Positive allosteric modulators of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor

L-glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a fundamental role in the control of motor function, cognition and mood. The physiological effects of glutamate are mediated through two functionally distinct receptor families. While activation of metabotropic (G-protein coupled) glutamate receptors results in modulation of neuronal excitability and transmission, the ionotropic glutamate receptors (ligand-gated ion channels) are responsible for mediating the fast synaptic response to extracellular glutamate

On the structure of phase transition maps for three or more coexisting phases

This paper is partly based on a lecture delivered by the author at the ERC workshop "Geometric Partial Differential Equations" held in Pisa in September 2012. What is presented here is an expanded version of that lecture.Comment: 23 pages, 6 figure

Quantifying the Detrimental Impacts of Land-Use and Management Change on European Forest Bird Populations

The ecological impacts of changing forest management practices in Europe are poorly understood despite European forests being highly managed. Furthermore, the effects of potential drivers of forest biodiversity decline are rarely considered in concert, thus limiting effective conservation or sustainable forest management. We present a trait-based framework that we use to assess the detrimental impact of multiple land-use and management changes in forests on bird populations across Europe. Major changes to forest habitats occurring in recent decades, and their impact on resource availability for birds were identified. Risk associated with these changes for 52 species of forest birds, defined as the proportion of each species' key resources detrimentally affected through changes in abundance and/or availability, was quantified and compared to their pan-European population growth rates between 1980 and 2009. Relationships between risk and population growth were found to be significantly negative, indicating that resource loss in European forests is an important driver of decline for both resident and migrant birds. Our results demonstrate that coarse quantification of resource use and ecological change can be valuable in understanding causes of biodiversity decline, and thus in informing conservation strategy and policy. Such an approach has good potential to be extended for predictive use in assessing the impact of possible future changes to forest management and to develop more precise indicators of forest health

Blood pressure variability and cardiovascular risk in the PROspective study of pravastatin in the elderly at risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects

Observations of Milky Way Dwarf Spheroidal galaxies with the Fermi-LAT detector and constraints on Dark Matter models

We report on the observations of 14 dwarf spheroidal galaxies with the Fermi Gamma-Ray Space Telescope taken during the first 11 months of survey mode operations. The Fermi telescope provides a new opportunity to test particle dark matter models through the expected gamma-ray emission produced by pair annihilation of weakly interacting massive particles (WIMPs). Local Group dwarf spheroidal galaxies, the largest galactic substructures predicted by the cold dark matter scenario, are attractive targets for such indirect searches for dark matter because they are nearby and among the most extreme dark matter dominated environments. No significant gamma-ray emission was detected above 100 MeV from the candidate dwarf galaxies. We determine upper limits to the gamma-ray flux assuming both power-law spectra and representative spectra from WIMP annihilation. The resulting integral flux above 100 MeV is constrained to be at a level below around 10^-9 photons cm^-2 s^-1. Using recent stellar kinematic data, the gamma-ray flux limits are combined with improved determinations of the dark matter density profile in 8 of the 14 candidate dwarfs to place limits on the pair annihilation cross-section of WIMPs in several widely studied extensions of the standard model. With the present data, we are able to rule out large parts of the parameter space where the thermal relic density is below the observed cosmological dark matter density and WIMPs (neutralinos here) are dominantly produced non-thermally, e.g. in models where supersymmetry breaking occurs via anomaly mediation. The gamma-ray limits presented here also constrain some WIMP models proposed to explain the Fermi and PAMELA e^+e^- data, including low-mass wino-like neutralinos and models with TeV masses pair-annihilating into muon-antimuon pairs. (Abridged)Comment: 25 pages, 4 figures, accepted to ApJ, Corresponding authors: J. Cohen-Tanugi, C. Farnier, T.E. Jeltema, E. Nuss, and S. Profum

Gamma-Ray and Radio Observations of PSR B1509-58

Abstract : We report concurrent radio and gamma-ray observations of PSR B1509-58 carried out by the Parkes Radio Telescope and by the Burst and Transient Source Experiment (BATSE) and the Oriented Scintillation Spectrometer Experiment (OSSE) on the Compton Gamma Ray Observatory (CGRO-Gamma-ray light curves fitted at several energies between ~ 20-500 keV yield a phase offset with respect to the radio pulse that is independent of energy, with an average value 0.32 plus or minus 0.02. Although this value is larger by 0.07 than that reported by Kawai et al., the difference is not statistically significant (only~2 sigma) when account is taken of the uncertainty associated with their result. We briefly discuss the possibility that the energy-independence of the gamma-ray pulse phase is a signature of non-thermal radiation in the X-ray/gamma-ray range and the suggestion of a dependence of pulsar radio-gamma-ray phase offset on pulse period

Dark Matter Candidates: A Ten-Point Test

An extraordinarily rich zoo of non-baryonic Dark Matter candidates has been proposed over the last three decades. Here we present a 10-point test that a new particle has to pass, in order to be considered a viable DM candidate: I.) Does it match the appropriate relic density? II.) Is it {\it cold}? III.) Is it neutral? IV.) Is it consistent with BBN? V.) Does it leave stellar evolution unchanged? VI.) Is it compatible with constraints on self-interactions? VII.) Is it consistent with {\it direct} DM searches? VIII.) Is it compatible with gamma-ray constraints? IX.) Is it compatible with other astrophysical bounds? X.) Can it be probed experimentally?Comment: 29 pages, 12 figure

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants