Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2.

Poly(ADP-ribose) polymerase-1 (PARP-1) has become an important pharmacological target in the treatment of cancer due to its cellular role as a 'DNA-strand break sensor', which leads in part to resistance to some existing chemo- and radiological treatments. Inhibitors have now been developed which prevent PARP-1 from synthesizing poly(ADP-ribose) in response to DNA-breaks and potentiate the cytotoxicity of DNA damaging agents. However, with the recent discoveries of PARP-2, which has a similar DNA-damage dependent catalytic activity, and additional members containing the 'PARP catalytic' signature, the isoform selectivity and resultant pharmacological effects of existing inhibitors are brought into question. We present here the crystal structure of the catalytic fragment of murine PARP-2, at 2.8 A resolution, and compare this to the catalytic fragment of PARP-1, with an emphasis on providing a possible framework for rational drug design in order to develop future isoform-specific inhibitors

How effective is the Forestry Commission Scotland's woodland improvement programme--'Woods In and Around Towns' (WIAT)--at improving psychological well-being in deprived urban communities? A quasi-experimental study

Introduction: There is a growing body of evidence that suggests that green spaces may positively influence psychological well-being. This project is designed to take advantage of a natural experiment where planned physical and social interventions to enhance access to natural environments in deprived communities provide an opportunity to prospectively assess impacts on perceived stress and mental well-being.<p></p> Study design and methods: A controlled, prospective study comprising a repeat cross-sectional survey of residents living within 1.5 km of intervention and comparison sites. Three waves of data will be collected: prephysical environment intervention (2013); postphysical environment intervention (2014) and postwoodland promotion social intervention (2015). The primary outcome will be a measure of perceived stress (Perceived Stress Scale) preintervention and postintervention. Secondary, self-report outcomes include: mental well-being (Short Warwick-Edinburgh Mental Well-being Scale), changes in physical activity (IPAQ-short form), health (EuroQoL EQ-5D), perception and use of the woodlands, connectedness to nature (Inclusion of Nature in Self Scale), social cohesion and social capital. An environmental audit will complement the study by evaluating the physical changes in the environment over time and recording any other contextual changes over time. A process evaluation will assess the implementation of the programme. A health economics analysis will assess the cost consequences of each stage of the intervention in relation to the primary and secondary outcomes of the study.<p></p> Ethics and dissemination: Ethical approval has been given by the University of Edinburgh, Edinburgh College of Art Research, Ethics and Knowledge Exchange Committee (ref. 19/06/2012). Findings will be disseminated through peer-reviewed publications, national and international conferences and, at the final stage of the project, through a workshop for those interested in implementing environmental interventions.<p></p&gt

Including Systematic Uncertainties in Confidence Interval Construction for Poisson Statistics

One way to incorporate systematic uncertainties into the calculation of confidence intervals is by integrating over probability density functions parametrizing the uncertainties. In this note we present a development of this method which takes into account uncertainties in the prediction of background processes, uncertainties in the signal detection efficiency and background efficiency and allows for a correlation between the signal and background detection efficiencies. We implement this method with the Feldman & Cousins unified approach with and without conditioning. We present studies of coverage for the Feldman & Cousins and Neyman ordering schemes. In particular, we present two different types of coverage tests for the case where systematic uncertainties are included. To illustrate the method we show the relative effect of including systematic uncertainties the case of dark matter search as performed by modern neutrino tel escopes.Comment: 23 pages, 10 figures, replaced to match published versio

A new 1.6-micron map of Titan’s surface

We present a new map of Titan's surface obtained in the spectral 'window' at ∼1.6 μm between strong methane absorption. This pre-Cassini view of Titan's surface was created from images obtained using adaptive optics on the W.M. Keck II telescope and is the highest resolution map yet made of Titan's surface. Numerous surface features down to the limits of the spatial resolution (∼200–300 km) are apparent. No features are easily identifiable in terms of their geologic origin, although several are likely craters

A Letter of Intent to Build a MiniBooNE Near Detector: BooNE

There is accumulating evidence for a difference between neutrino and antineutrino oscillations at the $\sim 1$ eV$^2$ scale. The MiniBooNE experiment observes an unexplained excess of electron-like events at low energies in neutrino mode, which may be due, for example, to either a neutral current radiative interaction, sterile neutrino decay, or to neutrino oscillations involving sterile neutrinos and which may be related to the LSND signal. No excess of electron-like events ($-0.5 \pm 7.8 \pm 8.7$), however, is observed so far at low energies in antineutrino mode. Furthermore, global 3+1 and 3+2 sterile neutrino fits to the world neutrino and antineutrino data suggest a difference between neutrinos and antineutrinos with significant ($\sin^22\theta_{\mu \mu} \sim 35$) $\bar \nu_\mu$ disappearance. In order to test whether the low-energy excess is due to neutrino oscillations and whether there is a difference between $\nu_\mu$ and $\bar \nu_\mu$ disappearance, we propose building a second MiniBooNE detector at (or moving the existing MiniBooNE detector to) a distance of $\sim 200$ m from the Booster Neutrino Beam (BNB) production target. With identical detectors at different distances, most of the systematic errors will cancel when taking a ratio of events in the two detectors, as the neutrino flux varies as $1/r^2$ to a calculable approximation. This will allow sensitive tests of oscillations for both $\nu_e$ and $\bar \nu_e$ appearance and $\nu_\mu$ and $\bar \nu_\mu$ disappearance. Furthermore, a comparison between oscillations in neutrino mode and antineutrino mode will allow a sensitive search for CP and CPT violation in the lepton sector at short baseline ($\Delta m^2 > 0.1$ eV$^2$).Comment: 43 pages, 40 figure

