Refine
Year of publication
- 2019 (3305) (remove)
Document Type
- Article (1597)
- Part of Periodical (400)
- Book (265)
- Doctoral Thesis (211)
- Contribution to a Periodical (195)
- Part of a Book (182)
- Preprint (163)
- Review (141)
- Working Paper (96)
- Conference Proceeding (35)
Language
- English (1828)
- German (1314)
- Portuguese (67)
- French (31)
- Multiple languages (23)
- Turkish (16)
- Spanish (15)
- Italian (5)
- Ukrainian (4)
- mis (2)
Is part of the Bibliography
- no (3305) (remove)
Keywords
- Literatur (69)
- Deutsch (61)
- taxonomy (60)
- Experiment (47)
- Sprache (33)
- new species (32)
- Literarisches Experiment (30)
- Deutsch als Fremdsprache (27)
- Geschichte (25)
- Digitalisierung (23)
Institute
- Medizin (574)
- Präsidium (346)
- Physik (291)
- Frankfurt Institute for Advanced Studies (FIAS) (189)
- Informatik (159)
- Wirtschaftswissenschaften (144)
- Biowissenschaften (117)
- Sustainable Architecture for Finance in Europe (SAFE) (106)
- Gesellschaftswissenschaften (104)
- Neuere Philologien (90)
ATP-binding cassette (ABC) transporters constitute an omnipresent superfamily of integral membrane proteins, which catalyze the translocation of a multitude of chemically diverse substrates across biological membranes. In humans, ABC transporters typically act as highly promiscuous exporters, responsible for many physiological processes, multi-drug resistance, and severe diseases, such as hypercholesterolemia, lipid trafficking disorders, and immune deficiency. In all ABC transporters, ATP-driven movements within two highly conserved nucleotide-binding domains (NBDs) are coupled to conformational changes of two transmembrane domains (TMDs), which provide a framework for substrate binding and release on the opposite side of the membrane and enable the transporter to cycle between inward-facing and outward-facing orientations. Several structures of ABC transporters determined either by X-ray crystallography or single-particle electron cryo-microscopy (cryo-EM) have been reported, mostly exhibiting a variation of the inward-facing state, which highlights their dynamic behavior. However, for a complete understanding of the conformational dynamics, further structural information on intermediates is needed – especially for heterodimeric ABC transporters, which are predominant in humans and for which only limited structural information is available.
One prime example of such human heterodimeric ABC transport complexes is the transporter associated with antigen processing (TAP). TAP is a key player of the adaptive immune response, because it translocates proteasomal degradation products into the ER lumen for loading of MHC I molecules. Many functional aspects of TAP have been disclosed in recent years. However, structural information is lacking far behind and a major challenge in the field of medical relevant transporters. Recently, the heterodimeric ABC export system TmrAB (Thermus thermophilus multidrug resistance proteins A and B) was identified as an ortholog of TAP, by sharing structural homology with TAP and, intriguingly, being able to restore antigen presentation in human TAP-deficient cells. Thus, TmrAB is a biochemically well-characterized ABC exporter that can be regarded as a functional ortholog of TAP and serves as a model system for (heterodimeric) ABC export systems in general.
Thus, to illuminate the molecular basis of substrate translocation by single-particle cryo-EM, one of the main objectives of this work was the generation of stabilizing chaperones (synthetic antibodies, nanobodies, cyclic peptides) to reduce the conformational heterogeneity of TAP and TmrAB. Selected antibodies were analyzed with respect to stable complex formation, conformational trapping, and the ability to serve as alignment tools for structural studies by single-particle cryo-EM. Both antibody types were shown to form sufficiently stable complexes to serve as a rigid body for EM analyses. However, all selected antibodies bound to the inward-facing state exclusively.
Hence, for EM studies, various ligands were added to elucidate the full spectrum of conformational states during the catalytic cycle. For TAP, first attempts by negative-stain EM revealed a homogenous distribution of particles on the grid. Surprisingly, no transporter-like features were observed although various attempts were applied to increase the overall sample quality.
