Functional analysis of the threonine motif in the β1 integrin cytoplasmic tail in mice

Integrins are ubiquitously expressed adhesion receptors with important functions in cellular adhesion, proliferation, migration and signaling. These functions are determined by integrin trafficking through endosomal compartments and receptor affinity regulation. In this thesis, we identified the distal NxxY motif of the β1 integrin cytoplasmic tail as a molecular switch modulating a spatiotemporally controlled binding of two FERM-domain proteins in different cellular compartments. Kindlins mediate integrin activation at the plasma membrane and they dislodge upon internalization. In the endosomal compartment, the free cytoplasmic domain is subsequently bound by sorting nexin 17 (SNX17) to inhibit integrin degradation. We identified SNX17 as a new β1 integrin adaptor protein, which uses the kindlin-binding site in endosomal compartments to stabilize integrins and to promote their recycling back to the plasma membrane.Integrine sind ubiquitär exprimierte Adhäsionsmoleküle mit entscheidender Bedeutung für die zelluläre Adhäsion, Wachstum, Migration und Signalgebung. Diese Funktionen werden durch konstantes Integrintrafficking durch endosomale Kompartimente sowie durch Modulation der Rezeptoraffinität kontrolliert. Im Rahmen der vorliegenden Dissertation wurde das distale NxxY-Motiv im zytoplasmatischen β1 Integrinschwanz als molekularer Schalter identifiziert, der die Bindung zweier FERM-Domänen-Proteine in unterschiedlichen zellulären Kompartimenten vermittelt. Während Kindline an der Zellmembran die Integrinaktivität regulieren, dislozieren sie nach der Internalisierung und Sorting Nexin 17 (SNX17) wird an den nun freien β1 Integrinschwanz rekrutiert, um die Integrindegradation zu hemmen. Wir haben SNX17 als neuen β1 Integrin-Bindungspartner identifiziert, der die Kindlin-Bindungsstelle im endosomalen Kompartiment verwendet, um Integrine zu stabilisieren und ihr Recycling zurück an die Zelloberfläche zu fördern

Comparable Analysis of Acute Changes in Vascular Tone after Coffee versus Energy Drink Consumption

Caffeinated beverages are popular throughout the world, especially due to their stimulating effects on body physiology. However, short- and long-term outcome studies have shown variable results on general health. In this pilot study, we exposed a cohort of 23 healthy individuals to 240 mg of caffeine either in the form of coffee or energy drinks and performed repetitive pulse wave analyses. This experimental approach was chosen to investigate the acute effects of caffeine consumption on vascular tone depending on the form of caffeine intake. Our data indicate that energy drinks, in contrast to coffee, might negatively impact systolic blood pressure and pulse wave velocity. This issue needs special attention in the light of cardiovascular health as the observed effects have been associated with an increased risk of cardiovascular events upon persistent exposure

Yolk sac macrophage progenitors traffic to the embryo during defined stages of development

Raw data, figure 5f, 6b, 6

Berichterstatter:

analysis of the threonine motif in the β

Synthesis, DNA-binding and antiproliferative properties of diarylquinolizinium derivatives

A series of ten 2,7- and 2,8-diarylquinolizinium derivatives was synthesized and their DNA-binding and cytotoxic properties were investigated. Except for one nitro-substituted derivative all tested diarylquinolizinium ions bind to DNA with sufficient affinity (2 7 104 M-1-2 7 105 M-1). It was shown with photometric, fluorimetric and polarimetric titrations as well as with flow-LD analysis that the ligands bind mainly by intercalation to duplex DNA, however, depending on the ligand-DNA ratio, groove binding and backbone association were also observed with some derivatives. The biological activity was further investigated with tests of cytotoxicity and antiproliferative properties towards non-tumor cells and selected cancer cells, along with cell cycle analysis and an annexin-V assay. Notably, substrates that carry donor-functionalities in the 4-position of the phenyl substituents revealed a strong, and in some cases selective, antiproliferative activity as quantified by the growth inhibition, GI50, at very low micromolar and even submicromolar level both in leukemia and solid tumors

Treatment of acute cardiac tamponade: A retrospective analysis of classical intermittent versus continuous pericardial drainage

Background Acute cardiac tamponade is a life-threatening pathology in modern cardiology as catheter-based interventions become increasingly relevant. Pericardiocentesis is usually the primary treatment of choice. However, protocols for handling of draining pigtail catheters are very variable due to limit data and require further investigation. Methods We retrospectively analyzed 52 patients with acute cardiac tamponade requiring immediate pericardiocentesis from January 2017 to August 2020. Patients were treated with a classical approach of intermittent manual aspiration or continuous pericardial drainage using a redon drainage system. Results Mean age of patients was 74 years in both groups. Most common causes for cardiac tamponade were percutaneous coronary interventions in about 50% and transaortic valve implantations in 25% of all cases. 28 patients were treated with classic intermittent drainage from 2017 to 2020. 24 patients were treated with continuous drainage from December 2018-2020. Compared to classical intermittent drainage treatment, continuous drainage was associated with a lower rate of a surgical intervention or cardiac re-tamponade and a lower mortality at 5 days (HR 0.2, 95% CI 0.1-0.9, log-rank p = 0.03). Despite a longer total drainage time under continuous suction, drainage volumes were comparable in both groups. Conclusion Acute cardiac tamponade can be efficiently treated by pericardiocentesis with subsequent continuous negative pressure drainage via a pigtail catheter. Our retrospective analysis shows a significantly lower mortality, a decreased rate of interventions and lower rates of cardiac re-tamponade without any relevant side effects when compared to classical intermittent manual drainage. These findings require further investigations in larger, randomized trials

Regiospecific Photocyclization of Mono- and Bis-Styryl-Substituted N‑Heterocycles: A Synthesis of DNA-Binding Benzo[<i>c</i>]quinolizinium Derivatives

Regiospecific C–N photocyclization of mono<i>-</i> and bis-styryl-substituted N-heterocycles was investigated. We demonstrated that the C–N regiospecificity of the photoinduced electrocyclization is a general feature of <i>ortho-</i>styryl-substituted N-heterocycles comprising one and two nitrogen atoms. This phototransformation provides a straightforward synthesis of the pharmaceutically important benzo­[<i>c</i>]­quinolizinium cation and its aza-analogues. Noticeably, bis-styryl derivatives undergo only one-fold cyclization with the second styryl fragment remaining uninvolved in the cyclization process. Photocyclization products of monostyryl derivativatives intercalate into calf thymus DNA (ct DNA), whereas photocyclization products of bis-styryl derivativatives possess a mixed binding mechanism with ct DNA. The results can be used for development of novel DNA-targeting chemotherapeutics based on benzo­[<i>c</i>]­quinolizinium derivatives