Use of a dual reporter plasmid to demonstrate bactofection with an attenuated aroa- derivative of Pasteurella multocida b:2

A reporter plasmid pSRG has been developed which expresses red fluorescent protein (RFP) from a constitutive prokaryotic promoter within Pasteurella multocida B:2 and green fluorescent protein (GFP) from a constitutive eukaryotic promoter within mammalian cells. This construct has been used to determine the location and viability of the bacteria when moving from the extracellular environment into the intracellular compartment of mammalian cells. Invasion assays with embryonic bovine lung (EBL) cells and an attenuated AroA- derivative of Pasteurella multocida B:2 (strain JRMT12), harbouring the plasmid pSRG, showed that RFP-expressing bacteria could be detected intracellularly at 3 h post-invasion. At this stage, some EBL cells harbouring RFP-expressing bacteria were observed to express GFP simultaneously, indicating release of the plasmid into the intracellular environment. At 5 h post-invasion, more EBL cells were expressing GFP, while still harbouring RFP-expressing bacteria. Concurrently, some EBL cells were shown to express only GFP, indicating loss of viable bacteria within these cells. These experiments proved the functionality of the pSRG dual reporter system and the potential of P. multocida B:2 JRMT12 for bactofection and delivery of a DNA vaccine

Aperture synthesis for gravitational-wave data analysis: Deterministic Sources

Gravitational wave detectors now under construction are sensitive to the phase of the incident gravitational waves. Correspondingly, the signals from the different detectors can be combined, in the analysis, to simulate a single detector of greater amplitude and directional sensitivity: in short, aperture synthesis. Here we consider the problem of aperture synthesis in the special case of a search for a source whose waveform is known in detail: \textit{e.g.,} compact binary inspiral. We derive the likelihood function for joint output of several detectors as a function of the parameters that describe the signal and find the optimal matched filter for the detection of the known signal. Our results allow for the presence of noise that is correlated between the several detectors. While their derivation is specialized to the case of Gaussian noise we show that the results obtained are, in fact, appropriate in a well-defined, information-theoretic sense even when the noise is non-Gaussian in character. The analysis described here stands in distinction to ``coincidence analyses'', wherein the data from each of several detectors is studied in isolation to produce a list of candidate events, which are then compared to search for coincidences that might indicate common origin in a gravitational wave signal. We compare these two analyses --- optimal filtering and coincidence --- in a series of numerical examples, showing that the optimal filtering analysis always yields a greater detection efficiency for given false alarm rate, even when the detector noise is strongly non-Gaussian.Comment: 39 pages, 4 figures, submitted to Phys. Rev.

The OscSNS White Paper

There exists a need to address and resolve the growing evidence for short-baseline neutrino oscillations and the possible existence of sterile neutrinos. Such non-standard particles require a mass of $\sim 1$ eV/c$^2$, far above the mass scale associated with active neutrinos, and were first invoked to explain the LSND $\bar \nu_\mu \rightarrow \bar \nu_e$ appearance signal. More recently, the MiniBooNE experiment has reported a $2.8 \sigma$ excess of events in antineutrino mode consistent with neutrino oscillations and with the LSND antineutrino appearance signal. MiniBooNE also observed a $3.4 \sigma$ excess of events in their neutrino mode data. Lower than expected neutrino-induced event rates using calibrated radioactive sources and nuclear reactors can also be explained by the existence of sterile neutrinos. Fits to the world's neutrino and antineutrino data are consistent with sterile neutrinos at this $\sim 1$ eV/c$^2$ mass scale, although there is some tension between measurements from disappearance and appearance experiments. In addition to resolving this potential major extension of the Standard Model, the existence of sterile neutrinos will impact design and planning for all future neutrino experiments. It should be an extremely high priority to conclusively establish if such unexpected light sterile neutrinos exist. The Spallation Neutron Source (SNS) at Oak Ridge National Laboratory, built to usher in a new era in neutron research, provides a unique opportunity for US science to perform a definitive world-class search for sterile neutrinos.Comment: This white paper is submitted as part of the SNOWMASS planning proces