9 research outputs found
Identification of a neurovascular signaling pathway regulating seizures in mice
ObjectiveA growing body of evidence suggests that increased bloodâbrain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.MethodsAn experimental model of kainateâinduced seizures was used in genetically modified mice, including mice deficient in tPA (tPAâ/â), its inhibitor neuroserpin (Nspâ/â), or both (Nsp:tPAâ/â), and in mice conditionally deficient in the plateletâderived growth factor receptor alpha (PDGFRα).ResultsCompared to wildâtype (WT) mice, Nspâ/â mice have significantly reduced latency to seizure onset and generalization; whereas tPAâ/â mice have the opposite phenotype, as do Nsp:tPAâ/â mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizureâresistant tPAâ/â mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPAâ/â, and Nspâ/â mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes.InterpretationTogether, these data identify a specific molecular pathway involving tPAâmediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112290/1/acn3209.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/112290/2/acn3209-sup-0001-TableS1.pd
XFEL serial crystallography reveals the room temperature structure of methyl-coenzyme M reductase
Methyl-Coenzyme M Reductase (MCR) catalyzes the biosynthesis of methane in methanogenic archaea, using a catalytic Ni-centered Cofactor F430 in its active site. It also catalyzes the reverse reaction, that is, the anaerobic activation and oxidation, including the cleavage of the CH bond in methane. Because methanogenesis is the major source of methane on earth, understanding the reaction mechanism of this enzyme can have massive implications in global energy balances. While recent publications have proposed a radical-based catalytic mechanism as well as novel sulfonate-based binding modes of MCR for its native substrates, the structure of the active state of MCR, as well as a complete characterization of the reaction, remain elusive. Previous attempts to structurally characterize the active MCR-Ni(I) state have been unsuccessful due to oxidation of the redox- sensitive catalytic Ni center. Further, while many cryo structures of the inactive Ni(II)-enzyme in various substrates-bound forms have been published, no room temperature structures have been reported, and the structure and mechanism of MCR under physiologically relevant conditions is not known. In this study, we report the first room temperature structure of the MCRred1-silent Ni(II) form using an X-ray Free-Electron Laser (XFEL), with simultaneous X-ray Emission Spectroscopy (XES) and X-ray Diffraction (XRD) data collection. In celebration of the seminal contributions of inorganic chemist Dick Holm to our understanding of nickel-based catalysis, we are honored to announce our findings in this special issue dedicated to this remarkable pioneer of bioinorganic chemistry
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XFEL serial crystallography reveals the room temperature structure of methyl-coenzyme M reductase.
Methyl-Coenzyme M Reductase (MCR) catalyzes the biosynthesis of methane in methanogenic archaea, using a catalytic Ni-centered Cofactor F430 in its active site. It also catalyzes the reverse reaction, that is, the anaerobic activation and oxidation, including the cleavage of the CH bond in methane. Because methanogenesis is the major source of methane on earth, understanding the reaction mechanism of this enzyme can have massive implications in global energy balances. While recent publications have proposed a radical-based catalytic mechanism as well as novel sulfonate-based binding modes of MCR for its native substrates, the structure of the active state of MCR, as well as a complete characterization of the reaction, remain elusive. Previous attempts to structurally characterize the active MCR-Ni(I) state have been unsuccessful due to oxidation of the redox- sensitive catalytic Ni center. Further, while many cryo structures of the inactive Ni(II)-enzyme in various substrates-bound forms have been published, no room temperature structures have been reported, and the structure and mechanism of MCR under physiologically relevant conditions is not known. In this study, we report the first room temperature structure of the MCRred1-silent Ni(II) form using an X-ray Free-Electron Laser (XFEL), with simultaneous X-ray Emission Spectroscopy (XES) and X-ray Diffraction (XRD) data collection. In celebration of the seminal contributions of inorganic chemist Dick Holm to our understanding of nickel-based catalysis, we are honored to announce our findings in this special issue dedicated to this remarkable pioneer of bioinorganic chemistry
Klassenspezifische Wahlabstinenz - Spielt das Vertrauen in politische Institutionen eine Rolle?
Hadjar A, Köthemann D. Klassenspezifische Wahlabstinenz - Spielt das Vertrauen in politische Institutionen eine Rolle? KZfSS Kölner Zeitschrift fĂŒr Soziologie und Sozialpsychologie. 2014;66(1):51-76
Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies
Flare frequency distributions represent a key approach to addressing one of
the largest problems in solar and stellar physics: determining the mechanism
that counter-intuitively heats coronae to temperatures that are orders of
magnitude hotter than the corresponding photospheres. It is widely accepted
that the magnetic field is responsible for the heating, but there are two
competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To
date, neither can be directly observed. Nanoflares are, by definition,
extremely small, but their aggregate energy release could represent a
substantial heating mechanism, presuming they are sufficiently abundant. One
way to test this presumption is via the flare frequency distribution, which
describes how often flares of various energies occur. If the slope of the power
law fitting the flare frequency distribution is above a critical threshold,
as established in prior literature, then there should be a
sufficient abundance of nanoflares to explain coronal heating. We performed
600 case studies of solar flares, made possible by an unprecedented number
of data analysts via three semesters of an undergraduate physics laboratory
course. This allowed us to include two crucial, but nontrivial, analysis
methods: pre-flare baseline subtraction and computation of the flare energy,
which requires determining flare start and stop times. We aggregated the
results of these analyses into a statistical study to determine that . This is below the critical threshold, suggesting that Alfv\'en
waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The
Astrophysical Journal on 2023-05-09, volume 948, page 7