Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein.

Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system

Zero-variance principle for Monte Carlo algorithms

We present a general approach to greatly increase at little cost the efficiency of Monte Carlo algorithms. To each observable to be computed we associate a renormalized observable (improved estimator) having the same average but a different variance. By writing down the zero-variance condition a fundamental equation determining the optimal choice for the renormalized observable is derived (zero-variance principle for each observable separately). We show, with several examples including classical and quantum Monte Carlo calculations, that the method can be very powerful.Comment: 9 pages, Latex, to appear in Phys. Rev. Let

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

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

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

Discovery of sultam-containing small-molecule disruptors of the huntingtin–calmodulin protein–protein interaction

The aberrant protein–protein interaction between calmodulin and mutant huntingtin protein in Huntington’s disease patients has been found to contribute to Huntington’s disease progression. A high-throughput screen for small molecules capable of disrupting this interaction revealed a sultam series as potent small-molecule disruptors. Diversification of the sultam scaffold afforded a set of 24 analogs or further evaluation. Several structure–activity trends within the analog set were found, most notably a negligible effect of absolute stereochemistry and a strong beneficial correlation with electron-withdrawing aromatic substituents. The most promising analogs were profiled for off-target effects at relevant kinases and, ultimately, one candidate molecule was evaluated for neuroprotection in a neuronal cell model of Huntington’s disease

Synthesis and receptor profiling of Stemona alkaloid analogues reveal a potent class of sigma ligands

Reported biological activities of Stemona natural products, such as antitussive activity, inspired the development of synthetic methods to access several alkaloids within this family and in so doing develop a general route to the core skeleta shared by the class of natural products. The chemistry was subsequently adapted to afford a series of analogue sets bearing simplified, diverse Stemona-inspired skeleta. Over 100 of these analogues were subjected to general G protein-coupled receptor profiling along with the known antitussive compound, neostenine; this led to the identification of hit compounds targeting several receptor types. The particularly rich hit subset for sigma receptors was expanded with two focused library sets, which resulted in the discovery of a fully synthetic, potent chemotype of sigma ligands. This collaborative effort combined the development of synthetic methods with extensive, flexible screening resources and exemplifies the role of natural products in bioactivity mining

DigiCam - Fully Digital Compact Read-out and Trigger Electronics for the SST-1M Telescope proposed for the Cherenkov Telescope Array

The SST-1M is one of three prototype small-sized telescope designs proposed for the Cherenkov Telescope Array, and is built by a consortium of Polish and Swiss institutions. The SST-1M will operate with DigiCam - an innovative, compact camera with fully digital read-out and trigger electronics. A high level of integration will be achieved by massively deploying state-of-the-art multi-gigabit transmission channels, beginning from the ADC flash converters, through the internal data and trigger signals transmission over backplanes and cables, to the camera's server link. Such an approach makes it possible to design the camera to fit the size and weight requirements of the SST-1M exactly, and provide low power consumption, high reliability and long lifetime. The structure of the digital electronics will be presented, along with main physical building blocks and the internal architecture of FPGA functional subsystems.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589

Using muon rings for the optical throughput calibration of the SST-1M prototype for the Cherenkov Telescope Array

Imaging Atmospheric Cherenkov Telescopes (IACTs) are ground-based instruments devoted to the study of very high energy gamma-rays coming from space. The detection technique consists of observing images created by the Cherenkov light emitted when gamma rays, or more generally cosmic rays, propagate through the atmosphere. While in the case of protons or gamma-rays the images present a filled and more or less elongated shape, energetic muons penetrating the atmosphere are visualised as characteristic circular rings or arcs. A relatively simple analysis of the ring images allows the reconstruction of all the relevant parameters of the detected muons, such as the energy, the impact parameter, and the incoming direction, with the final aim to use them to calibrate the total optical throughput of the given IACT telescope. We present the results of preliminary studies on the use of images created by muons as optical throughput calibrators of the single mirror small size telescope prototype SST-1M proposed for the Cherenkov Telescope Array.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589