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We analyze how schedule times, actual flight times and on-time performance have changed in the U.S. airline industry between 1990 and 2016. We find schedule times have increased in most years, with the largest increases after 2008. Actual flight times and total travel times have also increased but by less than schedule times and the gap has grown over time. This has resulted in reduced arrival delays even though flights are, in fact, taking longer to complete. We discuss the implications of these findings for quality provision and information disclosure within the airline industry. [ABSTRACT FROM AUTHOR]

Inflammasomes are protein complexes assembled upon recognition of infection or cell damage signals, and serve as platforms for clustering and activation of procaspase-1. Oligomerisation of initiating proteins such as AIM2 (absent in melanoma-2) and NLRP3 (NOD-like receptor family, pyrin domain-containing-3) recruits procaspase-1 via the inflammasome adapter molecule ASC (apoptosis-associated speck-like protein containing a CARD). Active caspase-1 is responsible for rapid lytic cell death termed pyroptosis. Here we show that AIM2 and NLRP3 inflammasomes activate caspase-8 and -1, leading to both apoptotic and pyroptotic cell death. The AIM2 inflammasome is activated by cytosolic DNA. The balance between pyroptosis and apoptosis depended upon the amount of DNA, with apoptosis seen at lower transfected DNA concentrations. Pyroptosis had a higher threshold for activation, and dominated at high DNA concentrations because it happens more rapidly. Gene knockdown showed caspase-8 to be the apical caspase in the AIM2- and NLRP3-dependent apoptotic pathways, with little or no requirement for caspase-9. Procaspase-8 localised to ASC inflammasome 'specks' in cells, and bound directly to the pyrin domain of ASC. Thus caspase-8 is an integral part of the inflammasome, and this extends the relevance of the inflammasome to cell types that do not express caspase-1. [ABSTRACT FROM AUTHOR]

P53-upregulated modifier of apoptosis (PUMA), a pro-apoptotic member of the Bcl-2 family, is transcriptionally activated by p53 and is a key effector of p53-dependent apoptosis. We show that PUMA protein is subject to rapid post-translational regulation by phosphorylation at a conserved residue, serine 10, following serum or interleukin-3 (IL-3) stimulation. Serine 10 is not within the Bcl-2 homology (BH3) domain, and PUMA phosphorylated at serine 10 retained the ability to co-immunoprecipitate with antiapoptotic Bcl-2 family members. However, phosphorylated PUMA was targeted for proteasomal degradation indicating that it is less stable than unphosphorylated PUMA. Importantly, we identified IKK1/IKK2/Nemo as the kinase complex that interacts with and phosphorylates PUMA, thereby also demonstrating that IL-3 activates NFκB signaling. The identification and characterization of this novel survival pathway has important implications for IL-3 signaling and hematopoietic cell development. [ABSTRACT FROM AUTHOR]

The article comments on the contribution of researcher Jürg Tschopp to the tumor necrosis factor (TNF) signalling field. The author observes that Tschopp was the first to identifiy perforin and at the same time as another group, characterised its role in cytolytic T-cell mediated lysis. He showed that Fas (CD95) also contributes to this process, which started his pathbreaking contributions to the TNF field. He describes the dissection of TNF receptor 1 (TNFR1) signalling.

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. [ABSTRACT FROM AUTHOR]

On TNF binding, receptor-interacting protein kinase 1 (RIPK1) is recruited to the cytoplasmic domain of TNFR1, at which it becomes ubiquitylated and serves as a platform for recruitment and activation of NEMO/IKK1/IKK2 and TAK1/TAB2. RIPK1 is commonly thought to be required for the activation of canonical NF-κB and for inhibition TNFR1-induced apoptosis. RIPK1 has, however, also been reported to be essential for TNFR1-induced apoptosis when cIAPs are depleted. To determine the role of RIPK1 in TNF/IAP antagonist-induced death, we compared wild type (WT) and RIPK1−/− mouse embryonic fibroblasts (MEFs) treated with these compounds. On being treated with TNF plus IAP antagonist, RIPK1−/− MEFs survived, unlike WT MEFs, demonstrating a killing activity of RIPK1. Surprisingly, however, on being treated with TNF alone, RIPK1−/− MEFs activated canonical NF-κB and did not die. Furthermore, several cell types from E18 RIPK1−/− embryos seem to activate NF-κB in response to TNF. These data indicate that models proposing that RIPK1 is essential for TNFR1 to activate canonical NF-κB are incorrect. [ABSTRACT FROM AUTHOR]

