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Of the hepatic cell lines developed for in vitro studies of hepatic functions as alternatives to primary human hepatocytes, many have lost major liver-like functions, but not HepaRG cells. The increasing use of the latter worldwide raises the need for establishing the reference functional status of early biobanked HepaRG cells. Using deep proteome and secretome analyses, the levels of master regulators of the hepatic phenotype and of the structural elements ensuring biliary polarity were found to be close to those in primary hepatocytes. HepaRG cells proved to be highly differentiated, with functional mitochondria, hepatokine secretion abilities, and an adequate response to insulin. Among differences between primary human hepatocytes and HepaRG cells, the factors that possibly support HepaRG transdifferentiation properties are discussed. The HepaRG cell system thus appears as a robust surrogate for primary hepatocytes, which is versatile enough to study not only xenobiotic detoxification, but also the control of hepatic energy metabolism, secretory function and disease-related mechanisms.
We analyze debt and debt management of Americans nearing retirement age. We show that older people have numerous financial obligations that can lead to financial distress. Using data from the 2015 National Financial Capability Study and an extensive literature review, we show that lack of financial literacy, lack of information, and behavioral biases help explain the prevalence of debt later in life. Our evidence indicates that debt at older ages can negatively influence retirement well-being.
Den Visitationen am Reichskammergericht (RKG) wurden in letzter Zeit zwei unterschiedliche wissenschaftliche Untersuchungen gewidmet. Während Alexander Denzler den Aussagewert medialer Schriftkultur im "Schriftalltag" am Beispiel der letzten Visitation des RKGs (1767–1776) untersucht hat,1 widmet sich Anette Baumann als quellenversierte langjährige Leiterin der "Forschungsstelle der Gesellschaft für Reichskammergerichtsforschung" in Wetzlar den Visitationen von 1529–1588.2 Sie werden von ihr als "Expertentreffen" von Juristen interpretiert, die auch für das Verfassungsverständnis im Alten Reich bedeutsam sind. Das tragende Quellenmaterial bildet – neben einschlägiger Sekundärliteratur – vor allem der reiche Korrespondenz- und Aktenbestand im Wiener Haus-, Hof- und Staatsarchiv in Gestalt von Visitationsabschieden, Protokollen, Korrespondenzen, Vollmachten, Gutachten, Voten, Ladungen, Instruktionen, Gravamina, Fragebögen, persönlichen Notizen, Schreiben, Berichten und Augenscheinkarten,3 die das analysierte Schriftgut der Visitationen repräsentieren. Mit Hilfe einer erstellten Datenbank, die übrigens verschiedenen Forschungsinstitutionen – darunter auch dem MPI für europäische Rechtsgeschichte – zur Verfügung steht, ist es Baumann möglich, in den Beständen gezielt "nach Visitationsbelangen zu suchen" (17). Ziel ihrer gründlichen Untersuchung ist es, die Arbeit der Visitationskommission (VK) in dem "komplexen Kommunikationsprozess" (5) aufzuhellen, in dessen Mittelpunkt die VK stand – eingebettet in das Beziehungsgeflecht zwischen Kaiser, Reichsständen, Reichstag und Reichskammergericht (RKG). Durch die Reichskammergerichtsordnung von 1521 war die Kommission erstmals als "Visitation" reichsgesetzlich eingesetzt worden, um als Kontrollorgan einerseits das RKG finanziell zu sichern und andererseits die Abstellung von "Gebrechen" zu garantieren, d.h. das Gericht arbeitsfähig zu machen und zu erhalten. Die VK war somit eine Institution des Alten Reiches, die ursprünglich zur jährlichen Kontrolle bestimmt war. Eingesetzt von Kaiser und Reichsständen stand sie im Spannungsverhältnis politischer und konfessioneller Konstellationen auf dem Reichstag. Folgerichtig legt Baumann ihre Untersuchung auch weniger als Institutionengeschichte an, sondern als eine Darstellung von Reichsverfassungspraxis am Beispiel der VK. Aus dem reichen Archivmaterial werden die "Kommunikationsprozesse" herausdestilliert, um auf verfassungsmäßige Regelhaftigkeiten als Ordnungskategorien der Visitationsverfahren schließen zu können. Dabei stellt sich immer die Frage, ob die beobachteten Verfahren zu rechtlicher "Verfassung" geronnen sind oder sich noch im vorrechtlichen Raum ritualisierter Verfasstheit bewegen. So gesehen bietet das geschilderte Geschehen um die und in der VK einen Blick in das Laboratorium über die Entwicklung rechtlicher und politischer Regelungs- und Verfassungsprozesse. ...
