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

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

Peak satellite cell proliferation for regenerative myogenesis takes place 24-72h post injury in mouse muscles

See Attached Abstrac

X-ray photoelectron spectroscopy study on gold nanoparticles supported on diamond

By exploiting the self-organization of metal salt-loaded diblock copolymer micelles followed by a plasma-induced removal of the polymer matrix, well-separated gold particles ranging in size from 1.6 to 10 nm have been prepared on top of diamond substrates. X-ray-induced photoelectron spectra of the valence-band region demonstrate that the electronic properties of such nanoparticles essentially reflect the metallic behavior of the bulk material as can be inferred from the evolution of the d-band shape and the finite density of states at the Fermi energy. This experimentally extends the lower limit for the metallic state of supported Au particles down to a diameter of 1.6 nm