Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts

Both of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P3 receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P3ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P3 receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors.

Safety and Efficacy of New-Generation Drug-Eluting Stents in Women at High Risk for Atherothrombosis: From the Women in Innovation and Drug-Eluting Stents Collaborative Patient-Level Pooled Analysis

BACKGROUND The safety and efficacy of new-generation drug-eluting stents (DES) in women with multiple atherothrombotic risk (ATR) factors is unclear. METHODS AND RESULTS We pooled patient-level data for women enrolled in 26 randomized trials. Study population was categorized based on the presence or absence of high ATR, which was defined as having history of diabetes mellitus, prior percutaneous or surgical coronary revascularization, or prior myocardial infarction. The primary end point was major adverse cardiovascular events defined as a composite of all-cause mortality, myocardial infarction, or target lesion revascularization at 3 years of follow-up. Out of 10 449 women included in the pooled database, 5333 (51%) were at high ATR. Compared with women not at high ATR, those at high ATR had significantly higher risk of major adverse cardiovascular events (15.8% versus 10.6%; adjusted hazard ratio: 1.53; 95% confidence interval: 1.34-1.75; P=0.006) and all-cause mortality. In high-ATR risk women, the use of new-generation DES was associated with significantly lower risk of 3-year major adverse cardiovascular events (adjusted hazard ratio: 0.69; 95% confidence interval: 0.52-0.92) compared with early-generation DES. The benefit of new-generation DES on major adverse cardiovascular events was uniform between high-ATR and non-high-ATR women, without evidence of interaction (Pinteraction=0.14). At landmark analysis, in high-ATR women, stent thrombosis rates were comparable between DES generations in the first year, whereas between 1 and 3 years, stent thrombosis risk was lower with new-generation devices. CONCLUSIONS Use of new-generation DES even in women at high ATR is associated with a benefit consistent over 3 years of follow-up and a substantial improvement in very-late thrombotic safety.

Th and U isotopes, dose rates and ages of marine shells and sediment of core GIK14350, north Germany

The ESR dating method was applied to marine shells taken from a sediment core from Dagebüll, Schleswig-Holstein. Four samples from two different depths of the core (17.5 m and 25-26 m), separated by a 2.76 meter thick clay layer (Turritella Clay), yielded identical ages within the limits of error. They indicated an assignment to the oxygen isotope stage 5, thus confirming the stratigraphic age. In addition, the ESR-ages confirm the interpretation of Lomitschka et al. (1997, doi:10.2312/meyniana.1997.49.85), that the Th/U-ages of shells below the clay layer are reliable, whereas shells located above the clay layer, which were strongly influenced by percolating groundwaters of an open system, yielded falsified Th/U-ages.

(Table 2) Characteristics of a turbidite flow inferred from physiography and morphology of the margin and the sediment waves

This paper presents the morpho-sedimentary characterization and interpretations of the assemblage of landforms of the East Greenland continental slope and Greenland Basin, based on swath bathymetry and sub-bottom TOPAS profiles. The interpretation of landforms reveals the glacial influence on recent sedimentary processes shaping the seafloor, including mass-wasting and turbidite flows. The timing of landform development points to a predominantly glacial origin of the sediment supplied to the continental margin, supporting the scenario of a Greenland Ice Sheet extending across the continental shelf, or even to the shelf-edge, during the Last Glacial Maximum (LGM). Major sedimentary processes along the central section of the eastern Greenland Continental Slope, the Norske margin, suggest a relatively high glacial sediment input during the LGM that, probably triggered by tectonic activity, led to the development of scarps and channels on the slope and debris flows on the continental rise. The more southerly Kejser Franz Josef margin has small-scale mass-wasting deposits and an extensive turbidite system that developed in relation to both channelised and unconfined turbidity flows which transferred sediments into the deep Greenland Basin.

Stable foraminifer isotope composition and age of ODP Sites 184-1147 and 184-1148, South China Sea

Sites 1147 (18°50.11'N, 116°33.28'E; water depth = 3246 m) and 1148 (18°50.17'N, 116°33.94'E; water depth = 3294 m) are located on the lowermost continental slope off southern China near the continent/ocean crust boundary of the South China Sea Basin. Site 1147 is located upslope ~0.45 nmi west of Site 1148. Three advanced piston corer holes at Site 1147 and two extended core barrel holes at Site 1148 were cored and combined into a composite (spliced) stratigraphic section, which provided a relatively continuous profile for the lower Oligocene to Holocene (Wang, Prell, Blum, et al., 2000, doi:10.2973/odp.proc.ir.184.2000; Jian, et al., 2001, doi:10.1007/BF02907088) for studying stratigraphy and paleoceanography. A total of 1047 planktonic foraminifers stable isotope measurements were performed on 975 samples covering the upper 409.58 meters composite depth (mcd) at ~42-cm intervals (Tables T1, T2), and a total of 1864 benthic foraminifers measurements were performed on 1650 samples in the upper 837.11 mcd at ~51-cm intervals (Tables T3, T4). We significantly improved the time resolution of the benthic stable isotope record in the upper 476.68 mcd by reducing the average sample spacing to ~29 cm. This translates into an average sampling resolution of ~16 k.y. for the Miocene sequence and ~8 k.y. for the Pliocene-Holocene interval, assuming a change in sedimentation rates from ~1.8 to ~3.5 cm/k.y., as suggested by shipboard stratigraphy. These data sets provide the basis for upcoming studies to establish an oxygen isotope stratigraphy and examine the Neogene evolution of deep and surface water signatures (temperature, salinity, and nutrients) in the South China Sea.