Over the life-cycle, wealth holdings tend to be highest in the early part of retirement. The quality of financial decisions among older adults is therefore an important determinant of their financial security during the asset drawdown phase. This paper assesses how financial literacy shapes financial decision-making at older ages. We devised a special module in the Singapore Life Panel survey to measure financial literacy to study its relationship with three aspects of household financial and investment behaviors: credit card debt repayment, stock market participation, and adherence to age-based investment glide paths. We found that the majority of respondents age 50+ has some grasp of concepts such as interest compounding and inflation, but fewer know about risk diversification. We provide evidence of a statistically significant positive association between financial literacy and each of the three aspects of suboptimal financial decision-making, controlling for many other factors, including education. A one-unit increase in the financial literacy score was associated with an 8.3 percentage point greater propensity to hold stocks, and a 1.7 percentage point higher likelihood of following an age-appropriate investment glide path. The financial literacy score is only weakly positively linked with timely credit card balance repayment, both in terms of statistical significance and estimate size.
This collection edited by Dave De ruysscher, Albrecht Cordes, Serge Dauchy and Heikki Pihlajamäki considers what size or varieties of business were considered to be the best. The answer to this question depends on the time period under examination, and it also differs between jurisdictions. The chapters in the collection take a broad approach as they collectively cover a long time span and have a wide geographical spread. They consider examples from the Middle Ages, the early modern period and the 19th century. The places examined here are now in the jurisdictions of Germany, Italy, Belgium, Spain and England. As a whole, the chapters address some of the tension between the perceived advantages and disadvantages of big business against the small and medium enterprises (SMEs) and also the limited liability corporation in comparison to the unlimited liability partnership form. The edited collection takes a deliberately integrative approach, as it combines concepts and ideas from legal studies with those of economic history, business studies and comparative political analysis. ...
Many Americans claim Social Security benefits early, though this leaves them with lower benefits throughout retirement. We build a lifecycle model that closely tracks claiming patterns under current rules, and we use it to predict claiming delays if, by delaying benefits, people received a lump sum instead of an annuity. We predict that current early claimers would defer claiming by a year given actuarially fair lump sums, and the predictions conform with respondents’ answers to a strategic survey about the lump sum. In other words, such a reform could provide an avenue for encouraging delayed retirement without benefit cuts or tax increases. Moreover, many people would still defer claiming even for smaller lump sums.
We show that firm liability structure and associated cash flow matter for firm behavior, and that financial market participants price stocks accordingly. Looking at firm level stock price changes around monetary policy announcements, we find that firms that have more cash flow exposure see their stock prices affected more. The stock price reaction depends on the maturity and type of debt issued by the firm, and the forward guidance provided by the Fed. This effect has remained intact during the ZLB period. Importantly, we show that the effect is not a rule of thumb behavior outcome and that the marginal stock market participant actually studies and reacts to the liability structure of firm balance sheets. The cash flow exposure at the time of monetary policy actions predicts future net worth, investment, and assets, verifying the stock pricing decision and also providing evidence of cash flow effects on firms' real behavior. The results hold for S&P500 firms that are usually thought of not being subject to tight financial constraints.
