Tribological properties of room temperature fluorinated graphite heat-treated under fluorine atmosphere

This work is concerned with the study of the tribologic properties of room temperature fluorinated graphite heat-treated under fluorine atmosphere. The fluorinated compounds all present good intrinsic friction properties (friction coefficient in the range 0.05–0.09). The tribologic performances are optimized if the materials present remaining graphitic domains (influenced by the presence of intercalated fluorinated species) whereas the perfluorinated compounds, where the fluorocarbon layers are corrugated (armchair configuration of the saturated carbon rings) present higher friction coefficients. Raman analyses reveal that the friction process induces severe changes in the materials structure especially the partial re-building of graphitic domains in the case of perfluorinated compounds which explains the improvement of μ during the friction tests for these last materials

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N^2,N^4-dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy

Dilated Cardiomyopathy: Phosphorus 31 MR Spectroscopy at 7 T

Purpose To test whether the increased signal-to-noise ratio of phosphorus 31 (31P) magnetic resonance (MR) spectroscopy at 7 T improves precision in cardiac metabolite quantification in patients with dilated cardiomyopathy (DCM) compared with that at 3 T. Materials and Methods Ethical approval was obtained, and participants provided written informe consent. In a prospective study, 31P MR spectroscopy was performed at 3 T and 7 T in 25 patients with DCM. Ten healthy matched control subjects underwent 31P MR spectroscopy at 7 T. Paired Student t tests were performed to compare results between the 3-T and 7-T studies. Results The phosphocreatine (PCr) signal-to-noise ratio increased 2.5 times at 7 T compared with that at 3 T. The PCr to adenosine triphosphate (ATP) concentration ratio (PCr/ATP) was similar at both field strengths (mean ± standard deviation, 1.48 ± 0.44 at 3 T vs 1.54 ± 0.39 at 7 T, P = .49), as expected. The Cramér-Rao lower bounds in PCr concentration (a measure of uncertainty in the measured ratio) were 45% lower at 7 T than at 3 T, reflecting the higher quality of 7-T 31P spectra. Patients with dilated cardioyopathy had a significantly lower PCr/ATP than did healthy control subjects at 7 T (1.54 ± 0.39 vs 1.95 ± 0.25, P = .005), which is consistent with previous findings. Conclusion 7-T cardiac 31P MR spectroscopy is feasible in patients with DCM and gives higher signal-to-noise ratios and more precise quantification of the PCr/ATP than that at 3 T. PCr/ATP was significantly lower in patients with DCM than in control subjects at 7 T, which is consistent with previous findings at lower field strengths

BAT3 Guides Misfolded Glycoproteins Out of the Endoplasmic Reticulum

Secretory and membrane proteins that fail to acquire their native conformation within the lumen of the Endoplasmic Reticulum (ER) are usually targeted for ubiquitin-dependent degradation by the proteasome. How partially folded polypeptides are kept from aggregation once ejected from the ER into the cytosol is not known. We show that BAT3, a cytosolic chaperone, is recruited to the site of dislocation through its interaction with Derlin2. Furthermore, we observe cytoplasmic BAT3 in a complex with a polypeptide that originates in the ER as a glycoprotein, an interaction that depends on the cytosolic disposition of both, visualized even in the absence of proteasomal inhibition. Cells depleted of BAT3 fail to degrade an established dislocation substrate. We thus implicate a cytosolic chaperone as an active participant in the dislocation of ER glycoproteins.United States. National Institutes of HealthBoehringer Ingelheim Fond

OTUB1 Overexpression in Mesangial Cells Is a Novel Regulator in the Pathogenesis of Glomerulonephritis through the Decrease of DCN Level

BACKGROUND: OTUB1 is a member of OTUs (Ovarian-tumor-domain-containing proteases), a deubiquitinating enzymes family (DUBs), which was shown as a proteasome-associated DUB to be involved in the proteins Ub-dependent degradation. It has been reported that OTUB1 was expressed in kidney tissue. But its concrete cellular location and function in the kidney remain unclear. Decorin (DCN) in mesangial cells (MC) is considered to be a potentially important factor for antagonizing glomerulonephritides, and its degradation is mediated by ubiquitination. The aim of this study is to investigate the role of OTUB1 expression in MC and its relationship with DCN during glomerulonephritis. METHODOLOGY/PRINCIPAL FINDINGS: Using quantitative RT-PCR and Western blot, we demonstrated that OTUB1 mRNA and protein were constitutively expressed in cultured rat MC and found to be upregulated by the stimulation of IL-1β or ATS. OTUB1 overexpression was detected in the mesangial area of glomeruli in some immunocomplex mediated nephritides such as IgA nephropathy, acute diffuse proliferative glomerulonephritis and lupus nephritis by immunohistochemistry. The immunoprecipitation assay demonstrated that OTUB1 interacted with DCN. The overexpression of OTUB1 enhanced the ubiquitination and degradation of DCN in MC. CONCLUSION/SIGNIFICANCE: These data showed the inflammatory injury could up-regulate OTUB1 expression in MC, which might attribute the promoting effect of OTUB1 on glomerulonephritides to the decrease of DCN level

Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila

The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (RhP23H). Unlike the wild-type Rh, mutant RhP23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded RhP23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that RhP23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1P37H (the equivalent of mammalian RhP23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1P37H retina. Despite this, Rh1P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1P37H retina. Pharmacological treatment of Rh1P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration