The Hidden Role of Non-Canonical Amyloid beta Isoforms in Alzheimer's Disease

Recent advances have placed the pro-inflammatory activity of amyloid β (Aβ) on microglia cells as the focus of research on Alzheimer’s Disease (AD). Researchers are confronted with an astonishing spectrum of over 100 different Aβ variants with variable length and chemical modifications. With the exception of Aβ1-42 and Aβ1-40, the biological significance of most peptides for AD is as yet insufficiently understood. We therefore aim to provide a comprehensive overview of the contributions of these neglected Aβ variants to microglia activation. First, the impact of Aβ receptors, signaling cascades, scavenger mechanisms, and genetic variations on the physiological responses towards various Aβ species is described. Furthermore, we discuss the importance of different types of amyloid precursor protein processing for the generation of these Aβ variants in microglia, astrocytes, oligodendrocytes, and neurons, and highlight how alterations in secondary structures and oligomerization affect Aβ neurotoxicity. In sum, the data indicate that gene polymorphisms in Aβ-driven signaling pathways in combination with the production and activity of different Aβ variants might be crucial factors for the initiation and progression of different forms of AD. A deeper assessment of their interplay with glial cells may pave the way towards novel therapeutic strategies for individualized medicine

Active deformation in the Pamir – Tian Shan collision zone, NW China

Abstract HKT-ISTP 2013 A

Power Laws, Precursors and Predictability During Failure

We investigate the dynamics of a modified Burridge-Knopoff model by introducing a dissipative term to mimic the bursts of acoustic emission (AE) from rock samples. The model explains many features of the statistics of AE signals observed in experiments such as the crossover in the exponent value from relatively small amplitude AE signals to larger regime, and their dependence on the pulling speed. Significantly, we find that the cumulative energy dissipated identified with acoustic emission can be used to predict a major slip event. We also find a data collapse of the acoustic activity for several major slip events describable by a universal stretched exponential with corrections in terms of time-to-failure.Comment: 7 pages, 6 figures, Final version with minor change

Temporal changes in rock uplift rates of folds in the foreland of the Tian Shan and the Pamir from geodetic and geologic data

Understanding the evolution of continental deformation zones relies on quantifying spatial and temporal changes in deformation rates of tectonic structures. Along the eastern boundary of the Pamir‐Tian Shan collision zone, we constrain secular variations of rock uplift rates for a series of five Quaternary detachment‐ and fault‐related folds from their initiation to the modern day. When combined with GPS data, decomposition of interferometric synthetic aperture radar time series constrains the spatial pattern of surface and rock uplift on the folds deforming at decadal rates of 1–5 mm/yr. These data confirm the previously proposed basinward propagation of structures during the Quaternary. By fitting our geodetic rates and previously published geologic uplift rates with piecewise linear functions, we find that gradual rate changes over >100 kyr can explain the interferometric synthetic aperture radar observations where changes in average uplift rates are greater than ~1 mm/yr among different time intervals (~10¹, 10⁴‾⁵, and 10⁵‾⁶ years)

Properties of Foreshocks and Aftershocks of the Non-Conservative SOC Olami-Feder-Christensen Model: Triggered or Critical Earthquakes?

Following Hergarten and Neugebauer [2002] who discovered aftershock and foreshock sequences in the Olami-Feder-Christensen (OFC) discrete block-spring earthquake model, we investigate to what degree the simple toppling mechanism of this model is sufficient to account for the properties of earthquake clustering in time and space. Our main finding is that synthetic catalogs generated by the OFC model share practically all properties of real seismicity at a qualitative level, with however significant quantitative differences. We find that OFC catalogs can be in large part described by the concept of triggered seismicity but the properties of foreshocks depend on the mainshock magnitude, in qualitative agreement with the critical earthquake model and in disagreement with simple models of triggered seismicity such as the Epidemic Type Aftershock Sequence (ETAS) model [Ogata, 1988]. Many other features of OFC catalogs can be reproduced with the ETAS model with a weaker clustering than real seismicity, i.e. for a very small average number of triggered earthquakes of first generation per mother-earthquake.Comment: revtex, 19 pages, 8 eps figure

Rupture by damage accumulation in rocks

The deformation of rocks is associated with microcracks nucleation and propagation, i.e. damage. The accumulation of damage and its spatial localization lead to the creation of a macroscale discontinuity, so-called "fault" in geological terms, and to the failure of the material, i.e. a dramatic decrease of the mechanical properties as strength and modulus. The damage process can be studied both statically by direct observation of thin sections and dynamically by recording acoustic waves emitted by crack propagation (acoustic emission). Here we first review such observations concerning geological objects over scales ranging from the laboratory sample scale (dm) to seismically active faults (km), including cliffs and rock masses (Dm, hm). These observations reveal complex patterns in both space (fractal properties of damage structures as roughness and gouge), time (clustering, particular trends when the failure approaches) and energy domains (power-law distributions of energy release bursts). We use a numerical model based on progressive damage within an elastic interaction framework which allows us to simulate these observations. This study shows that the failure in rocks can be the result of damage accumulation

Probenecid Inhibits the Human Bitter Taste Receptor TAS2R16 and Suppresses Bitter Perception of Salicin

Bitter taste stimuli are detected by a diverse family of G protein-coupled receptors (GPCRs) expressed in gustatory cells. Each bitter taste receptor (TAS2R) responds to an array of compounds, many of which are toxic and can be found in nature. For example, human TAS2R16 (hTAS2R16) responds to β-glucosides such as salicin, and hTAS2R38 responds to thiourea-containing molecules such as glucosinolates and phenylthiocarbamide (PTC). While many substances are known to activate TAS2Rs, only one inhibitor that specifically blocks bitter receptor activation has been described. Here, we describe a new inhibitor of bitter taste receptors, p-(dipropylsulfamoyl)benzoic acid (probenecid), that acts on a subset of TAS2Rs and inhibits through a novel, allosteric mechanism of action. Probenecid is an FDA-approved inhibitor of the Multidrug Resistance Protein 1 (MRP1) transporter and is clinically used to treat gout in humans. Probenecid is also commonly used to enhance cellular signals in GPCR calcium mobilization assays. We show that probenecid specifically inhibits the cellular response mediated by the bitter taste receptor hTAS2R16 and provide molecular and pharmacological evidence for direct interaction with this GPCR using a non-competitive (allosteric) mechanism. Through a comprehensive analysis of hTAS2R16 point mutants, we define amino acid residues involved in the probenecid interaction that result in decreased sensitivity to probenecid while maintaining normal responses to salicin. Probenecid inhibits hTAS2R16, hTAS2R38, and hTAS2R43, but does not inhibit the bitter receptor hTAS2R31 or non-TAS2R GPCRs. Additionally, structurally unrelated MRP1 inhibitors, such as indomethacin, fail to inhibit hTAS2R16 function. Finally, we demonstrate that the inhibitory activity of probenecid in cellular experiments translates to inhibition of bitter taste perception of salicin in humans. This work identifies probenecid as a pharmacological tool for understanding the cell biology of bitter taste and as a lead for the development of broad specificity bitter blockers to improve nutrition and medical compliance