A common prediction of macroeconomic models of credit market frictions is that the tightness of financial constraints is countercyclical. As a result, theory implies a negative collateralizability premium; that is, capital that can be used as collateral to relax financial constraints provides insurance against aggregate shocks and commands a lower risk compensation compared with non-collateralizable assets. We show that a longshort portfolio constructed using a novel measure of asset collateralizability generates an average excess return of around 8% per year. We develop a general equilibrium model with heterogeneous firms and financial constraints to quantitatively account for the collateralizability premium.
Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis
(2019)
Background: Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.
Methods: Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein.
Results: While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001).
Conclusions: Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.
Trial registration: ClinicalTrials.gov identifier: NCT03584204.
Aims: The examination of histological sections is still the gold standard in diagnostic pathology. Important histopathological diagnostic criteria are nuclear shapes and chromatin distribution as well as nucleus-cytoplasm relation and immunohistochemical properties of surface and intracellular proteins. The aim of this investigation was to evaluate the benefits and drawbacks of three-dimensional imaging of CD30+ cells in classical Hodgkin Lymphoma (cHL) in comparison to CD30+ lymphoid cells in reactive lymphoid tissues.
Materials and results: Using immunoflourescence confocal microscopy and computer-based analysis, we compared CD30+ neoplastic cells in Nodular Sclerosis cHL (NScCHL), Mixed Cellularity cHL (MCcHL), with reactive CD30+ cells in Adenoids (AD) and Lymphadenitis (LAD). We confirmed that the percentage of CD30+ cell volume can be calculated. The amount in lymphadenitis was approx. 1.5%, in adenoids around 2%, in MCcHL up to 4,5% whereas the values for NScHL rose to more than 8% of the total cell cytoplasm. In addition, CD30+ tumour cells (HRS-cells) in cHL had larger volumes, and more protrusions compared to CD30+ reactive cells. Furthermore, the formation of large cell networks turned out to be a typical characteristic of NScHL.
Conclusion: In contrast to 2D histology, 3D laser scanning offers a visualisation of complete cells, their network interaction and spatial distribution in the tissue. The possibility to differentiate cells in regards to volume, surface, shape, and cluster formation enables a new view on further diagnostic and biological questions. 3D includes an increased amount of information as a basis of bioinformatical calculations.
Natural history collections are fundamental for biodiversity research as well as for any applied environment-related research. These collections can be seen as archives of earth´s life providing the basis to address highly relevant scientific questions such as how biodiversity changes in certain environments, either through evolutionary processes in a geological timescale, or by man-made transformation of habitats throughout the last decades and/or centuries. A prominent example is the decline of the European flat oyster Ostrea edulis Linneaus, 1758 in the North Sea and the concomitant invasion of the common limpet slipper Crepidula fornicata, which has been implicated to have negative effects on O. edulis. We used collections to analyse population changes in both species in the North Sea. In order to reconstruct the change in distribution and diversity over the past 200 years, we combined the temporal and spatial information recorded with the collected specimens contained in several European natural history collections. Our data recover the decline of O. edulis in the North Sea from the 19th century to the present and the process of invasion of C. fornicata. Importantly, the decline of O. edulis was nearly completed before C. fornicata appeared in the North Sea, suggesting that the latter had nothing to do with the local extinction of O. edulis in the North Sea.
Klar scheinen die Berge vor dem nachtblauen Himmel. Ihre sanften Wölbungen geben in ihrer Mitte den Blick frei auf einen hell leuchtenden Stern. Die Landschaft ist ausgestorben, der Boden von Schnee bedeckt, die aus ihm herausragenden Bäume karg und ausgedörrt. Der einzige Abdruck menschlicher Existenz ist kaum sichtbar. Er zeigt sich in einem kleinen Kreuz an der Spitze des höchsten Berges. Doch die Szenerie hat nichts Bedrohliches oder gar Trauriges an sich, vielmehr strahlt das Gemälde eine inhärente Ruhe aus. Die Komposition ist harmonisch, die Anwendung verschiedener Nuancen von Blau tragen zur Ausgewogenheit bei. Bei der Betrachterin hinterlässt die dargestellte Landschaft, trotz ihrer Kargheit, den Eindruck einer Vollkommenheit der Natur. ...
