218 research outputs found
Phenylbutyric Acid Rescues Endoplasmic Reticulum Stress-Induced Suppression of APP Proteolysis and Prevents Apoptosis in Neuronal Cells
BACKGROUND: The familial and sporadic forms of Alzheimer's disease (AD) have an identical pathology with a severe disparity in the time of onset [1]. The pathological similarity suggests that epigenetic processes may phenocopy the Familial Alzheimer's disease (FAD) mutations within sporadic AD. Numerous groups have demonstrated that FAD mutations in presenilin result in 'loss of function' of gamma-secretase mediated APP cleavage [2], [3], [4], [5]. Accordingly, ER stress is prominent within the pathologically impacted brain regions in AD patients [6] and is reported to inhibit APP trafficking through the secretory pathway [7], [8]. As the maturation of APP and the cleaving secretases requires trafficking through the secretory pathway [9], [10], [11], we hypothesized that ER stress may block trafficking requisite for normal levels of APP cleavage and that the small molecular chaperone 4-phenylbutyrate (PBA) may rescue the proteolytic deficit. METHODOLOGY/PRINCIPAL FINDINGS: The APP-Gal4VP16/Gal4-reporter screen was stably incorporated into neuroblastoma cells in order to assay gamma-secretase mediated APP proteolysis under normal and pharmacologically induced ER stress conditions. Three unrelated pharmacological agents (tunicamycin, thapsigargin and brefeldin A) all repressed APP proteolysis in parallel with activation of unfolded protein response (UPR) signaling-a biochemical marker of ER stress. Co-treatment of the gamma-secretase reporter cells with PBA blocked the repressive effects of tunicamycin and thapsigargin upon APP proteolysis, UPR activation, and apoptosis. In unstressed cells, PBA stimulated gamma-secretase mediated cleavage of APP by 8-10 fold, in the absence of any significant effects upon amyloid production, by promoting APP trafficking through the secretory pathway and the stimulation of the non-pathogenic alpha/gamma-cleavage. CONCLUSIONS/SIGNIFICANCE: ER stress represses gamma-secretase mediated APP proteolysis, which replicates some of the proteolytic deficits associated with the FAD mutations. The small molecular chaperone PBA can reverse ER stress induced effects upon APP proteolysis, trafficking and cellular viability. Pharmaceutical agents, such as PBA, that stimulate alpha/gamma-cleavage of APP by modifying intracellular trafficking should be explored as AD therapeutics
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Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.
Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis
Corrections to the Nonrelativistic Ground Energy of a Helium Atom
Considering the nuclear motion, the authors give out the nonrelativistic
ground energy of a helium atom by using a simple but effective variational wave
function with a flexible parameter . Based on this result, the relativistic
and radiative corrections to the nonrelativistic Hamiltonian are discussed. The
high precision value of the helium ground energy is evaluated to be -2.90338
a.u., and the relative error is 0.00034%.Comment: 8 pages, no figures, 2 table
Hypergraph model of social tagging networks
The past few years have witnessed the great success of a new family of
paradigms, so-called folksonomy, which allows users to freely associate tags to
resources and efficiently manage them. In order to uncover the underlying
structures and user behaviors in folksonomy, in this paper, we propose an
evolutionary hypergrah model to explain the emerging statistical properties.
The present model introduces a novel mechanism that one can not only assign
tags to resources, but also retrieve resources via collaborative tags. We then
compare the model with a real-world dataset: \emph{Del.icio.us}. Indeed, the
present model shows considerable agreement with the empirical data in following
aspects: power-law hyperdegree distributions, negtive correlation between
clustering coefficients and hyperdegrees, and small average distances.
