The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer's, Parkinson's, Huntington's, and prion disease. The utility of this system lies in ...the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer's disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background and recurred on reintroduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds, indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.
The H.E.S.S. Galactic plane survey Angüner, E. O.; Arakawa, M.; Aubert, P. ...
Astronomy & astrophysics,
04/2018, Volume:
612
Journal Article
Peer reviewed
Open access
We present the results of the most comprehensive survey of the Galactic plane in very high-energy (VHE) γ-rays, including a public release of Galactic sky maps, a catalog of VHE sources, and the ...discovery of 16 new sources of VHE γ-rays. The High Energy Spectroscopic System (H.E.S.S.) Galactic plane survey (HGPS) was a decade-long observation program carried out by the H.E.S.S. I array of Cherenkov telescopes in Namibia from 2004 to 2013. The observations amount to nearly 2700 h of quality-selected data, covering the Galactic plane at longitudes from ℓ = 250° to 65° and latitudes |b|≤ 3°. In addition to the unprecedented spatial coverage, the HGPS also features a relatively high angular resolution (0.08° ≈ 5 arcmin mean point spread function 68% containment radius), sensitivity (≲1.5% Crab flux for point-like sources), and energy range (0.2–100 TeV). We constructed a catalog of VHE γ-ray sources from the HGPS data set with a systematic procedure for both source detection and characterization of morphology and spectrum. We present this likelihood-based method in detail, including the introduction of a model component to account for unresolved, large-scale emission along the Galactic plane. In total, the resulting HGPS catalog contains 78 VHE sources, of which 14 are not reanalyzed here, for example, due to their complex morphology, namely shell-like sources and the Galactic center region. Where possible, we provide a firm identification of the VHE source or plausible associations with sources in other astronomical catalogs. We also studied the characteristics of the VHE sources with source parameter distributions. 16 new sources were previously unknown or unpublished, and we individually discuss their identifications or possible associations. We firmly identified 31 sources as pulsar wind nebulae (PWNe), supernova remnants (SNRs), composite SNRs, or gamma-ray binaries. Among the 47 sources not yet identified, most of them (36) have possible associations with cataloged objects, notably PWNe and energetic pulsars that could power VHE PWNe.
The nine-year H.E.S.S. Galactic Plane Survey (HGPS) has yielded the most uniform observation scan of the inner Milky Way in the TeV gamma-ray band to date. The sky maps and source catalogue of the ...HGPS allow for a systematic study of the population of TeV pulsar wind nebulae found throughout the last decade. To investigate the nature and evolution of pulsar wind nebulae, for the first time we also present several upper limits for regions around pulsars without a detected TeV wind nebula. Our data exhibit a correlation of TeV surface brightness with pulsar spin-down power Ė. This seems to be caused both by an increase of extension with decreasing Ė, and hence with time, compatible with a power law RPWN(Ė) ~Ė−0.65±0.20, and by a mild decrease of TeV gamma-ray luminosity with decreasing Ė, compatible with L1−10 TeV ~Ė0.59±0.21. We also find that the offsets of pulsars with respect to the wind nebula centre with ages around 10 kyr are frequently larger than can be plausibly explained by pulsar proper motion and could be due to an asymmetric environment. In the present data, it seems that a large pulsar offset is correlated with a high apparent TeV efficiency L1−10 TeV∕Ė. In addition to 14 HGPS sources considered firmly identified pulsar wind nebulae and 5 additional pulsar wind nebulae taken from literature, we find 10 HGPS sources that are likely TeV pulsar wind nebula candidates. Using a model that subsumes the present common understanding of the very high-energy radiative evolution of pulsar wind nebulae, we find that the trends and variations of the TeV observables and limits can be reproduced to a good level, drawing a consistent picture of present-day TeV data and theory.
Alternative splicing makes a major contribution to proteomic diversity in higher eukaryotes with ∼70% of genes encoding two or more isoforms. In most cases, the molecular mechanisms responsible for ...splice site choice remain poorly understood. Here, we used a randomization-selection approach in vitro to identify sequence elements that could silence a proximal strong 5′ splice site located downstream of a weakened 5′ splice site. We recovered two exonic and four intronic motifs that effectively silenced the proximal 5′ splice site both in vitro and in vivo. Surprisingly, silencing was only observed in the presence of the competing upstream 5′ splice site. Biochemical evidence strongly suggests that the silencing motifs function by altering the U1 snRNP/5′ splice site complex in a manner that impairs commitment to specific splice site pairing. The data indicate that perturbations of non-rate-limiting step(s) in splicing can lead to dramatic shifts in splice site choice.
