Universitätspublikationen
Refine
Year of publication
Document Type
- Article (12971)
- Part of Periodical (3427)
- Doctoral Thesis (3167)
- Contribution to a Periodical (2075)
- Book (2051)
- Working Paper (1869)
- Preprint (1297)
- Review (1048)
- Report (910)
- Conference Proceeding (659)
Language
- English (16251)
- German (13540)
- Portuguese (231)
- Spanish (123)
- Italian (65)
- French (64)
- Multiple languages (57)
- Turkish (12)
- Ukrainian (10)
- slo (7)
Keywords
- Deutschland (132)
- COVID-19 (93)
- inflammation (91)
- Financial Institutions (90)
- ECB (67)
- Capital Markets Union (64)
- SARS-CoV-2 (63)
- Financial Markets (61)
- Adorno (58)
- Banking Union (50)
Institute
- Medizin (6245)
- Präsidium (4979)
- Physik (3058)
- Wirtschaftswissenschaften (2242)
- Gesellschaftswissenschaften (2009)
- Biowissenschaften (1675)
- Frankfurt Institute for Advanced Studies (FIAS) (1455)
- Biochemie und Chemie (1370)
- Sustainable Architecture for Finance in Europe (SAFE) (1369)
- Informatik (1350)
Mutations are the ultimate basis of evolution, yet their occurrence rate is known only for few species. We directly estimated the spontaneous mutation rate and the mutational spectrum in the nonbiting midge C. riparius with a new approach. Individuals from ten mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing parental genotypes. We identified 51 new single site mutations of which 25 were insertions or deletions and 26 single nucleotide mutations. This shift in the mutational spectrum compared to other organisms was explained by the high A/T content of the species. We estimated a haploid mutation rate of 2.1 × 10−9 (95% confidence interval: 1.4 × 10−9 – 3.1 × 10-9) that is in the range of recent estimates for other insects and supports the drift barrier hypothesis. We show that accurate mutation rate estimation from a high number of observed mutations is feasible with moderate effort even for nonmodel species.
The comprehensive assessment of pain-related human phenotypes requires combinations of nociceptive measures that produce complex high-dimensional data, posing challenges to bioinformatic analysis. In this study, we assessed established experimental models of heat hyperalgesia of the skin, consisting of local ultraviolet-B (UV-B) irradiation or capsaicin application, in 82 healthy subjects using a variety of noxious stimuli. We extended the original heat stimulation by applying cold and mechanical stimuli and assessing the hypersensitization effects with a clinically established quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain). This study provided a 246 × 10-sized data matrix (82 subjects assessed at baseline, following UV-B application, and following capsaicin application) with respect to 10 QST parameters, which we analyzed using machine-learning techniques. We observed statistically significant effects of the hypersensitization treatments in 9 different QST parameters. Supervised machine-learned analysis implemented as random forests followed by ABC analysis pointed to heat pain thresholds as the most relevantly affected QST parameter. However, decision tree analysis indicated that UV-B additionally modulated sensitivity to cold. Unsupervised machine-learning techniques, implemented as emergent self-organizing maps, hinted at subgroups responding to topical application of capsaicin. The distinction among subgroups was based on sensitivity to pressure pain, which could be attributed to sex differences, with women being more sensitive than men. Thus, while UV-B and capsaicin share a major component of heat pain sensitization, they differ in their effects on QST parameter patterns in healthy subjects, suggesting a lack of redundancy between these models.