Furthermore, the model indicates that most tagging behaviors are motivated by
labeling tags to resources, and tags play a significant role in effectively
retrieving interesting resources and making acquaintance with congenial
friends. The proposed model may shed some light on the in-depth understanding
of the structure and function of folksonomy.Comment: 7 pages,7 figures, 32 reference
Shaping point- and mirror-symmetric proto-planetary nebulae by the orbital motion of the central binary system
We present 3D hydrodynamical simulations of a jet launched from the secondary
star of a binary system inside a proto-planetary nebula. The secondary star
moves around the primary in a close eccentric orbit. From the gasdynamic
simulations we compute synthetic [NII] 6583 emission maps. Different jet axis
inclinations with respect to the orbital plane, as well as different
orientations of the flow with respect to the observer are considered. For some
parameter combinations, we obtain structures that show point- or
mirror-symmetric morphologies depending on the orientation of the flow with
respect to the observer. Furthermore, our models can explain some of the
emission distribution asymmetries that are summarized in the classification
given by Soker & hadar (2002).Comment: 15 pages, 3 figures, 2 tables, Accepted in Apj Letter
Solar-like oscillations with low amplitude in the CoRoT target HD 181906
Context: The F8 star HD 181906 (effective temperature ~6300K) was observed
for 156 days by the CoRoT satellite during the first long run in the centre
direction. Analysis of the data reveals a spectrum of solar-like acoustic
oscillations. However, the faintness of the target (m_v=7.65) means the
signal-to-noise (S/N) in the acoustic modes is quite low, and this low S/N
leads to complications in the analysis. Aims: To extract global variables of
the star as well as key parameters of the p modes observed in the power
spectrum of the lightcurve. Methods: The power spectrum of the lightcurve, a
wavelet transform and spot fitting have been used to obtain the average
rotation rate of the star and its inclination angle. Then, the autocorrelation
of the power spectrum and the power spectrum of the power spectrum were used to
properly determine the large separation. Finally, estimations of the mode
parameters have been done by maximizing the likelihood of a global fit, where
several modes were fit simultaneously. Results: We have been able to infer the
mean surface rotation rate of the star (~4 microHz) with indications of the
presence of surface differential rotation, the large separation of the p modes
(~87 microHz), and therefore also the ridges corresponding to overtones of the
acoustic modes.Comment: Paper Accepted to be published in A&A. 10 Pages, 12 figure
Determination of aluminium in groundwater samples by GF-AAS, ICP-AES, ICP-MS and modelling of inorganic aluminium complexes
The energy gap of intermediate-valent SmB6 studied by point-contact spectroscopy
We have investigated the intermediate valence narrow-gap semiconductor SmB6
at low temperatures using both conventional spear-anvil type point contacts as
well as mechanically controllable break junctions. The zero-bias conductance
varied between less than 0.01 mikrosiemens and up to 1 mS. The position of the
spectral anomalies, which are related to the different activation energies and
band gaps of SmB6, did not depend on the the contact size. Two different
regimes of charge transport could be distinguished: Contacts with large zero -
bias conductance are in the diffusive Maxwell regime. They had spectra with
only small non-linearities. Contacts with small zero - bias conductance are in
the tunnelling regime. They had larger anomalies, but still indicating a finite
45 % residual quasiparticle density of states at the Fermi level at low
temperatures of T = 0.1 K. The density of states derived from the tunelling
spectra can be decomposed into two energy-dependent parts with Eg = 21 meV and
Ed = 4.5 meV wide gaps, respectively.Comment: 9 pages incl. 13 figure
Control Software for the SST-1M Small-Size Telescope prototype for the Cherenkov Telescope Array
The SST-1M is a 4-m Davies--Cotton atmospheric Cherenkov telescope optimized
to provide gamma-ray sensitivity above a few TeV. The SST-1M is proposed as
part of the Small-Size Telescope array for the Cherenkov Telescope Array (CTA),
the first prototype has already been deployed. The SST-1M control software of
all subsystems (active mirror control, drive system, safety system,
photo-detection plane, DigiCam, CCD cameras) and the whole telescope itself
(master controller) uses the standard software design proposed for all CTA
telescopes based on the ALMA Common Software (ACS) developed to control the
Atacama Large Millimeter Array (ALMA). Each subsystem is represented by a
separate ACS component, which handles the communication to and the operation of
the subsystem. Interfacing with the actual hardware is performed via the OPC UA
communication protocol, supported either natively by dedicated industrial
standard servers (PLCs) or separate service applications developed to wrap
lower level protocols (e.g. CAN bus, camera slow control) into OPC UA. Early
operations of the telescope without the camera were already carried out. The
camera is fully assembled and is capable to perform data acquisition using
artificial light source.Comment: In Proceedings of the 35th International Cosmic Ray Conference
(ICRC2017), Busan, Korea. All CTA contributions at arXiv:1709.0348
Point-contact spectra of the heavy-fermion superconductors U Be
We have measured the current-voltage characteristics of point contacts between UBe13 or UPt3 and the normal metals W or Pt (metallic point contacts) or GaAs (Schottky-barrier tunneling contact) in the temperature range between 50 mK and 1 K. In the metal-point-contact characteristics (dVdI vs V) there appear zero-bias minima of width 2 below Tc. The ratio 2 kBTc is close to the BCS value. The tunneling spectra of UPt3 exhibit weak additional structure below Tc. A value 2 has been estimated, which is a factor of 2 larger than that for the metal point contacts. © 1987 The American Physical Society
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