Mineral XRD peak areas and ratios of ODP Site 184-1146 clays, South China Sea

Site 1146 (19°27.40'N, 116°16.37'E) was drilled in ~2092 m water depth in a rift basin on the continental slope of the South China Sea. A total of 607 m of sediment was cored in Hole 1146A, and a composite section from three holes extends down to 640 meters composite depth (mcd). Three stratigraphic sedimentary units were recognized at this site: late Pliocene to Pleistocene nannofossil clay (Unit I), middle Miocene to late Pliocene foraminifer and nannofossil clay mixed sediment (Unit II), and early to middle Miocene nannofossil clay (Unit III). This study reports the mineralogy from the late Miocene through early Pleistocene, 150-440 mcd.

Modeled integrated responses of ppERK1 and ppERK2 of normal and elevated ERK1 and ERK2 levels (Figure 5b)

The present dataset contain source data for Figure 5b from Schilling et al., 2009. Cell fate decisions are regulated by the coordinated activation of signalling pathways such as the extracellular signal-regulated kinase (ERK) cascade, but contributions of individual kinase isoforms are mostly unknown. The authors combined quantitative data from erythropoietin-induced pathway activation in primary erythroid progenitor (colony-forming unit erythroid stage, CFU-E) cells with mathematical modelling, in order to predict and experimentally confirmed a distributive ERK phosphorylation mechanism in CFU-E cells. The authors found evidences that double-phosphorylated ERK1 attenuates proliferation beyond a certain activation level, whereas activated ERK2 enhances proliferation with saturation kinetics. They show integrated responses of double-phosphorylated ERK1 and ERK2 that were calculated for different Epo concentrations for the original model as well as for models with elevated ERK1 or ERK2 levels.

Depth and ages of calcareous nannofossil events from ODP Leg 184 sites, South China Sea

Sites 1146 and 1148 of Ocean Drilling Program Leg 184, in the South China Sea (SCS), comprise long sediment sections with a time span from the early Oligocene to the Pleistocene. Calcareous nannofossils from these two sites were biostratigraphically studied. We recognized 53 early Oligocene to Pleistocene events that are commonly found in open sea areas and can therefore be correlated within a large geographic range. This study also revealed that a few conventionally used nannofossil events are not suitable for the SCS, and further evaluation is needed. The lower Oligocene to Pleistocene sequences recovered at Sites 1146 and 1148 were subdivided into the 4 Paleogene zones and 21 Neogene to Quaternary zones of Martini, in correlation with the Paleogene to Quaternary zones of Okada and Bukry. This provided a lower Oligocene through Pleistocene nannofossil biostratigraphic framework. A significant unconformity was recognized in the Oligocene-Miocene transition, in which the upper part of Oligocene Zone NP25 and lower part of Miocene Zone NN1 were missing. The time span of the unconformity was estimated to be ~1 m.y. Very high sedimentation rates were seen in the Oligocene, relative low values were seen in the Miocene, and the highest values were seen in the Pleistocene, which was believed to be the result of tectonic and sedimentation history of the SCS.

Planktonic foraminifera stratigraphy and datums of ODP Site 184-1143 and Hole 184-1146A, South China Sea

The biostratigraphy of Miocene-age sediment samples recovered from Ocean Drilling Program Sites 1143 and 1146, South China Sea, is presented. The preservation of the planktonic foraminifers recovered from both sites varies widely, from poor to very good. The volume of biogenic sediment in the >63-µm size fraction also varies considerably, with many samples being dominated by mud. In comparison to shipboard biostratigraphy, based on core catcher analyses with a depth resolution of ~10 m, we analyzed samples from the two stratigraphic columns every 2-3 m (~45- to 93-k.y. resolution). The placement of planktonic foraminifer zonal boundaries was made at a resolution of ~1.5 m at Site 1146 and ~3.0 m at Site 1143. The higher resolution has resulted in significant changes in biostratigraphic zonal boundary locations compared to shipboard results. For the time interval of 5.54-10.49 Ma, the changes in zonation reveal similar age-depth models at both sites, with three segments of changing sedimentation rate through the upper Miocene, though the differences in sedimentation rates at Site 1146 are subtler than those at Site 1143. The boundary between lithologic Units II and III at Site 1146 corresponds to a sharp change in sedimentation rate (58 to 21 m/m.y.) at 15.1 Ma (the first occurrence of Orbulina suturalis). At this site, the interval from 16.4 to 15.1 Ma is characterized by very high mass accumulation rates in the noncarbonate fraction. Above this interval the carbonate fraction becomes increasingly important in the sediment flux to the South China Sea. At Site 1143, sedimentation rates increase from 8 to 99 m/m.y. at 8.6 Ma. This corresponds to a dramatic increase in both carbonate and noncarbonate mass accumulation rates at the site, but no change in lithology.