For TmrAB, in contrast, the complete conformational space in a native-like lipid environment under turnover conditions was mapped. Cryo-EM analysis of TmrAB incubated with ATP-Mg2+ and substrate revealed two distinct inward-facing conformations (IFwide and IFnarrow) as well as two asymmetric conformations with dimerized NBDs, which were markedly different from all previously reported structures. Here, the catalytically active site was slightly wider and contained ADP, while ATP was still bound at the catalytically-inactive site within the NBDs, demonstrating an asymmetric post-hydrolysis state. Intriguingly for the inward-facing conformations, a weak additional density close to residues M139TmrB and W297TmrB was observed in the inward-facing conformation, which displayed a higher degree of cytosolic gate opening (IFwide) indicating the presence of substrate. To verify that this density corresponds to substrate, single alanine mutations of M139TmrB and W297TmrB were introduced, leading to a strong reduction in substrate binding and transport. Since substrate release requires the opening of the extracellular gate, the absence of an outward-facing open conformation indicated that the opening must be highly transient. In order to explore the outward-facing open conformation, a cryo-EM analysis of the catalytically-inactive TmrAE523QB mutant upon incubation with ATP-Mg2+ was performed. Remarkably, within the same dataset, two different outward-facing conformations (occluded and open) were resolved, both in an ATP-bound state, which indicated that binding of ATP is sufficient to drive the large-scale conformational transition from inward-facing to outward-facing open. To explore the effect of nucleotide hydrolysis, TmrAB was trapped by vanadate. Again, two populations were observed, representing the outward-facing open and outward-facing occluded conformation.
Based on several structures of key intermediates, determined under turnover conditions or trapped in the pre-hydrolysis and hydrolysis transition state, for the first time the complete description of the ATP hydrolysis and translocation cycle of a heterodimeric ABC transport complex was elucidated in one single study. By mapping the conformational landscape during active turnover, aided by mutational and chemical modulation of kinetic rates, fundamental and so-far hidden steps of the substrate translocation cycle of asymmetric ABC transporters were resolved and a general template for (heterodimeric) ABC exporter-catalyzed substrate translocation was provided.
We discuss the diffusion currents occurring in a dilute system and show that the charge currents do not only depend on gradients in the corresponding charge density, but also on the other conserved charges in the system—the diffusion currents are therefore coupled. Gradients in one charge thus generate dissipative currents in a different charge. In this approach, we model the Navier-Stokes term of the generated currents to consist of a diffusion coefficient matrix, in which the diagonal entries are the usual diffusion coefficients and the off-diagonal entries correspond to the coupling of different diffusion currents. We evaluate the complete diffusion matrix for a specific hadron gas and for a simplified quark-gluon gas, including baryon, electric and strangeness charge. Our findings are that the off-diagonal entries can range within the same magnitude as the diagonal ones.
Proteostasis stressors that destabilize the cellular proteome, like heat shock, trigger transcription and translational reactions leading to the accumulation of heat shock proteins, also called molecular chaperones. During stress, induction of stress response genes is prioritized so that molecular chaperones and other stress response proteins are synthesized to cope with proteome misfolding and aggregation. In order to promote the selective translation of stress-specific genes, translation of others genes that are nonessential for cell survival has to stop. Nonessential protein-coding mRNAs accumulate in the cytosol with the associated proteins to form granular structures called stress granules (SG). These membrane-less organelles are thought to be involved in cell survival, mRNA stabilization and mRNA triage. They were proposed to form via the liquid-liquid phase separation which can be triggered by the high local concentration of RNA-binding proteins. mRNAs were long thought to simply play a scaffolding role by bringing RNA-binding proteins together and allowing their concentration and local aggregation. Recently, the active role of mRNAs in the SG assembly became apparent, too. For example, the spontaneous assembly of total yeast RNA into granules was observed, and these RNA granules showed a large overlap with SG transcriptome. Furthermore, cytosolic mRNAs can be released from polyribosomes under stress and be exposed to the cytosolic contents as free mRNAs. It has been suggested that this massive increase of free mRNA in the cytosol might overload the capacities of RNA-stabilizing proteins. The remaining free mRNA molecules would then become exposed to misfolded and aggregation-prone proteins and trigger granulation.
