Essential role of proteasomes in maintaining self-renewal in neural progenitor cells

Protein turnover and homeostasis are regulated by the proteasomal system, which is critical for cell function and viability. Pluripotency of stem cells also relies on normal proteasomal activity that mitigates senescent phenotypes induced by intensive cell replications, as previously demonstrated in human bone marrow stromal cells. In this study, we investigated the role of proteasomes in self-renewal of neural progenitor cells (NPCs). Through both in vivo and in vitro analyses, we found that the expression of proteasomes was progressively decreased during aging. Likewise, proliferation and self-renewal of NPCs were also impaired in aged mice, suggesting that the down-regulation of proteasomes might be responsible for this senescent phenotype. Lowering proteasomal activity by loss-of-function manipulations mimicked the senescence of NPCs both in vitro and in vivo; conversely, enhancing proteasomal activity restored and improved self-renewal in aged NPCs. These results collectively indicate that proteasomes work as a key regulator in promoting self-renewal of NPCs. This potentially provides a promising therapeutic target for age-dependent neurodegenerative diseases

Inhibition of protein ubiquitination by paraquat and 1-methyl-4-phenylpyridinium impairs ubiquitin-dependent protein degradation pathways

Intracytoplasmic inclusions of protein aggregates in dopaminergic cells (Lewy bodies) are the pathological hallmark of Parkinson’s disease (PD). Ubiquitin (Ub), alpha [α]-synuclein, p62/sequestosome 1 and oxidized proteins are major components of Lewy bodies. However, the mechanisms involved in the impairment of misfolded/oxidized protein degradation pathways in PD are still unclear. PD is linked to mitochondrial dysfunction and environmental pesticide exposure. In this work, we evaluated the effect of the pesticide paraquat (PQ) and the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) on Ub-dependent protein degradation pathways. No increase in the accumulation of Ub-bound proteins or aggregates was observed in dopaminergic cells (SK-N-SH) treated with PQ or MPP+, or in mice chronically exposed to PQ. PQ decreased Ub protein content, but not its mRNA transcription. Protein synthesis inhibition with cycloheximide depleted Ub levels and potentiated PQ–induced cell death. Inhibition of proteasomal activity by PQ was found to be a late event in cell death progression, and had no effect on either the toxicity of MPP+ or PQ, or the accumulation of oxidized sulfenylated, sulfonylated (DJ-1/PARK7 and peroxiredoxins) and carbonylated proteins induced by PQ. PQ- and MPP+-induced Ub protein depletion prompted the dimerization/inactivation of the Ub-binding protein p62 that regulates the clearance of ubiquitinated proteins by autophagic. We confirmed that PQ and MPP+ impaired autophagy flux, and that the blockage of autophagy by the overexpression of a dominant-negative form of the autophagy protein 5 (dnAtg5) stimulated their toxicity, but there was no additional effect upon inhibition of the proteasome. PQ induced an increase in the accumulation of α-synuclein in dopaminergic cells and membrane associated foci in yeast cells. Our results demonstrate that inhibition of protein ubiquitination by PQ and MPP+ is involved in the dysfunction of Ub-dependent protein degradation pathways

Azimuthal anisotropy from eikonal tomography: example from ambient-noise measurements in the AlpArray network