The Gini index is a measure of the inequality of a distribution that can be derived from Lorenz curves. While commonly used in, e.g., economic research, it suffers from ambiguity via lack of Lorenz dominance preservation. Here, investigation of large sets of empirical distributions of incomes of the World’s countries over several years indicated firstly, that the Gini indices are centered on a value of 33.33% corresponding to the Gini index of the uniform distribution and secondly, that the Lorenz curves of these distributions are consistent with Lorenz curves of log-normal distributions. This can be employed to provide a Lorenz dominance preserving equivalent of the Gini index. Therefore, a modified measure based on log-normal approximation and standardization of Lorenz curves is proposed. The so-called UGini index provides a meaningful and intuitive standardization on the uniform distribution as this characterizes societies that provide equal chances. The novel UGini index preserves Lorenz dominance. Analysis of the probability density distributions of the UGini index of the World’s counties income data indicated multimodality in two independent data sets. Applying Bayesian statistics provided a data-based classification of the World’s countries’ income distributions. The UGini index can be re-transferred into the classical index to preserve comparability with previous research.
Ziel dieser Dissertation war es, die biologische Rolle der Autophagie für die Entwicklung, Alterung und mitochondriale Qualitätskontrolle in dem Ascomyceten Podospora anserina zu untersuchen. Folgende Ergebnisse wurden dabei erzielt:
1. Der Verlust einer funktionalen Autophagie-Maschinerie ist in P. anserina mit einem Defekt der Sporen-Entwicklung bzw. -Keimung charakterisiert.
2. Es konnten drei Methoden zur Untersuchung der Autophagie in P. anserina etabliert werden: 1) Die Verwendung eines Gfp::PaAtg8-Stamms ermöglicht die Fluoreszenzmikroskopische Bestimmung der Autophagosomen-Anzahl; 2) Die phänotypische Charakterisierung des PaAtg1-Deletionsstamms unter verschiedenen Stressbedingungen (z. B. Stickstoffmangel, Rapamycin) liefert Hinweise auf eine mögliche Autophagie-abhängige Stressadaption; 3) Die Verwendung des „GFPcleavage assays“ ermöglicht einen quantitativen Nachweis genereller und selektiver Autophagie (hier: Mitophagie).
3. In zwei voneinander unabhängigen Experimenten wurde ein altersabhängiger Anstieg der Autophagie für P. anserina demonstriert: Das Autophagie-Niveau nimmt in gealterten P. anserina-Kulturen zu. Gleichzeitig resultiert der Verlust der Autophagie in ∆PaAtg1 in eine reduzierte Lebensspanne. Unter Stressbedingungen (hier: Stickstoffmangel) wird dieser positive Einfluss der Autophagie auf die Lebensspanne im Wildtyp sogar noch verstärkt.
4. Der unerwartet „gesunde“ Phänotyp der PaSod3-Deletionsmutante ist abhängig von einer funktionalen Autophagie-Maschinerie. Der Mitophagie wurde eine besondere Rolle als Kompensationsmechanismus für den Verlust von PaSOD3 zugeteilt, da das Mitophagie-Niveau in dieser Mutante erhöht ist. Am Beispiel dieser Mutante, für die ein erhöhter Superoxid-Ausstoß nachgewiesen wurde, konnte eine Dosis-abhängige Wirkung von ROS in P. anserina identifiziert werden. Eine geringe zelluläre ROSMenge verursacht eine mitohormetische Reaktion, die eine Induktion der Mitophagie zur Folge hat und sich positiv auf den Organismus auswirkt. Übersteigt die zelluläre ROS-Dosis einen kritischen Punkt, kommt es zur Induktion des autophagischen Zelltods und damit zum vorzeitigen Tod des Individuums.
5. Der Verlust der PaCLPXP-Protease führt zu Beeinträchtigungen in der Funktion und Zusammensetzung der mitochondrialen Atmungskette. Dieses Defizit im Energiemetabolismus wird über eine Induktion der AOX, vor allem aber über eine ZUSAMMENFASSUNG 127 gesteigerte Autophagie kompensiert. Die deutlich verlängerte Lebensspanne der verschiedenen PaClpXP-Deletionsmutanten (∆PaClpX, ∆PaClpP und ∆PaClpXP) ist abhängig von einer funktionalen Autophagie-Maschinerie. Interessanterweise konnte keine kompensatorische Funktion der Autophagie oder Mitophagie für den Verlust der mitochondrialen i-AAA-Protease PaIAP in P. anserina nachgewiesen werden.
