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Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer’s disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.
Wir konnten unseren eigenen Weg gehen, jeder von uns hatte am Ende ein anderes Ergebnis und es war keines falsch. Das macht für mich die Qualität beim Lernen aus, dass mir genug Platz für meine Gedanken gegeben wird und ich ernst genommen werde. […] Dieses Gefühl ist bis heute nicht verloren gegangen und der Gedanke, wie es sein könnte, hilft mir, aus mir raus zukommen und andere zu motivieren, das ebenfalls zu tun, um auch um mich herum anregende Gespräche zu führen, die an die während der Akademie geführten heranreichen. (Feedback einer Teilnehmerin der HSAKA-M 2018)
Bildung durch Wissenschaft im Sinne des Forschenden Lernens ist ein zentrales Thema schulischer Bildung und findet beispielsweise im Konzept Kultur.Forscher! eine didaktische, schulische Umsetzung und wird vom Wissenschaftsrat als Leitgedanke ebenfalls für Universitäten mit dem Ziel empfohlen, Studium und Lehre deutlicher an der Forschung auszurichten.
Dieser Beitrag befasst sich mit der Entwicklung von Wissen und Praktiken der Dada-Bewegung im Hinblick auf die 8. Dada-Soirée in Zürich am 9. April 1919. Innerhalb der Dada-Gruppe sticht insbesondere die Figur von Walter Serner hervor, der mit anderen als VertreterInnen der Dada-Bewegung mit zentralen Themen dieser Avantgarde auftritt, wie zum Beispiel: der Ablehnung der Autorschaft, der Vermischung von Kunst und Leben, mit Spiel oder Nihilismus als Reaktion auf den Krieg oder dem propagandistischen Element.
The title compound, C4H9N5O2+·SO42−·H2O, is the monohydrate of the commercially available compound `C4H7N5O·H2SO4·xH2O'. It is obtained by reprecipitation of C4H7N5O·H2SO4·xH2O from dilute sodium hydroxide solution with dilute sulfuric acid. The crystal structure of anhydrous 2,4,5-triamino-1,6-dihydropyrimidin-6-one sulfate is known, although called by the authors 5-amminium-6-amino-isocytosinium sulfate [Bieri et al. (1993[Bieri, J. H., Prewo, R. & Linden, A. (1993). Private communication (refcode HACDEU). CCDC, Cambridge, England]). Private communication (refcode HACDEU). CCDC, Cambridge, England]. In the structure, the sulfate group is deprotonated, whereas one of the amino groups is protonated (R2C—NH3+) and one is rearranged to a protonated imine group (R2C=NH2+). This arrangement is very similar to the known crystal structure of the anhydrate. Several tautomeric forms of the investigated molecule are possible, which leads to questionable proton attributions. The measured data allowed the location of all hydrogen atoms from the residual electron density. In the crystal, ions and water molecules are linked into a three-dimensional network by N—H⋯O and O—H⋯O hydrogen bonds.
The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that peripheral antiinflammatory mechanisms contribute to antinociception. In this study, we investigated the impact of AICAR on the immune cell composition in inflamed paws, as well as the regulation of inflammatory and resolving markers in macrophages. By using fluorescence-activated cell sorting (FACS) analysis and immunofluorescence, we found a significantly increased fraction of proresolving M2 macrophages and anti-inflammatory interleukin (IL)-10 in inflamed tissue, while M1 macrophages and proinflammatory cytokines such as IL-1 were decreased by AICAR in wild type mice. In AMPKα2 knock-out mice, the M2 polarization of macrophages in the paw was missing. The results were supported by experiments in primary macrophage cultures which also showed a shift to a proresolving phenotype with decreased levels of proinflammatory mediators and increased levels of antiinflammatory mediators. However, in the cell cultures, we did not observe differences between the AMPKα2+/+ and −/− cells, thus indicating that the AICAR-induced effects are at least partially AMPK-independent. In summary, our results indicate that AICAR has potent antiinflammatory and proresolving properties in inflammation which are contributing to a reduction of inflammatory edema and antinociception.
48Si: An atypical nucleus?
(2019)
Using the relativistic Hartree–Fock Lagrangian PKA1, we investigate the properties of the exotic nucleus 48Si, which is predicted to be an atypical nucleus characterized by i) the onset of doubly magicity, ii) its location at the drip line, iii) the presence of dual semi-bubble structure (distinct central depletion in both of neutron and proton density profiles) in the ground state, and iv) the occurrence of pairing reentrance at finite temperature. While not being new for each, these phenomena are found to simultaneously occur in 48Si. For instance, the dual semi-bubble structure reduces the spin–orbit splitting of low-ℓ orbitals and upraises the s orbitals, leading therefore to distinct N=34 and Z=14 magic shells in 48Si. Consequently, the doubly magicities provide extra stability for such extreme neutron-rich system at the drip line. Associating with the neutron shell N=34 and continuum above, the pairing correlations are reengaged interestingly at finite temperature. Theoretical nuclear modelings are known to be poorly predictive in general, and we asset our confidence in the prediction of our modeling on the fact that the predictions of PKA1 in various regions of the nuclear chart have systematically been found correct and more specifically in the region of pf shell. Whether our predictions are confirmed or not, 48Si provides a concrete benchmark for the understanding of the nature of nuclear force.
