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Many processes in living cells involve interaction and cooperation of multiple proteins to fulfill a specific function. To understand biological processes in their full complexity, it is not sufficient to only identify the molecules being involved but also to understand the kinetic aspects of a reaction. Mass spectrometry (MS) is a very powerful tool which allows to precisely identify the molecules of a reaction. Usually this is done with tandem-MS experiments for purpose of de-novo peptide sequencing. However, since this involves protein digestion, a statement of the in-vivo constitution of non-covalently bound protein complexes is not possible. In order to detect an intact protein complex it is necessary to analyze the biological system softly and in a near-native environment with native MS. Native MS allows the non-destructive analysis of these non-covalent protein complexes as well as to detect their components. However, up to now native MS does not offer a possibility to resolve the timing of the constitution of protein complexes on a fast time-scale. Therefore, the progress of reactions on fast time-scales is invisible. However, a method which delivers both types of information - identification of the components of a protein complex, as well as time-resolving their interaction - would be of high interest.
A suitable ionization technique for native MS is laser-induced liquid-bead ion desorption (LILBID). LILBID employs well-defined droplets which are irradiated by IR laser pulses to generate gas phase ions. The not-continuous, repetitive nature of ion generation offers itself to the development of a time-resolved (TR) native MS system which is able to investigate protein complexes on a fast time scale. The LILBID-droplets can serve as reaction vessels if they are levitated in an electrodynamic Paul-trap. This new setup would allow sample manipulation and MS analysis on precise and fast reaction time-scales. The first part of this dissertation presents the construction and characterization of a setup for TR-LILBID-MS.
An example for a complex biological system is the self-assembly of beta-amyloid (Aβ). This small peptide is the major component in plaques related to Alzheimer’s disease. Clinically relevant is especially the 42 amino acid peptide Aβ42 which aggregates from monomers to oligomers through to fibrils. The oligomers are the neurotoxic species in this process and thus of high interest. Nevertheless, standard analytical techniques are unable to detect those oligomers which makes MS an optimal tool to study the oligomerization process of Aβ with the focus on disease relevant oligomers. TR-LILBID-MS allows to follow the oligomerization of Aβ enabling to study molecules which influence this kinetic. Combining MS with ion-mobility spectrometry adds an additional dimension - the collision cross section - to the mass-to-charge ratio obtained from MS. Therewith structural alterations induced by ligands can be correlated to differences in the aggregation kinetic. This allows to draw a picture of the aggregation process of Aβ for the development of disease-relevant small oligomers on a molecular level.
Die in der vorliegenden Arbeit gewonnenen Erkenntnisse zur Reaktivität zweifach reduzierter 9,10-Dihydro-9,10-diboraanthracene [A]2– erweitern das Einsatzspektrum von Hauptgruppenverbindungen im Hinblick auf die Aktivierung kleiner Moleküle. Komplementär zu Übergangsmetallkomplexen und FLPs ermöglichen die Salze M2[A] (M+ = Li+, Na+, K+) die Entwicklung neuartiger Synthesestrategien. Als besondere Herausforderung gilt die Aktivierung des stabilen H2-Moleküls, dessen Bindung die Dianionen [A]2– homolytisch in einer konzertierten Reaktion spalten.
Untersuchungen zur Kinetik der H2-Addition an M2[A] stellten die Abhängigkeit dieses Reaktionsschritts vom borgebundenen Substituenten und vom Kation heraus. Eine geringe sterische Abschirmung der Boratome durch kleine borgebundene Substituenten (C≡CtBu, Me, H) begünstigt die H2-Aufnahme gegenüber großen Substituenten (pTol, Xyl, Et). Die maximale Ausbeute an M2[A-H2] wird für M+ = Li+ erst nach mehreren Tagen bei 100 °C erhalten, während einige Stunden bei nur 50 °C für die quantitative Bildung von K2[A-H2] ausreichen.
