Influence of ovarian hormones on cortical spreading depression and its suppression by L-kynurenine in rat.

Migraine is sexually dimorphic and associated in 20-30% of patients with an aura most likely caused by cortical spreading depression (CSD). We have previously shown that systemic L-kynurenine (L-KYN), the precursor of kynurenic acid, suppresses CSD and that this effect depends on the stage of the estrous cycle in female rats. The objectives here are to determine the influence of ovarian hormones on KCl-induced CSD and its suppression after L-KYN by directly modulating estradiol or progesterone levels in ovariectomized rats. Adult female rats were ovariectomized and subcutaneously implanted with silastic capsules filled with progesterone or 17β-estradiol mixed with cholesterol, with cholesterol only or left empty. Two weeks after the ovariectomy/capsule implantation, the animals received an i.p. injection of L-KYN (300 mg/kg) or NaCl as control. Thirty minutes later CSDs were elicited by applying KCl over the occipital cortex and recorded by DC electrocorticogram for 1 hour. The results show that both estradiol and progesterone increase CSD frequency after ovariectomy. The suppressive effect of L-KYN on CSD frequency, previously reported in normal cycling females, is not found anymore after ovariectomy, but reappears after progesterone replacement therapy. Taken together, these results emphasize the complex role of sex hormones on cortical excitability. The CSD increase by estradiol and, more surprisingly, progesterone may explain why clinically migraine with aura appears or worsens during pregnancy or with combined hormonal treatments

Use of the big liquid argon spectrometer BARS for neutrino and cosmic ray studies

The design of the fine grained 300 t liquid argon calorimeter BARS is described. The BARS electronics include about 30 K channels of low noise amplifiers and ADCs. The DAQ system makes it possible to select channels with signals above the chosen threshold. 48 scintillation hodoscopes placed inside the liquid argon are used to form the first level trigger. The total number of scintillation counters in liquid argon is 384. Sums of ionization signals are used to produce the second level trigger. Results of the first use of liquid argon calorimetry for the measurements of tagged neutrino interactions, cosmic-ray muon spectra and composition of extensive atmospheric showers are discussed. (C) 1998 Elsevier Science B.V. All rights reserved

Efficacy and mode of action of external trigeminal neurostimulation in migraine

Introduction: Available preventive drug treatments for migraine lack complete efficacy and often have unpleasant adverse effects. Hence, their clinical utility and therapeutic adherence are limited. Noninvasive neurostimulation methods applied over various peripheral sites (forehead, mastoid, upper arm, cervical vagus nerve) have raised great interest because of their excellent efficacy/tolerance profile. Among them external trigeminal nerve stimulation (eTNS) was first to obtain FDA approval for migraine therapy. Areas covered: All clinical trials of eTNS as preventive or acute migraine treatment published in extenso or presented at congresses are reviewed. The paper analyzes neuroimaging and neurophysiological studies on mechanisms of action of eTNS. As many of these studies point toward the anterior cingulate cortex (ACC) as a likely eTNS target, the paper scrutinizes the available literature on the ACC implication in migraine pathophysiology. Expert commentary: eTNS is a viable alternative to standard pharmacological antimigraine strategies both for prevention and abortive therapy. eTNS could chiefly exert its action by modulating the perigenual ACC, which might also be of interest for treating other disorders like fibromyalgia or depression. It remains to be determined if this might be a common mechanism to other peripheral noninvasive neurostimulation methods

Structural and mechanistic insights into the biosynthesis of CDP-archaeol in membranes

The divergence of archaea, bacteria and eukaryotes was a fundamental step in evolution. One marker of this event is a major difference in membrane lipid chemistry between these kingdoms. Whereas the membranes of bacteria and eukaryotes primarily consist of straight fatty acids ester-bonded to glycerol-3-phosphate, archaeal phospholipids consist of isoprenoid chains ether-bonded to glycerol-1-phosphate. Notably, the mechanisms underlying the biosynthesis of these lipids remain elusive. Here, we report the structure of the CDP-archaeol synthase (CarS) of Aeropyrum pernix (ApCarS) in the CTP- and Mg(2+)-bound state at a resolution of 2.4 Å. The enzyme comprises a transmembrane domain with five helices and cytoplasmic loops that together form a large charged cavity providing a binding site for CTP. Identification of the binding location of CTP and Mg(2+) enabled modeling of the specific lipophilic substrate-binding site, which was supported by site-directed mutagenesis, substrate-binding affinity analyses, and enzyme assays. We propose that archaeol binds within two hydrophobic membrane-embedded grooves formed by the flexible transmembrane helix 5 (TM5), together with TM1 and TM4. Collectively, structural comparisons and analyses, combined with functional studies, not only elucidated the mechanism governing the biosynthesis of phospholipids with ether-bonded isoprenoid chains by CTP transferase, but also provided insights into the evolution of this enzyme superfamily from archaea to bacteria and eukaryotes.Cell Research advance online publication 29 September 2017; doi:10.1038/cr.2017.122