Context. We present a detailed view of the pulsar wind nebula (PWN) HESS J1825–137. We aim to constrain the mechanisms dominating the particle transport within the nebula, accounting for its ...anomalously large size and spectral characteristics. Aims. The nebula was studied using a deep exposure from over 12 years of H.E.S.S. I operation, together with data from H.E.S.S. II that improve the low-energy sensitivity. Enhanced energy-dependent morphological and spatially resolved spectral analyses probe the very high energy (VHE, E > 0.1 TeV) γ-ray properties of the nebula. Methods. The nebula emission is revealed to extend out to 1.5° from the pulsar, ~1.5 times farther than previously seen, making HESS J1825–137, with an intrinsic diameter of ~100 pc, potentially the largest γ-ray PWN currently known. Characterising the strongly energy-dependent morphology of the nebula enables us to constrain the particle transport mechanisms. A dependence of the nebula extent with energy of R ∝ Eα with α = −0.29 ± 0.04stat ± 0.05sys disfavours a pure diffusion scenario for particle transport within the nebula. The total γ-ray flux of the nebula above 1 TeV is found to be (1.12 ± 0.03stat ± 0.25sys) × 10−11 cm−2 s−1, corresponding to ~64% of the flux of the Crab nebula. Results. HESS J1825–137 is a PWN with clearly energy-dependent morphology at VHE γ-ray energies. This source is used as a laboratory to investigate particle transport within intermediate-age PWNe. Based on deep observations of this highly spatially extended PWN, we produce a spectral map of the region that provides insights into the spectral variation within the nebula.
The integrated stress response (ISR) plays a pivotal role in adaptation of translation machinery to cellular stress. Here, we demonstrate an ISR-independent osmoadaptation mechanism involving ...reprogramming of translation via coordinated but independent actions of mTOR and plasma membrane amino acid transporter SNAT2. This biphasic response entails reduced global protein synthesis and mTOR signaling followed by translation of SNAT2. Induction of SNAT2 leads to accumulation of amino acids and reactivation of mTOR and global protein synthesis, paralleled by partial reversal of the early-phase, stress-induced translatome. We propose SNAT2 functions as a molecular switch between inhibition of protein synthesis and establishment of an osmoadaptive translation program involving the formation of cytoplasmic condensates of SNAT2-regulated RNA-binding proteins DDX3X and FUS. In summary, we define key roles of SNAT2 in osmotolerance.
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•SNAT2 activity mediates biphasic translational control in osmoadaptation•Early-phase stress inhibits translation and induces distinct RBP condensates•Late-phase SNAT2-mediated uptake of amino acids reverses translation inhibition•SNAT2 activity disassembles early-phase RBP condensates
Krokowski et al. report that osmotolerance, in response to mild hypertonic stress, involves a biphasic response of translational control that includes the amino acid transporter SNAT2 and mTOR, independently of ISR. SNAT2-mediated amino acid uptake functions as a critical molecular switch of the biphasic response and thus establishment of osmoadaptation.
Context. NGC 253 is one of only two starburst galaxies found to emit γ-rays from hundreds of MeV to multi-TeV energies. Accurate measurements of the very-high-energy (VHE; E > 100 GeV) and ...high-energy (HE; E > 60 MeV) spectra are crucial to study the underlying particle accelerators, probe the dominant emission mechanism(s) and to study cosmic-ray interaction and transport. Aims. The measurement of the VHE γ-ray emission of NGC 253 published in 2012 by H.E.S.S. was limited by large systematic uncertainties. Here, the most up to date measurement of the γ-ray spectrum of NGC 253 is investigated in both HE and VHE γ-rays. Assuming a hadronic origin of the γ-ray emission, the measurement uncertainties are propagated into the interpretation of the accelerated particle population. Methods. The data of H.E.S.S. observations are reanalysed using an updated calibration and analysis chain. The improved Fermi–LAT analysis employs more than 8 yr of data processed using pass 8. The cosmic-ray particle population is evaluated from the combined HE–VHE γ-ray spectrum using NAIMA in the optically thin case. Results. The VHE γ-ray energy spectrum is best fit by a power-law distribution with a flux normalisation of (1.34 ± 0.14stat ± 0.27sys) × 10−13 cm−2 s−1 TeV1 at 1 TeV – about 40% above, but compatible with the value obtained in Abramowski et al. (2012). The spectral index Γ = 2.39 ± 0.14stat ± 0.25sys is slightly softer than but consistent with the previous measurement within systematic errors. In the Fermi energy range an integral flux of F(E > 60 MeV) = (1.56 ± 0.28stat ± 0.15sys) × 10−8 cm−2 s−1 is obtained. At energies above ∼3 GeV the HE spectrum is consistent with a power-law ranging into the VHE part of the spectrum measured by H.E.S.S. with an overall spectral index Γ = 2.22 ± 0.06stat. Conclusions. Two scenarios for the starburst nucleus are tested, in which the gas in the starburst nucleus acts as either a thin or a thick target for hadronic cosmic rays accelerated by the individual sources in the nucleus. In these two models, the level to which NGC 253 acts as a calorimeter is estimated to a range of fcal = 0.1 to 1 while accounting for the measurement uncertainties. The presented spectrum is likely to remain the most accurate measurements until the Cherenkov Telescope Array (CTA) has collected a substantial set of data towards NGC 253.
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