Diapirs as the source of the sediment signature in arc lavas

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Geoscience 4 (2011): 641-646, doi:10.1038/ngeo1214Many arc lavas show evidence for the involvement of subducted sediment in the melting process. There is debate whether this “sediment melt” signature forms at relatively low temperature near the fluid-saturated solidus or at higher temperature beyond the breakdown of trace-element-rich accessory minerals. We present new geochemical data from high- to ultrahigh-pressure rocks that underwent subduction and show no significant depletion of key trace elements in the sediment melt component until peak metamorphic temperatures exceeded ~1050ºC from 2.7 to 5 GPa. These temperatures are higher than for the top of the subducting plate at similar pressures based on thermal models. To address this discrepancy, we use instability calculations for a non-Newtonian buoyant layer in a viscous half-space to show that, in typical subduction zones, solid-state sediment diapirs initiate at temperatures between 500–850ºC. Based on these calculations, we propose that the sediment melt component in arc magmas is produced by high degrees of dehydration melting in buoyant diapirs of metasediment that detach from the slab and rise into the hot mantle wedge. Efficient recycling of sediments into the wedge by this mechanism will alter volatile fluxes into the deep mantle compared to estimates based solely on devolatilization of the slab.Funding for this work was provided by NSF and WHOI’s Deep Ocean Exploration Institute

The Discovery of Nonpeptide Endothelin Receptor Antagonists. Progression towards Bosentan

Since its discovery, endothelin-1 has attracted considerable scientific interest for its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. The endothelins appear to be part of a functional regulatory system in the circulation and strong evidence has accumulated for their involvement in clinical disorders associated with vasoconstriction (e.g. renal failure, congestive heart failure).In a program aimed at identifying nonpeptide ET receptor antagonists, a distinct class of substituted arylsulfonamido pyrimidines was discovered from a chemical substance library. Lead optimization led to orally active antagonists of ETA and ETB receptors possessing mixed or receptor-subtype-selective profiles in the low nanomolar range. From these compounds, the mixed antagonist bosentan was selected for development; it shows efficacy in several pathophysiological models of local and systemic vasoconstriction and promising clinical results in patients suffering from congestive heart failure.Chemical modifications in this structural class in combination with X-ray crystal data analysis for key compounds led to more in-depth understanding of antagonist-receptor interaction. Structural determinants of bosentan binding to the ETA receptor were defined on the molecular level by site-directed mutagenesis experiments. This led to a 3D model of the antagonist binding domain which proved valuable to rationalize structure-activity relationships

CO-independent modification of K+ channels by tricarbonyldichlororuthenium(II) dimer (CORM-2)

Although toxic when inhaled in high concentrations, the gas carbon monoxide (CO) is endogenously produced in mammals, and various beneficial effects are reported. For potential medicinal applications and studying the molecular processes underlying the pharmacological action of CO, so-called CO-releasing molecules (CORMs), such as tricabonyldichlororuthenium(II) dimer (CORM-2), have been developed and widely used. Yet, it is not readily discriminated whether an observed effect of a CORM is caused by the released CO gas, the CORM itself, or any of its intermediate or final breakdown products. Focusing on Ca2+- and voltage-dependent K+ channels (KCa1.1) and voltage-gated K+ channels (Kv1.5, Kv11.1) relevant for cardiac safety pharmacology, we demonstrate that, in most cases, the functional impacts of CORM-2 on these channels are not mediated by CO. Instead, when dissolved in aqueous solutions, CORM-2 has the propensity of forming Ru(CO)2 adducts, preferentially to histidine residues, as demonstrated with synthetic peptides using mass-spectrometry analysis. For KCa1.1 channels we show that H365 and H394 in the cytosolic gating ring structure are affected by CORM-2. For Kv11.1 channels (hERG1) the extracellularly accessible histidines H578 and H587 are CORM-2 targets. The strong CO-independent action of CORM-2 on Kv11.1 and Kv1.5 channels can be completely abolished when CORM-2 is applied in the presence of an excess of free histidine or human serum albumin; cysteine and methionine are further potential targets. Off-site effects similar to those reported here for CORM-2 are found for CORM-3, another ruthenium-based CORM, but are diminished when using iron-based CORM-S1 and absent for manganese-based CORM-EDE1

STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing

Signal transducer and activator of transcription (STAT) 3 is a pleiotropic transcription factor with important functions in cytokine signaling in a variety of tissues. However, the role of STAT3 in the intestinal epithelium is not well understood. We demonstrate that development of colonic inflammation is associated with the induction of STAT3 activity in intestinal epithelial cells (IECs). Studies in genetically engineered mice showed that epithelial STAT3 activation in dextran sodium sulfate colitis is dependent on interleukin (IL)-22 rather than IL-6. IL-22 was secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3IEC-KO mice, upon induction of colitis, showed a striking defect of epithelial restitution. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and pathways associated with wound healing in IECs. Consistently, both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. In summary, our data suggest that intestinal epithelial STAT3 activation regulates immune homeostasis in the gut by promoting IL-22–dependent mucosal wound healing

SCD1 Inhibition Causes Cancer Cell Death by Depleting Mono-Unsaturated Fatty Acids

Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway

Modelle zur Marktmikrostruktur

Veröffentlichung der Wirtschaftswissenschaftlichen Fakultä

Handelsfrequenz und Nichtmengenanpassung

Handelsfrequenz und Nichtmengenanpassung Mit der Abkehr von einer Mengenanpassung sind nicht nur Wirkungen auf den aktuellen Kurs, sondern auch auf zukünftige Kurse zu berücksichtigen. Diese intertemporale Verbundenheit führt in Verbindung mit rationalen Erwartungen aller Marktteilnehmer dazu, daß die Handelsfrequenz den aktuellen Kurs beeinflußt. Im Ergebnis nähert sich bereits der aktuelle Kurs bei einer höheren Handelsfrequenz demjenigen Kurs an, der sich bei optimaler Risikoallokation ergeben würde. Gleichzeitig erhöht sich die Marktliquidität, gemessen an der Unempfindlichkeit des Kurses gegenüber Schwankungen im Transaktionsvolumen.Trading Frequency and Non-Pricetaking In light of non-pricetaking, account has to be taken of effects not only on current, but also on future prices. This intertemporal link, together with rational expectations of all market participants, results in the trading frequency determining current prices. It turns out that, with a higher trading frequency, current prices tend to draw closer to those prices that would be the outcome of optimized risk allocation. At the same time, the liquidity of the market increases when measured by the insensitivity of prices to fluctuations in the volume of transactions

Modelle zur Marktmikrostruktur

Modelle zur Marktmikrostruktu