Intein Inhibitors as Novel Antimicrobials: Protein Splicing in Human Pathogens, Screening Methods, and Off-target Considerations

Protein splicing is a post-translational process by which an intervening polypeptide, or intein, catalyzes its own removal from the flanking polypeptides, or exteins, concomitant with extein ligation. Although inteins are highly abundant in the microbial world, including within several human pathogens, they are absent in the genomes of metazoans. As protein splicing is required to permit function of essential proteins within pathogens, inteins represent attractive antimicrobial targets. Here we review key proteins interrupted by inteins in pathogenic mycobacteria and fungi, exciting discoveries that provide proof of concept that intein activity can be inhibited and that this inhibition has an effect on the host organism’s fitness, and bioanalytical methods that have been used to screen for intein activity. We also consider potential off-target inhibition of hedgehog signaling, given the similarity in structure and function of inteins and hedgehog autoprocessing domains

Cosmology of Axions and Moduli: A Dynamical Systems Approach

This paper is concerned with string cosmology and the dynamics of multiple scalar fields in potentials that can become negative, and their features as (Early) Dark Energy models. Our point of departure is the "String Axiverse", a scenario that motivates the existence of cosmologically light axion fields as a generic consequence of string theory. We couple such an axion to its corresponding modulus. We give a detailed presentation of the rich cosmology of such a model, ranging from the setting of initial conditions on the fields during inflation, to the asymptotic future. We present some simplifying assumptions based on the fixing of the axion decay constant $f_a$, and on the effective field theory when the modulus trajectory is adiabatic, and find the conditions under which these assumptions break down. As a by-product of our analysis, we find that relaxing the assumption of fixed $f_a$ leads to the appearance of a new meta-stable de-Sitter region for the modulus without the need for uplifting by an additional constant. A dynamical systems analysis reveals the existence of many fixed point attractors, repellers and saddle points, which we analyse in detail. We also provide geometric interpretations of the phase space. The fixed points can be used to bound the couplings in the model. A systematic scan of certain regions of parameter space reveals that the future evolution of the universe in this model can be rich, containing multiple epochs of accelerated expansion.Comment: 27 pages, 12 figures, comments welcome, v2 minor correction

The ATLAS SCT grounding and shielding concept and implementation

This paper presents a complete description of Virgo, the French-Italian gravitational wave detector. The detector, built at Cascina, near Pisa (Italy), is a very large Michelson interferometer, with 3 km-long arms. In this paper, following a presentation of the physics requirements, leading to the specifications for the construction of the detector, a detailed description of all its different elements is given. These include civil engineering infrastructures, a huge ultra-high vacuum (UHV) chamber (about 6000 cubic metres), all of the optical components, including high quality mirrors and their seismic isolating suspensions, all of the electronics required to control the interferometer and for signal detection. The expected performances of these different elements are given, leading to an overall sensitivity curve as a function of the incoming gravitational wave frequency. This description represents the detector as built and used in the first data-taking runs. Improvements in different parts have been and continue to be performed, leading to better sensitivities. These will be detailed in a forthcoming paper

Hormonal signaling in cnidarians : do we understand the pathways well enough to know whether they are being disrupted?

Author Posting. © The Author, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Ecotoxicology 16 (2007): 5-13, doi:10.1007/s10646-006-0121-1.Cnidarians occupy a key evolutionary position as basal metazoans and are ecologically important as predators, prey and structure-builders. Bioregulatory molecules (e.g., amines, peptides and steroids) have been identified in cnidarians, but cnidarian signaling pathways remain poorly characterized. Cnidarians, especially hydras, are regularly used in toxicity testing, but few studies have used cnidarians in explicit testing for signal disruption. Sublethal endpoints developed in cnidarians include budding, regeneration, gametogenesis, mucus production and larval metamorphosis. Cnidarian genomic databases, microarrays and other molecular tools are increasingly facilitating mechanistic investigation of signaling pathways and signal disruption. Elucidation of cnidarian signaling processes in a comparative context can provide insight into the evolution and diversification of metazoan bioregulation. Characterizing signaling and signal disruption in cnidarians may also provide unique opportunities for evaluating risk to valuable marine resources, such as coral reefs

Characterisation of the muon beams for the Muon Ionisation Cooling Experiment

A novel single-particle technique to measure emittance has been developed and used to characterise seventeen different muon beams for the Muon Ionisation Cooling Experiment (MICE). The muon beams, whose mean momenta vary from 171 to 281 MeV/c, have emittances of approximately 1.2–2.3 π mm-rad horizontally and 0.6–1.0 π mm-rad vertically, a horizontal dispersion of 90–190 mm and momentum spreads of about 25 MeV/c. There is reasonable agreement between the measured parameters of the beams and the results of simulations. The beams are found to meet the requirements of MICE

Nova light curves from the Solar Mass Ejection Imager (SMEI) - II. The extended catalogue

