Fos co-operation with PTEN loss elicits keratoacanthoma not carcinoma due to p53/p21^WAF-induced differentiation triggered by GSK3b inactivation and reduced AKT activity

To investigate gene synergism in multistage skin carcinogenesis, the RU486-inducible cre/lox system was employed to ablate PTEN function [K14.cre/D5PTENflx] in mouse epidermis expressing activated v-fos [HK1.fos]. RU486-treated HK1.fos/D5PTENflx mice exhibited hyperplasia, hyperkeratosis and tumours that progressed to highly differentiated keratoacanthomas rather than carcinomas, due to re-expression of high p53 and p21WAF levels. Despite elevated MAP kinase activity, cyclin D1/E2 over expression and increased AKT activity forming areas of highly proliferative, papillomatous keratinocytes, increasing levels of GSK3b inactivation exceeded a threshold that induced p53/p21WAF expression to halt proliferation and accelerate differentiation, giving the hallmark keratosis of keratoacanthomas. A pivotal facet to this GSK3b-triggered mechanism centred on increasing p53 expression in basal layer keratinocytes. This reduced activated AKT expression and released inhibition of p21WAF, which accelerated keratinocyte differentiation, as indicated by unique basal layer expression of differentiation-specific keratin K1, alongside premature filaggrin and loricrin expression. Thus, fos synergism with PTEN loss elicited a benign tumour context where GSK3b-induced, p53/p21WAF expression continually switched AKT-associated proliferation into one of differentiation, preventing further progression. This putative compensatory mechanism required the critical availability of normal p53 and/or p21WAF otherwise deregulated fos, Akt and GSK3b associate with malignant progression

Reuse as heuristic : from transmission to nurture in learning activity design

In recent years a combination of ever more flexible and sophisticated Web technologies and an explosion in the quantity of online content has sparked learning technologists around the world to pursue the promise of the 'reusable learning object' or RLO with the idea that RLOs could be reused in different educational contexts, thereby providing greater overall flexibility and return on investment. In 2002 the ACETS Project undertook a three-year study in the UK to investigate whether RLOs worked in practice and how the pursuit of reuse affected the teacher and their teaching. Teachers working in healthcare-related subjects in Higher and Further Education were asked to create an original learning design or activity from third-party digital resources and to reflect both on the process and its outcomes. The expectation was that teachers would be the ones selecting and reusing third-party materials. This paper describes how one of the ACETS exemplifiers reinterpreted this remit, challenged the anticipated transmissive model of learning, and instead, gave their students an opportunity to create their own original learning designs and learning activities from third-party digital resources. By describing the educational enhancements, the resulting heightened levels of critical thinking, and sensitivity to patient needs, 'reuse' will be shown to be an effective heuristic for student self-direction and professional development

The distribution of transit durations for Kepler planet candidates and implications for their orbital eccentricities

‘In these times, during the rise in the popularity of institutional repositories, the Society does not forbid authors from depositing their work in such repositories. However, the AAS regards the deposit of scholarly work in such repositories to be a decision of the individual scholar, as long as the individual's actions respect the diligence of the journals and their reviewers.’ Original article can be found at : http://iopscience.iop.org/ Copyright American Astronomical SocietyDoppler planet searches have discovered that giant planets follow orbits with a wide range of orbital eccentricities, revolutionizing theories of planet formation. The discovery of hundreds of exoplanet candidates by NASA's Kepler mission enables astronomers to characterize the eccentricity distribution of small exoplanets. Measuring the eccentricity of individual planets is only practical in favorable cases that are amenable to complementary techniques (e.g., radial velocities, transit timing variations, occultation photometry). Yet even in the absence of individual eccentricities, it is possible to study the distribution of eccentricities based on the distribution of transit durations (relative to the maximum transit duration for a circular orbit). We analyze the transit duration distribution of Kepler planet candidates. We find that for host stars with T > 5100 K we cannot invert this to infer the eccentricity distribution at this time due to uncertainties and possible systematics in the host star densities. With this limitation in mind, we compare the observed transit duration distribution with models to rule out extreme distributions. If we assume a Rayleigh eccentricity distribution for Kepler planet candidates, then we find best fits with a mean eccentricity of 0.1-0.25 for host stars with T ≤ 5100 K. We compare the transit duration distribution for different subsets of Kepler planet candidates and discuss tentative trends with planetary radius and multiplicity. High-precision spectroscopic follow-up observations for a large sample of host stars will be required to confirm which trends are real and which are the results of systematic errors in stellar radii. Finally, we identify planet candidates that must be eccentric or have a significantly underestimated stellar radius.Peer reviewedFinal Accepted Versio

