Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Predicting the resilience and recovery of aquatic systems: A framework for model evolution within environmental observatories

Maintaining the health of aquatic systems is an essential component of sustainable catchment management, however, degradation of water quality and aquatic habitat continues to challenge scientists and policy-makers. To support management and restoration efforts aquatic system models are required that are able to capture the often complex trajectories that these systems display in response to multiple stressors. This paper explores the abilities and limitations of current model approaches in meeting this challenge, and outlines a strategy based on integration of flexible model libraries and data from observation networks, within a learning framework, as a means to improve the accuracy and scope of model predictions. The framework is comprised of a data assimilation component that utilizes diverse data streams from sensor networks, and a second component whereby model structural evolution can occur once the model is assessed against theoretically relevant metrics of system function. Given the scale and transdisciplinary nature of the prediction challenge, network science initiatives are identified as a means to develop and integrate diverse model libraries and workflows, and to obtain consensus on diagnostic approaches to model assessment that can guide model adaptation. We outline how such a framework can help us explore the theory of how aquatic systems respond to change by bridging bottom-up and top-down lines of enquiry, and, in doing so, also advance the role of prediction in aquatic ecosystem management

Potential effects of climate change on Australian estuaries and fish utilising estuaries: a review

Estuaries are especially vulnerable to the impacts of climate change because changes in climatic and hydrologic variables that influence freshwater and marine systems will also affect estuaries. We review potential impacts of climate change on Australian estuaries and their fish. Geographic differences are likely because southern Australian climates are predicted to become warmer and drier, whereas northern regions may see increased precipitation. Environmental factors, including salinity gradients, suspended sediment, dissolved oxygen and nutrient concentrations, will be influenced by changing freshwater input and other climate variables. Potential impacts will vary depending on the geomorphology of the estuary and the level of build-up of sand bars across estuarine entrances. Changes to estuarine fish assemblages will depend on associated changes to salinity and estuarine-mouth morphology. Marine migrants may be severely affected by closure of estuarine mouths, depending on whether species 'must' use estuarine habitat and the level of migratory v. resident individuals. Depending on how fish in coastal waters locate estuaries, there may be reduced cues associated with estuarine mouths, particularly in southern Australia, potentially influencing abundance. In summary, climate change is expected to have major consequences for Australian estuaries and associated fish, although the nature of impacts will show significant regional variation