Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Linear ubiquitination in immunity

Linear ubiquitination is a post-translational protein modification recently discovered to be crucial for innate and adaptive immune signaling. The function of linear ubiquitin chains is regulated at multiple levels: generation, recognition, and removal. These chains are generated by the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin E3 capable of forming the linear ubiquitin linkage de novo. LUBAC is not only relevant for activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in various signaling pathways, but importantly, it also regulates cell death downstream of immune receptors capable of inducing this response. Recognition of the linear ubiquitin linkage is specifically mediated by certain ubiquitin receptors, which is crucial for translation into the intended signaling outputs. LUBAC deficiency results in attenuated gene activation and increased cell death, causing pathologic conditions in both, mice, and humans. Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, are constitutively associated with LUBAC. Here, we review the current knowledge on linear ubiquitination in immune signaling pathways and the biochemical mechanisms as to how linear polyubiquitin exerts its functions distinctly from those of other ubiquitin linkage types

Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans

17/12/14 meb. OA paper, Ok to add.Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the mu-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-beta-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption

Prime Focus Spectrograph (PFS) for the Subaru telescope: Its start of the last development phase

PFS (Prime Focus Spectrograph), a next generation facility instrument on the Subaru telescope, is now being tested on the telescope. The instrument is equipped with very wide (1.3 degrees in diameter) field of view on the Subaru’s prime focus, high multiplexity by 2394 reconfigurable fibers, and wide waveband spectrograph that covers from 380nm to 1260nm simultaneously in one exposure. Currently engineering observations are ongoing with Prime Focus Instrument (PFI), Metrology Camera System (MCS), the first spectrpgraph module (SM1) with visible cameras and the first fiber cable providing optical link between PFI and SM1. Among the rest of the hardware, the second fiber cable has been already installed on the telescope and in the dome building since April 2022, and the two others were also delivered in June 2022. The integration and test of next SMs including near-infrared cameras are ongoing for timely deliveries. The progress in the software development is also worth noting. The instrument control software delivered with the subsystems is being well integrated with its system-level layer, the telescope system, observation planning software and associated databases. The data reduction pipelines are also rapidly progressing especially since sky spectra started being taken in early 2021 using Subaru Nigh Sky Spectrograph (SuNSS), and more recently using PFI during the engineering observations. In parallel to these instrumentation activities, the PFS science team in the collaboration is timely formulating a plan of large-sky survey observation to be proposed and conducted as a Subaru Strategic Program (SSP) from 2024. In this article, we report these recent progresses, ongoing developments and future perspectives of the PFS instrumentation

What is the value and impact of quality and safety teams? A scoping review

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to conduct a scoping review of the literature about the establishment and impact of quality and safety team initiatives in acute care.</p> <p>Methods</p> <p>Studies were identified through electronic searches of Medline, Embase, CINAHL, PsycINFO, ABI Inform, Cochrane databases. Grey literature and bibliographies were also searched. Qualitative or quantitative studies that occurred in acute care, describing how quality and safety teams were established or implemented, the impact of teams, or the barriers and/or facilitators of teams were included. Two reviewers independently extracted data on study design, sample, interventions, and outcomes. Quality assessment of full text articles was done independently by two reviewers. Studies were categorized according to dimensions of quality.</p> <p>Results</p> <p>Of 6,674 articles identified, 99 were included in the study. The heterogeneity of studies and results reported precluded quantitative data analyses. Findings revealed limited information about attributes of successful and unsuccessful team initiatives, barriers and facilitators to team initiatives, unique or combined contribution of selected interventions, or how to effectively establish these teams.</p> <p>Conclusions</p> <p>Not unlike systematic reviews of quality improvement collaboratives, this broad review revealed that while teams reported a number of positive results, there are many methodological issues. This study is unique in utilizing traditional quality assessment and more novel methods of quality assessment and reporting of results (SQUIRE) to appraise studies. Rigorous design, evaluation, and reporting of quality and safety team initiatives are required.</p

Prime Focus Spectrograph (PFS) for the Subaru telescope: Ongoing integration and future plans

PFS (Prime Focus Spectrograph), a next generation facility instrument on the 8.2-meter Subaru Telescope, is a very wide-field, massively multiplexed, optical and near-infrared spectrograph. Exploiting the Subaru prime focus, 2394 reconfigurable fibers will be distributed over the 1.3 deg field of view. The spectrograph has been designed with 3 arms of blue, red, and near-infrared cameras to simultaneously observe spectra from 380nm to 1260nm in one exposure at a resolution of ∼ 1.6-2.7Å. An international collaboration is developing this instrument under the initiative of Kavli IPMU. The project recently started undertaking the commissioning process of a subsystem at the Subaru Telescope side, with the integration and test processes of the other subsystems ongoing in parallel. We are aiming to start engineering night-sky operations in 2019, and observations for scientific use in 2021. This article gives an overview of the instrument, current project status and future paths forward

The role of the TRAF-interacting protein in proliferation and differentiation.

Ubiquitination of proteins is a post-translational modification, which decides on the cellular fate of the protein. Addition of ubiquitin moieties to proteins is carried out by the sequential action of three enzymes: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; and E3, ubiquitin ligase. The TRAF-interacting protein (TRAIP, TRIP, RNF206) functions as Really Interesting New Gene (RING)-type E3 ubiquitin ligase, but its physiological substrates are not yet known. TRAIP was reported to interact with TRAF [tumor necrosis factor (TNF) receptor-associated factors] and the two tumor suppressors CYLD and Syk (spleen tyrosine kinase). Ectopically expressed TRAIP was shown to inhibit nuclear factor-kappa B (NF-κB) signalling. However, recent results suggested a role for TRAIP in biological processes other than NF-κB regulation. Knock-down of TRAIP in human epidermal keratinocytes repressed cellular proliferation and induced a block in the G1/S phase of the cell cycle without affecting NF-κB signalling. TRAIP is necessary for embryonal development as mutations affecting the Drosophila homologue of TRAIP are maternal effect-lethal mutants, and TRAIP knock-out mice die in utero because of aberrant regulation of cell proliferation and apoptosis. These findings underline the tight link between TRAIP and cell proliferation. In this review, we summarize the data on TRAIP and put them into a larger perspective regarding the role of TRAIP in the control of tissue homeostasis

Adaptive adjustment of starting price for agents in continuous double auctions

\u3cp\u3eSoftware agents can act flexibly in a variety of electronic marketplaces. Continuous Double Auction (CDA) is an efficient and common form of these marketplaces. There are several bidding strategies proposed in the literature for agents to adopt to compute their asks or bids in CDAs. For all of these bidding strategies, starting price has not been taken into account. However, in online auction marketplaces, the starting price is an important parameter for sellers to set and has been discussed many a time in the literature. Given the importance of starting price, the main objective of our work is to explore the effect of starting price on agents using various bidding strategies and how to adjust it adaptively within a dynamic CDA market. Experimental results confirm that when agents set their starting prices at varying values in different market situations, their profit changes significantly no matter which strategy they adopt. In order to guide agents to adjust their starting prices in dynamic and unknown markets, an adaptive mechanism is proposed. Experimental results show that agents adopting the adaptive mechanism generally outperform the corresponding agents without. Furthermore, another set of experiments are carried out to let all the agents use the adaptive mechanism and compete together in one market. Not surprisingly, the profit of agents is observed to drop down a lot in this situation.\u3c/p\u3