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Natural Killer (NK) cells act as the front line of the body´s defense in the immune system and they are key players in efficiently recognizing and eliminating virus-infected and tumor cells. Individual NK cells can eliminate multiple target cells in a sequential manner during a process named serial killing. There are two major pathways NK cells use to induce apoptosis in their target cells: By releasing the content of cytotoxic granules containing the serine protease granzyme B (GrzB) and the...
Most metallo-supramolecular assemblies of low nuclearity adopt simple topologies, with bridging ligands spanning neighboring metal centers in a direct fashion. Here we contribute a new structural motif to the family of host compounds with low metal count (two) that consists of a pair of doubly-interlocked, figure-eight-shaped subunits, also termed “lemniscates”. Each metal is chelated by two chiral bidentate ligands, composed of a peptidic macrocycle that resembles a natural product with two ...
Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of liver diseases and is the leading cause of liver diseases worldwide. Features of the metabolic syndrome and extrahepatic diseases, like cardiovascular diseases and kidney stone disease, strongly associate with NAFLD. A previously identified steatosis-associated downregulation of the alanine-glyoxylate aminotransferase (AGXT) was suggested to be one molecular link explaining the connection of NAFLD with the development of c...
Ten-eleven-translocation (TET) dioxygenases catalyze the oxidation of 5-methylcytosine (5mC), the central epigenetic regulator of mammalian DNA. This activity dynamically reshapes the epigenome and transcriptome by depositing oxidized 5mC derivatives and initiating active DNA demethylation. However, studying this dynamic is hampered by the inability to selectively activate individual TETs with temporal control in cells. We report activation of TETs in mammalian cells by incorporation of genet...
Biomolecular condensates consisting of proteins and nucleic acids can serve critical biological functions—so much so that some condensates are referred as membrane‐less organelles. They can also be disease‐causing if their assembly is misregulated. A major physico‐chemical basis of the formation of biomolecular condensates is liquid‐liquid phase separation (LLPS). In general, LLPS depends on environmental variables such as temperature and hydrostatic pressure. We investigated the effects of p...
Two new heterobimetallic cages, atrigonal-bipyr-amidal and acubic one, were assembled from the same mononuclear metalloligand by adopting the molecular library approach,using iron(II) and palladium(II) building blocks. The ligand system was designed to readily assemble through subcomponent self-assembly. It allowed the introduction of steric strain at the iron(II) centres, which stabilizes its para-magnetic high-spin state.This steric strain was utilized to drive dynamic complex-to-complex tr...
An acridone-based, interpenetrated double cage [3BF4Pd4L8] acts as a photosensitizer for generating singlet oxygen which adds to 1,3-cyclohexadiene in a [2+4] hetero-Diels-Alder reaction to form 2,3-dioxabicyclo[2.2.2]oct-5-ene. Photocatalytic activity was exclusively observed for the assembled cage, whereas the free organic ligand L decomposes upon irradiation. While cage [3BF4Pd4L8] does not accept any organic guests, NMR, MS and single crystal X-ray results reveal that both substrate and p...
Die nachhaltige Gestaltung chemischer Prozesse vom Labor- bis zum Industriemaßstab unter Beachtung der Aspekte der Grünen Chemie ist ein Kernbestandteil moderner Syntheseplanung. Hierzu zählen neben der Katalyse an sich auch die Atomökonomie, Katalysatorrückgewinnung, Vermeidung von Abfallprodukten, die Verwendung günstiger und umweltfreundlicher Ausgangsstoffe und Lösungsmittel sowie Arbeitssicherheit. Um diese Punkte miteinander zu verbinden, wurden im Rahmen der vorliegenden Dissertation K...
In all organisms, the genetic information of cells is stored in the nucleotide sequence of deoxyribonucleic acid (DNA). The human organism consists of more than 200 different somatic cell types with the same genetic information (genotype). Even though, they drastically differ in their morphology and function (phenotype), which is related to different gene expression levels. Gene expression is controlled by macromolecular interactions and epigenetic modifications on chromatin that are highly l...
Every cell in the human body contains the exact same genetic information in their nucleus but despite this cell function, structure and content can differs significantly. The reason for this is found in the epigenetic information, a complex code of chemical modification on the chromatin proteins and DNA which determines cellular identity. This code recently grew in complexity with the discovery of lysine acylation on histone proteins. Lysine acylation is related to lysine acetylation and...
