Observations of the Crab Nebula with H.E.S.S. Phase II

The High Energy Stereoscopic System (H.E.S.S.) phase I instrument was an array of four $100\,\mathrm{m}^2$ mirror area Imaging Atmospheric Cherenkov Telescopes (IACTs) that has very successfully mapped the sky at photon energies above $\sim 100\,$GeV. Recently, a $600\,\mathrm{m}^2$ telescope was added to the centre of the existing array, which can be operated either in standalone mode or jointly with the four smaller telescopes. The large telescope lowers the energy threshold for gamma-ray observations to several tens of GeV, making the array sensitive at energies where the Fermi-LAT instrument runs out of statistics. At the same time, the new telescope makes the H.E.S.S. phase II instrument. This is the first hybrid IACT array, as it operates telescopes of different size (and hence different trigger rates) and different field of view. In this contribution we present results of H.E.S.S. phase II observations of the Crab Nebula, compare them to earlier observations, and evaluate the performance of the new instrument with Monte Carlo simulations.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherland

Factors Associated with Unmet Needs among African-American Dementia Care Providers

Racial and ethnic minorities currently comprise 20% of the U.S. population; in 2050, this figure is expected to rise to 42%. As a result, Alzheimer’s disease (AD), the 5th leading cause of death for people aged 65 and older, is likely to increase in these groups. Most dementia caregiving for these populations comes from family and friends, especially among families with lower socioeconomic status. A convenience sample of 30 African-American dementia caregivers was interviewed to determine unmet needs. Participants expressed a limited desire for formal services, such as support groups, legal advice, case management, and homemaker services. Instead, commonly expressed needs were daytime respite care and especially a desire for family and social support. Many caregivers expressed a need for other family members to share responsibility in the process; therefore, methods for caregiver support that address multiple family members in care provision may be beneficial for this group

Status van de van oorsprong Nederlandse rassen

Net als in 2013 wordt de status van de van oorsprong Nederlandse rassen besproken. Het betreft het aantal volwassen stamboekgeregistreerde vrouwelijke dieren van rund, schaap, geit, varken, paard, hond, kip, konijn, duif, gans, eend en honingbij. En de trend in de afgelopen 15 jaar

Fitting the Gamma-Ray Spectrum from Dark Matter with DMFIT: GLAST and the Galactic Center Region

We study the potential of GLAST to unveil particle dark matter properties with gamma-ray observations of the Galactic center region. We present full GLAST simulations including all gamma-ray sources known to date in a region of 4 degrees around the Galactic center, in addition to the diffuse gamma-ray background and to the dark matter signal. We introduce DMFIT, a tool that allows one to fit gamma-ray emission from pair-annihilation of generic particle dark matter models and to extract information on the mass, normalization and annihilation branching ratios into Standard Model final states. We assess the impact and systematic effects of background modeling and theoretical priors on the reconstruction of dark matter particle properties. Our detailed simulations demonstrate that for some well motivated supersymmetric dark matter setups with one year of GLAST data it will be possible not only to significantly detect a dark matter signal over background, but also to estimate the dark matter mass and its dominant pair-annihilation mode.Comment: 37 pages, 16 figures, submitted to JCA

Pressure and temperature effects on metal-to-metal charge transfer in cyano-bridged Co-III-Fe-II complexes

The effects of pressure and temperature on the energy (E-op) of the metal-to-metal charge transfer (MMCT, Fe-II --> Co-III) transition of the cyano-bridged complexes trans - [(LCoNCFe)-Co-14(CN)(5)](-) and cis-[(LCoNCFe)-Co-14(CN)(5)](-) (where L-14 = 6-methyl-1,4,8,11-tetraazacyclotetradecan-6-amine) were examined. The changes in the redox potentials of the cobalt and iron metal centres with pressure and temperature were also examined and the results interpreted with Marcus Hush theory. The observed redox reaction volumes can mainly be accounted for in terms of localised electrostriction effects. The shifts in E-op due to both pressure and temperature were found to be less than the shifts in the energy difference (E degrees) between the Co-III-Fe-II and Co-II-Fe-III redox isomers. The pressure and temperature dependence of the reorganisational energy, as well as contributions arising from the different spin states of Co-II, are discussed in order to account for this trend. To study the effect of pressure on Co-III electronic absorption bands, a new cyano-bridged complex, trans - [(LCoNCCo)-Co-14(CN)(5)], was prepared and characterised spectroscopically and structurally. X-Ray crystallography revealed this complex to be isostructural with trans -[(LCoNCFe)-Co-14(CN)(5)] center dot 5H(2)O

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor that Attenuates Disease Progression in Alzheimer\u27s Disease Mouse Models

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150\u27s exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior

Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction

Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will facilitate future kinase inhibitor design. Overall, our studies deliver highly selective in vivo probes appropriate for CNS investigations and demonstrate that modulation of p38αMAPK activity can attenuate synaptic dysfunction