The Uncertainty in Newton's Constant and Precision Predictions of the Primordial Helium Abundance

The current uncertainty in Newton's constant, G_N, is of the order of 0.15%. For values of the baryon to photon ratio consistent with both cosmic microwave background observations and the primordial deuterium abundance, this uncertainty in G_N corresponds to an uncertainty in the primordial 4He mass fraction, Y_P, of +-1.3 x 10^{-4}. This uncertainty in Y_P is comparable to the effect from the current uncertainty in the neutron lifetime, which is often treated as the dominant uncertainty in calculations of Y_P. Recent measurements of G_N seem to be converging within a smaller range; a reduction in the estimated error on G_N by a factor of 10 would essentially eliminate it as a source of uncertainty in the calculation of the primordial 4He abundance.Comment: 3 pages, no figures, fixed typos, to appear in Phys. Rev.

Correlated variability of Mkn 421 at X-ray and TeV wavelengths on timescales of hours

Mkn 421 was observed for about two days with BeppoSAX, prior to and partly overlapping the start of a 1 week continuous exposure with ASCA in April 1998, as part of a world-wide multiwavelength campaign. A pronounced, well defined, flare observed in X-rays was also observed simultaneously at TeV energies by the Whipple Observatory's 10 m gamma-ray telescope. These data provide the first evidence that the X-ray and TeV intensities are well correlated on time-scales of hours.Comment: 4 pages, 1 figure, presented at the VERITAS Workshop on the TeV Astrophysics of Extragalactic Object

Dissolution of Committed Partnerships during Incarceration and STI/HIV-Related Sexual Risk Behavior after Prison Release among African American Men

Incarceration is strongly associated with post-release STI/HIV risk. One pathway linking incarceration and STI/HIV risk may be incarceration-related dissolution of protective network ties. Among African American men released from prison who were in committed partnerships with women at the time of incarceration (N = 207), we measured the association between committed partnership dissolution during incarceration and STI/HIV risk in the 4 weeks after release. Over one-quarter (28%) experienced incarceration-related partnership dissolution. In adjusted analyses, incarceration-related partnership dissolution was strongly associated with post-release binge drinking (adjusted odds ratio (AOR) 4.2, 95% confidence interval (CI); 1.4–15.5). Those who experienced incarceration-related partnership dissolution were much more likely to engage in multiple/concurrent partnerships or sex trade defined as buying or selling sex (64%) than those who returned to the partner (12%; AOR 20.1, 95% CI 3.4–175.6). Policies that promote maintenance of relationships during incarceration may be important for protecting health

The First VERITAS Telescope

The first atmospheric Cherenkov telescope of VERITAS (the Very Energetic Radiation Imaging Telescope Array System) has been in operation since February 2005. We present here a technical description of the instrument and a summary of its performance. The calibration methods are described, along with the results of Monte Carlo simulations of the telescope and comparisons between real and simulated data. The analysis of TeV $\gamma$-ray observations of the Crab Nebula, including the reconstructed energy spectrum, is shown to give results consistent with earlier measurements. The telescope is operating as expected and has met or exceeded all design specifications.Comment: Accepted by Astroparticle Physic

Pharmacology and Surface Electrostatics of the K Channel Outer Pore Vestibule

In spite of a generally well-conserved outer vestibule and pore structure, there is considerable diversity in the pharmacology of K channels. We have investigated the role of specific outer vestibule charged residues in the pharmacology of K channels using tetraethylammonium (TEA) and a trivalent TEA analog, gallamine. Similar to Shaker K channels, gallamine block of Kv3.1 channels was more sensitive to solution ionic strength than was TEA block, a result consistent with a contribution from an electrostatic potential near the blocking site. In contrast, TEA block of another type of K channel (Kv2.1) was insensitive to solution ionic strength and these channels were resistant to block by gallamine. Neutralizing either of two lysine residues in the outer vestibule of these Kv2.1 channels conferred ionic strength sensitivity to TEA block. Kv2.1 channels with both lysines neutralized were sensitive to block by gallamine, and the ionic strength dependence of this block was greater than that for TEA. These results demonstrate that Kv3.1 (like Shaker) channels contain negatively charged residues in the outer vestibule of the pore that influence quaternary ammonium pharmacology. The presence of specific lysine residues in wild-type Kv2.1 channels produces an outer vestibule with little or no net charge, with important consequences for quaternary ammonium block. Neutralizing these key lysines results in a negatively charged vestibule with pharmacological properties approaching those of other types of K channels

Very-high energy gamma-ray astronomy: A 23-year success story in high-energy astroparticle physics

Very-high energy (VHE) gamma quanta contribute only a minuscule fraction - below one per million - to the flux of cosmic rays. Nevertheless, being neutral particles they are currently the best "messengers" of processes from the relativistic/ultra-relativistic Universe because they can be extrapolated back to their origin. The window of VHE gamma rays was opened only in 1989 by the Whipple collaboration, reporting the observation of TeV gamma rays from the Crab nebula. After a slow start, this new field of research is now rapidly expanding with the discovery of more than 150 VHE gamma-ray emitting sources. Progress is intimately related with the steady improvement of detectors and rapidly increasing computing power. We give an overview of the early attempts before and around 1989 and the progress after the pioneering work of the Whipple collaboration. The main focus of this article is on the development of experimental techniques for Earth-bound gamma-ray detectors; consequently, more emphasis is given to those experiments that made an initial breakthrough rather than to the successors which often had and have a similar (sometimes even higher) scientific output as the pioneering experiments. The considered energy threshold is about 30 GeV. At lower energies, observations can presently only be performed with balloon or satellite-borne detectors. Irrespective of the stormy experimental progress, the success story could not have been called a success story without a broad scientific output. Therefore we conclude this article with a summary of the scientific rationales and main results achieved over the last two decades.Comment: 45 pages, 38 figures, review prepared for EPJ-H special issue "Cosmic rays, gamma rays and neutrinos: A survey of 100 years of research

Gamma-ray Observations Under Bright Moonlight with VERITAS

Imaging atmospheric Cherenkov telescopes (IACTs) are equipped with sensitive photomultiplier tube (PMT) cameras. Exposure to high levels of background illumination degrades the efficiency of and potentially destroys these photo-detectors over time, so IACTs cannot be operated in the same configuration in the presence of bright moonlight as under dark skies. Since September 2012, observations have been carried out with the VERITAS IACTs under bright moonlight (defined as about three times the night-sky-background (NSB) of a dark extragalactic field, typically occurring when Moon illumination > 35%) in two observing modes, firstly by reducing the voltage applied to the PMTs and, secondly, with the addition of ultra-violet (UV) bandpass filters to the cameras. This has allowed observations at up to about 30 times previous NSB levels (around 80% Moon illumination), resulting in 30% more observing time between the two modes over the course of a year. These additional observations have already allowed for the detection of a flare from the 1ES 1727+502 and for an observing program targeting a measurement of the cosmic-ray positron fraction. We provide details of these new observing modes and their performance relative to the standard VERITAS observations