Capability of Cherenkov Telescopes to Observe Ultra-fast Optical Flares

The large optical reflector (~ 100 m^2) of a H.E.S.S. Cherenkov telescope was used to search for very fast optical transients of astrophysical origin. 43 hours of observations targeting stellar-mass black holes and neutron stars were obtained using a dedicated photometer with microsecond time resolution. The photometer consists of seven photomultiplier tube pixels: a central one to monitor the target and a surrounding ring of six pixels to veto background events. The light curves of all pixels were recorded continuously and were searched offline with a matched-filtering technique for flares with a duration of 2 us to 100 ms. As expected, many unresolved (500 us) background events originating in the earth's atmosphere were detected. In the time range 3 to 500 us the measurement is essentially background-free, with only eight events detected in 43 h; five from lightning and three presumably from a piece of space debris. The detection of flashes of brightness ~ 0.1 Jy and only 20 us duration from the space debris shows the potential of this setup to find rare optical flares on timescales of tens of microseconds. This timescale corresponds to the light crossing time of stellar-mass black holes and neutron stars.Comment: Accepted for publication in Astroparticle Physics, 8 pages, 9 figures, 1 tabl

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

Targeting Astrocytes Ameliorates Neurologic Changes in a Mouse Model of Alzheimer\u27s Disease

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer\u27s disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically activated phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes in APP/PS1 mice. AAV-Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with the immune/inflammatory calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway, shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation. After several months of treatment with Gfa2-VIVIT, APP/PS1 mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies

Challenges and Considerations Related to Studying Dementia in Blacks/African Americans

Blacks/African Americans have been reported to be ~2–4 times more likely to develop clinical Alzheimer’s disease (AD) compared to Whites. Unfortunately, study design challenges (e.g., recruitment bias), racism, mistrust of healthcare providers and biomedical researchers, confounders related to socioeconomic status, and other sources of bias are often ignored when interpreting differences in human subjects categorized by race. Failure to account for these factors can lead to misinterpretation of results, reification of race as biology, discrimination, and missed or delayed diagnoses. Here we provide a selected historical background, discuss challenges, present opportunities, and suggest considerations for studying health outcomes among racial/ethnic groups. We encourage neuroscientists to consider shifting away from using biologic determination to interpret data, and work instead toward a paradigm of incorporating both biological and socio-environmental factors known to affect health outcomes with the goal of understanding and improving dementia treatments for Blacks/African Americans and other underserved populations

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

First detection of a VHE gamma-ray spectral maximum from a Cosmic source: H.E.S.S. discovery of the Vela X nebula

The Vela supernova remnant (SNR) is a complex region containing a number of sources of non-thermal radiation. The inner section of this SNR, within 2 degrees of the pulsar PSR B0833-45, has been observed by the H.E.S.S. gamma-ray atmospheric Cherenkov detector in 2004 and 2005. A strong signal is seen from an extended region to the south of the pulsar, within an integration region of radius 0.8 deg. around the position (RA = 08h 35m 00s, dec = -45 deg. 36' J2000.0). The excess coincides with a region of hard X-ray emission seen by the ROSAT and ASCA satellites. The observed energy spectrum of the source between 550 GeV and 65 TeV is well fit by a power law function with photon index = 1.45 +/- 0.09(stat) +/- 0.2(sys) and an exponential cutoff at an energy of 13.8 +/- 2.3(stat) +/- 4.1(sys) TeV. The integral flux above 1 TeV is (1.28 +/- 0.17 (stat) +/- 0.38(sys)) x 10^{-11} cm^{-2} s^{-1}. This result is the first clear measurement of a peak in the spectral energy distribution from a VHE gamma-ray source, likely related to inverse Compton emission. A fit of an Inverse Compton model to the H.E.S.S. spectral energy distribution gives a total energy in non-thermal electrons of ~2 x 10^{45} erg between 5 TeV and 100 TeV, assuming a distance of 290 parsec to the pulsar. The best fit electron power law index is 2.0, with a spectral break at 67 TeV.Comment: 5 pages, 4 figures, accepted for publication in Astronomy and Astrophysics letter