Ambient-noise records from the AlpArray network are used to measure Rayleigh wave phase velocities between more than 150 000 station pairs. From these, azimuthally anisotropic phase-velocity maps are obtained by applying the eikonal tomography method. Several synthetic tests are shown to study the bias in the Psi(2) anisotropy. There are two main groups of bias, the first one caused by interference between refracted/reflected waves and the appearance of secondary wave fronts that affect the phase traveltime measurements. This bias can be reduced if the amplitude field can be estimated correctly. Another source of error is related to the incomplete reconstruction of the traveltime field that is only sparsely sampled due to the receiver locations. Both types of bias scale with the magnitude of the velocity heterogeneities. Most affected by the spurious Psi(2) anisotropy are areas inside and at the border of low-velocity zones. In the isotropic velocity distribution, most of the bias cancels out if the azimuthal coverage is good. Despite the lack of resolution in many parts of the surveyed area, we identify a number of anisotropic structures that are robust: in the central Alps, we find a layered anisotropic structure, arc-parallel at mid-crustal depths and arc-perpendicular in the lower crust. In contrast, in the eastern Alps, the pattern is more consistently E-W oriented which we relate to the eastward extrusion. The northern Alpine forleand exhibits a preferential anisotropic orientation that is similar to SKS observations in the lower most crust and uppermost mantle

Surface-wave tomography using SeisLib: a Python package for multiscale seismic imaging

To improve our understanding of the Earth's interior, seismologists often have to deal with enormous amounts of data, requiring automatic tools for their analyses. It is the purpose of this study to present SeisLib, an open-source Python package for multiscale seismic imaging. At present, SeisLib includes routines for carrying out surface-wave tomography tasks based on seismic ambient noise and teleseismic earthquakes. We illustrate here these functionalities, both from the theoretical and algorithmic point of view and by application of our library to seismic data from North America. We first show how SeisLib retrieves surface-wave phase velocities from the ambient noise recorded at pairs of receivers, based on the zero crossings of their normalized cross-spectrum. We then present our implementation of the two-station method, to measure phase velocities from pairs of receivers approximately lying on the same great-circle path as the epicentre of distant earthquakes. We apply these methods to calculate dispersion curves across the conterminous United States, using continuous seismograms from the transportable component of USArray and earthquake recordings from the permanent networks. Overall, we measure 144 272 ambient-noise and 2055 earthquake-based dispersion curves, that we invert for Rayleigh-wave phase-velocity maps. To map the lateral variations in surface-wave velocity, SeisLib exploits a least-squares inversion algorithm based on ray theory. Our implementation supports both equal-area and adaptive parametrizations, with the latter allowing for a finer resolution in the areas characterized by high density of measurements. In the broad period range 4-100 s, the retrieved velocity maps of North America are highly correlated (on average, 96 per cent) and present very small average differences (0.14 +/- 0.1 per cent) with those reported in the literature. This points to the robustness of our algorithms. We also produce a global phase-velocity map at the period of 40 s, combining our dispersion measurements with those collected at global scale in previous studies. This allows us to demonstrate the reliability and optimized computational speed of SeisLib, even in presence of very large seismic inverse problems and strong variability in the data coverage. The last part of the manuscript deals with the attenuation of Rayleigh waves, which can be estimated through SeisLib based on the seismic ambient noise recorded at dense arrays of receivers. We apply our algorithm to produce an attenuation map of the United States at the period of 4 s, which we find consistent with the relevant literature

Slab break-offs in the Alpine subduction zone

After the onset of plate collision in the Alps, at 32\u201334\ua0Ma, the deep structure of the orogen is inferred to have changed dramatically: European plate break-offs in various places of the Alpine arc, as well as a possible reversal of subduction polarity in the eastern Alps have been proposed. We review different high-resolution tomographic studies of the upper mantle and combine shear- and body-wave models to assess the most reliable geometries of the slabs. Several hypotheses for the tectonic evolution are presented and tested against the tomographic model interpretations and constraints from geologic and geodetic observations. We favor the interpretation of a recent European slab break-off under the western Alps. In the eastern Alps, we review three published scenarios for the subduction structure and propose a fourth one to reconcile the results from tomography and geology. We suggest that the fast slab anomalies are mainly due to European subduction; Adriatic subduction plays no or only a minor role along the Tauern window sections, possibly increasing towards the Dinarides. The apparent northward dip of the slab under the eastern Alps may be caused by imaging a combination of Adriatic slab, from the Dinaric subduction system, and a deeper lying European one, as well as by an overturned, retreating European slab