45 research outputs found
Funktionelle SelektivitÀt und Vermittlung des myogenen Tonus am Angiotensin II Typ-1-Rezeptor in der perfundierten Mausniere
Hintergrund: Die Angiotensin II-Typ-1-Rezeptoren (AT1R) sind 7-Transmembran- und G-Protein-gekoppelte Rezeptoren, die mechanisch aktiviert werden können. Der native Agonist Angiotensin II (Ang II) stimuliert sowohl den klassischen G-Protein-abhĂ€ngigen als auch den alternativen ÎČ-Arrestin-2-vermittelten Weg, wĂ€hrend der funktionell selektive Agonist Sar, Ile-Angiotensin II (S II) nur den alternativen Weg aktiviert. Diese funktionelle SelektivitĂ€t verspricht vorteilhafte therapeutische Effekte bei kleinem Nebenwirkungsspektrum gegenĂŒber dem konventionellen Rezeptoragonismus. Der myogene Tonus ist die angeborene, autoregulatorische FĂ€higkeit kleiner Arterien â insbesondere der Arteriolen â sich bei steigendem Perfusionsdruck zu kontrahieren oder bei sinkendem Perfusionsdruck zu erweitern, um die Organperfusion konstant zu halten, ohne dass das autonome Nervensystem aktiviert wird.
Fragestellung: In dieser Studie wurde anhand verschiedener muriner Tiermodelle die Hypothesen untersucht, ob 1) der Angiotensin II Typ-1a-Rezeptor der vorherrschende Rezeptorsubtyp bei der Regulation des myogenen GefĂ€Ătonus ist und ob 2) der myogene Tonus ĂŒber den klassischen Gq/11-Protein-gekoppelten und/oder den alternativen ÎČ-Arrestin vermittelten Signalweg vermittelt wird.
Methoden: Agtr1a+/+, Agtr1a-/- und Tamoxifen-induzierbare glatte Muskelzell-spezifische Einzel- oder Doppel-Knockout-MĂ€use (SMMHCâAgtr1a-/- x Agtr1b-/-) wurden fĂŒr die isolierte Nierenperfusion verwendet, um Unterschiede des Perfusionsdrucks in den jeweiligen Gruppen zu messen und diese in Relation zu setzen. Um eine Beteiligung der untersuchten Signaltransduktionswege beurteilen zu können, wurden Substanzen wie der native Agonist Ang II, der funktionell selektive Agonisten S II und der Gαq/11-Inhibitor FR900359 verwendet.
Ergebnisse: Die myogene und Ang II-abhĂ€ngige Vasokonstriktion waren unauffĂ€llig in der perfundierten Niere von Agtr1b-/- MĂ€usen, jedoch vermindert in perfundierten Nieren von Agtr1a-/- MĂ€usen. Der selektive Gαq/11-Inhibitor verringerte den myogenen Tonus und die Ang II-abhĂ€ngige Vasokonstriktion, wĂ€hrend der ÎČ-Arrestin-abhĂ€ngige Ligand S II keinerlei Wirkung auf den Perfusionsdruck zeigte.
Schlussfolgerung: Mechanisch aktivierte AT1aR vermitteln die myogene Auto-regulation in perfundierten Nierenarterien ĂŒber kanonische Gq/11-Signalwege.Background: The AT1 receptors are seven-transmembrane- and well described
mechano-activated G-Protein-coupled receptors. The balanced agonist Angiotensin
II (Ang II) stimulates both the classical G-protein-dependent pathway and the
alternative ÎČ-arrestin-2 pathway, whereas the biased agonist Sar, Ile-Angiotensin II (S
II) only activates the alternative pathway. This selective activation promises beneficial
therapeutic effects, with a small spectrum of side effects, compared to conventional
agonism. The myogenic tone is an inherent, auto-regulatory ability of small arteries â
especially of the arterioles â to contract in response to increasing perfusion pressure
or to dilate in response to decreasing perfusion pressure to maintain constant organ
perfusion without activating the autonomic nervous system.
Question: This study used various murine animal models to investigate the
hypotheses of 1) whether the Angiotensin II type 1a receptor is the predominant
receptor subtype in the regulation of myogenic vascular tone and 2) whether myogenic
tone is elicited via the classical Gq/11-protein-coupled and/or the alternative ÎČ-arrestin mediated signalling pathway.
Methods: Agtr1a+/+, Agtr1a-/-and tamoxifen-inducible smooth muscle cell-specific
single or double knockout mice (SMMHCâAgtr1a-/- x Agtr1b-/-
) were used for the
perfusion of isolated kidneys to measure differences in perfusion pressure in the
respective groups and to relate them to each other. In order to assess the involvement
of the signal transduction pathways studied, we used compounds such as the native
agonist angiotensin II, the functionally selective agonist Sar, Ile- Ang II and the Gαq/11
inhibitor FR900359.