We investigated the role of free mRNAs in different stress conditions during the early and chronic phases of stress response and explored their involvement in SGs assembly and amlyoidogenesis. We identified and studied the interactome of a free mRNA probe incubated with heat shocked cell lysate by means of quantitative mass spectrometry. Proteomics analysis allowed us to identify 79 interactors of free mRNA. Among these interactors, we focused on the translation initiation factor eIF2α and on the RNA methyltransferase TRMT6/61A. Both interactions were verified biochemically, which confirmed that the association is enhanced in heat shocked lysate. In vitro reconstitution showed that free mRNA and TRMT6 interact directly. Ex vivo pulldowns revealed that eIF2α and TRMT6/61A interact under stress conditions and that this interaction is RNA-dependent.
TRMT6/61A is a tRNA methytransferase responsible for the methylation of the adenosine 58 at the position 1 producing m1A. However, also mRNAs have been recently found to be methylated by TRMT6/61A. Our bioinformatics analyses revealed that significantly more mRNAs enriched in SG contain the motif for methylation than SG-depleted mRNAs. We hypothesized that m1A methylation of mRNAs could constitute a tag for the mRNAs targeting to SGs. TRMT61A knock-down (KD) cell lines were generated using the CRISPR-Cas9 technique. In TRMT61A KD cells, m1A was significantly reduced on mRNAs, which correlated with an increased sensitivity of the cells to proteostasis stress. KD cells also showed defects in SG assembly. In heat shocked cells, an m1A motif-containing mRNA recovered better after returning to normal temperature than a control mRNA with mutated motif. In addition, we could isolate SGs and analyze their m1A and m6A content by mass spectrometry. While m6A content in SG mRNAs was very similar to cytosolic mRNAs, m1A was almost 8 times enriched in SGs. Thus, we could confirm experimentally the results of the bioinformatics analysis and directly support the hypothesis that m1A is a tag to direct mRNAs for sequestration. Finally, we compared amyloidogenesis in wild-type and TRMT61A KD cell lines. Cells with reduced levels of TRMT61A demonstrated an increased accumulation of transfected Aβ and an impaired aggregate clearance. Various assays led us to conclude that the lack of m1A deposition on mRNAs enhanced RNA co-aggregation with amyloids.
Based on our results, we propose a model explaining the fate of free mRNA during proteostasis stress. Upon polysome disassembly, free mRNA is released and becomes free to interact with other proteins, including the methyltransferase TRMT6/61A. TRMT6/61A methylates the freed mRNAs containing the cognate motif. The m1A tag then targets mRNAs to SGs promoting sequestration. Upon stress release, SGs disassemble, thus releasing rescued mRNAs which could now reenter translation and support cell recovery. On the other hand, non-sequestered mRNAs increasingly co-aggregate with aggregating proteins. Thus, deficiency of the N1-adenine methylation of mRNAs due to the lack of TRMT6/61A increases the amount of unpacked mRNAs. The deposition of m1A on mRNAs could then be a way to protect them during exposure to stress, to limit their co-aggregation with misfolded proteins and to allow a faster recovery upon stress release.
Enolase is a glycolytic enzyme, which catalyzes the inter-conversion of 2-phosphoglycerate to phosphoenolpyruvate. Altered expression of this enzyme is frequently observed in cancer and accounts for the Warburg effect, an adaptive response of tumor cells to hypoxia. In addition to its catalytic function, ENO-1 exhibits other activities, which strongly depend on its cellular and extracellular localization. For example, the association of ENO-1 with mitochondria membrane was found to be important for the stability of the mitochondrial membrane, and ENO-1 sequestration on the cell surface was crucial for plasmin-mediated pericellular proteolysis. The latter activity of ENO-1 enables many pathogens but also immune and cancer cells to invade the tissue, leading further to infection, inflammation or metastasis formation. The ability of ENO-1 to conduct so many diverse processes is reflected by its contribution to a high number of pathologies, including type 2 diabetes, cardiovascular hypertrophy, fungal and bacterial infections, cancer, systemic lupus erythematosus, hepatic fibrosis, Alzheimer’s disease, rheumatoid arthritis, and systemic sclerosis. These unexpected non-catalytic functions of ENO-1 and their contributions to diseases are the subjects of this review.