We present the results from observing nine Galactic novae in eruption with the Solar Mass Ejection Imager (SMEI) between 2004 and 2009. While many of these novae reached peak magnitudes that were either at or approaching the detection limits of SMEI, we were still able to produce light curves that in many cases contained more data at and around the initial rise, peak, and decline than those found in other variable star catalogs. For each nova, we obtained a peak time, maximum magnitude, and for several an estimate of the decline time (t2). Interestingly, although of lower quality than those found in Hounsell et al. (2010a), two of the light curves may indicate the presence of a pre-maximum halt. In addition the high cadence of the SMEI instrument has allowed the detection of low amplitude variations in at least one of the nova light curves

To support and not to cure: general practitioner management of loneliness

Loneliness is associated with numerous detrimental effects on physical health, mental health, cognition and lifestyle. Older adults are one of the groups at highest risk of loneliness, and indeed about 46% of older adults in England feel lonely. Those experiencing loneliness visit their general practitioner (GP) more frequently than those who are not, which has the capacity to put a strain on GPs and primary care waiting lists and costs. This study's aim was to explore GPs' views and experiences of loneliness within their older adult patients, and to understand GPs' awareness and feelings of agency within this. Nineteen UK GPs were recruited using purposive sampling and snowballing techniques. Individual semi‐structured interviews were conducted either in person or over the telephone. Data were analysed using thematic analysis. Four overarching themes were identified from the data: Whose responsibility is it anyway?, Pandora's box of shame; Keeping distance; and Community responsibility. Themes emphasise that GPs tend to hold a medicalised and individualistic view of loneliness. This intensifies stigma which in turn creates barriers to raising the topic. GPs felt powerless in their ability to fix the ‘problem’ and tended to believe that the solution had to lie in the community, the individual or in social care rather than in primary care. The findings are discussed in the context of literature on GP management of other social problems which give rise to similar issues concerning the restrictions of the medical model and the need for joined‐up approaches in which the GP is one part of a wider social support structure. It is suggested that it might be useful for training and support for GPs to address management of social problems jointly rather than training specific to loneliness which GPs tend to see as peripheral to their core remit

Solar-like oscillations in low-luminosity red giants: first results from Kepler

We have measured solar-like oscillations in red giants using time-series photometry from the first 34 days of science operations of the Kepler Mission. The light curves, obtained with 30-minute sampling, reveal clear oscillations in a large sample of G and K giants, extending in luminosity from the red clump down to the bottom of the giant branch. We confirm a strong correlation between the large separation of the oscillations (Delta nu) and the frequency of maximum power (nu_max). We focus on a sample of 50 low-luminosity stars (nu_max > 100 muHz, L <~ 30 L_sun) having high signal-to-noise ratios and showing the unambiguous signature of solar-like oscillations. These are H-shell-burning stars, whose oscillations should be valuable for testing models of stellar evolution and for constraining the star-formation rate in the local disk. We use a new technique to compare stars on a single echelle diagram by scaling their frequencies and find well-defined ridges corresponding to radial and non-radial oscillations, including clear evidence for modes with angular degree l=3. Measuring the small separation between l=0 and l=2 allows us to plot the so-called C-D diagram of delta nu_02 versus Delta nu. The small separation delta nu_01 of l=1 from the midpoint of adjacent l=0 modes is negative, contrary to the Sun and solar-type stars. The ridge for l=1 is notably broadened, which we attribute to mixed modes, confirming theoretical predictions for low-luminosity giants. Overall, the results demonstrate the tremendous potential of Kepler data for asteroseismology of red giants.Comment: accepted by ApJ Letters, to appear in special Kepler issue. Updated reference

Informing the design of a national screening and treatment programme for chronic viral hepatitis in primary care: qualitative study of at-risk immigrant communities and healthcare professionals

n Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedThis paper presents independent research funded by the National Institute for Health Research (NIHR) under the Programme Grants for Applied Research programme (RP-PG-1209-10038).

Characteristics of general practice care: What do senior citizens value? A qualitative study

<p>Abstract</p> <p>Background</p> <p>In view of the increasing number of senior citizens in our society who are likely to consult their GP with age-related health problems, it is important to identify and understand the preferences of this group in relation to the non-medical attributes of GP care. The aim of this study is to improve our understanding about preferences of this group of patients in relation to non-medical attributes of primary health care. This may help to develop strategies to improve the quality of care that senior citizens receive from their GP.</p> <p>Methods</p> <p>Semi-structured interviews (N = 13) with senior citizens (65-91 years) in a judgement sample were recorded and transcribed verbatim. The analysis was conducted according to qualitative research methodology and the frame work method.</p> <p>Results</p> <p>Continuity of care providers, i.e. GP and practice nurses, GPs' expertise, trust, free choice of GP and a kind open attitude were highly valued. Accessibility by phone did not meet the expectations of the interviewees. The interviewees had difficulties with the GP out-of-office hours services. Spontaneous home visits were appreciated by some, but rejected by others. They preferred to receive verbal information rather than collecting information from leaflets. Distance to the practice and continuity of caregiver seemed to conflict for respondents.</p> <p>Conclusions</p> <p>Preferences change in the process of ageing and growing health problems. GPs and their co-workers should be also aware of the changing needs of the elderly regarding non-medical attributes of GP care. Meeting their needs regarding non-medical attributes of primary health care is important to improve the quality of care.</p