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

Workplace Health Promotion and Mental Health: Three-Year Findings from Partnering Healthy@Work

This study aimed to investigate the association between mental health and comprehensive workplace health promotion (WHP) delivered to an entire state public service workforce (~28,000 employees) over a three-year period. Government departments in a state public service were supported to design and deliver a comprehensive, multi-component health promotion program, Healthy@Work, which targeted modifiable health risks including unhealthy lifestyles and stress. Repeated cross-sectional surveys compared self-reported psychological distress (Kessler-10; K10) at commencement (N = 3406) and after 3 years (N = 3228). WHP availability and participation over time was assessed, and associations between the K10 and exposure to programs estimated. Analyses were repeated for a cohort subgroup (N = 580). Data were weighted for non-response. Participation in any mental health and lifestyle programs approximately doubled after 3 years. Both male and female employees with poorer mental health participated more often over time. Women's psychological distress decreased over time but this change was only partially attributable to participation in WHP, and only to lifestyle interventions. Average psychological distress did not change over time for men. Unexpectedly, program components directly targeting mental health were not associated with distress for either men or women. Cohort results corroborated findings. Healthy@Work was successful in increasing participation across a range of program types, including for men and women with poorer mental health. A small positive association of participation in lifestyle programs with mental health was observed for women but not men. The lack of association of mental health programs may have reflected program quality, its universality of application or other contextual factors

Accounting for Ecosystem Alteration Doubles Estimates of Conservation Risk in the Conterminous United States

Previous national and global conservation assessments have relied on habitat conversion data to quantify conservation risk. However, in addition to habitat conversion to crop production or urban uses, ecosystem alteration (e.g., from logging, conversion to plantations, biological invasion, or fire suppression) is a large source of conservation risk. We add data quantifying ecosystem alteration on unconverted lands to arrive at a more accurate depiction of conservation risk for the conterminous United States. We quantify ecosystem alteration using a recent national assessment based on remote sensing of current vegetation compared with modeled reference natural vegetation conditions. Highly altered (but not converted) ecosystems comprise 23% of the conterminous United States, such that the number of critically endangered ecoregions in the United States is 156% higher than when calculated using habitat conversion data alone. Increased attention to natural resource management will be essential to address widespread ecosystem alteration and reduce conservation risk

Methane-carbon flow into the benthic food web at cold seeps – a case study from the Costa Rica subduction zone

Cold seep ecosystems can support enormous biomasses of free-living and symbiotic chemoautotrophic organisms that get their energy from the oxidation of methane or sulfide. Most of this biomass derives from animals that are associated with bacterial symbionts, which are able to metabolize the chemical resources provided by the seeping fluids. Often these systems also harbor dense accumulations of non-symbiotic megafauna, which can be relevant in exporting chemosynthetically fixed carbon from seeps to the surrounding deep sea. Here we investigated the carbon sources of lithodid crabs (Paralomis sp.) feeding on thiotrophic bacterial mats at an active mud volcano at the Costa Rica subduction zone. To evaluate the dietary carbon source of the crabs, we compared the microbial community in stomach contents with surface sediments covered by microbial mats. The stomach content analyses revealed a dominance of epsilonproteobacterial 16S rRNA gene sequences related to the free-living and epibiotic sulfur oxidiser Sulfurovum sp. We also found Sulfurovum sp. as well as members of the genera Arcobacter and Sulfurimonas in mat-covered surface sediments where Epsilonproteobacteria were highly abundant constituting 10% of total cells. Furthermore, we detected substantial amounts of bacterial fatty acids such as i-C15:0 and C17:1ω6c with stable carbon isotope compositions as low as −53‰ in the stomach and muscle tissue. These results indicate that the white microbial mats at Mound 12 are comprised of Epsilonproteobacteria and that microbial mat-derived carbon provides an important contribution to the crab's nutrition. In addition, our lipid analyses also suggest that the crabs feed on other 13C-depleted organic matter sources, possibly symbiotic megafauna as well as on photosynthetic carbon sources such as sedimentary detritus

Analysis of arterial intimal hyperplasia: review and hypothesis

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Despite a prodigious investment of funds, we cannot treat or prevent arteriosclerosis and restenosis, particularly its major pathology, arterial intimal hyperplasia. A cornerstone question lies behind all approaches to the disease: what causes the pathology? Hypothesis: I argue that the question itself is misplaced because it implies that intimal hyperplasia is a novel pathological phenomenon caused by new mechanisms. A simple inquiry into arterial morphology shows the opposite is true. The normal multi-layer cellular organization of the tunica intima is identical to that of diseased hyperplasia; it is the standard arterial system design in all placentals at least as large as rabbits, including humans. Formed initially as one-layer endothelium lining, this phenotype can either be maintained or differentiate into a normal multi-layer cellular lining, so striking in its resemblance to diseased hyperplasia that we have to name it "benign intimal hyperplasia". However, normal or "benign " intimal hyperplasia, although microscopically identical to pathology, is a controllable phenotype that rarely compromises blood supply. It is remarkable that each human heart has coronary arteries in which a single-layer endothelium differentiates earl

Models and measurements of energy-dependent quenching

Energy-dependent quenching (qE) in photosystem II (PSII) is a pH-dependent response that enables plants to regulate light harvesting in response to rapid fluctuations in light intensity. In this review, we aim to provide a physical picture for understanding the interplay between the triggering of qE by a pH gradient across the thylakoid membrane and subsequent changes in PSII. We discuss how these changes alter the energy transfer network of chlorophyll in the grana membrane and allow it to switch between an unquenched and quenched state. Within this conceptual framework, we describe the biochemical and spectroscopic measurements and models that have been used to understand the mechanism of qE in plants with a focus on measurements of samples that perform qE in response to light. In addition, we address the outstanding questions and challenges in the field. One of the current challenges in gaining a full understanding of qE is the difficulty in simultaneously measuring both the photophysical mechanism of quenching and the physiological state of the thylakoid membrane. We suggest that new experimental and modeling efforts that can monitor the many processes that occur on multiple timescales and length scales will be important for elucidating the quantitative details of the mechanism of qE