The modeling of a tokamak plasma discharge, from first principles to a flight simulator

A newly developed tool to simulate a tokamak full discharge is presented. The tokamak \u27flight simulator\u27 Fenix couples the tokamak control system with a fast and reduced plasma model, which is realistic enough to take into account several of the plasma non-linearities. A distinguishing feature of this modeling tool is that it only requires the pulse schedule (PS) as input to the simulator. The output is a virtual realization of the full discharge, whose time traces can then be used to judge if the PS satisfies control/physics goals or needs to be revised. This tool is envisioned for routine use in the control room before each pulse is performed, but can also be used off-line to correct PS in advance, or to develop and validate reduced models, control schemes for future machines like a commercial reactor, simulating realistic actuators and sensors behavior

Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors

HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an E-box motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression

SPINAL ANTINOCICEPTION BY MORPHINE IN RATS IS ANTAGONIZED BY GALANIN RECEPTOR ANTAGONISTS

Galanin, a 29 amino acid peptide, has been reported to possess antinociceptive properties at the spinal site and to potentiate opioid-induced antinociception. Our aim was to investigate whether also endogenous galanin interacts with an exogenously administered opioid, morphine, in the rat spinal cord. This question was investigated by use of the recently developed galanin receptor antagonists galantide [M-15, galanin-(1-13)-substance P-(5-11) amide] and M-35 [galanin-(1-13)-bradykinin-(2-9) amide]. Nociception was assessed in the rat tail-flick test using radiant heat and the rat Randall-Selitto model of inflammatory pain using vocalization as the nociceptive criterion. Intrathecal (i.t.) injections were performed in rats under ether anaesthesia. Morphine was administered either i.t. or intraperitoneally (i.p.), and the antagonists were injected i.t. [I-125]Galanin binding experiments were performed on crude synaptosomal membranes of the rat spinal cord. In the rat tail-flick test, i.t. injection of 3 mu g morphine evoked antinociception of about 75% of the maximal possible effect (% MPE). Co-injection of either 2 mu g galantide or 2 mu g M-35 with morphine almost completely abolished the antinociceptive effect of morphine. I.p. injection of 2.15 mg/kg morphine elicited about 80% MPE when given 10 min prior to i.t. saline injection. Injection of the antagonists instead of saline antagonised the antinociceptive effect of morphine partially thus showing the spinal proportion of the overall antinociceptive effect. In the rat Randall-Selitto test, 3 mu g morphine, injected i.t., produced antinociception of almost 100% MPE. Co-injection of the antagonists reduced the maximum effect partially by about 25-35%. I.p. injection of 7.5 mg/kg morphine 10 min prior to i.t. injection of saline elicited an antinociceptive effect of 90-100% MPE; injection of the antagonists instead of saline reduced the peak effect to a similar degree as after i.t. injection of 3 mu g morphine. To exclude a direct interference by morphine with the galanin receptor, in vitro binding of [I-125]galanin to a spinal synaptosomal fraction was assessed. Morphine, 10 mu M, did not interfere with the specific [I-125]galanin binding. These results provide further evidence that galanin is involved in spinal nociceptive processing. It seems to be involved in the mediation of the effects of morphine at this site, either as a co-transmitter, or subsequent to mu-receptor activation on nerve terminals or on interneurones

SPINAL ANTINOCICEPTION BY MORPHINE IN RATS IS ANTAGONIZED BY GALANIN RECEPTOR ANTAGONISTS

Galanin, a 29 amino acid peptide, has been reported to possess antinociceptive properties at the spinal site and to potentiate opioid-induced antinociception. Our aim was to investigate whether also endogenous galanin interacts with an exogenously administered opioid, morphine, in the rat spinal cord. This question was investigated by use of the recently developed galanin receptor antagonists galantide [M-15, galanin-(1-13)-substance P-(5-11) amide] and M-35 [galanin-(1-13)-bradykinin-(2-9) amide]. Nociception was assessed in the rat tail-flick test using radiant heat and the rat Randall-Selitto model of inflammatory pain using vocalization as the nociceptive criterion. Intrathecal (i.t.) injections were performed in rats under ether anaesthesia. Morphine was administered either i.t. or intraperitoneally (i.p.), and the antagonists were injected i.t. [I-125]Galanin binding experiments were performed on crude synaptosomal membranes of the rat spinal cord. In the rat tail-flick test, i.t. injection of 3 mu g morphine evoked antinociception of about 75% of the maximal possible effect (% MPE). Co-injection of either 2 mu g galantide or 2 mu g M-35 with morphine almost completely abolished the antinociceptive effect of morphine. I.p. injection of 2.15 mg/kg morphine elicited about 80% MPE when given 10 min prior to i.t. saline injection. Injection of the antagonists instead of saline antagonised the antinociceptive effect of morphine partially thus showing the spinal proportion of the overall antinociceptive effect. In the rat Randall-Selitto test, 3 mu g morphine, injected i.t., produced antinociception of almost 100% MPE. Co-injection of the antagonists reduced the maximum effect partially by about 25-35%. I.p. injection of 7.5 mg/kg morphine 10 min prior to i.t. injection of saline elicited an antinociceptive effect of 90-100% MPE; injection of the antagonists instead of saline reduced the peak effect to a similar degree as after i.t. injection of 3 mu g morphine. To exclude a direct interference by morphine with the galanin receptor, in vitro binding of [I-125]galanin to a spinal synaptosomal fraction was assessed. Morphine, 10 mu M, did not interfere with the specific [I-125]galanin binding. These results provide further evidence that galanin is involved in spinal nociceptive processing. It seems to be involved in the mediation of the effects of morphine at this site, either as a co-transmitter, or subsequent to mu-receptor activation on nerve terminals or on interneurones