Cortical spreading depression as a target for anti-migraine agents

Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K+ and glutamate, as well as rises in intracellular Na+ and Ca2+. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow. CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the effectiveness of these drugs as anti-migraine agents. CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine

The reversal of the SF-density relation in a massive, X-ray selected galaxy cluster at z=1.58: results from Herschel

Dusty, star-forming galaxies have a critical role in the formation and evolution of massive galaxies in the Universe. Using deep far-infrared imaging in the range 100-500um obtained with the Herschel telescope, we investigate the dust-obscured star formation in the galaxy cluster XDCP J0044.0-2033 at z=1.58, the most massive cluster at z >1.5, with a measured mass M200= 4.7x10$^{14}$ Msun. We perform an analysis of the spectral energy distributions (SEDs) of 12 cluster members (5 spectroscopically confirmed) detected with >3$\sigma$ significance in the PACS maps, all ULIRGs. The individual star formation rates (SFRs) lie in the range 155-824 Ms/yr, with dust temperatures of 24$\pm$35 K. We measure a strikingly high amount of star formation (SF) in the cluster core, SFR ( 1875$\pm$158 Ms/yr, 4x higher than the amount of star formation in the cluster outskirts. This scenario is unprecedented in a galaxy cluster, showing for the first time a reversal of the SF-density relation at z~1.6 in a massive cluster.Comment: Letter accepted for publication in MNRAS, ESA Press Release on 18 December 201

Progress in cardiovascular anastomoses: will the vascular join replace Carrel's technique?

Background: Vascular reconstructions are becoming challenging due to the comorbidity of the aging population and since the introduction of minimally invasive approaches. Many sutureless anastomosis devices have been designed to facilitate the cardiovascular surgeon's work and the vascular join (VJ) is one of these. We designed an animal study to assess its reliability and long-term efficacy. Methods: VJ allows the construction of end-to-end and end-to-side anastomoses. It consists of two metallic crowns fixed to the extremity of the two conduits so that vessel edges are joined layer by layer. There is no foreign material exposed to blood. In adult sheep both carotid arteries were prepared and severed. End-to-end anastomoses were performed using the VJ device on one side and the classical running suture technique on the other side. Animals were followed-up with Duplex-scan every 3 months and sacrificed after 12 months. Histopathological analysis was carried out. Results: In 20 animals all 22 sutureless anastomoses were successfully completed in less than 2min versus 6±3min for running suture. Duplex showed the occlusion of three controls and one sutureless anastomosis. Two controls and one sutureless had stenosis >50%. Histology showed very thin layer of myointimal hyperplasia (50±10μm) in the sutureless group versus 300±27μm in the control. No significant inflammatory reaction was detected. Conclusions: VJ provides edge-to-edge vascular repair that can be considered the most physiological way to restore vessel continuity. For the first time, in healthy sheep, an anastomotic device provided better results than suture techniqu

N-Glycans mutations rule oligomeric assembly and functional expression of P2X3 receptor for extracellular ATP

N-Glycosylation affects the function of ion channels at the level of multisubunit assembly, protein trafficking, ligand binding and channel opening. Like the majority of membrane proteins, ionotropic P2X receptors for extracellular ATP are glycosylated in their extracellular moiety. Here, we used site-directed mutagenesis to the four predicted N-glycosylation sites of P2X3 receptor (Asn139, Asn170, Asn194 and Asn290) and performed comparative analysis of the role of N-glycans on protein stability, plasma membrane delivery, trimer formation and inward currents. We have found that in transiently transfected HEK293 cells, Asn170 is apparently the most important site for receptor stability, since its mutation causes a primary loss in protein content and indirect failure in membrane expression, oligomeric association and inward current responses. Even stronger effects are obtained when mutating Thr172 in the same glycosylation consensus. Asn194 and Asn290 are the most dispensable, since even their simultaneous mutation does not affect any tested receptor feature. All double mutants containing Asn170 mutation or the Asn139/Asn290 double mutant are instead almost unable to assemble into a functional trimeric structure. The main emerging finding is that the inability to assemble into trimers might account for the impaired function in P2X3 mutants where residue Asn170 is replaced. These results improve our knowledge about the role of N-glycosylation in proper folding and oligomeric association of P2X3 recepto

Low-power Radio Galaxies in the Distant Universe: A search for FRI at 1<z<2 in the COSMOS field

We present a search for FRI radio galaxies between 1 < z < 2 in the COSMOS field. In absence of spectroscopic redshift measurements, the selection method is based on multiple steps which make use of both radio and optical constraints. The basic assumptions are that 1) the break in radio power between low-power FRIs and the more powerful FRIIs does not change with redshift, and 2) that the photometric properties of the host galaxies of low power radio galaxies in the distant universe are similar to those of FRIIs in the same redshift bin, as is the case for nearby radio galaxies. We describe the results of our search, which yields 37 low-power radio galaxy candidates that are possibly FRIs. We show that a large fraction of these low-luminosity radio galaxies display a compact radio morphology, that does not correspond to the FRI morphological classification. Furthermore, our objects are apparently associated with galaxies that show clear signs of interactions, at odds with the typical behavior observed in low-z FRI hosts. The compact radio morphology might imply that we are observing intrinsically small and possibly young objects, that will eventually evolve into the giant FRIs we observe in the local universe. One of the objects appears as point-like in HST images. This might belong to a population of FRI-QSOs, which however would represent a tiny minority of the overall population of high-z FRIs. As for the local FRIs, a large fraction of our objects are likely to be associated with groups or clusters, making them "beacons" for high redshift clusters of galaxies. Our search for candidate high-z FRIs we present in this paper constitutes a pilot study for objects to be observed with future high-resolution and high-sensitivity instruments (shortened)Comment: 44 pages, 11 figures, version accepted for publication in Ap

A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice

BACKGROUND: Parkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO) mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT) was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR) of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD) was absent in corticostriatal slices from old transgenic mice. CONCLUSIONS/SIGNIFICANCE: Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches

Results from the centers for disease control and prevention's predict the 2013-2014 Influenza Season Challenge

Background: Early insights into the timing of the start, peak, and intensity of the influenza season could be useful in planning influenza prevention and control activities. To encourage development and innovation in influenza forecasting, the Centers for Disease Control and Prevention (CDC) organized a challenge to predict the 2013-14 Unites States influenza season. Methods: Challenge contestants were asked to forecast the start, peak, and intensity of the 2013-2014 influenza season at the national level and at any or all Health and Human Services (HHS) region level(s). The challenge ran from December 1, 2013-March 27, 2014; contestants were required to submit 9 biweekly forecasts at the national level to be eligible. The selection of the winner was based on expert evaluation of the methodology used to make the prediction and the accuracy of the prediction as judged against the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet). Results: Nine teams submitted 13 forecasts for all required milestones. The first forecast was due on December 2, 2013; 3/13 forecasts received correctly predicted the start of the influenza season within one week, 1/13 predicted the peak within 1 week, 3/13 predicted the peak ILINet percentage within 1 %, and 4/13 predicted the season duration within 1 week. For the prediction due on December 19, 2013, the number of forecasts that correctly forecasted the peak week increased to 2/13, the peak percentage to 6/13, and the duration of the season to 6/13. As the season progressed, the forecasts became more stable and were closer to the season milestones. Conclusion: Forecasting has become technically feasible, but further efforts are needed to improve forecast accuracy so that policy makers can reliably use these predictions. CDC and challenge contestants plan to build upon the methods developed during this contest to improve the accuracy of influenza forecasts. © 2016 The Author(s)

Mitochondria and the Link Between Neuroinflammation and Neurodegeneration

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