ABSTRACT
Integrated sediment multiproxy studies and modeling were used to reconstruct past changes in the Baltic Sea ecosystem. Results of natural changes over the past 6000 years in the Baltic Sea ecosystem suggest that forecasted climate warming might enhance environmental problems of the Baltic Sea. Integrated modeling and sediment proxy studies reveal increased sea surface temperatures and expanded seafloor anoxia (in deep basins) during earlier natural warm climate phases, such as the Medieval Climate Anomaly. Under future IPCC scenarios of global warming, there is likely no improvement of bottom water conditions in the Baltic Sea. Thus, the measures already designed to produce a healthier Baltic Sea are insufficient in the long term. The interactions between climate change and anthropogenic impacts on the Baltic Sea should be considered in management, implementation of policy strategies in the Baltic Sea environmental issues, and adaptation to future climate change.
Subject(s)
Climate Change , Ecosystem , Baltic States , Geologic Sediments , Oceans and SeasABSTRACT
Precursor cells of the embryonic cortex sequentially generate neurons and then glial cells, but the mechanisms regulating this neurogenic-to-gliogenic transition are unclear. Using cortical precursor cultures, which temporally mimic this in vivo differentiation pattern, we demonstrate that cortical neurons synthesize and secrete the neurotrophic cytokine cardiotrophin-1, which activates the gp130-JAK-STAT pathway and is essential for the timed genesis of astrocytes in vitro. Our data indicate that a similar phenomenon also occurs in vivo. In utero electroporation of neurotrophic cytokines in the environment of embryonic cortical precursors causes premature gliogenesis, while acute perturbation of gp130 in cortical precursors delays the normal timed appearance of astrocytes. Moreover, the neonatal cardiotrophin-1-/- cortex contains fewer astrocytes. Together, these results describe a neural feedback mechanism; newly born neurons produce cardiotrophin-1, which instructs multipotent cortical precursors to generate astrocytes, thereby ensuring that gliogenesis does not occur until neurogenesis is largely complete.
Subject(s)
Cell Differentiation/physiology , Cerebral Cortex/cytology , Cytokines/physiology , Neuroglia/physiology , Neurons/physiology , Stem Cells , Analysis of Variance , Animals , Blotting, Western/methods , Cell Count/methods , Cell Differentiation/drug effects , Cells, Cultured , Cerebral Cortex/embryology , Ciliary Neurotrophic Factor/pharmacology , Contactins , Culture Media, Conditioned/pharmacology , Cyclin-Dependent Kinase 2/metabolism , Cytokines/deficiency , Cytokines/pharmacology , Drug Interactions , ELAV Proteins/metabolism , Embryo, Mammalian , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Fluorescent Antibody Technique/methods , Glial Fibrillary Acidic Protein/metabolism , Green Fluorescent Proteins/metabolism , Hyaluronan Receptors/metabolism , Interleukin-6/pharmacology , Intermediate Filament Proteins/metabolism , Leukemia Inhibitory Factor , Mice , Mice, Transgenic , Nerve Growth Factors/metabolism , Nerve Tissue Proteins/metabolism , Nestin , Neural Cell Adhesion Molecules/metabolism , Neurofilament Proteins/metabolism , Organogenesis , Phosphopyruvate Hydratase/metabolism , Protein-Tyrosine Kinases/metabolism , RNA, Messenger/biosynthesis , RNA, Small Interfering/pharmacology , Reverse Transcriptase Polymerase Chain Reaction/methods , S100 Calcium Binding Protein beta Subunit , S100 Proteins/metabolism , STAT Transcription Factors/metabolism , Stem Cells/drug effects , Time Factors , Transfection/methods , Tubulin/metabolism , Tyrphostins/pharmacologyABSTRACT
Clopidogrel is an effective and specific inhibitor of ADP-induced platelet aggregation. After metabolic activation, the active clopidogrel metabolite irreversibly impairs the human platelet P2Y12 ADP receptor. Gialpha-protein activation and inhibition of vasodilator-stimulated phosphoprotein (VASP) phosphorylation are two key elements of the P2Y12 receptor pathway suitable for quantitation of clopidogrel effects. So far, only limited data exist about a diminished responsiveness to clopidogrel and underlying possible mechanisms. We investigated clopidogrel effects in 57 patients after percutaneous coronary intervention and stent implantation by flow cytometry for the analysis of intracellular VASP phosphorylation. Patients were treated with a 300 mg clopidogrel loading dose, followed by 75 mg/day clopidogrel in combination with 100 mg/day aspirin. Samples were drawn after a median of 5 days of clopidogrel treatment. Considerable differences in the responsiveness to clopidogrel could be observed and it was shown that 17.5% (10/57) of the patients revealed an inadequate responsiveness to clopidogrel despite continuation of clopidogrel intake. Comparable amounts of Gialpha and VASP were found in two clopidogrel low-responding patients as well as in two responding patients. To exclude a molecular defect of P2Y12 ADP receptor, the P2Y12 receptor gene of eight clopidogrel treated patients (seven patients with inadequate responsiveness, one responder) was sequenced. We only found a single silent mutation in exon 2 at position 1828 (GA). We suggest that individual differences in clopidogrel metabolization could cause relevant variations in clopidogrel responsiveness despite the use of a 300 mg clopidogrel loading dose.