Unter den Salzen M2[A] eignet sich Li2[68] mit borgebundenen Me-Substituenten besonders gut für den Einsatz als Hydrierungskatalysator. Mit Li2[68] konnten das Imin Ph(H)C=NtBu, das terminale Alken Ph2C=CH2 und Anthracen erfolgreich im NMR-Maßstab hydriert werden (Katalysatorladung 37 mol%, THF-d8, 1 atm H2-Initialdruck, 100 °C, 16 h). Im Reaktionsautoklaven war für die Hydrierung von Ph(H)C=NtBu eine Verringerung der Katalysatorladung auf 10 mol% Li2[68] möglich (THF, 7 atm H2-Initialdruck, 100 °C, 18 h). Konkurrenzreaktionen begründen Einschränkungen in Bezug auf die Substratpalette, da M2[68] (M+ = Li+, Na+) mit elektronenarmen ungesättigten Verbindungen, die C=C-, C≡C-, C=O- oder C=N-Bindungen enthalten, [4+2]-Cycloadditionsprodukte bilden können. Die Reversibilität dieser Reaktion entscheidet, ob Li2[68] als Katalysator fungiert oder irreversibel in den Strukturen gebunden bleibt.
Vielseitiger sind die H2-Aktivierungsprodukte M2[A-H2] als H–-Donoren geeignet: Na2[68-H2] ersetzt Halogenid- durch H–-Substituenten in Bromethan, sowie in Chlorsilanen und PCl3; CO2 wird in Natriumformiat überführt. Unabhängig von der Anzahl der Chlorliganden werden die Produkte immer vollständig hydriert. Eine erneute Reduktion von 68 kann wieder Na2[68] bereitstellen, das H2 aufnimmt und Na2[68-H2] regeneriert, welches für neue H–-Abgaben zur Verfügung steht. Bei der experimentellen Umsetzung des Kreislaufs ist es wichtig, die beschriebenen Reaktionsschritte nacheinander auszuführen und jeweils nur stöchiometrische Mengen des Elektrophils zuzugeben. Bei Abweichungen vom schrittweisen Syntheseprotokoll finden formale nukleophile Substitutionen mit M2[68] statt und monoanionische Spezies entstehen, z. B. wenn Et3SiBr als Elektrophil anwesend ist.
Gegenüber CO2 zeigt Li2[68] eine hohe Reaktivität, durch die selektiv CO und [CO3]2– gebildet werden. Wie zuvor bei den H–-Transferreaktionen ermöglicht die Reduktion der Neutralverbindung 68 die Regeneration von Li2[68].
Die Dianionen [A]2– stechen unter anderen cyclischen Borverbindungen in niedrigen Oxidationsstufen heraus, da mit [A]2– nicht nur die Aktivierung von H2 oder CO2 gelang, sondern erstmalig über die Einbindung der Additionsprodukte in zum Teil katalytische Folgereaktionen berichtet werden konnte.
Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.
Purpose: Bacterial biofilms are a major problem in the treatment of infected dental and orthopedic implants. The purpose of this study is to investigate the cleaning effect of an electrolytic approach (EC) compared to a powder-spray system (PSS) on titanium surfaces. Materials and Methods: The tested implants (different surfaces and alloys) were collated into six groups and treated ether with EC or PSS. After a mature biofilm was established, the implants were treated, immersed in a nutritional solution, and streaked on Columbia agar. Colony-forming units (CFUs) were counted after breeding and testing (EC), and control (PSS) groups were compared using a paired sample t-test. Results: No bacterial growth was observed in the EC groups. After thinning to 1:1,000,000, 258.1 ± 19.9 (group 2), 264.4 ± 36.5 (group 4), and 245.3 ± 40.7 (group 6) CFUs could be counted in the PSS groups. The difference between the electrolytic approach (test groups 1, 3, and 5) and PSS (control groups 2, 4, and 6) was statistically extremely significant (p-value < 2.2 × 10−16). Conclusion: Only EC inactivated the bacterial biofilm, and PSS left reproducible bacteria behind. Within the limits of this in vitro test, clinical relevance could be demonstrated.