Visual aesthetic experiences unfold over time, yet most of our understanding of such experiences comes from experiments using static visual stimuli and measuring static responses. Here, we investigated the temporal dynamics of subjective aesthetic experience using temporally extended stimuli (movie clips) in combination with continuous behavioral ratings. Two groups of participants, a rate group (n = 25) and a view group (n = 25), watched 30-second video clips of landscapes and dance performances in test and retest blocks. The rate group reported continuous ratings while watching the videos, with an overall aesthetic judgment at the end of each video, in both test and retest blocks. The view group, however, passively watched the videos in the test block, reporting only an overall aesthetic judgment at the end of each clip. In the retest block, the view group reported both continuous and overall judgments. When comparing the two groups, we found that the task of making continuous ratings did not influence overall ratings or agreement across participants. In addition, the degree of temporal variation in continuous ratings over time differed substantially by observer (from slower "integrators" to "fast responders"), but less so by video. Reliability of continuous ratings across repeated exposures was in general high, but also showed notable variance across participants. Together, these results show that temporally extended stimuli produce aesthetic experiences that are not the same from person to person, and that continuous behavioral ratings provide a reliable window into the temporal dynamics of such aesthetic experiences while not materially altering the experiences themselves.
Cardiovascular diseases are the most prominent cause of death in Western society, especially in the elderly. With the increasing life expectancy, the number of patients with cardiovascular diseases will rise in the near future, leading to an increased healthcare burden. There is a need for new therapies to treat this growing number of patients. The discovery of long non-coding RNAs has led to a novel group of molecules that could be considered for their potential as therapeutic targets. This review presents an overview of long non-coding RNAs that are regulated in vascular disease and aging and which might therefore give insight into new pathways that could be targeted to diagnose, prevent, and/or treat vascular diseases.
Chaperone-assisted selective autophagy (CASA) initiated by the cochaperone Bcl2-associated athanogene 3 (BAG3) represents an important mechanism for the disposal of misfolded and damaged proteins in mammalian cells. Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin. This is essential for muscle maintenance in flies, fish, mice and men. Here, we identify the serine/threonine protein kinase 38 (STK38), which is part of the Hippo signaling network, as a novel interactor of BAG3. STK38 was previously shown to facilitate cytoskeleton assembly and to promote mitophagy as well as starvation and detachment induced autophagy. Significantly, our study reveals that STK38 exerts an inhibitory activity on BAG3-mediated autophagy. Inhibition relies on a disruption of the functional interplay of BAG3 with HSPB8 and SYNPO2 upon binding of STK38 to the cochaperone. Of note, STK38 attenuates CASA independently of its kinase activity, whereas previously established regulatory functions of STK38 involve target phosphorylation. The ability to exert different modes of regulation on central protein homeostasis (proteostasis) machineries apparently allows STK38 to coordinate the execution of diverse macroautophagy pathways and to balance cytoskeleton assembly and degradation.
The long-awaited detection of a gravitational wave from the merger of a binary neutron star in August 2017 (GW170817) marks the beginning of the new field of multi-messenger gravitational wave astronomy. By exploiting the extracted tidal deformations of the two neutron stars from the late inspiral phase of GW170817, it is now possible to constrain several global properties of the equation of state of neutron star matter. However, the most interesting part of the high density and temperature regime of the equation of state is solely imprinted in the post-merger gravitational wave emission from the remnant hypermassive/supramassive neutron star. This regime was not observed in GW170817, but will possibly be detected in forthcoming events within the current observing run of the LIGO/VIRGO collaboration. Numerous numerical-relativity simulations of merging neutron star binaries have been performed during the last decades, and the emitted gravitational wave profiles and the interior structure of the generated remnants have been analysed in detail. The consequences of a potential appearance of a hadron-quark phase transition in the interior region of the produced hypermassive neutron star and the evolution of its underlying matter in the phase diagram of quantum cromo dynamics will be in the focus of this article. It will be shown that the different density/temperature regions of the equation of state can be severely constrained by a measurement of the spectral properties of the emitted post-merger gravitational wave signal from a future binary compact star merger event.
