No abstract

Proteasomes, the primary mediators of ubiquitin-protein conjugate degradation, are regulated through complex and poorly understood mechanisms. Here we show that Usp14, a proteasome-associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin-protein conjugates, in vivo and in vitro. A catalytically inactive variant of Usp14 has reduced inhibitory activity, suggesting that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human Usp14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. Usp14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of Usp14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.

The adverse impact of ignoring multicollinearity on findings and data interpretation in regression analysis is very well documented in the statistical literature. The failure to identify and report multicollinearity could result in misleading interpretations of the results. A review of epidemiological literature in PubMed from January 2004 to December 2013, illustrated the need for a greater attention to identifying and minimizing the effect of multicollinearity in analysis of data from epidemiologic studies. We used simulated datasets and real life data from the Cameron County Hispanic Cohort to demonstrate the adverse effects of multicollinearity in the regression analysis and encourage researchers to consider the diagnostic for multicollinearity as one of the steps in regression analysis.

Introduction We studied the effect of Tumor Necrosis Factor-Alpha (TNF)-inhibitors on progressive spine damage in Ankylosing Spondylitis (AS) patients. Methods All AS patients (satisfying the modified New York criteria) prospectively followed and with at least two sets of spinal radiographs at a minimum gap of 1.5 years were included (n=334). Patients received clinical standard of care, which included non-steroidal anti-inflammatory drugs and TNF-inhibitors. Radiographic severity was assessed by the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of progression more than 1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching (PSM) and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNF-inhibitor on change in mSASSS with varying follow-up periods. Potential confounders like Bath AS Disease Activity Index (BASDAI), ESR, CRP, HLA-B27, gender, age of onset, smoking and baseline damage were included in the model. Results TNF-inhibitor treatment was associated with a 50% reduction in the odds of progression (OR: 0.52; CI: 0.30-0.88; p=0.02). Patients with a delay in starting therapy of more than 10 years were more likely to progress compared to those who started earlier (OR=2.4; 95% CI: 1.09-5.3; p=0.03). In the ZINB model TNF-inhibitor use significantly reduced progression when the gap between x-rays was more than 3.9 years. The protective effect of TNF-inhibitors was stronger after propensity score matching. Conclusions TNF-inhibitors appear to reduce radiographic progression in AS, especially with early initiation and longer duration of follow up.