This article unpacks Margarete Susman’s political and theological arguments at the core of her reading of the Book of Job. As I show through a reading of her oeuvre, Susman rejects political projects that she takes to be based on eschatology such as political Zionism. However, Susman should not be viewed merely as a critic of Zionism. I argue that an analysis tuned to the historical circumstances of her writing should recognize her stance on the nation-building project in Palestine as ambivalent rather than antagonistic. Susman’s conception of the Jewish spirit as rooted in self-sacrifice allows her to appreciate the national aspirations at the core of the Zionist project while rejecting Zionism’s exclusion of other Jewish national projects. I contend that Susman’s understanding of Jewish messianism as immanent rather than teleological informs her ambivalence toward Zionism as well as her original vision of Jewish political action. I argue in closing that Susman’s theodicy offers a novel vision for Jewish ethics that is not limited to the historical moment of its formulation. Susman’s theodicy also resonates within contemporary debates on Jewish diaspora in providing a non-centralized vision of Jewish national projects.
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans.
Implications of money-back guarantees for individual retirement accounts: protection then and now
(2019)
In the wake of the financial crisis and continued volatility in international capital markets, there is growing interest in mechanisms that can protect people against retirement account volatility. This paper explores the consequences for savers’ wellbeing of implementing market-based retirement account guarantees, using a life cycle consumption and portfolio choice model where investors have access to stocks, bonds, and tax-qualified retirement accounts. We evaluate the case of German Riester plans adopted in 2002, an individual retirement account produce that includes embedded mandatory money-back guarantees. These guarantees influenced participant consumption, saving, and investment behavior in the higher interest rate environment of that era, and they have even larger impacts in a low-return world such as the present. Importantly, we conclude that abandoning these guarantees could enhance old-age consumption for over 80% of retirees, particularly lower earners, without harming consumption during the accumulation phase. Our results are of general interest for other countries implementing default investment options in individual retirement accounts, such as the U.S. 401(k) defined contribution plans and the Pan European Pension Product (PEPP) recently launched by the European Parliament.
Welch ein Auftakt! Mit drei Büchern auf einmal präsentiert der Augsburger Rechtshistoriker Phillip Hellwege sein großes Forschungsfeld, die Geschichte des Versicherungsrechts, der Öffentlichkeit. Zwei Sammelbände und eine Monografie, im Sommer 2018 fast gleichzeitig erschienen, werden dem Projekt die gebührende Aufmerksamkeit sichern. Die Forschungsmittel entstammen dem "Horizon 2020"-Programm des European Research Council (ERC), von dem Hellwege einen "Consolidator Grant" erhalten hat. Mit diesen Mitteln finanziert er sein Vorhaben "Comparative History of Insurance Law in Europe" – kurz: CHILE. ...
Seit vielen Jahren beschäftigt sich Sheilagh Ogilvie, kanadische Wirtschaftshistorikerin an der Universität Cambridge und Mitglied der British Academy, mit Gilden und Zünften und ihrer wirtschaftlichen Bedeutung. Sie begann einst mit den württembergischen "Engelsaitwebern" (wohl von "English satin" – Hersteller wertvoller Tuche) in Calw und Wildberg im Nordschwarzwald im 17. Jahrhundert und hat seitdem den Fokus zeitlich wie räumlich immer weiter geöffnet. 2011 erschien ihr Buch über die Kaufmannsgilden ("Institutions and European Trade. Merchant Guilds 1000–1800"), und nun folgt unter der gleichen Leitfrage das Pendant auf der Ebene der Handwerkerzünfte: Haben Gilden und Zünfte zum Wirtschaftswachstum beigetragen? Ihre Antwort ist negativ. Von einem wirtschaftsliberalen Standpunkt aus charakterisiert Ogilvie die Zusammenschlüsse der Kaufleute und Handwerker als am Gemeinwohl kaum interessierte Vereinigungen, denen es vor allem um die Sicherung der Vorteile ihrer Mitglieder zum Nachteil der Konkurrenz, der Kunden und des technischen Fortschritts ging und die dazu hohe Eingangsbarrieren errichteten, nach besten Kräften mit den Regierungen der Länder und Städte kollaborierten und die Märkte manipulierten, indem sie die Lieferketten kontrollierten und die Preise hochhielten. ...
1H-detected solid-state NMR experiments feasible at fast magic-angle spinning (MAS) frequencies allow accessing 1H chemical shifts of proteins in solids, which enables their interpretation in terms of secondary structure. Here we present 1H and 13C-detected NMR spectra of the RNA polymerase subunit Rpo7 in complex with unlabeled Rpo4 and use the 13C, 15N, and 1H chemical-shift values deduced from them to study the secondary structure of the protein in comparison to a known crystal structure. We applied the automated resonance assignment approach FLYA including 1H-detected solid-state NMR spectra and show its success in comparison to manual spectral assignment. Our results show that reasonably reliable secondary-structure information can be obtained from 1H secondary chemical shifts (SCS) alone by using the sum of 1Hα and 1HN SCS rather than by TALOS. The confidence, especially at the boundaries of the observed secondary structure elements, is found to increase when evaluating 13C chemical shifts, here either by using TALOS or in terms of 13C SCS.
Alle 18 Beiträge des Sammelbandes entstammen einem internationalen Kolloquium am Deutschen Historischen Institut in London aus dem Jahr 2014, das Aspekten der Rechtsgeschichte allein des Dominikanerordens gewidmet war. So reiht es sich in eine Tradition der Ordensforschung ein, hebt sich aber durch die thematische Konzentration mit diachronem wie raumübergreifendem Zugriff deutlich hervor. Die titelgebende Dichotomie durchzieht die Gesamtanlage des inspirierenden Bandes, umkreist sie doch ein Spannungsfeld selbst gesetzter normativer Ansprüche vor der sprichwörtlichen Wirklichkeit. Und auch dies stellt das Buch in einen traditionellen Zusammenhang. ...
Die Frage nach Entstehung und Quellen des Schwabenspiegels ist ein gewissermaßen traditionelles Thema der germanistischen Rechtsgeschichte, es betrifft "das große Unbekannte" und sein Verhältnis zum Augsburger Stadtrecht von 1276, ein "klassisches Forschungsfeld", auf dem sich nun die zu besprechende Bayreuther Dissertation von Lucas Wüsthof bewegt. Wüsthof verweist auf Karl August Eckhardt, der 1927 als letzter Forscher die Abhängigkeit beider Rechtsquellen untersucht und festgestellt habe, dass die Verfasser des Augsburger Stadtrechts "eine Art Urtext" des Deutschen- und des Schwabenspiegels gekannt haben müssten (1–5). ...
Über die Geschichte des kanonischen Rechts im Mittelalter ist reichlich geforscht worden. Wenn nun ein Sammelband zum Gebrauch dieses Rechtes in der kirchlichen Verwaltungspraxis des Früh- und Hochmittelalters vorgelegt wird, weckt das die Aufmerksamkeit der mediävistischen Rechtshistoriker, die sich – vor allem unter dem von Hermann Nehlsen am Beispiel der frühmittelalterlichen Leges Barbarorum geprägten Aspekt der »Effektivität« – mit der normativen Praxis in vormodernen Gesellschaften beschäftigen. Oftmals bewegen sich die Forschungen entweder auf der rein normativen Seite mit einem breiten Horizont oder auf der praktischen anhand von mehr oder minder begrenzten Untersuchungsräumen. ...
Launching and manipulation of polaritons in van der Waals materials offers novel opportunities for field-enhanced molecular spectroscopy and photodetection, among other applications. Particularly, the highly confined hyperbolic phonon polaritons (HPhPs) in h-BN slabs attract growing interest for their capability of guiding light at the nanoscale. An efficient coupling between free space photons and HPhPs is, however, hampered by their large momentum mismatch. Here, we show —by far-field infrared spectroscopy, infrared nanoimaging and numerical simulations— that resonant metallic antennas can efficiently launch HPhPs in thin h-BN slabs. Despite the strong hybridization of HPhPs in the h-BN slab and Fabry-Pérot plasmonic resonances in the metal antenna, the efficiency of launching propagating HPhPs in h-BN by resonant antennas exceeds significantly that of the non-resonant ones. Our results provide fundamental insights into the launching of HPhPs in thin polar slabs by resonant plasmonic antennas, which will be crucial for phonon-polariton based nanophotonic devices.