Autophagie/Mitophagie stellt einen übergeordneten Qualitätskontrollmechanismus in P. anserina dar, der den Organismus sehr effektiv vor zellulären Schäden und Dysfunktionen bewahrt und einen positiven Einfluss auf die Alterung, Entwicklung und Energieversorgung einnimmt.
Multicellular organisms require that cells adhere to each other. This cell-cell adhesion is indispensable for the formation and the integrity of epithelial structures, tissues and organs. Mammals have developed four different cell-cell adhesion structures, the adhering junctions, which ensure the tight contact between cells but are also important platforms for communication and exchange in tissues. Two of these adhering junctions are cadherin based, the belt-like adherens junctions and the spot-like desmosomes. Both structures have in common that they are composed of single membrane spanning proteins, the cadherins, which accomplish adhesion in a calcium-dependent manner. The intracellular parts of classical as well as desmosomal cadherins bind to different adaptor proteins of the armadillo-protein family and others which build a protein plaque underneath the membrane and link the cadherins to the actin or intermediate filament cytoskeleton.
Desmosomes are of special importance for tissues that have to withstand mechanical stress. Although they are essential to stabilize tissues they have to be highly flexible and dynamic structures, as processes like wound healing or tissue remodeling require that adhesive interactions can be modulated. The molecular dynamics within desmosomes are not jet understood in detail, but it is assumed that two different membrane associated pools of desmosomal cadherins exist in cells. Cadherins that are incorporated in mature desmosomes are part of the junctional pool, whereas cadherins that are not associated with firm desmosomes and the intermediate filament cytoskeleton belong to the non-junctional pool. Lateral movements between the two pools results in a dynamic equilibrium and allows for example the exchange of old cadherins. Little is known about the breakdown of desmosomal cadherins. Several studies found that desmosome assembly or endocytosis are cholesterol dependent processes and claimed that membrane microdomains play a role in the regulation of desmosome dynamics. Moreover, membrane rafts may be involved in the pathomechanism of the desmosome associated disease pemphigus, were autoantibodies bind to the cadherin desmoglein-3 and trigger its internalization which results in a loss of adhesion in skin cells.
Membrane rafts are cholesterol dependent nanoscale structures of cellular membranes that are able to regulate the distribution of proteins within the plasma membrane and thus form platforms for cell signaling and membrane trafficking. Flotillins are proteins that are associated with membrane rafts and are reported to be involved in processes like endocytosis, endosomal sorting and a multitude of different signaling events. We could recently show that the membrane raft associated proteins flotillin-1 and flotillin-2 bind directly to the armadillo protein y-catenin which can be part of both, the adherens junction and the desmosome. The aim of this study was to eluciadate a possible role of flotillins in the regulation of desmosomes.
HaCaT keratinocytes were chosen as the main cell system for this study and at first the association of desmosomal components with flotillins was analyzed in detail. It was found that flotillins are clearly associated with desmosomal proteins. They colocalize with desmoglein-3 at cell borders and precipitate the other desmogleins. Further binding assays revealed that both flotillins bind to all desmogleins and the long isoforms of the second class of desmosomal cadherins, the desmocollins. The interaction is a direct one and was mapped to the ICS sequence within the cadherins. This close association rendered the question whether flotillins are functionally implicated in desmosome regulation. To address this issue, stable flotillin knockdown HaCaT cells were analyzed in detail. The molecular morphology of desmoglein-3, desmoglein-1 and two plaque proteins was clearly altered in the absence of flotillins. The membrane staining of all tested desmosomal proteins was derailed and disordered. Furthermoore, the loss of flotillins had an impact on the adhesive capacity of HaCaT keratinocytes. The cell-cell adhesion was weakened in the absence of flotillins, which was monitored by an increased fragmentation of knockdown cells in a cell dissociation assay.