Formation of the anteroposterior and dorsoventral body axis in Caenorhabditis elegans depends on cortical flows and advection of polarity determinants. The role of this patterning mechanism in tissue polarization after formation of cell-cell contacts is not fully understood. Here, we demonstrate that planar asymmetries are established during left-right symmetry breaking: Centripetal cortical flows asymmetrically and differentially advect anterior polarity determinants (aPARs) from contacts to the medial cortex, resulting in their unmixing from apical myosin. Contact localization and advection of PAR-6 requires balanced CDC-42 activation, while asymmetric retention and advection of PAR-3 can occur independently of PAR-6. Concurrent asymmetric retention of PAR-3, E-cadherin/HMR-1 and opposing retention of antagonistic CDC-42 and Wnt pathway components leads to planar asymmetries. The most obvious mark of planar asymmetry, retention of PAR-3 at a single cell-cell contact, is required for proper cytokinetic cell intercalation. Hence, our data uncover how planar polarity is established in a system without the canonical planar cell polarity pathway through planar asymmetric retention of aPARs.
Die Dissertation (Universität Eichstätt-Ingolstadt) beginnt mit dem Satz "Am Ende stritt man um Akten" und endet auf Seite 483 mit eben dem gleichen Satz. Zwischen Anfang und Ende dieser akribisch gearbeiteten Publikation, die Denzler bescheiden eine "Studie" nennt, werden die massenweise in den Archiven vorhandenen Akten, die während der letzten Visitation des Reichskammergerichts von 1767–1776 produziert wurden, nach ihrer Entstehung und Funktion untersucht. Als Leitbild der Untersuchung dient der "Reformhorizont" der Aufklärung, vor dessen Hintergrund das Visitationsgeschehen in Gestalt seiner Hand- und Druckschriften analysiert wird. "Reform"-zeiten, -räume, -akteure, -verfahren sowie -inhalte geben dem engagiert geschriebenen Buch eine klare Gliederung für die Untersuchung aller Schriftgattungen von den Protokollen, Schreiben, Diktaten, Abschriften, Diarien, Korrespondenzen, Instruktionen, Berichten bis zu Gutachten und Notizen, die alle das Visitationsgeschehen in und als "Akten" repräsentieren: 562 Aktenbündel; von 1056 Sitzungen sind 13 Bände Beratungsprotokolle überliefert, die 15732 Folioseiten umfassen; 50 Visitationsbeschlüsse liegen vor; die schriftlichen Befragungen von 92 Gerichtsmitgliedern ergaben 25000 Antworten (355, 478); hinzu kommen noch die Produktion aus der visitationseigenen Druckerei sowie 200 Einzelpublikationen zur Visitation und eine visitationseigene Zeitschrift als schriftliches Untersuchungsmaterial. Daraus entsteht ein höchst umfassendes und anschauliches Bild über Medientechnik, Schriftkultur, Justizkontrolle und Dienstaufsicht im Rahmen der Visitation. Aus dem quantitativen Befund in diesem "tintenklecksenden Saeculum", wie es Schiller genannt hat, leitet Denzler die These ab, dass die Visitation von 1767 eine enorme Vermehrung und Aufwertung von Schriftlichkeit schlechthin dokumentiert (16). Vor diesem Hintergrund soll die alltägliche Bedeutung der Schriftlichkeit für die Visitation analysiert und der "Entstehungs- und Überlieferungskontext" möglichst genau im "Schriftalltag" rekonstruiert werden. Dieser "Schriftalltag" reflektiert auch den Justizalltag in seiner rechtshistorischen Bedeutung. Diesen zu beschreiben ist zwar nicht Denzlers vorrangiges Ziel, aber die Kulturgeschichte des Geschriebenen beleuchtet und ergänzt die Geschichte der Rechtspraxis am Beispiel der Visitation von 1767 in vielfältiger Weise. Das belegen auch das reiche Quellen- und Literaturverzeichnis (489–562) und die Statistiken über Personalia, Visitationskosten, Examina, Gesandtschaftsquartiere, Verfahren usw. (565–604). ...