Results: Myogenic and Ang II-dependent vasoconstriction was normal in perfused
kidneys of Agtr1b-/-mice but fell in Agtr1a-/-mice. The Gαq/11 blocker reduced myogenic
tone and Ang II-dependent vasoconstriction, whereas the ÎČ-arrestin-biased agonist S
II had no effect.
Conclusion: Mechano-activated AT1aR mediate myogenic autoregulation in perfused
renal arteries via canonical Gq/11 signalling pathways
Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy
Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. Immune checkpoint inhibitors have limited efficacy in tumors with lower mutational burden and non-permissive microenvironment. Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment
Making sense of big data in health research: Towards an EU action plan.
Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans
Public Painting - Malerei und Handlung
Das Magazin "Public Painting â Malerei und Handlung" versammelt kĂŒnstlerischen Projekte, die auf unterschiedliche Weise VerhĂ€ltnisse von Malerei zum öffentlichen Raum reflektieren, und VerhĂ€ltnisse thematisieren, die im öffentlichen Raum ausagiert werden. Die BeitrĂ€ge entstanden als Resultat der Kooperation des kunstwissenschaftlichen Seminars "Malerei als Handlung" von Anne Röhl und des kunstpraktischen Seminars "public painting" von Sebastian Freytag wĂ€hrend des Sommersemesters 2021 an der UniversitĂ€t Siegen. Unter dem Titel "public painting" wurden Schnittstellen von malerischer Praxis und öffentlichen Raum diskutiert. Die Studierenden des Seminars "Malerei als Handlung" haben sich wiederum damit beschĂ€ftigt, wie die Gattung Malerei im Verlauf des 20. Jahrhunderts durch die Abkehr von traditionellen Entstehungsprozessen und Malhandlungen befragt wurde und skulptural und/oder performativ wird. Daneben widmeten sich die Studierenden des kunsthistorischen Seminars der schriftlichen Auseinandersetzung mit den kĂŒnstlerischen Resultaten des kunstpraktischen Seminars. Die Auseinandersetzung mit dem öffentlichen Raum stellte im Sommersemester 2021 eine besondere Herausforderung dar, da er pandemiebedingt nur eingeschrĂ€nkt nutzbar war. Die kĂŒnstlerischen Ergebnisse dokumentieren somit auch diese Zeit
The United States COVID-19 Forecast Hub dataset
Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages
A multimodal cell census and atlas of the mammalian primary motor cortex
ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties
Photodynamic Therapy for Choroidal Neovascularization Associated With Submacular Hemorrhage in Age-Related Macular Degeneration
Siegener BeitrÀge zur Geschichte und Philosophie der Mathematik 2013
Die Siegener BeitrĂ€ge bieten ein Forum fĂŒr den Diskurs im Bereich von Philosophie und Geschichte der Mathematik. Dabei stehen die folgenden inhaltlichen Aspekte im Zentrum:
1. Philosophie und Geschichte der Mathematik sollen einander wechselseitig
fruchtbar irritieren: Ohne Bezug auf die real existierende Mathematik und
ihre Geschichte lÀuft das philosophische Fragen nach der Mathematik leer,
ohne Bezug auf die systematische Reflexion ĂŒber Mathematik wird ein BemĂŒhen
um die Mathematikgeschichte blind.
2. Geschichte ermöglicht ein Kontingenzbewusstsein, philosophische Reflexion
fordert Kontextualisierungen heraus. Damit stellen sich u. a. Fragen nach der
Rolle der Mathematik fĂŒr die Wissenschaftsgeschichte, aber auch nach einer
gesellschaftlichen Rolle der Mathematik und deren historischer Bedingtheit.
3. Ein spezieller Aspekt betrifft das (schulische) Lehren und Lernen von Mathematik und deren Wandel im historischen Verlauf; der reichhaltigen Zeitschriftenlandschaft im Bereich der mathematischen Fachdidaktik soll allerdings keine Konkurrenz gemacht werden.Inhaltsverzeichnis:
Gregor Nickel: WidersprĂŒche und Unendlichkeit â Beobachtungen bei Nikolaus von Kues und Georg Cantor
Ingo Witzke: Die Reihendarstellung der Exponentialfunktion â zu Eulers Umgang mit unendlichen GröĂen
Anna-Sophie Heinemann: KalkĂŒl der Logik und Logische Maschine: George Boole und William Stanley Jevons
Matthias Wille: Zwischen Algebra und Erlanger Schule. Paul Lorenzens BeitrÀge zur Beweistheorie
Philipp Karschuck: Die Implementierung der EDV in der Kernforschungsanlage JĂŒlich und das Projekt âSupercomputingâ
Ralf Krömer & David Corfield: The duality of space and function, and category-theoretic dualitie