Mycolactone-dependent depletion of endothelial cell thrombomodulin is strongly associated with fibrin deposition in Buruli ulcer lesions

A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin's substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells' ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone's effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tisischemia could contribute to the development of the tissue necrosis seen in BU lesions

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Evaluation of CMIP6 AMIP climate simulations with the ACCESS-AM2 model

The most recent version of the ACCESS-AM2 atmosphere-only climate model is introduced with results from the CMIP6 Atmospheric Model Intercomparison Project (AMIP) experiments configured with two land-surface models: CABLE and JULES. AMIP simulations are required as part of the CMIP6 core experiments. They are forced by prescribed time-varying observed sea surface temperature and sea-ice variations as well as variations in natural and anthropogenic external forcings. We evaluate the performance of the two configurations using three historical realisations for each. Model biases are estimated both globally and for the Australian region. The model shows close agreement with observed interannual variations of global-mean temperature across the latitude range 65°N–65°S. This is also true for the land-only temperature for 65°N–65°S, and a more stringent test of the model is driven by specified observed sea surface temperatures. Patterns of mean precipitation are simulated reasonably well, although there are biases in the amount and distribution of precipitation, typical of longstanding problems in representing this aspect of the climate. Selected features of the atmospheric circulation are discussed, including air temperatures and wind speeds. For the Australian region, in addition to examining the climatological patterns of temperature and precipitation, important drivers of climate variability are reviewed: El Niño-Southern Oscillation, the Indian Ocean Dipole and the Southern Annular Mode. In general, the correlation patterns for precipitation simulated by ACCESS-AM2 are somewhat weaker than in observations, although the ensemble means show better agreement than individual ensemble members. Overall, the two different land-surface schemes perform similarly. ACCESS-AM2 has reduced root mean square errors for both temperature and precipitation of around 15–20% at the global scale compared to the older CMIP5 versions of the model: ACCESS 1.0 and ACCESS 1.3

Refining global warming projections

Accurately determining the warming associated with scenarios of greenhouse gas emissions remains an overarching aim of climate modelling. Research now shows that contemporary measurements significantly reduce uncertainty bounds and indicate that some more extreme warming predictions may be less likel

Uncertainty in temperature projections reduced using carbon cycle and climate observations

The future behaviour of the carbon cycle is a major contributor to uncertainty in temperature projections for the twenty-first century1,2. Using a simplified climate model3, we show that, for a given emission scenario, it is the second most important contributor to this uncertainty after climate sensitivity, followed by aerosol impacts. Historical measurements of carbon dioxide concentrations4 have been used along with global temperature observations5 to help reduce this uncertainty. This results in an increased probability of exceeding a 2 °C global–mean temperature increase by 2100 while reducing the probability of surpassing a 6 °C threshold for non-mitigation scenarios such as the Special Report on Emissions Scenarios A1B and A1FI scenarios6, as compared with projections from the Fourth Assessment Report7 of the Intergovernmental Panel on Climate Change. Climate sensitivity, the response of the carbon cycle and aerosol effects remain highly uncertain but historical observations of temperature and carbon dioxide imply a trade–off between them so that temperature projections are more certain than they would be considering each factor in isolation. As well as pointing out the promise from the formal use of observational constraints in climate projection, this also highlights the need for an holistic view of uncertainty