Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596

Alpha7 nicotinic acetylcholine receptors (α7 nAChR) are widely distributed throughout the central nervous system and are found at particularly high levels in the hippocampus and cortex. Several lines of evidence indicate that pharmacological enhancement of α7 nAChRs function could be a potential therapeutic route to alleviate disease-related cognitive deficits. A recent pharmacological approach adopted to increase α7 nAChR activity has been to identify selective positive allosteric modulators (PAMs). α7 nAChR PAMs have been divided into two classes: type I PAMs increase agonist potency with only subtle effects on kinetics, whereas type II agents produce additional dramatic effects on desensitization and deactivation kinetics. Here we report novel observations concerning the pharmacology of the canonical type II PAM, PNU120596. Using patch clamp analysis of acetylcholine (ACh)-mediated currents through recombinant rat α7 nAChR we show that positive allosteric modulation measured in two different ways is greatly attenuated when the temperature is raised to near physiological levels. Furthermore, PNU120596 largely removes the strong inward rectification usually exhibited by α7 nAChR-mediated responses

Comparison of Back-Thinned Detector Ultraviolet Quantum Efficiency for Two Commercially Available Passivation Treatments

Back-thinned silicon detectors offer a high response over a very broad spectrum for direct detection by providing an efficient optical path into the sensing silicon avoiding front face structures manufactured from metal, polysilicon, nitrides, and oxides that may absorb the incident light before reaching the sensing silicon. We have tested two CCDs with different back-surface shallow p+ implant thicknesses (basic and enhanced) at the M4 line (wavelength between 40 and 400 nm) at Physikalisch-Technische Bundesanstalt (PTB)’s Metrology Light Source in Berlin. This characterization in the ultraviolet spectral range extends the soft X-ray quantum efficiency (QE) data set previously acquired with the exact same devices. Due to the short absorption depth and the scope for many types of interactions of the device materials with ultraviolet photons, QE measurement and stability of the device against extended exposure in the UV are of ongoing interest. Therefore, QE measurements have been carried out before and after exposures to quantify any change in behavior. To allow characterization of the passivation processes only, the devices have no antireflection coating. The measured QE of the standard back-thinned CCD is below 10% between 70 and 370 nm. An average additional 5% efficiency is achieved in the enhanced device within the same range. At the limits of the measured spectrum, toward soft X-rays or toward the visible range, the QE increases and the difference between the standard and the enhanced process is reduced as the photon absorption length increases beyond the immediate back-surface. The measured QE after long high-flux exposures at 200 nm shows remarkable improvement

Altered synaptic plasticity in the mossy fibre pathway of transgenic mice expressing mutant amyloid precursor protein

Aβ peptides derived from the cleavage of amyloid precursor protein are widely believed to play an important role in the pathophysiology of Alzheimer's disease. A common way to study the impact of these molecules on CNS function is to compare the physiology of transgenic mice that overproduce Aβ with non-transgenic animals. In the hippocampus, this approach has been frequently applied to the investigation of synaptic transmission and plasticity in the perforant and Schaffer collateral commissural pathways, the first and third components of the classical hippocampal trisynaptic circuit, respectively. Similar studies however have not been carried out on the remaining component of the trisynaptic circuit, the mossy fibre pathway. Using transverse hippocampal slices prepared from ~2 year old animals we have compared mossy fibre synaptic function in wild-type mice and their Tg2576 littermates which age-dependently overproduce Aβ. Input-output curves were not altered in slices from Tg2576 mice, but these animals exhibited a significant loss of the prominent frequency-facilitation expressed by the mossy fibre pathway. In addition to this change in short term synaptic plasticity, high frequency stimulation-induced, NMDA-receptor-independent LTP was absent in slices from the transgenic mice. These data represent the first description of functional deficits in the mossy fibre pathway of Aβ-overproducing transgenic mice

The SMC SNR 1E0102.2-7219 as a Calibration Standard for X-ray Astronomy in the 0.3-2.5 keV Bandpass

The flight calibration of the spectral response of CCD instruments below 1.5 keV is difficult in general because of the lack of strong lines in the on-board calibration sources typically available. We have been using 1E 0102.2-7219, the brightest supernova remnant in the Small Magellanic Cloud, to evaluate the response models of the ACIS CCDs on the Chandra X-ray Observatory (CXO), the EPIC CCDs on the XMM-Newton Observatory, the XIS CCDs on the Suzaku Observatory, and the XRT CCD on the Swift Observatory. E0102 has strong lines of O, Ne, and Mg below 1.5 keV and little or no Fe emission to complicate the spectrum. The spectrum of E0102 has been well characterized using high-resolution grating instruments, namely the XMM-Newton RGS and the CXO HETG, through which a consistent spectral model has been developed that can then be used to fit the lower-resolution CCD spectra. We have also used the measured intensities of the lines to investigate the consistency of the effective area models for the various instruments around the bright O (~570 eV and 654 eV) and Ne (~910 eV and 1022 eV) lines. We find that the measured fluxes of the O VII triplet, the O VIII Ly-alpha line, the Ne IX triplet, and the Ne X Ly-alpha line generally agree to within +/-10 % for all instruments, with 28 of our 32 fitted normalizations within +/-10% of the RGS-determined value. The maximum discrepancies, computed as the percentage difference between the lowest and highest normalization for any instrument pair, are 23% for the O VII triplet, 24% for the O VIII Ly-alpha line, 13% for the Ne IX triplet, and 19% for the Ne X Ly-alpha line. If only the CXO and XMM are compared, the maximum discrepancies are 22% for the O VII triplet, 16% for the O VIII Ly-alpha line, 4% for the Ne IX triplet, and 12% for the Ne X Ly-alpha line.Comment: 16 pages, 11 figures, to be published in Proceedings of the SPIE 7011: Space Telescopes and Instrumentation II: Ultraviolet to Gamma Ray 200