There have been a number of recent discoveries relating to the functions of inhibitors of apoptosis (IAPs) and TNF receptor-associated factors (TRAFs) in regulating signalling from TNF receptor superfamily (TNFRSF) members and some tantalizing glimpses into a wider area of influence, that of innate immune signalling. Discoveries relating to the function of these ubiquitin E3 ligases in regulating signalling from the eponymous member of the family, TNF-R1, are dealt with superbly in a separate review by Wertz and Dixit and so we will confine our discussion to the subset of the TNFRSF that does not contain a death domain (DD). In line with the available data we will divide the review into two parts, the first is restricted to the role of TRAFs 2 and 3 and cIAPs in regulating TNFRSF signalling, whereas the second will be more speculative, asking what role IAPs and TRAFs have in innate immune signalling. [ABSTRACT FROM AUTHOR]

MDM2, a ubiquitin E3-ligase of the RING family, has a key role in regulating p53 abundance. During normal non-stress conditions p53 is targeted for degradation by MDM2. MDM2 can also target itself and MDMX for degradation. MDMX is closely related to MDM2 but the RING domain of MDMX does not possess intrinsic E3-ligase activity. Instead, MDMX regulates p53 abundance by modulating the levels and activity of MDM2. Dimerization, mediated by the conserved C-terminal RING domains of both MDM2 and MDMX, is critical to this activity. Here we report the crystal structure of the MDM2/MDMX RING domain heterodimer and map residues required for functional interaction with the E2 (UbcH5b). In both MDM2 and MDMX residues C-terminal to the RING domain have a key role in dimer formation. In addition we show that these residues are part of an extended surface that is essential for ubiquitylation in trans. This study provides a molecular basis for understanding how heterodimer formation leads to stabilization of MDM2, yet degradation of p53, and suggests novel targets for therapeutic intervention.Cell Death and Differentiation (2008) 15, 841–848; doi:10.1038/sj.cdd.4402309; published online 25 January 2008 [ABSTRACT FROM AUTHOR]

Human GraB (hGraB) preferentially induces apoptosis via Bcl-2-regulated mitochondrial damage but can also directly cleave caspases and caspase substrates in cell-free systems. How hGraB kills cells when it is delivered by cytotoxic lymphocytes (CL) and the contribution of hGraB to CL-induced death is still not clear. We show that primary human natural killer (hNK) cells, which specifically used hGraB to induce target cell death, were able to induce apoptosis of cells whose mitochondria were protected by Bcl-2. Purified hGraB also induced apoptosis of Bcl-2-overexpressing targets but only when delivered at 5- to 10-fold the concentration required to kill cells expressing endogenous Bcl-2. Caspases were critical in this process as inhibition of caspase activity permitted clonogenic survival of Bcl-2-overexpressing cells treated with hGraB or hNK cells but did not protect cells that only expressed endogenous Bcl-2. Our data therefore show that hGraB triggers caspase activation via mitochondria-dependent and mitochondria-independent mechanisms that are activated in a hierarchical manner, and that the combined effects of Bcl-2 and direct caspase inhibition can block cell death induced by hGraB and primary hNK cells.Cell Death and Differentiation (2008) 15, 708–717; doi:10.1038/sj.cdd.4402300; published online 18 January 2008 [ABSTRACT FROM AUTHOR]

Direct IAP binding protein with low pI/second mitochondrial activator of caspases, HtrA2/Omi and GstPT/eRF3 are mammalian proteins that bind via N-terminal inhibitor of apoptosis protein (IAP) binding motifs (IBMs) to the baculoviral IAP repeat (BIR) domains of IAPs. These interactions can prevent IAPs from inhibiting caspases, or displace active caspases, thereby promoting cell death. We have identified several additional potential IAP antagonists, including glutamate dehydrogenase (GdH), Nipsnap 3 and 4, CLPX, leucine-rich pentatricopeptide repeat motif-containing protein and 3-hydroxyisobutyrate dehydrogenase. All are mitochondrial proteins from which N-terminal import sequences are removed generating N-terminal IBMs. Whereas most of these proteins have alanine at the N-terminal position, as observed for previously described antagonists, GdH has an N-terminal serine residue that is essential for X-linked IAP (XIAP) interaction. These newly described IAP binding proteins interact with XIAP mainly via BIR2, with binding eliminated or significantly reduced by a single point mutation (D214S) within this domain. Through this interaction, many are able to antagonise XIAP inhibition of caspase 3 in vitro.Cell Death and Differentiation (2007) 14, 348–357. doi:10.1038/sj.cdd.4402001; published online 23 June 2006 [ABSTRACT FROM AUTHOR]

