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

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 $k$. 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

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