Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria

Growing evidence suggests persistent mitochondrial permeability transition pore (mPTP) opening is a key pathophysiological event in cell death underlying a variety of diseases. While it has long been clear the mPTP is a druggable target, current agents are limited by off-target effects and low therapeutic efficacy. Therefore identification and development of novel inhibitors is necessary. To rapidly screen large compound libraries for novel mPTP modulators, a method was exploited to cryopreserve large batches of functionally active mitochondria from cells and tissues. The cryopreserved mitochondria maintained respiratory coupling and ATP synthesis, Ca(2+) uptake and transmembrane potential. A high-throughput screen (HTS), using an assay of Ca(2+)-induced mitochondrial swelling in the cryopreserved mitochondria identified ER-000444793, a potent inhibitor of mPTP opening. Further evaluation using assays of Ca(2+)-induced membrane depolarisation and Ca(2+) retention capacity also indicated that ER-000444793 acted as an inhibitor of the mPTP. ER-000444793 neither affected cyclophilin D (CypD) enzymatic activity, nor displaced of CsA from CypD protein, suggesting a mechanism independent of CypD inhibition. Here we identified a novel, CypD-independent inhibitor of the mPTP. The screening approach and compound described provides a workflow and additional tool to aid the search for novel mPTP modulators and to help understand its molecular nature

Accelerator Testing of the General Antiparticle Spectrometer, a Novel Approach to Indirect Dark Matter Detection

We report on recent accelerator testing of a prototype general antiparticle spectrometer (GAPS). GAPS is a novel approach for indirect dark matter searches that exploits the antideuterons produced in neutralino-neutralino annihilations. GAPS captures these antideuterons into a target with the subsequent formation of exotic atoms. These exotic atoms decay with the emission of X-rays of precisely defined energy and a correlated pion signature from nuclear annihilation. This signature uniquely characterizes the antideuterons. Preliminary analysis of data from a prototype GAPS in an antiproton beam at the KEK accelerator in Japan has confirmed the multi-X-ray/pion star topology and indicated X-ray yields consistent with prior expectations. Moreover our success in utilizing solid rather than gas targets represents a significant simplification over our original approach and offers potential gains in sensitivity through reduced dead mass in the target area.Comment: 18 pages, 9 figures, submitted to JCA

Innovation in a Legal Vacuum: The Uncertain Legal Landscape for Shared Micro-Mobility

The last few years have seen an explosion in the number and size shared micro-mobility systems (“SMMS”) across the United States. Some of these systems have seen extraordinary success and the potential benefit of these systems to communities is considerable. However, SMMS have repeatedly ran into legal barriers that either prevent their implementation entirely, confuse and dissuade potential users, or otherwise limit SMMS’s potential positive impact. This paper reflects a detailed study of state laws relating to SMMS and the platforms commonly used in these systems. The study uncovered many inconsistencies with micro-mobility laws across the country. Currently, many states lack clear definitions for these emerging forms of transportation, which do not otherwise fit neatly in the categories contemplated by existing law. Several states lack clear, state-level policies, which has led to discrepancies between state and local regulations. Further, there are several areas of micro-mobility law that are sharply inconsistent between states. All of these differences leave users confused as to what the law is and may discourage them from riding. A number of states are attempting to remedy inconsistencies and legislative silence by passing and proposing laws that regulate the use of electric bikes (“e-bikes”) and electric scooters (“e-scooters”), but even these efforts are unlikely to bring the consistency that is needed. Federal authorities should act to create uniform laws and work with states to adopt them, otherwise, the lack of a legal infrastructure may threaten to stifle the innovation and undermine SMMS’s promised returns