We have reconstituted the Apaf-1-activated apoptosis mechanism in Sacchromyces cerevisiae such that the presence of a constitutively active form of Apaf-1 together with both Caspase-9 and Caspase-3 results in yeast death. This system is a good model of the Apaf-1-activated pathway in mammalian cells: MIHA (XIAP/hILP), and to a lesser degree MIHB (c-IAP1/HIAP2) and MIHC (c-IAP-2/HIAP1) can inhibit caspases in this system, and protection by IAPs (inhibitor of apoptosis) can be abrogated by coexpression of the Drosophila pro-apoptotic proteins HID and GRIM or the mammalian protein DIABLO/Smac. Using this system we demonstrate that unlike DIABLO/Smac, other proteins which interact with mammalian IAPs (TAB-1, Zap-1, Traf-1 and Traf-2) do not act to antagonise IAP- mediated caspase inhibition. [ABSTRACT FROM AUTHOR]

Caspases are the key effector molecules of the physiological death process known as apoptosis, although some are involved in activation of cytokines, rather than cell death. They exist in most of our cells as inactive precursors (zymogens) that kill the cell once activated. Caspases can be controlled in two ways. The processing and activation of a caspase can be regulated by molecules such as FADD, APAF-1, Bcl-2 family members, FLIP and lAPs. Active caspases can be controlled by a variety of inhibitors that directly interact with the protease. This review describes the later direct caspase inhibitors that have been identified, products of both viral and cellular genes, and artificial caspase inhibitors that have been developed both as research tools and as pharmaceutical agents to inhibit cell death in vivo. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the paper "Cytoplasmic p53 is not required for PUMA-induced apoptosis," by J.E. Chipuk and D.R. Green, in the 2008 issue is presented.

The article presents the evidence of TWEAK (tumour necrosis factor-like weak inducer of apoptosis) and FN14 (fibroblast growth factor (FGF) - inducible 14 kDa protein) in the wound response in cancer, immune regulation and tumour growth and its involvement in cell death. The role of TWEAK and FN14 in the wound response is discussed in newborn mouse tissues.

Discusses current studies of baculoviral inhibitor of apoptosis repeat domains (BIR) containing proteins which illustrate the fundamental importance of the ubiquitin system in the regulation of protein function and abundance during cell death and cell division. Finding that the zinc-binding RING domain of proteins such as c-cbl allows them to function as ubiquitin ligases; Identification of giant protein BRUCE as a BIR-bearing protein that has a UBC-like domain, but not a RING domain.

Identification of a conserved IAP binding motif shared by the separate Drosophila IAP antagonists and DIABLO. Existence of the model of the functional interactions between XIAP, caspasses and DIABLO; Identification of IAPs in baculoviruses; Characterization of IAPs by one or more copies of a baculoviral IAP repeat.

Information about several topics discussed during the Cold Spring Harbor Asia meeting that was held at the Suzhou Dushu Lake Conference Center from April 15-19, 2013 is presented. Topics include tumor necrosis factor (TNF) or necroptosis, mixed lineage kinase domain-like (MLKL) antibodies, and receptor-interacting protein kinase 3 (RIPL3) inhibitors. The meeting featured several speakers which include Liming Sun, Alexei Degterev, and Bill Kaiser.

Azaspiracid (AZA) poisoning was unknown until 1995 when shellfish harvested in Ireland caused illness manifesting by vomiting and diarrhoea. Further in vivo/vitro studies showed neurotoxicity linked with AZA exposure. However, the biological target of the toxin which will help explain such potent neurological activity is still unknown. A region of Irish coastline was selected and shellfish were sampled and tested for AZA using mass spectrometry. An outbreak was identified in 2010 and samples collected before and after the contamination episode were compared for their metabolite profile using high resolution mass spectrometry. Twenty eight ions were identified at higher concentration in the contaminated samples. Stringent bioinformatic analysis revealed putative identifications for seven compounds including, glutarylcarnitine, a glutaric acid metabolite. Glutaric acid, the parent compound linked with human neurological manifestations was subjected to toxicological investigations but was found to have no specific effect on the sodium channel (as was the case with AZA). However in combination, glutaric acid (1mM) and azaspiracid (50nM) inhibited the activity of the sodium channel by over 50%. Glutaric acid was subsequently detected in all shellfish employed in the study. For the first time a viable mechanism for how AZA manifests itself as a toxin is presented. [ABSTRACT FROM AUTHOR]

Discusses the mammalian protein DIABLO/Smac. Restriction of the sequence similarity between the pro-apoptotic proteins Grim, Reaper and Hid to their N-terminal 14 amino acids; Suggestion that the sequences and functions of DIABLO/Smac and the insect apoptosis inducing proteins are structural and functional homologues.