Since the turn of the millennium, historical research has become increasingly interested in knowledge-based societies and their cultures, not least medieval ones. Whereas legal historical medieval studies have joined the interdisciplinary discussion about the notion of order as well as that of law, the notion of knowledge, and especially that of legal knowledge, has not been in the focus of interest. This observation serves as the starting point for Stephan Dusil’s habilitation thesis, which he submitted in 2016 at the Faculty of Law of the University of Zurich and which is now available as a monograph. ...
Background and aims: Patients with gastric cancer often show signs of malnutrition. We sought to evaluate the influence of sarcopenia in patients with locally advanced, not metastasized, gastric or gastro-esophageal junction (GEJ) cancer undergoing curative treatment (perioperative chemotherapy and surgery) on morbidity and mortality in order to identify patients in need for nutritional intervention.
Patients and methods: Two-centre study, conducted in the Frankfurt University Clinic and Krankenhaus Nordwest (Frankfurt) as part of the University Cancer Center Frankfurt (UCT). 47/83 patients were treated in the FLOT trial (NCT01216644). Patients´ charts were reviewed for clinical data. Two consecutive CT scans were retrospectively analyzed to determine the degree of sarcopenia. Survival was calculated using the Kaplan-Meier method, multivariate analysis was performed using the Cox regression.
Results: 60 patients (72.3%) were male and 23 (27.7%) female. 45 patients (54.2%) had GEJ type 1–3 and 38 (45.8%) gastric tumors, respectively. Sarcopenic patients were significantly older than non-sarcopenic patients (mean age 65.1 years vs. 59.5 years, p = 0.042), terminated the chemotherapy significantly earlier (50% vs. 22.6%, p = 0.037) and showed higher Clavien-Dindo scores, indicating more severe perioperative complications (score ≥3 43.3 vs. 17.0%, p = 0.019). Sarcopenic patients had a significantly shorter survival than non-sarcopenic patients (139.6 ± 19.5 [95% CI, 101.3–177.9] vs. 206.7 ± 13.8 [95% CI, 179.5–233.8] weeks, p = 0.004). Multivariate Cox regression analysis showed that, besides UICC stage, sarcopenia significantly influenced survival.
Conclusion: Sarcopenia is present in a large proportion of patients with locally advanced gastric or GEJ cancer and significantly influences tolerability of chemotherapy, surgical complications and survival.
Die Monographie des Kopenhagener Historikers Niels Hybel folgt einem ungewöhnlichen und im Ergebnis ausgesprochen ertragreichen Programm. Er zeichnet die Entwicklung des dänischen Königtums durch ein halbes Jahrtausend in Bezug zur gesamteuropäischen Ideen- und Rechtsgeschichte nach, behandelt also ein Thema der Nationalgeschichte aus einer dezidiert globalen Sicht, so dass der Blick aus einer epistemologisch sehr fruchtbaren Außenperspektive erfolgt. Zugleich werden so die klassischen Quellen zur Geschichte des dänischen Königtums den Narrationen der Nationalgeschichte produktiv verfremdet. Dass die Arbeit in englischer Sprache vorliegt, ist äußerst begrüßenswert, wird doch so die Geschichte des dänischen Königtums einem internationalen Publikum in einem weitgehend aktuellen Überblick zugänglich gemacht. Hybel knüpft mit seiner vom europäischen Ideen- und Strukturkontext her angelegten Studie an frühere Dekonstruktionen etablierter Meistererzählungen zur dänischen Geschichte an, die mit der Infragestellung älterer Lesarten von Chroniken und archäologischen Funden zum Frühmittelalter bzw. der als "Wikingerzeit" bezeichneten und seit dem 19. Jh. im Nationalbewusstsein so bedeutsamen späten Eisenzeit provozierten. Dieser kritische Impetus zeigt sich auch im vorliegenden Werk, dessen erstes von insgesamt zehn Kapiteln ("Historiography") den Zugang über die Forschungsdebatte zum Status des dänischen Königtums zwischen "Wikingerzeit" und Hochmittelalter wählt. Dänische "Könige" sind seit dem 8. Jh. in fränkischen