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.

Projected incremental changes to extreme wind-driven wave heights for the twenty-first century.

Global climate change will alter wind sea and swell waves, modifying the severity, frequency and impact of episodic coastal flooding and morphological change. Global-scale estimates of increases to coastal impacts have been typically attributed to sea level rise and not specifically to changes to waves on their own. This study provides a reduced complexity method for applying projected extreme wave changes to local scale impact studies. We use non-stationary extreme value analysis to distil an incremental change signal in extreme wave heights and associate this with a change in the frequency of events globally. Extreme wave heights are not projected to increase everywhere. We find that the largest increases will typically be experienced at higher latitudes, and that there is high ensemble model agreement on an increase (doubling of events) for the waters south of Australia, the Arabian Sea and the Gulf of Guinea by the end of the twenty-first century.

Characterization of a ceramide kinase activity from human leukemia (HL-60) cells. Separation from diacylglycerol kinase activity.

This laboratory first provided evidence for a potential signal transduction pathway involving sphingomyelin and its derivatives (Kolesnick, R.N., and Clegg, S. (1988) J. Biol. Chem. 263, 6534-6537). Recently, this laboratory demonstrated the existence of the novel sphingolipid ceramide 1-phosphate in human leukemia (HL-60) cells. Ceramide 1-phosphate was synthesized from ceramide derived from sphingomyelin but not glycosphingolipids. This suggested that a specific pathway extended from sphingomyelin to ceramide 1-phosphate. The present studies provide additional support for this notion by demonstrating the existence of a ceramide kinase activity distinct from diacylglycerol (DG) kinase in HL-60 cells. Microsomal membranes contained a kinase activity that phosphorylated ceramide but not 1,2-DG in the presence of physiologic and higher Ca2+ concentrations (60 nM-3 mM). Kinetic analyses demonstrated an apparent Vmax for ceramide and ATP of 70 pmol.min-1.mg protein-1; apparent Km values were 45 and 25 microM, respectively. The pH optimum was within the physiologic range (pH 6-8). Magnesium but not other divalent cations (Mn2+, Ba2+, Cd2+, Zn2+) also stimulated ceramide phosphorylation. Magnesium also induced 1,2-DG phosphorylation. Since DG kinase is a Mg2(+)-stimulable enzyme that may utilize ceramide as substrate, additional studies separated calcium-dependent ceramide kinase from DG kinase activity. 1,2-DGs competitively inhibited magnesium- but not calcium-dependent ceramide phosphorylation. Hence, calcium-dependent ceramide kinase activity neither utilized DG as substrate nor was inhibited by DG. These activities were physically separable. Both activities were solubilized by n-octyl-beta-D-glucopyranoside and stabilized by glycerol. Ceramide kinase activity bound weakly to a DEAE-cellulose anion exchange column and eluted with 4-fold purification as a single peak of activity in the flow-through and 0.05 M NaCl elutions. In contrast, the majority of DG kinase activity bound more tightly and was recovered as a broad peak in the 0.2-0.35 M NaCl elutions. These studies demonstrate the existence of a ceramide kinase activity in HL-60 cells which is functionally and physically separable from DG kinase. These studies provide further support for the notion of a specific pathway from sphingomyelin to ceramide 1-phosphate.

Physiologic 1,2-diacylglycerol levels induce protein kinase C-independent translocation of a regulatory enzyme.

Phorbol esters and 1,2-diacylglycerols have been used interchangeably to study protein kinase C action. This laboratory first suggested that 1,2-diacylglycerols may also act independent of protein kinase C using protein kinase C-"down-modulated" cells (Kolesnick, R. N., and Paley, A. E. (1987) J. Biol. Chem. 262, 9204-9210). Unfortunately, down-modulation was never complete. The present studies establish an in vitro system of enzyme translocation to resolve this issue. Choline phosphate cytidylyltransferase (EC 2.7.7.15), the regulatory enzyme for phosphatidylcholine biosynthesis, was utilized. Cytidylyltransferase translocation from cytosol to membranes mediates phorbol ester-induced phosphatidylcholine synthesis in GH3 pituitary cells. In the present studies, 1,2-diacylglycerols similarly induced phosphatidylcholine synthesis and cytidylyltransferase translocation. 1,2-Diacylglycerol-induced phosphatidylcholine synthesis, however, was not concentration-dependent but proportional to the moles of 1,2-diacylglycerol added per cell, i.e. subject to surface dilution. For instance, at constant cell number (1.67 x 10(6)/sample) and 1,2-dioctanoylglycerol concentration (diC8; 20 micrograms/ml), 32Pi incorporation into phosphatidylcholine varied from 150 to 350% above control as the incubation volume increased from 0.3 to 1.2 ml. Hence, the effective diC8 concentrations 0.5-30 micrograms/ml are preferably referred to as doses and reported as 0.25-15 nmol/10(6) cells. These doses increased cellular 1,2-diacylglycerol levels within a few fold of basal (374 pmol/10(6) cells). In vitro, diC8 also induced translocation of purified cytidylyltransferase devoid of protein kinase C to microsomes. Translocation was again subject to surface dilution. Translocation occurred with the same ratio of diC8 to microsomal membrane as phosphatidylcholine synthesis in intact cells (1-10 nmol of diC8/10(6) cell membranes). Despite stimulating cytidylyltransferase translocation in intact cells, phorbol esters failed to stimulate translocation in vitro. Hence, 1,2-diacylglycerols are not always interchangeable with phorbol esters and at physiologic levels may stimulate enzyme translocation by an alternative mechanism to protein kinase C.

Trifluoperazine stimulates the coordinate degradation of sphingomyelin and phosphatidylcholine in GH3 pituitary cells.

Prior studies demonstrated that 1,2-diacylglycerols stimulated degradation of the choline-containing phospholipids, phosphatidylcholine and sphingomyelin, in GH3 pituitary cells by a phospholipase A2 and a sphingomyelinase, respectively (Kolesnick, R. N. (1987) J. Biol. Chem. 262, 16759-16762). The present studies demonstrate that the phenothiazine trifluoperazine also stimulates degradation of these phospholipids. Trifluoperazine (25 microM) reduced phosphatidylcholine and sphingomyelin levels to 81 and 58% of control, respectively, after 30 min in cells labeled for 48 h with [3H] choline. Choline-containing metabolites were released specifically into the cytosolic fraction. The level of cytosolic phosphocholine, but not choline or CDP-choline, increased to 150% of control. These events were not mediated by inhibition of phosphatidylcholine synthesis. The level of 1,2-diacylglycerols, but not lysophosphatidylcholine or glycerol-3-phosphocholine, also increased. These data are most consistent with phosphatidylcholine degradation via a phospholipase C. Trifluoperazine-stimulated sphingomyelin degradation was accompanied by quantitative generation of ceramides consistent with activation of a sphingomyelinase. In contrast to trifluoperazine, choline-containing metabolites were released into the medium during stimulation by the 1,2-diacylglycerol 1,2-dioctanoyl-glycerol. Although both trifluoperazine and 1,2-dioctanoylglycerol increased ceramide levels, only 1,2-dioctanoylglycerol increased the sphingoid base level from 24 to 43 pmol/10(6) cells. Hence, trifluoperazine appears to deplete an intracellular pool of phosphatidylcholine and sphingomyelin by a different mechanism than 1,2-diacylglycerols. This is the first report of phenothiazine-induced degradation of choline-containing phospholipids.