Molecular determinants of Smac mimetic induced degradation of cIAP1 and cIAP2

The inhibitors of apoptosis (IAP) proteins cIAP1 and cIAP2 have recently emerged as key ubiquitin-E3 ligases regulating innate immunity and cell survival. Much of our knowledge of these IAPs stems from studies using pharmacological inhibitors of IAPs, dubbed Smac mimetics (SMs). Although SMs stimulate auto-ubiquitylation and degradation of cIAPs, little is known about the molecular determinants through which SMs activate the E3 activities of cIAPs. In this study, we find that SM-induced rapid degradation of cIAPs requires binding to tumour necrosis factor (TNF) receptor-associated factor 2 (TRAF2). Moreover, our data reveal an unexpected difference between cIAP1 and cIAP2. Although SM-induced degradation of cIAP1 does not require cIAP2, degradation of cIAP2 critically depends on the presence of cIAP1. In addition, degradation of cIAP2 also requires the ability of the cIAP2 RING finger to dimerise and to bind to E2s. This has important implications because SM-mediated degradation of cIAP1 causes non-canonical activation of NF-κB, which results in the induction of cIAP2 gene expression. In the absence of cIAP1, de novo synthesised cIAP2 is resistant to the SM and suppresses TNFα killing. Furthermore, the cIAP2-MALT1 oncogene, which lacks cIAP2's RING, is resistant to SM treatment. The identification of mechanisms through which cancer cells resist SM treatment will help to improve combination therapies aimed at enhancing treatment response

Hydrogen Absorption into Copper-Coated Titanium Measured by In Situ Neutron Reflectometry and Electrochemical Impedance Spectroscopy

One concern regarding the used nuclear fuel containers proposed for use in a Canadian deep geological repository (DGR) is the possibility that a small amount of hydrogen might be absorbed into their copper coating, potentially altering its mechanical properties. Reported herein is a study of hydrogen absorption into 50 nm of copper, coated on 4 nm of Ti using in situ neutron reflectometry (NR) and electrochemical impedance spectroscopy (EIS). NR results show that hydrogen is absorbed when the copper is cathodically polarized below the threshold for the hydrogen evolution reaction (HER), but that the hydrogen concentrates in the underlying titanium layer rather than concentrating in the copper coating. The hydrogen concentration in titanium rapidly rose when the HER was initiated and was observed to reach a steady state at TiH1.5. Over the course of 55h of cathodic polarization, the concentration of hydrogen in the copper remained below the NR detection limit (2 at %). The portion of hydrogen atoms produced that diffused through the copper layer was initially 3.2%, suggesting a possible upper limit for hydrogen uptake by the copper coating of the UFC, although definitive conclusions can only be drawn from studies on 3 mm copper-coated steel samples.</p

Hydrogen Absorption into Copper-Coated Titanium Measured by In Situ Neutron Reflectometry and Electrochemical Impedance Spectroscopy

Abstract One concern regarding the used nuclear fuel containers proposed for use in a Canadian deep geological repository is the possibility that a small amount of hydrogen might be absorbed into their copper coating, potentially altering its mechanical properties. Reported herein is a study of hydrogen absorption into 50 nm of copper, coated on 4 nm of Ti using in situ neutron reflectometry (NR) and electrochemical impedance spectroscopy. NR results show that hydrogen is absorbed when the copper is cathodically polarized below the threshold for the hydrogen evolution reaction (HER), but that the hydrogen concentrates in the underlying titanium layer rather than concentrating in the copper coating. The hydrogen concentration in titanium rapidly rose when the HER was initiated and was observed to reach a steady state at TiH1.5. Over the course of 55 hours of cathodic polarization, the concentration of hydrogen in the copper remained below the NR detection limit (2 at. %). The portion of hydrogen atoms produced that diffused through the copper layer was initially 3.2%, suggesting a possible upper limit for hydrogen uptake by the copper coating of the used fuel container, although definitive conclusions can only be drawn from studies on 3 mm copper-coated steel samples.</jats:p

Sea ice rheology

The polar oceans of Earth are covered by sea ice. On timescales much greater than a day, the motion and deformation of the sea ice cover (i.e., its dynamics) are primarily determined by atmospheric and oceanic tractions on its upper and lower surfaces and by internal ice forces that arise within the ice cover owing to its deformation. This review discusses the relationship between the internal ice forces and the deformation of the ice cover, focusing on representations suitable for inclusion within global climate models. I first draw attention to theories that treat the sea ice cover as an isotropic continuum and then to the recent development of anisotropic models that deal with the presence of oriented weaknesses in the ice cover, known as leads

Competencies through the eyes of the psychologist: A closer look at assessing competencies

Competencies have become a leading construct in human resource practices. However, empirical research on competencies has lagged behind resulting in a gap between practice and science. In this study, the focus was on the nature of competencies by examining the relationships of three competency dimensions with cognitive ability, personality and performance during assessment center exercises. Data of 932 applicants participating in a 1-day selection procedure were used. Results showed that to assess the competency dimension Thinking psychologists focus on cognitive ability. To assess the competency dimension Feeling psychologists rely on performance during interview simulation exercises and on measures of personality. In assessing the dimension Power psychologists focus mainly on personality, although they also rely on cognitive ability and performance during interview simulation exercises. © 2007 Blackwell Publishing Ltd

Smac Mimetics Activate the E3 Ligase Activity of cIAP1 Protein by Promoting RING Domain Dimerization*

The inhibitor of apoptosis (IAP) proteins are important ubiquitin E3 ligases that regulate cell survival and oncogenesis. The cIAP1 and cIAP2 paralogs bear three N-terminal baculoviral IAP repeat (BIR) domains and a C-terminal E3 ligase RING domain. IAP antagonist compounds, also known as Smac mimetics, bind the BIR domains of IAPs and trigger rapid RING-dependent autoubiquitylation, but the mechanism is unknown. We show that RING dimerization is essential for the E3 ligase activity of cIAP1 and cIAP2 because monomeric RING mutants could not interact with the ubiquitin-charged E2 enzyme and were resistant to Smac mimetic-induced autoubiquitylation. Unexpectedly, the BIR domains inhibited cIAP1 RING dimerization, and cIAP1 existed predominantly as an inactive monomer. However, addition of either mono- or bivalent Smac mimetics relieved this inhibition, thereby allowing dimer formation and promoting E3 ligase activation. In contrast, the cIAP2 dimer was more stable, had higher intrinsic E3 ligase activity, and was not highly activated by Smac mimetics. These results explain how Smac mimetics promote rapid destruction of cIAP1 and suggest mechanisms for activating cIAP1 in other pathways