In order to find out the mechanism by which flotillins influence the membrane morphology and the adhesiveness in keratinocytes, the association of desmosomal proteins with membrane microdomains was examined, at first. A predominant part of desmoglein-3 is associated with membrane rafts in HaCaT keratinocytes, whereas only a minor part of desmoglein-1 is found there. However, the raft-association of none of the examined proteins was altered in the absence of flotillins. Furthermore, flotillin depletion did not change the distribution of desmogleins with the two different cadherin pools. Less desmoglein-3 is found in the junctional pool of the flotillin depleted cells compared to the control cells, but this is due to an overall diminished desmoglein-3 protein level in these cells.
Flotillins are involved in endocytic processes but their exact role there is under debate. The endocytic uptake of desmosomal cadherins requires intact membrane rafts, but the precise mechanism is still unknown. A possible involvement of flotillins on the endocytosis of desmoglein-3 was addressed next. It is known that the internalization of desmoglein-2 is dependent on the GTPase dynamin, arguing for an involvement of dynamin in the endocytosis of desmoglein-3 as well. When dynamin and thus desmoglein-3 endocytosis was inhibited using chemical compounds, the mislocalization of desmoglein-3 that was observed in flotillin knockdown cells was restored. This suggest that inhibition of desmoglein-3 endocytosis enhances the amount and/or availability of desmoglein-3 at the plasma membrane, which then normalizes the morphological alterations caused by a knockdown of flotillins. Furthermore the morphological alterations in the flotillin knockdown HaCaT cells were found to be similar to the localization of desmoglein-3 that was observed upon treatment of keratinocytes with PV IgG These structures have been described before as linear arrays and are assumed to be sites of endocytic uptake. This strengthens the idea that enhanced desmoglein-3 internalization takes place in the absence of flotillins, which then results in a weakened adhesion.
Altogether this study revealed flotillins as novel players in desmosome mediated cell-cell adhesion processes. By binding to desmosomal cadherins and desmosomal plaque proteins, flotillins stabilize desmosomes at the plasma membrane and are required for a proper cell-cell adhesion.
Tissue integrity is defined by the composition and connection of cells as a structural and functional unit. It is modulated by a magnitude of processes including differentiation, survival, controlled death and adhesion of cells. Besides, external factors such as physical forces are also involved. A suitable model system to study all modalities of tissue integrity is the mammary gland. Postnatally and within the reproductive phase, the mammary gland undergoes morphological and functional modifications that periodically loosen or strengthen tissue integrity. An important point in the development of the mammary gland is the regression during weaning, also termed involution. The transition from lactation to involution is important for a controlled loss of tissue integrity. In this transition, collective cell death is initiated but not yet prominent enabling the mammary gland to fully recover lactation.
In this thesis, modalities of tissue integrity were investigated using three-dimensional cell cultures (i.e. spheroids) and the mammary gland as model systems. In the context of this thesis, I established (1) an immunofluorescence staining protocol and its detailed evaluation. Furthermore, I studied (2) the role of cell survival during mammary gland development, (3) the effect of physical forces that modulate tissue integrity and (4) the contribution of proteins to cell adhesion and growth.
Since a homogeneous fluorescence stain of the specimen is necessary for quantitative analysis, an immunofluorescence staining protocol was established to stain large spheroids in toto. The evaluation contributes qualitative and quantitative criteria that judge the specificity, intensity and homogeneity of the stain. Based on this approach, it was possible to demonstrate the morphological and functional characteristics that spheroids share with the mammary gland in vivo. These characteristics included the synthesis of extracellular matrix, the development of polarized acinar structures and lactogenic differentiation.