Post-transcriptional gene regulation through microRNA (miRNA) has emerged as a major control mechanism of multiple biological processes, including development and function of T cells. T cells are vital components of the immune system, with conventional T cells playing a central role in adaptive immunity and unconventional T cells having additional functions reminiscent of both innate and adaptive immunity, such as involvement in stress responses and tissue homeostasis. Unconventional T cells encompass cells expressing semi-invariant T cell receptors (TCRs), such as invariant Natural Killer T (iNKT) and Mucosal-Associated Invariant T (MAIT) cells. Additionally, some T cells with diverse TCR repertoires, including γδT cells, intraepithelial lymphocytes (IEL) and regulatory T (Treg) cells, share some functional and/or developmental features with their semi-invariant unconventional counterparts. Unconventional T cells are particularly sensitive to disruption of miRNA function, both globally and on the individual miRNA level. Here, we review the role of miRNA in the development and function of unconventional T cells from an iNKT-centric point of view. The function of single miRNAs can provide important insights into shared and individual pathways for the formation of different unconventional T cell subsets.
A hypothesis regarding the development of imitation learning is presented that is rooted in intrinsic motivations. It is derived from a recently proposed form of intrinsically motivated learning (IML) for efficient coding in active perception, wherein an agent learns to perform actions with its sense organs to facilitate efficient encoding of the sensory data. To this end, actions of the sense organs that improve the encoding of the sensory data trigger an internally generated reinforcement signal. Here it is argued that the same IML mechanism might also support the development of imitation when general actions beyond those of the sense organs are considered: The learner first observes a tutor performing a behavior and learns a model of the the behavior's sensory consequences. The learner then acts itself and receives an internally generated reinforcement signal reflecting how well the sensory consequences of its own behavior are encoded by the sensory model. Actions that are more similar to those of the tutor will lead to sensory signals that are easier to encode and produce a higher reinforcement signal. Through this, the learner's behavior is progressively tuned to make the sensory consequences of its actions match the learned sensory model. I discuss this mechanism in the context of human language acquisition and bird song learning where similar ideas have been proposed. The suggested mechanism also offers an account for the development of mirror neurons and makes a number of predictions. Overall, it establishes a connection between principles of efficient coding, intrinsic motivations and imitation.
Multidomain enzymes, such as fatty acid synthases (FASs) or polyketide synthases (PKSs), play a crucial role in the biosynthesis of important natural products. They have a high significance in the development of new pharmaceuticals and various research approaches focus on the engineering of these proteins. For example, human type I FAS is an interesting therapeutic target. Owing to its importance in lipogenesis, upregulation of human type I FAS expression has been observed in numerous cancers. Type I FAS is also regarded as important target in antiobesity treatment. Both multidomain enzyme classes - FASs and PKSs - show high structural and functional similarities. Particularly animal type I FAS is most relevant as evolutionary precursor of the PKS family. Therefore, the well characterized FASs are suitable model proteins for the poorly characterized PKSs, to gain deeper understanding in these megasynthases.
Furthermore, fatty acids are considered to be strategically important platform chemicals accessible through sustainable microbial approaches. The recently acquired structural information on FASs provides an excellent understanding of the molecular basis of fatty acid synthesis. The specific understanding of chain-length control, the characterization of a multitude of substrate-specific thioesterases, and the emerging tools and means for metabolic engineering have fostered targeted approaches for modulating chain length. There is large interest in short-chain fatty acids, since these compounds are biotechnologically valuable platform chemicals and biofuel precursors, and attempts on the synthesis of short-chain fatty acids have been reported during the last years.
