finding that, among other changes to the spinal reflex circuitries, BWS robotic-assisted step training in SCI patients resulted in the re-emergence of a physiological phase modulation of the soleus H-reflex during walking. Stretch reflexes elicited by joint rotations constitute a tool of interest to probe spinal circuitry since the technology necessary to produce these perturbations could be integrated as a natural part of robotic devices. Presently, ad-hoc devices with an actuator capable of producing perturbations powerful enough to elicit the reflex are available but are not part of robotic devices used for training purposes. A further development of robotic devices that include the technology to elicit stretch reflexes would allow for the spinal circuitry to be routinely tested as a part of the training and evaluation protocols

A cohort study of post-weaning multisystemic wasting syndrome and PCV2 in 178 pigs from birth to 14 weeks on a single farm in England

Our hypothesis was that pigs that develop post-weaning multisystemic wasting syndrome (PMWS) are detectable from an early age with signs of weight loss and other clinical and serological abnormalities. Therefore, the objective of this study was to investigate the temporally varying and fixed events linked with the clinical incidence of PMWS by comparing affected and unaffected pigs in a cohort of 178 male piglets. Piglets were enrolled at birth and examined each week. Samples of blood were collected at regular intervals. The exposures measured were porcine circovirus type 2 (PCV2) antibody titres in all 178 and PCV2 antigen in a subset of 75 piglets. We also observed piglet health and measured their weight, and a post-mortem examination was performed by an external laboratory on all pigs between 6 and 14 weeks of age that died. From the cohort, 14 (8%) pigs died from PMWS and 4% from other causes. A further 37 pigs between 6 and 14 weeks of age died from PMWS (30) and ileitis and other causes (7). PMWS was only apparent in pigs from 1 to 2 weeks before death when they wasted rapidly. There were no other characteristic clinical signs and no obvious gross clinical lesions post-mortem. There was no strong link with PCV2 antibody throughout life but PCV2 antigen level was higher from 4 to 6 weeks of age in pigs that died from PMWS compared with pigs that died from other causes

Supersymmetry and the positron excess in cosmic rays

Recently the HEAT balloon experiment has confirmed an excess of high-energy positrons in cosmic rays. They could come from annihilation of dark matter in the galactic halo. We discuss expectations for the positron signal in cosmic rays from the lightest superpartner. The simplest interpretations are incompatible with the size and shape of the excess if the relic LSPs evolved from thermal equilbrium. Non-thermal histories can describe a sufficient positron rate. Reproducing the energy spectrum is more challenging, but perhaps possible. The resulting light superpartner spectrum is compatible with collider physics, the muon anomalous magnetic moment, Z-pole electroweak data, and other dark matter searches.Comment: 4 pages, 2 figures, references added, minor wording change

Enhancing Communication about Paediatric Medicines: Lessons from a Qualitative Study of Parents' Experiences of Their Child's Suspected Adverse Drug Reaction

Background: There is little research on parents’ experiences of suspected adverse drug reactions in their children and hence little evidence to guide clinicians when communicating with families about problems associated with medicines. Objective: To identify any unmet information and communication needs described by parents whose child had a suspected adverse drug reaction. Methods: Semi-structured qualitative interviews with parents of 44 children who had a suspected adverse drug reaction identified on hospital admission, during in-patient treatment or reported by parents using the Yellow Card Scheme (the UK system for collecting spontaneous reports of adverse drug reactions). Interviews were conducted face-to-face or by telephone; most interviews were audiorecorded and transcribed. Analysis was informed by the principles of the constant comparative method. Results: Many parents described being dissatisfied with how clinicians communicated about adverse drug reactions and unclear about the implications for their child’s future use of medicines. A few parents felt that clinicians had abandoned their child and reported refusing the use of further medicines because they feared a repeated adverse drug reaction. The accounts of parents of children with cancer were different. They emphasised their confidence in clinicians’ management of adverse drug reactions and described how clinicians prospectively explained the risks associated with medicines. Parents linked symptoms to medicines in ways that resembled the established reasoning that clinicians use to evaluate the possibility that a medicine has caused an adverse drug reaction. Conclusion: Clinicians’ communication about adverse drug reactions was poor from the perspective of parents, indicating that improvements are needed. The accounts of parents of children with cancer indicate that prospective explanation about adverse drug reactions at the time of prescription can be effective. Convergence between parents and clinicians in their reasoning for linking children’s symptoms to medicines could be a starting point for improved communication

The cosmic gravitational wave background in a cyclic universe

Inflation predicts a primordial gravitational wave spectrum that is slightly ``red,'' i.e., nearly scale-invariant with slowly increasing power at longer wavelengths. In this paper, we compute both the amplitude and spectral form of the primordial tensor spectrum predicted by cyclic/ekpyrotic models. The spectrum is blue and exponentially suppressed compared to inflation on long wavelengths. The strongest observational constraint emerges from the requirement that the energy density in gravitational waves should not exceed around 10 per cent of the energy density at the time of nucleosynthesis.Comment: 4 pages, 3 figuer

MeV-mass dark matter and primordial nucleosynthesis

The annihilation of new dark matter candidates with masses $m_X$ in the MeV range may account for the galactic positrons that are required to explain the 511 keV $\gamma$-ray flux from the galactic bulge. We study the impact of MeV-mass thermal relic particles on the primordial synthesis of $^2$H, $^4$He, and $^7$Li. If the new particles are in thermal equilibrium with neutrinos during the nucleosynthesis epoch they increase the helium mass fraction for m_X\alt 10 MeV and are thus disfavored. If they couple primarily to the electromagnetic plasma they can have the opposite effect of lowering both helium and deuterium. For $m_X=4$--10 MeV they can even improve the overall agreement between the predicted and observed $^2$H and $^4$He abundances.Comment: 11 pages, 10 figures, references and two appendices added, conclusions unchanged; accepted for publication in Phys.Rev.