The role of cell survival during mammary gland development was analyzed by means of the expression profile of the pro-survival protein BAG3. The expression of BAG3 differed in the progress of mammary gland development. While the expression was low during pregnancy, it rose in the lactation phase and peaked within the first days of involution, indicating that BAG3 is associated with early involution in the mammary gland. In vitro experiments related the expression of BAG3 to cell survival in mammary epithelial cells.
Physical forces naturally occur during developmental processes influence tissue integrity during the initiation of mammary gland involution. The influence of physical force applied as compression on mammary epithelial spheroids was investigated. A morphological analysis showed that following a lag, the cell nuclei volume changed upon compression. A short-term compression induced the activation of caspases. A prolonged compression reduced the activity of caspases. This suggests the induction of a process that allows cells the adaption to changing environmental conditions. BAG3 is known to be involved in mechanical stress-induced autophagy, also known as chaperone assisted selective autophagy (CASA). Compression of spheroids did not induce CASA. The experimentally applied strain was not comparable to the strain found in the alveolar cells during involution in vivo. Thus, whether or not CASA is activated during mammary gland involution remains elusive. Nevertheless, the methodical approach to apply compression on spheroids in vitro is a model to study the influence of physical forces on cell aggregates.
Apart from cell survival and physical forces, growth and adhesion of cells affect tissue integrity. A spheroid formation assay and subsequent data analysis and computational modeling enabled the investigation of these processes in a non-adhesive environment. The analysis suggested that spheroid formation follows a reaction-controlled process, in which cells do not necessarily form a connection when they collide. The loss of function of either E-cadherin or actin strongly inhibited the formation of a spheroid. The analysis further revealed that neither E-cadherin nor actin influence the chance of the cells to form a connection when they collide. Both molecules are more important in stabilizing established connections. Depolymerization of microtubules still allowed spheroids to form, but the formation was decelerated and growth of the final spheroids was inhibited. The results from computational modeling suggested that microtubules act on cell adhesion through different mechanisms, which also vary among different cell types. The inhibition of FAK phosphorylation at Y397, a downstream target of integrin signaling, and the analysis of FAK protein levels in spheroids showed that integrin-mediated signaling is not prominent in three-dimensional spheroids formed from non-invasive cells. A deletion of BAG3 gene expression increased the number of dead cells in forming spheroids suggesting that BAG3 predominantly affects cell survival.
The results of this thesis identified and characterized adhesion- and survival-associated proteins that are important for tissue integrity. This thesis suggests that a BAG3-dependent cell survival mechanism is prominent at the beginning of mammary gland involution. Future studies will have to identify the related factors and inducers of tissue integrity loss in the mammary gland. This will shed light on the physiology of the organ and could explain the disorders that destroy its integrity. In addition, this thesis contributes to a better understanding of spontaneous cell aggregation, the aggregate organization and implies a role of cell migration in these processes. Future studies that focus on three-dimensional cell migration could explain, how cell migration is promoted and to which extent it supports tissue integrity.
The Capital Markets Union-project of the European Commission aims for an increase of marketbased debt financing of small and medium-sized enterprises (SMEs), complementing bank lending. In this essay we argue that rather than focussing on pure non-bank lending, a reasonable mix of bankand market-based financing should be considered. Banks are said to have a comparative advantage in critical lending functions such as credit screening, debtor monitoring and debt renegotiation. All forms of lending require a persistent skin-in-the-game of critical players in order to be effective. The regulator should insist on full disclosure of skin-in-the-game, thereby improving capital allocation and reducing systemic risks.
Die Mittelalterabteilung des Liebieghauses unter der Leitung von Stefan Roller, stellt seit dem 6. Dezember seine neueste, spektakuläre Erwerbung vor. Das spätgotische (um 1470/75), noch original polychrom gefasste Christuskind wurde schon 2011 bei der Ausstellung "Niclaus Gerhaert. Der Bildhauer des Mittelalters" im Liebieghaus gezeigt und stammt aus Privatbesitz. ...