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Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Die Interaktionen von DNA mit Umwelt, die Kopplungen zwischen biologischen Prozessen und mentaler Erfahrung, deren mögliche Vererbbarkeit sowie das Aufzeigen der potentiellen Reversibilität von "krankhaften" Entwicklungen innerhalb solcher Wechselspiele bilden Faszinationen, die jenseits der molekularbiologischen Labore das öffentliche Interesse entzündet haben. Diese Faszinationen sollen hier im Mittelpunkt stehen. Denn fast unvermeidlich verfallen die Forschungsbefunde einem Deutungsanspruch auf Humankultur, auf einen Bereich, der zunächst einmal jenseits der konkreten Forschung liegt und weit über diesen hinaus zeigt. Die folgende Mischung aus Glosse und Essay zur epigenetischen Weltbildproduktion – höher kann der Anspruch angesichts einer unabgeschlossenen, derzeit noch emergierenden Publizistik nicht sein – hat mehrere Teile. Die beiden ersten sind dem Auftritt der Epigenetik in der Öffentlichkeit gewidmet: Zuerst in einer impressionistischen Bestandsaufnahme der diesbezüglichen Publizistik, danach, um einen prominenten Bildbereich festzuhalten, wie er sich in der öffentlichen Diskussion der Epigenetik sedimentiert hat. Die darauf folgenden Teile widmen sich dem Emporkommen einer molekularen Vergemeinschaftungsrhetorik. Abschließend soll kurz die soteriologische Hoffnung erörtert werden, mit welcher der epigenetischen Forschung zumindest in ausgewählten theologischen Diskursen begegnet wird.
Die in der Neuzeit so auf Universalität abzielende Neubewertung der Geste erscheint in komprimierter Form in den Schriften des Londoner Arztes John Bulwer, der in vielerlei Hinsicht weniger einen radikalen Neuansatz als eine Synthese zeitgenössischer psychophysiologischer Gebärdentheorien vorlegt. Seine Erstschrift Chirologia: or the Naturall Language of the Hand, Composed of the Speaking Motions, and Discoursing Gestures thereof (1644), veröffentlicht im Kontext einer in England zur Mitte des 17. Jahrhunderts bereits blühenden Suche nach einer universalen Sprache, offenbart noch die Nähe zur Rhetorik und der ihr inbegriffenen Affektlehre als Deutungsmuster der Gebärde; und in der Tat ist, wenngleich unter separater Paginierung, diesem Buch ein zweites Buch zur Chironomia angefügt, welches sich explizit mit der Geste als rhetorischem Mittel befasst. Zuvor nimmt Bulwers Chirologia allerdings Anregungen Ciceros, Quintilians und vor allem Giovanni Bonifacios auf und verabsolutiert die Geste selbst zum Universal: "It speakes all languages, and as an universall character of Reason, is generally understood and knowne by all Nations, among all formal differences of their Tongue."
Zu Karl dem Kühnen gibt es sowohl einen Berner Bezug als auch einen Malte-Bezug. Der Schweizer oder Berner Bezug ist, daß der "Fall" Karls des Kühnen, sein "Untergang", wie es in den "Aufzeichnungen des Malte Laurids Brigge" heißt, entscheidend
vorbereitet wurde durch zwei Schlachten, die er gegen die Eidgenossen verloren hatte, bei Grandson und Murten, nicht weit von Bern, beide 1476. Im "Malte Laurids Brigge" spielen diese Schlachten zwar keine Rolle (auch die Schlacht
bei Nancy, von Anfang Januar 1477, die den Fall und den Tod Karls brachte, interessiert nur in ihren Folgen), es wird aber mit den "Hörnern von Uri" auf diese Ereignisse und deren zentrale Bedeutung angespielt. Der zweite Schweizer oder
Berner Bezug sind die Teile der Burgunder Beute, die mit dem Lager der Feinde bei Grandson in die Hände der Sieger gefallen waren und die zum Teil im Historischen Museum in Bern aufbewahrt werden.
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
The cell division cycle protein 37 (Cdc37) and the 90-kDa heat shock protein (Hsp90) are molecular chaperones, which are crucial elements in the protein signaling pathway. The largest class of client proteins for Cdc37 and Hsp90 are protein kinases. The catalytic domains of these kinases are stabilized by Cdc37, and their proper folding and functioning is dependent on Hsp90. Here, we present the x-ray crystal structure of the 16-kDa middle domain of human Cdc37 at 1.88 angstroms resolution and the structure of this domain in complex with the 23-kDa N-terminal domain of human Hsp90 based on heteronuclear solution state NMR data and docking. Our results demonstrate that the middle domain of Cdc37 exists as a monomer. NMR and mutagenesis experiments reveal Leu-205 in Cdc37 as a key residue enabling complex formation. These findings can be very useful in the development of small molecule inhibitors against cancer.
Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.
Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.
Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.
Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.