Die Tagung bot eine breite Themenvielfalt in insgesamt neun parallel verlaufenden Sektionen. Zwei davon waren praxisorientierten Fragestellungen gewidmet, in drei anderen wurden wiederum Projekte der Aussteller präsentiert und vier weitere Sektionen beschäftigten sich mit folgenden fachlichen Blickwinkeln: "Europäische Literatur im Zusammenhang der Sprach- und Kulturvermittlung", "Unterrichtsinteraktion und Zweitspracherwerb Deutsch", "Niederschwellige Deutschangebote im A1-/A2-Bereich" und Zielgruppenspezifik" und "Evaluatives Feedback und Qualitätsentwicklung".
Patient therapy is based mainly on a combination of diagnosis, suitable monitoring or support devices and drug treatment and is usually employed for a pre-existing disease condition. Therapy remains predominantly symptom-based, although it is increasingly clear that individual treatment is possible and beneficial. However, reasonable precision medicine can only be realized with the coordinated use of diagnostics, devices and drugs in combination with extensive databases (4Ds), an approach that has not yet found sufficient implementation. The practical combination of 4Ds in health care is progressing, but several obstacles still hamper their extended use in precision medicine.
An improved value for the lifetime of the (anti-)hypertriton has been obtained using the data sample of Pb-Pb collisions at sNN−−−√= 5.02 TeV collected by the ALICE experiment at the LHC. The (anti-)hypertriton has been reconstructed via its charged two-body mesonic decay channel and the lifetime has been determined from an exponential fit to the dN/d(ct) spectrum. The measured value, τ = 242+34−38 (stat.) ± 17 (syst.) ps, is compatible with all the available theoretical predictions, thus contributing to the solution of the longstanding hypertriton lifetime puzzle.
An improved value for the lifetime of the (anti-)hypertriton has been obtained using the data sample of Pb-Pb collisions at sNN−−−√= 5.02 TeV collected by the ALICE experiment at the LHC. The (anti-)hypertriton has been reconstructed via its charged two-body mesonic decay channel and the lifetime has been determined from an exponential fit to the dN/d(ct) spectrum. The measured value, τ = 242+34−38 (stat.) ± 17 (syst.) ps, is compatible with all the available theoretical predictions, thus contributing to the solution of the longstanding hypertriton lifetime puzzle.
Aims: The examination of histological sections is still the gold standard in diagnostic pathology. Important histopathological diagnostic criteria are nuclear shapes and chromatin distribution as well as nucleus-cytoplasm relation and immunohistochemical properties of surface and intracellular proteins. The aim of this investigation was to evaluate the benefits and drawbacks of three-dimensional imaging of CD30+ cells in classical Hodgkin Lymphoma (cHL) in comparison to CD30+ lymphoid cells in reactive lymphoid tissues.
Materials and results: Using immunoflourescence confocal microscopy and computer-based analysis, we compared CD30+ neoplastic cells in Nodular Sclerosis cHL (NScCHL), Mixed Cellularity cHL (MCcHL), with reactive CD30+ cells in Adenoids (AD) and Lymphadenitis (LAD). We confirmed that the percentage of CD30+ cell volume can be calculated. The amount in lymphadenitis was approx. 1.5%, in adenoids around 2%, in MCcHL up to 4,5% whereas the values for NScHL rose to more than 8% of the total cell cytoplasm. In addition, CD30+ tumour cells (HRS-cells) in cHL had larger volumes, and more protrusions compared to CD30+ reactive cells. Furthermore, the formation of large cell networks turned out to be a typical characteristic of NScHL.
Conclusion: In contrast to 2D histology, 3D laser scanning offers a visualisation of complete cells, their network interaction and spatial distribution in the tissue. The possibility to differentiate cells in regards to volume, surface, shape, and cluster formation enables a new view on further diagnostic and biological questions. 3D includes an increased amount of information as a basis of bioinformatical calculations.
Holographic imaging techniques, which exploit the coherence properties of light, enable the reconstruction of the 3D scenery being viewed. While the standard approaches for the recording of holographic images require the superposition of scattered light with a reference field, heterodyne detection techniques enable direct measurement of the amplitude and relative phase of the electric light field. Here, we explore heterodyne Fourier imaging and its capabilities using active illumination with continuous-wave radiation at 300 GHz and a raster-scanned antenna-coupled field-effect transistor (TeraFET) for phase-sensitive detection. We demonstrate that the numerical reconstruction of the scenery provides access to depth resolution together with the capability to numerically refocus the image and the capability to detect an object obscured by another object in the beam path. In addition, the digital refocusing capability allows us to employ Fourier imaging also in the case of small lens-object distances (virtual imaging regime), thus allowing high spatial frequencies to pass through the lens, which results in enhanced lateral resolution.