Quellen zu fassen, und mit dem großen Runenstein von Jelling liegt ein Selbstzeugnis vor, das Harald Blauzahn (ca. 970–86) als König "ganz Dänemarks" ausweist. Bis heute deutet eine von zwei konkurrierenden Schulen dies als Beweis für die Existenz eines dänischen Königtums und eines souveränen "Reichs", jedenfalls aber als Nachweis einer seither existierenden Zentralmacht, während eine zweite Schule die Konsolidierung eines solchen mittelalterlichen Königtums erst nach der Mitte des 11. Jh.s erkennen will. Der Dissens basiert v.a. auf der Frage, ob ausnahmslos erst im 12. Jh. einsetzende, heimische chronikalische Quellen in ihrem Geschichtsbild ernst zu nehmen und archäologische Funde des 10. Jh.s wie die Ringburgen ("Trælleborge"), die auf eine Zentralmacht hinweisen, in ihrem Lichte zu interpretieren oder ob Geschichtsbilder primär als Zeugnisse synchroner Diskurse aufzufassen sind. Analoges gilt für Rechtstexte und Urkunden. Diese grundlegende Frage, von der aus Hybel das Material erschließt und die aus der deutschsprachigen Diskussion um den Status des Frankenreichs oder ottonischer Herrschaft durchaus vertraut wirkt, erweist sich als ganz aktuell, wie sich etwa an der Interpretation des unlängst neu ergrabenen und datierten Danewerks an der alten Südgrenze dieses (vermeintlichen?) dänischen "Reichs" zeigt. ...
The molecular basis of vitamin D signaling implies that the metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) of the secosteroid vitamin D3 activates the transcription factor vitamin D receptor (VDR), which in turn modulates the expression of hundreds of primary vitamin D target genes. Since the evolutionary role of nuclear receptors, such as VDR, was the regulation of cellular metabolism, the control of calcium metabolism became the primary function of vitamin D and its receptor. Moreover, the nearly ubiquitous expression of VDR enabled vitamin D to acquire additional physiological functions, such as the support of the innate immune system in its defense against microbes. Monocytes and their differentiated phenotypes, macrophages and dendritic cells, are key cell types of the innate immune system. Vitamin D signaling was most comprehensively investigated in THP-1 cells, which are an established model of human monocytes. This includes the 1,25(OH)2D3-modulated cistromes of VDR, the pioneer transcription factors PU.1 and CEBPA and the chromatin modifier CTCF as well as of the histone markers of promoter and enhancer regions, H3K4me3 and H3K27ac, respectively. These epigenome-wide datasets led to the development of our chromatin model of vitamin D signaling. This review discusses the mechanistic basis of 189 primary vitamin D target genes identified by transcriptome-wide analysis of 1,25(OH)2D3-stimulated THP-1 cells and relates the epigenomic basis of four different regulatory scenarios to the physiological functions of the respective genes.
The changing shape of the rapidity spectrum of net protons over the SPS energy range is still lacking theoretical understanding. In this work, a model for string excitation and string fragmentation is implemented for the description of high energy collisions within a hadronic transport approach. The free parameters of the string model are tuned to reproduce the experimentally measured particle production in proton-proton collisions. With the fixed parameters we advance to calculations for heavy ion collisions, where the shape of the proton rapidity spectrum changes from a single peak to a double peak structure with increasing beam energy in the experiment. We present calculations of proton rapidity spectra at different SPS energies in heavy ion collisions. Qualitatively, a good agreement with the experimental findings is obtained. In a future work, the formation process of string fragments will be studied in detail aiming to quantitatively reproduce the measurement.
Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I n = 61, WHO°II n = 88, and WHO°III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.