Primary focus of this thesis lies on the animal type I FASs, which exhibit large conformational variety, as seen in electron microscopy and high-speed atomic force microscopy. Conformational dynamics facilitate productive protein-protein interactions between catalytic domains within the enzyme and aid acyl carrier protein (ACP)-mediated substrate shuttling during the catalytic cycle of fatty acid biosynthesis. To gain deeper insight into the fundamental processes of ACP-mediated substrate shuttling and the underlying conformational dynamics, spectroscopic methods like Förster resonance energy transfer and electron paramagnetic resonance spectroscopy shall be employed. These spectroscopic methods demand site-specific labeling of proteins with fluorophore or spin labels, which can be accomplished with the amber codon suppression technology. Through amber codon suppression, a non-canonical amino acid (ncAA) with an orthogonal functional group is incorporated site-specifically into the protein sequence, which can be used in chemoselective reactions for protein labeling.
This thesis is at the forefront of employing the technology of amber codon suppression for addressing complex biological questions on megasynthases. The successful production of ncAA-modified FASs is challenging. With the aim of incorporating ncAAs into the multidomain 540 kDa large murine FAS, we by far exceed boundaries of documented application of amber codon suppression. Most of the proteins that are reported by Liu & Schultz in applications of amber codon suppression are in the range of 30kDa - for example the TE domain of human FAS. In the same review, the largest protein amber codon suppression was applied to is a potassium channel with roughly 80 kDa. Thus, to the best of my knowledge no protein exceeding 100 kDa has been used in amber codon suppression so far.
In this thesis a low-complex, well-plate based reporter assay is presented, based on an ACP-GFP fusion protein for fast and efficient screening of ncAA incorporation. Reliability and applicability of the reporter assay is demonstrated by successful upscaling to larger protein constructs and increased expression scale.
As outlined in this thesis, we have carefully set up methods for the modification of murine FAS and made several achievements:
(i) We have created our own toolbox with a multitude of suppressor plasmids and various orthogonal pairs. pACU and pACE plasmids are compatible for fast exchange of cassettes, and cloning procedures are optimized for modification of synthetases by site-directed mutagenesis. (ii) We have organic synthesis of several ncAAs stably running in the lab and synthesis of other ncAAs can be established when required. Therefore, extensive screening at moderate costs is possible. (iii) We have established a reporter assay for screening our own library of vectors for amber codon suppression and for optimizing incorporation of ncAAs. (iv) We successfully incorporated ncAAs into subconstructs and full-length murine FAS, and collected initial promising results for the application of these proteins in spectroscopic methods. Thus, laying the foundation for future studies to address fundamental questions of the ACP-mediated substrate shuttling and other conformational dynamics of these enzymes.
Paramyxo- and pneumoviruses include many pathogens with great relevance for human and animal health. To identify common host factors involved in the Paramyxo- and Pneumoviridae life cycle as a basis for new insights in the biology of these viruses and the development of rationally designed therapeutics, genome scale siRNA screens with wild-type measles, mumps, and respiratory syncytial viruses in A549 cells, a human lung adenocarcinoma cell line, were performed. A comparative bioinformatics analysis yielded different members of the coatomer complex I, the translation factors ABCE1 and eIF3A, and several RNA binding proteins as cellular proteins with proviral activity for all three viruses. The strongest common hit, ABCE1, an ATP-binding cassette transporter member, was chosen for further study. We found that ABCE1 supports replication of all three viruses, confirming its importance for both virus families. While viral protein kinetics showed that ABCE1 knockdown resulted in a drastic decrease of MeV protein expression, viral mRNA kinetics are not directly affected by a reduction of ABCE1.
The impact of ABCE1 on viral and global cellular translation was investigated using both 35S metabolic labelling and non radioactive fluorescent protein labelling. ABCE1 knockdown strongly inhibited the production of MeV proteins, while only modestly affecting global cellular protein synthesis and showed that ABCE1 is specifically required for efficient viral, but not general cellular, protein synthesis, indicating that paramyxoand pneumoviral mRNAs may exploit specific translation mechanisms.
