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

Direct electrosynthesis of a series of novel caffeic acid analogues through a clean and serendipitous domino oxidation/thia-Michael reaction

A series of novel caffeic acid analogues have been synthesized in an experimentally simple electrochemical procedure employing electrons as the only reagents in aqueous solution without introducing any catalyst or oxidant. It has been shown that the reactions proceed via a domino of electrochemical and chemical events (EC mechanism) with an interesting regioselectivity in the formation of arylsulfonyl-functionalized N-caffeoyl amides and caffeate esters. All products were purely obtained at the surface of anode (carbon rods) in excellent yields and no extra purification was needed. Structural characterization of these novel compounds was also performed using various spectroscopic techniques: FT-IR, 1HNMR, 13CNMR and HR-mas

Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: When should we stop?

Purpose: We evaluated biochemical parameters and pathological features, as well as biopsy related morbidity of prostate cancer detected on biopsies 2, 3 and 4 in men with total serum prostate specific antigen (PSA) between 4 and 10 ng./ml. These features were compared to those detected on prostate biopsy 1. Materials and Methods: In this prospective European Prostate Cancer Detection study 1,051 men with total PSA between 4 and 10 ng./ml. underwent transrectal ultrasound guided sextant biopsy and 2 additional transition zone biopsies. All patients in whom biopsy samples were negative for prostate cancer underwent biopsy 2 after 6 weeks. If also negative, biopsies 3 and even 4 were performed at 8-week intervals. Those patients with clinically localized cancer underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either biopsy 1 or 2 and clinically organ confined disease who agreed to undergo radical prostatectomy were compared. Results: Cancer detection rates on biopsies 1, 2, 3 and 4 were 22% (231 of 1,051), 10% (83 of 820), 5% (36 of 737) and 4% (4 of 94), respectively. Overall, of the patients with clinically localized disease, which was 67% of cancers detected, 86% underwent radical prostatectomy and 14% opted for watchful waiting or radiation therapy. Overall, 58.0%, 60.9%, 86.3% and 100% of patients had organ confined disease on biopsies 1, 2, 3 and 4, respectively. Despite statistically significant differences in regard to multifocality (p=0.009) and cancer location (p=0.001), including cancer on biopsy 2 showing a lower rate of multifocality and a more apico-dorsal location, there were no differences in regard to stage (p=0.2), Gleason score (p=0.3), percent Gleason grade 4/5 (p=0.2), serum PSA and patient age between biopsies 1 and 2. However, cancer detected on biopsies 3 and 4 had a significantly lower Gleason score (p=0.001 and 0.001), lower rate of grade 4/5 (p=0.02), and lower volume (p=0.001 and 0.001) and stage (p=0.001), respectively. Conclusions: Despite differences in location and multifocality, pathological and biochemical features of cancer detected on biopsies 1 and 2 were similar, suggesting comparable biological behaviors. Cancer detected on biopsies 3 and 4 had a lower grade, stage and volume compared with that on biopsies i and 2. Morbidity on biopsies 1 and 2 was similar, whereas biopsies 3 and 4 had a slightly higher complication rate. Therefore, biopsy 2 in all cases of a negative finding on biopsy 1 appears justified. However, biopsies 3 and 4 should only be obtained in select patients with a high suspicion of cancer and/or poor prognostic factors on biopsy 1 or 2.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Acceleration of electrons in THz driven structures for AXSIS

info:eu-repo/semantics/publishe

Zagros Foreland Fold Belt Timing Across Lurestan to Constrain Arabia-Iran Collision

A forward sequence of folding is interpreted in the northwest Zagros fold belt using two new magnetostratigraphic studies to date non-marine foreland successions in the Afrineh and Chaman Goli growth synclines and integrating previous studies in the Lurestan and Fars arcs. The onset of growth is younger from the hinterland to the foreland and established at 13.5, 11.8, and 7.6 million years ago (Ma), spanning from Middle to Late Miocene, although the end of folding is in the Middle Pleistocene at about 1.5 Ma in the foreland front. In-sequence folding propagation toward the foreland occurred at a mean rate of 30 km/Myr with shortening rates of ¿1.9 mm/yr, using the onset of growth for Chaman Goli, Afrineh, and Changuleh well-dated synclines. The greater shortening of the Zagros continental collision occurred in its hinterland with continental overrriding of the Iranian block above the Arabian plate partially predating Neogene folding in the Zagros fold belt.The research was partially funded by projects and ALPIMED (PIE–CSIC–201530E082)