Am 16. April 1994 fanden sich 18 Personen in einem Tagungsraum des Bielefelder Mövenpick-Hotels zusammen, um eine literarische Gesellschaft neuartigen Typs zu gründen: das Forum Vormärz Forschung. Neuartig insofern, als diese Vereinigung nicht zu dem Zweck gegründet wurde, einer Autorin/ einem Autor die Ehre zu erweisen, ihr/sein Andenken zu pflegen und ihrem/ seinem Werk neue LeserInnen zuzuführen, sondern um eine ganze Epoche zum Gegenstand ihrer vielfältigen Bemühungen zu machen und zwar möglichst interdisziplinär: den Vormärz. Für die LiteraturwissenschaftlerInnen, HistorikerInnen, TheologInnen, Kunst- und MusikwissenschaftlerInnen, die sich hier zusammenfanden, galt und gilt es als ausgemacht, dass Vormärz die einzig sachgerechte Bezeichnung für den Zeitraum zwischen 1815 (Wiener Kongress) und 1849 (Ende der Revolution von 1848/49) ist und eben nicht die konkurrierenden Epochenbezeichnungen Biedermeier oder Restaurationszeit. [...]
Gleich zwei Anlässe bestehen für unser Gespräch mit dem Politikwissenschaftler Prof. Dr. Lothar Brock (Jg. 1939) über die „Kunst, Kriege zu beenden“: ein weltordnungspolitischer Anlass mit dem 100-jährigen Jahrestag des Beginns der Pariser Friedenskonferenz – und ein biografischer Anlass unseres Gesprächspartners. Am 30. Januar 2019 feierte Lothar Brock, der an der Goethe-Universität zunächst seit 1992 als Professor und seit 2004 als Senior-Professor lehrt, seinen 80. Geburtstag. Überlegungen zu Krieg und Frieden in Geschichte und Gegenwart.
Kaum ein Name ist so eng mit dem "Projekt HSAKA" verbunden wie der von Wolf Aßmus: Seit der ersten Hessischen Schülerakademie für die Oberstufe im Jahre 2004 ist er als Leiter des Physik-Kurses dabei; die Gründung der Mittelstufenakademie 2011 wurde von ihm tatkräftig unterstützt und gefördert; einen Sitz im Kuratorium hat er ebenso übernommen wie das Amt des Ersten Vorsitzenden des Trägervereins von Burg Fürsteneck – der inzwischen pensionierte Professor für Festkörperphysik verkörpert geradezu die Idee vom "Un-Ruhestand". Wer mag es ihm da verübeln, wenn Wolf beschließt, im nächsten Sommer mal mehr Zeit mit seinen Enkeln zu verbringen, statt auf die Burg zu fahren? Weil es daher 2020 zum ersten Mal eine Oberstufenakademie ohne Wolf und ohne Physik-Kurs geben wird (stattdessen Philosophie und Informatik), haben wir auf der vergangenen Akademie die Gelegenheit genutzt, Wolf für 15 Jahre Schülerakademie zu danken. Genauer gesagt: für 15 Jahre, 16 Fachkurse in Physik (15 auf der Oberstufenakademie und einer bei der Mittelstufe), 15 kursübergreifende Naturkunde-Angebote, für die Betreuung Dutzender Studierender und weit über 200 Schüler*innen, für unzählige gemeinsame Aha-Erlebnisse und humorvolle Geschichten, für unermüdliches Engagement und geduldigen Beistand – und nicht zuletzt für viele, viele Liter Speiseeis. Unsere Dankbarkeit wollen wir hier mit allen Leser*innen dieser Dokumentation teilen.
Introduction: Epoxyeicosatrienoic acids (EETs) are able to enhance angiogenesis and regulate inflammation that is especially important in wound healing under ischemic conditions. Thus, we evaluated the effect of local EET application on ischemic wounds in mice.
Methods: Ischemia was induced by cautherization of two of the three supplying vessels to the mouse ear. Wounding was performed on the ear three days later. Wounds were treated either with 11,12 or 14,15 EET and compared to untreated control and normal wounds. Epithelialization was measured every second day. VEGF, TNF-α, TGF-β, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP), Ki67, and SDF-1α were evaluated immunohistochemically in wounds on day 3, 6, and 9.
Results: Ischemia delayed wound closure (12.8 days ± 1.9 standard deviation (SD) for ischemia and 8.0 days ± 0.94 SD for control). 11,12 and14,15 EET application ameliorated deteriorated wound healing on ischemic ears (7.6 ± 1.3 SD for 11,12 EET and 9.2 ± 1.4 SD for 14,15 EET). Ischemia did not change VEGF, TNF-α, TGF-β, SDF-1α, TIMP, MMP7 or MMP9 level significantly compared to control. Local application of 11,12 as well as 14,15 EET induced a significant elevation of VEGF, TGF-β, and SDF-1α expression as well as proliferation during the whole phase of wound healing compared to control and ischemia alone.
Conclusion: In summary, EET improve impaired wound healing caused by ischemia as they enhance neovascularization and alter inflammatory response in wounds. Thus elevating lipid mediator level as 11,12 and 14,15 EET in wounds might be a successful strategy for amelioration of deranged wound healing under ischemia.