A twentieth century-long coupled atmosphere-ocean regional climate simulation with COSMO-CLM (Consortium for Small-Scale Modeling, Climate Limited-area Model) and NEMO (Nucleus for European Modelling of the Ocean) is studied here to evaluate the added value of coupled marginal seas over continental regions. The interactive coupling of the marginal seas, namely the Mediterranean, the North and the Baltic Seas, to the atmosphere in the European region gives a comprehensive modelling system. It is expected to be able to describe the climatological features of this geographically complex area even more precisely than an atmosphere-only climate model. The investigated variables are precipitation and 2 m temperature. Sensitivity studies are used to assess the impact of SST (sea surface temperature) changes over land areas. The different SST values affect the continental precipitation more than the 2 m temperature. The simulated variables are compared to the CRU (Climatic Research Unit) observational data, and also to the HOAPS/GPCC (Hamburg Ocean Atmosphere Parameters and Fluxes from Satellite Data, Global Precipitation Climatology Centre) data. In the coupled simulation, added skill is found primarily during winter over the eastern part of Europe. Our analysis shows that, over this region, the coupled system is dryer than the uncoupled system, both in terms of precipitation and soil moisture, which means a decrease in the bias of the system. Thus, the coupling improves the simulation of precipitation over the eastern part of Europe, due to cooler SST values and in consequence, drier soil.
Libra – a global virtual currency project initiated by Facebook – has been the subject of many controversial discussions since its announcement in June 2019. This paper provides a differentiated view on Libra, recognising that different development scenarios of Libra are conceivable.
Libra could serve purely as an alternative payment system in combination with a dedicated payment token, the Libra coin. Alternatively, the Libra project could develop into a broader financial infrastructure for advanced financial services such as savings and loan products operating on the Libra blockchain. Based on a comparison of the Libra architecture with other cryptocurrencies, the opportunities and challenges for the development of the respective Libra ecosystems are investigated form a commercial, regulatory and monetary policy perspective.
Wir lassen die überwältigende Fülle an Werken im Arsenale hinter uns. Das Ziel sind die Giardini, der ursprüngliche und neben dem Arsenale zweite große Ausstellungsort der Kunstschau. Dort befindet sich einer der Hauptanziehungspunkte der Biennale: Im Zentralpavillon steht die in den Medien bereits oft erwähnte und gezeigte sogenannte "Blutmaschine". Ein riesiger Roboterarm mit überdimensionaler Wischschaufel, wirkt sie in ihrer Motorik dennoch ausgesprochen menschlich. Die 32 Bewegungen, die das chinesische Künstlerduo Sun Yuan und Peng Yu dem Industrieroboter "in den Leib" programmiert haben, erinnern an Winken, Tanzen, Po-Wackeln, Innehalten und Überlegen. ...
Local crowding out in China
(2019)
In China, between 2006 and 2013, local public debt crowded out the investment of private firms by tightening their funding constraints, while leaving state-owned firms’ investment unaffected. We establish this result using a purpose-built dataset for Chinese local public debt. Private firms invest less in cities with more public debt, the reduction in investment being larger for firms located farther from banks in other cities or more dependent on external funding. Moreover, in cities where public debt is high, private firms’ investment is more sensitive to internal cash flow, also when cash-flow sensitivity is estimated jointly with the probability of being credit-constrained.
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.
Die Arbeit untersucht die Ad-hoc-Publizität unter der Geltung der MAR. In der Arbeit werden zuerst das Informationsmodell auf dem Kapitalmarkt und die Erforderlichkeit und Notwendigkeit der Regulierung des Kapitalmarkts durch gesetzliche Informationspflichten analysiert. Mithilfe eines Rückblicks auf die Entwicklung der Ad-hoc-Publizität in den Rechtsnormen wird ihr Sinn und Zweck untersucht. Die rechtlichen Anforderungen an Ad-hoc-Publizität unter der Geltung der MAR werden in einem weiteren Schritt untersucht. Der Schwerpunkt liegt dabei auf den Tatbestandsmerkmalen der Ad-hoc-Publizitätspflicht und dem Aufschub der Veröffentlichung. Darüber hinaus werden die Rechtsfolgen im Falle von Pflichtverstößen, insbesondere Anspruchsgrundlagen nach §§ 97, 98 WpHG analysiert. Im Hinblick auf die Ad-hoc-Publizität nach dem chinesischen Recht werden ihre historische Entwicklung in Rechtsnormen und ihr Sinn und Zweck untersucht. Eine dogmatische Analyse der Ad-hoc-Publizitätspflicht und der Rechtsfolgen beim Pflichtverstoß nach dem geltenden chinesischen Recht wird dann durchgeführt. Schließlich wird die Ad-hoc-Publizität nach der MAR und dem chinesischen Recht verglichen.