In a second approach the efficacy of the small-molecule polymerase inhibitor ERDRP-0519 against MeV was assessed in squirrel monkeys. Animals treated with the drug experienced less severe clinical disease compared to untreated controls, and this effect correlated with the onset of drug treatment.
We observed a reduction of levels of PBMC-associated viremia and virus release in the upper airways, illustrating effective inhibition of virus replication by the drug treatment. ERDRP-0519 drug treatment also alleviated MeV-induced immunosuppression. In addition to providing proof-of-concept for the support of MeV eradication efforts by preventing disease and transmission with a small-molecule polymerase inhibitor, this dissertation provides a novel perspective on cellular proteins that impact the replication of MeV, MuV and HRSV and highlights the role of ABCE1 as host factor that is required for efficient paramyxo- and pneumovirus translation.
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.
Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany.
Methods: A validated 3–12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany.
Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months–33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis.
Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.
Global Histories and Cultures of Statehood, libro editado por John L. Brooke, Julia Strauss y Greg Anderson, es una propuesta interesante de reflexión interdisciplinaria sobre las formaciones estatales en un marco temporal amplísimo: desde la Antigüedad hasta el siglo XX. Los capítulos que componen el libro fueron presentados en un programa de dos años en la Universidad Estatal de Ohio. La publicación es claramente el producto de un ejercicio de discusión colectiva de una red académica con sede en los Estados Unidos y, por tal motivo, la mayoría de sus miembros pertenecen a instituciones académicas en este país. ...
Circular RNAs (circRNAs), an important class of regulatory RNAs, have been shown to be the most prevalent in the brain compared with other tissues. However the processes governing their biogenesis in neurons are still elusive. Moreover, little is known about whether and how different biogenesis factors work in synchrony to generate neuronal circRNAs. To address this question, we pharmacologically inhibited the spliceosome and profiled rat neuronal circRNAs using RNA sequencing. We identified over 100 circRNAs that were up-regulated and a few circRNAs that were down-regulated upon spliceosome inhibition. Bioinformatic analysis revealed that up-regulated circRNAs possess significantly longer flanking introns compared with the un-changed circRNA population. Moreover, the flanking introns of up-regulated circRNAs harbor a higher number of distinct repeat sequences and more reverse complementary motifs compared with the unchanged circRNAs. Taken together, our data demonstrate that the biogenesis of circRNAs containing distinct intronic features becomes favored under conditions of limited spliceosome activity.
Every now and again, one is overcome by a sense of utter disbelief. How can it be that some conventional narratives are still so persistent and influential in this day and age? In fact, they are so pervasive that one feels compelled to put pen to paper in order to combat them. Among these narratives, we find the tale of cultural evolution, where law plays a fundamental role as an instrument for rationalizing archaic societies. Having rejected this kind of historiography in his last essay on the early history of law (ZRG RA 127, 1–13), the late Raymond Westbrook instead postulated new paradigms. Moving in the same direction, Philipp Ruch thwarts this story of civilizing progress in a twofold manner: In his eyes, honor and vengeance are not the anthropological factors that law has to contain in order to create civilization. According to Ruch, and the main thrust of his 2016 dissertation, it was in fact law in the context of honor and vengeance that produced emotionality. ...
The synthesis of polynitrogen compounds is of fundamental importance due to their potential as environmentally-friendly high energy density materials. Attesting to the intrinsic difficulties related to their formation, only three polynitrogen ions, bulk stabilized as salts, are known. Here, magnesium and molecular nitrogen are compressed to about 50 GPa and laser-heated, producing two chemically simple salts of polynitrogen anions, MgN4 and Mg2N4. Single-crystal X-ray diffraction reveals infinite anionic polythiazyl-like 1D N-N chains in the crystal structure of MgN4 and cis-tetranitrogen N44− units in the two isosymmetric polymorphs of Mg2N4. The cis-tetranitrogen units are found to be recoverable at atmospheric pressure. Our results respond to the quest for polynitrogen entities stable at ambient conditions, reveal the potential of employing high pressures in their synthesis and enrich the nitrogen chemistry through the discovery of other nitrogen species, which provides further possibilities to design improved polynitrogen arrangements.