Design, Commissioning and Performance of the PIBETA Detector at PSI

We describe the design, construction and performance of the PIBETA detector built for the precise measurement of the branching ratio of pion beta decay, pi+ -> pi0 e+ nu, at the Paul Scherrer Institute. The central part of the detector is a 240-module spherical pure CsI calorimeter covering 3*pi sr solid angle. The calorimeter is supplemented with an active collimator/beam degrader system, an active segmented plastic target, a pair of low-mass cylindrical wire chambers and a 20-element cylindrical plastic scintillator hodoscope. The whole detector system is housed inside a temperature-controlled lead brick enclosure which in turn is lined with cosmic muon plastic veto counters. Commissioning and calibration data were taken during two three-month beam periods in 1999/2000 with pi+ stopping rates between 1.3*E3 pi+/s and 1.3*E6 pi+/s. We examine the timing, energy and angular detector resolution for photons, positrons and protons in the energy range of 5-150 MeV, as well as the response of the detector to cosmic muons. We illustrate the detector signatures for the assorted rare pion and muon decays and their associated backgrounds.Comment: 117 pages, 48 Postscript figures, 5 tables, Elsevier LaTeX, submitted to Nucl. Instrum. Meth.

First results from NuSTAR observations of Mkn 421

Mkn 421 is a nearby active galactic nucleus dominated at all wavelengths by a very broad nonthermal continuum thought to arise from a relativistic jet seen at a small angle to the line of sight. Its spectral energy distribution peaks in the X-ray and TeV γ-ray bands, where the energy output is dominated by cooling of high-energy electrons in the jet. In order to study the electron distribution and its evolution, we carried out a dedicated multi-wavelength campaign, including extensive observations by the recently launched highly sensitive hard X-ray telescope NuSTAR, between December 2012 and May 2013. Here we present some initial results based on NuSTAR data from January through March 2013, as well as calibration observations conducted in 2012. Although the observations cover some of the faintest hard X-ray flux states ever observed forMkn 421, the sensitivity is high enough to resolve intra-day spectral variability. We find that in this low state the dominant flux variations are smooth on timescales of hours, with typical intra-hour variations of ≲ 5%. We do not find evidence for either a cutoff in the hard X-ray spectrum, or a rise towards a high-energy component, but rather that at low flux the spectrum assumes a power law shape with a photon index of approximately 3. The spectrum is found to harden with increasing brightness

The Nuclear Spectroscopic Telescope Array (NuSTAR) High-Energy X-ray Mission

High-energy X-ray telescope in orbit. NuSTAR operates in the band from 3 to 79 keV, extending the sensitivity of focusing far beyond the 10 keV high-energy cutoff achieved by all previous X-ray satellites. The inherently low background associated with concentrating the X-ray light enables NuSTAR to probe the hard X-ray sky with a more than 100-fold improvement in sensitivity over the collimated or coded mask instruments that have operated in this bandpass. Using its unprecedented combination of sensitivity and spatial and spectral resolution, NuSTAR will pursue five primary scientific objectives: (1) probe obscured active galactic nucleus (AGN) activity out to thepeak epoch of galaxy assembly in the universe (at z 2) by surveying selected regions of the sky; (2) study the population of hard X-ray-emitting compact objects in the Galaxy by mapping the central regions of the Milky Way; (3) study the non-thermal radiation in young supernova remnants, both the hard X-ray continuum and the emission from the radioactive element 44Ti; (4) observe blazars contemporaneously with ground-based radio, optical, and TeV telescopes, as well as with Fermi and Swift, to constrain the structure of AGN jets; and (5) observe line and continuum emission from core-collapse supernovae in the Local Group, and from nearby Type Ia events, to constrain explosion models. During its baseline two-year mission, NuSTAR will also undertake a broad program of targeted observations. The observatory consists of two co-aligned grazing-incidence X-ray telescopes pointed at celestial targets by a three-axis stabilized spacecraft. Deployed into a 600 km, near-circular, 6 inclination orbit, the observatory has now completed commissioning, and is performing consistent with pre-launch expectations. NuSTAR is now executing its primary science mission, and with an expected orbit lifetime of 10 yr, we anticipate proposing a guest investigator program, to begin in late 2014