Die Proteinkinase B (auch: Akt) spielt eine essenzielle Rolle in einer Vielzahl zellulärer Signaltransduktionskaskaden, welche grundlegende Prozesse wie Proliferation, Überleben und Apoptose regulieren. Eine Fehlregulation von Akt ist mit diversen kardiovaskulären, neurodegenerativen sowie onkologischen Krankheitsbildern assoziiert. Häufig sind genetische Läsionen in den vorgeschalteten Proteinen wie PI3K und PTEN ursächlich für derartige Erkrankungen, aber auch Alterationen in membranständig...
Überdosierungen an APAP führen zu hepatotoxischen Auswirkungen in der Leber von Säugetieren. Die Hepatotoxizität ist u.a. eine Folge der metabolischen Aktivierung des Acetaminophens durch CYP. Dabei treten pericentrale Schadensmuster in den Leberläppchen auf. Es fehlten bisher Informationen über die räumlich-zeitliche Verteilung vom APAP und seinen Biotransformationsprodukten in der Leber bis zur Veröffentlichung von Teilen dieser vorliegenden Arbeit. Um die Fragestellung zu beantworten, wurd...
We report programmable receptors for the imaging‐based analysis of 5‐methylcytosine (5mC) in user‐defined DNA sequences of single cells. Using fluorescent transcription‐activator‐like effectors (TALEs) that can recognize sequences of canonical and epigenetic nucleobases through selective repeats, we imaged cellular SATIII DNA, the origin of nuclear stress bodies (nSB). We achieve high nucleobase selectivity of natural repeats in imaging and demonstrate universal nucleobase binding by an engin...
Liquid-liquid phase separation (LLPS) phenomena have contributed immensely to the field of cell biophysics and cell biology in providing rational answers to the process of formation of membraneless organelles. These membraneless organelles play a vital role in understanding the origin of life in terms of cellular compartmentalisation. An increasing number of proteins and protein-nucleic acid mixtures has been shown to undergo LLPS at high concentrations forming two liquid phases - a protein-r...
Cytoskeletal networks, the filamentous systems in the cytoplasm of cells, are giving the cell its shape and supporting the mechanical structure of the cell, as well as organizing the cytoplasmic organelles in the cell. The cytoskeleton microtubules are reorganizing and maintaining the global morphology of the cell. This is the result of the signals that regulate microtubule filaments. The geometry of the membrane also affects these signaling pathways, which leads to the recursive interaction ...
Die Identifikation von EGFR-Mutationen in Exon19 und Exon21 als prädiktive Biomarker, die mit einer erhöhten Sensitivität gegenüber EGFR-Inhibitoren der ersten Generation assoziiert werden konnten, leitete einen Paradigmenwechsel in der Behandlung von NSCLC-Patienten ein.[1-2] In entsprechenden Studien konnte retrospektiv gezeigt werden, dass lediglich Tumore auf die Behandlung mit Gefitinib ansprachen, wenn eine somatische EGFR-Mutation vorlag und im Umkehrschluss Patienten ohne die entsprec...
Im ersten Teil dieser Arbeit wurden die Einflüsse von Y3+Ionen auf die Struktur sowie das Phasenverhalten und spezifische thermodynamische Parameter von Modellmembransystemen verschiedener Komplexität und Ladung untersucht. Es konnte gezeigt werden, dass die Anwesenheit dieser Ionen zu einer dichteren Lipidpackung und partieller Dehydratation der Kopfgruppenregion, sowie zu einem ausgeprägten Anstieg der Gel-zu-flüssig Phasenübergangstemperatur der Lipidmembranen führt. Dies ist auf einen ges...
Interactions between proteins and ligands, which are fundamental to many biochemical processes essential to life, are mostly studied at dilute buffer conditions. The effects of the highly crowded nature of biological cells and the effects of liquid-liquid phase separation inducing biomolecular droplet formation as a means of membrane-less compartmentalization have been largely neglected in protein binding studies. We investigated the binding of a small ligand (ANS) to one of the most multifun...
The title compound, C22H22O2S2, 1, represents an example of an ortho-vanillin-based functionalized dithioether, which could be useful as a potential chelating ligand or bridging ligand for coordination chemistry. This dithioacetal 1 crystallizes in the orthorhombic space group Pbca. The phenyl rings of the benzyl groups and that of the vanillin unit form dihedral angles of 35.38 (6) and 79.77 (6)°, respectively. The crystal structure, recorded at 100 K, displays both weak intramolecula...
The crystal structure of the title compound, C10H13N·3H2O, a heterocyclic amine, was determined in the presence of water. The compound co-crystallizes with three water molecules in the asymmetric unit, which leads to the formation of hydrogen bonding in the crystal.