Kunstmekka und kitschig-schöne Serenissima : Teil 1/2: Rundgang über die 58. Biennale in Venedig
(2019)
Ein guter Grund alle zwei Jahre in die Serenissima zu reisen ist ihre Kunstbiennale. Seit über 100 Jahren, genauer seit 1895, öffnet von Mai bis November die größte Kunstschau der Welt in Venedig ihre Pforten.
Die Biennale verteilt sich auf mehrere Ausstellungsorte. Da sind die Giardini, ein für venezianische Verhältnisse großzügiger Park und zudem die einzige Grünanlage der Stadt. Sie beherbergen neben dem Zentralpavillon auch 28 nationale Länderpavillons, darunter einen deutschen Pavillon. 1999 kam aus Platzgründen das Arsenale, die Schiffswerft des ehemaligen Militärhafens, als Ausstellungsfläche hinzu. Zusätzlich verteilen sich weitere Länderpavillons und Ausstellungen über die Stadt, in angemieteten Etagen verschiedener Palazzi. Letztere zeigen sich zumeist als sehenswerte Architektur. Nicht selten lassen sich dort Kronleuchter aus Muranoglas, wertvolle Stofftapeten oder Wandmalereien sowie monumentale und reichverzierte Treppen bewundern.
May You Live in Interesting Times lautet der Titel, den der Amerikaner Ralph Rugoff, diesjähriger Kurator für die zentrale Ausstellung, der 58. Kunstbiennale gegeben hat. Die Besonderheit in diesem Jahr: Es stellen nur lebende Künstler aus und davon sind alle einmal sowohl in den Giardini als auch im Arsenale mit Werken vertreten. Die nationalen Länderpavillons haben jeweils eigene nationale Kuratoren und Künstler ausgewählt und bespielen ihre Häuser unabhängig vom Hauptmotto. Es kommen darüber hinaus auch noch viele sogenannte Kollateral-Ausstellungen in den berühmten Museen oder in bekannten Kirchen und Palazzi hinzu. Selbst ein einwöchiger Aufenthalt böte nicht genug Zeit, um alles zu sehen.
We investigate the default probability, recovery rates and loss distribution of a portfolio of securitised loans granted to Italian small and medium enterprises (SMEs). To this end, we use loan level data information provided by the European DataWarehouse platform and employ a logistic regression to estimate the company default probability. We include loan-level default probabilities and recovery rates to estimate the loss distribution of the underlying assets. We find that bank securitised loans are less risky, compared to the average bank lending to small and medium enterprises.
In this paper, we investigate the relation between buildings' energy efficiency and the probability of mortgage default. To this end, we construct a novel panel dataset by combining Dutch loan-level mortgage information with provisional building energy ratings that are calculated by the Netherlands Enterprise Agency. By employing the Logistic regression and the extended Cox model, we find that buildings' energy efficiency is associated with lower likelihood of mortgage default. The results hold for a battery of robustness checks. Additional findings indicate that credit risk varies with the degree of energy efficiency.
An album of 50 watercolour illustrations depicting Norfolk Island plants attributed to convict artist John Doody, in the early 1790s, and associated notes apparently written by William Paterson (1755-1810), one-time commander of the military detachment on Norfolk Island, Lieutenant Governor of New South Wales, and amateur botanist, are described and assessed. Illustrated are 48 plant species growing on Norfolk Island at the time, all but three of which are indigenous. The notes and the watercolours represent the only treatment of the island's flora in the 18th century and include descriptive and ecological material for the species at the time of first European occupation. Two of the species are now extinct. Paterson's notes also include an introductory description of the flora and fauna of the Island. The importance of this material to the modern study of the Norfolk Island flora is highlighted.