Uncertainty and Bias in Global to Regional Scale Assessments of Current and Future Coastal Flood Risk.

This study provides a literature-based comparative assessment of uncertainties and biases in global to world-regional scale assessments of current and future coastal flood risks, considering mean and extreme sea-level hazards, the propagation of these into the floodplain, people and coastal assets exposed, and their vulnerability. Globally, by far the largest bias is introduced by not considering human adaptation, which can lead to an overestimation of coastal flood risk in 2100 by up to factor 1300. But even when considering adaptation, uncertainties in how coastal societies will adapt to sea-level rise dominate with a factor of up to 27 all other uncertainties. Other large uncertainties that have been quantified globally are associated with socio-economic development (factors 2.3-5.8), digital elevation data (factors 1.2-3.8), ice sheet models (factor 1.6-3.8) and greenhouse gas emissions (factors 1.6-2.1). Local uncertainties that stand out but have not been quantified globally, relate to depth-damage functions, defense failure mechanisms, surge and wave heights in areas affected by tropical cyclones (in particular for large return periods), as well as nearshore interactions between mean sea-levels, storm surges, tides and waves. Advancing the state-of-the-art requires analyzing and reporting more comprehensively on underlying uncertainties, including those in data, methods and adaptation scenarios. Epistemic uncertainties in digital elevation, coastal protection levels and depth-damage functions would be best reduced through open community-based efforts, in which many scholars work together in collecting and validating these data.

Inhibition of class I HDACs abrogates the dominant effect of MLL-AF4 by activation of wild-type MLL.

The ALOX5 gene encodes 5-lipoxygenase (5-LO), a key enzyme of inflammatory reactions, which is transcriptionally activated by trichostatin A (TSA). Physiologically, 5-LO expression is induced by calcitriol and/or transforming growth factor-ß. Regulation of 5-LO mRNA involves promoter activation and elongation control within the 3'-portion of the ALOX5 gene. Here we focused on the ALOX5 promoter region. Transcriptional initiation was associated with an increase in histone H3 lysine 4 trimethylation in a TSA-inducible manner. Therefore, we investigated the effects of the MLL (mixed lineage leukemia) protein and its derivatives, MLL-AF4 and AF4-MLL, respectively. MLL-AF4 was able to enhance ALOX5 promoter activity by 47-fold, which was further stimulated when either vitamin D receptor and retinoid X receptor or SMAD3/SMAD4 were co-transfected. In addition, we investigated several histone deacetylase inhibitors (HDACi) in combination with gene knockdown experiments (HDAC1-3, MLL). We were able to demonstrate that a combined inhibition of HDAC1-3 induces ALOX5 promoter activity in an MLL-dependent manner. Surprisingly, a constitutive activation of ALOX5 by MLL-AF4 was inhibited by class I HDAC inhibitors, by relieving inhibitory functions deriving from MLL.Conversely, a knockdown of MLL increased the effects mediated by MLL-AF4. Thus, HDACi treatment seems to switch 'inactive MLL' into 'active MLL' and overwrites the dominant functions deriving from MLL-AF4.