Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Bayesian learning with multiple priors and nonvanishing ambiguity

The existing models of Bayesian learning with multiple priors by Marinacci (Stat Pap 43:145–151, 2002) and by Epstein and Schneider (Rev Econ Stud 74:1275–1303, 2007) formalize the intuitive notion that ambiguity should vanish through statistical learning in an one-urn environment. Moreover, the multiple priors decision maker of these models will eventually learn the “truth.” To accommodate nonvanishing violations of Savage’s (The foundations of statistics, Wiley, New York, 1954) sure-thing principle, as reported in Nicholls et al. (J Risk Uncertain 50:97–115, 2015), we construct and analyze a model of Bayesian learning with multiple priors for which ambiguity does not necessarily vanish in an one-urn environment. Our decision maker only forms posteriors from priors that survive a prior selection rule which discriminates, with probability one, against priors whose expected Kullback–Leibler divergence from the “truth” is too far off from the minimal expected Kullback–Leibler divergence over all priors. The “stubbornness” parameter of our prior selection rule thereby governs how much ambiguity will remain in the limit of our learning model.ERSA (Economic Research Southern Africa)http://link.springer.com/journal/1992018-10-30hj2018Economic

Iliopsoas bursitis and pseudogout of the knee mimicking L2-L3 radiculopathy: case report and review of the literature.

We report the case of a 74-year-old woman who presented with acute-onset right groin pain irradiating to the thigh anteriorly after having suffered for a few weeks from slight knee pain. As a CT scan showed multiple herniated intervertebral discs and spinal stenosis at the L3-L4 level, she was referred to a neurosurgical unit with the tentative diagnosis of L2-L3 radicular pain. Investigations (MR, myelography with CT scan) showed severe acquired lumbar canal stenosis. Decompression surgery was finally postponed because of the patient's serious cardiac medical history and she was referred to us for conservative treatment. She was found to have iliopsoas bursitis with chondrocalcinosis of the knee. Local steroid injections of the two sites abolished her symptoms. We draw attention to the possible pitfalls that the radiographic appearance and one of the multiple clinical presentations of this unrare pathology may represent. Whenever a patient comes walking with crutches, avoids putting weight on his or her leg, and radicular pain is suspected, we advise consideration of other extra-spinal causes for the pain