Im rechtsvergleichenden Teil der Untersuchung identifiziert der Verfasser bestimmte Besonderheiten und Defizite im chinesischen Recht. Den Regelungsansätzen der beiden Rechtssysteme liegen unterschiedliche rechtpolitische Zielsetzungen zugrunde. In der EU und in Deutschland steht der Konnex zum Insiderhandel im Vordergrund, denn diesem wird durch die Ad-Hoc Meldung der Boden entzogen. In China handelt es sich bei der Ad-hoc-Publizität konzeptionell eher um einen Annex zur Regelpublizität. Damit geht Hand in Hand, dass die Verfolgung zivilrechtlicher Ansprüche aufgrund falscher Ad-hoc-Meldungen in China der behördlichen Genehmigung bedarf. Der Verfasser macht auf dieser Grundlage Vorschläge zur (behutsamen) Rechtsfortbildung in China nach europäischem Vorbild.
This inventory intends to provide updated numbers of vascular plants occurring in Cyprus. Currently, 1649 indigenous taxa (species and subspecies) are known to occur in Cyprus. In addition 254 taxa belong to various categories of neophytes. The endemism rate of the indigenous flora amounts to 8.55 %, i. e. 141 taxa, while 33 species and subspecies belong to the category of near-endemic for which Cyprus bears significant responsibility for their conservation.
The recently described Phelipanche hedypnoidis from the Orobanche (Phelipanche) ramosa group has been found in Cyprus for the first time. So far, it is known only from one site at the south coast. Hedypnois rhagadioloides as host plant is confirmed. To meet the demands of a more traditional generic treatment the new combination Orobanche hedypnoidis is proposed.
Further noteworthy records of vascular plants in Cyprus (1997–2018) and some status clarifications
(2019)
This paper deals with specimen-based records of 74 taxa, most of them having a scattered occurrence or restricted distribution range in Cyprus. The following taxa are new to Cyprus or have been found in the wild for the first time: Aristida adscensionis subsp. adscensionis, Buglossoides incrassata subsp. splitgerberi, Cenchrus setaceus, Chenopodium rubrum, Gazania rigens, Malus domestica, Mespilus germanica, Mirabilis jalapa, Pyrus communis, Sambucus nigra and Spartium junceum. The new combination Urtica cypria (H. Lindb.) Hand for the endemic nettle species is proposed.
Tradescantia fluminensis is an invasive weed that has been recorded for the first time in Cyprus. The species occurs in river banks, mainly under shady conditions. It has been recorded in three sites, always at low density: Marathasa river (Lefkosia district), Kargotis river (Lefkosia district), Kryos river (Lemesos district).
The influence of temperature is regarded as particularly important for a structural health monitoring system based on ultrasonic guided waves. Since the temperature effect causes stronger signal changes than a typical defect, the former must be addressed and compensated for reliable damage assessment. Development of new temperature compensation techniques as well as the comparison of existing algorithms require high-quality benchmark measurements. This paper investigates a carbon fiber reinforced plastic (CFRP) plate that was fully characterized in previous research in terms of stiffness tensor and guided wave propagation. The same CFRP plate is used here for the analysis of the temperature effect for a wide range of ultrasound frequencies and temperatures. The measurement data are a contribution to the Open Guided Waves (OGW) platform: http://www.open-guided-waves.de. The technical validation includes initial results on the analysis of phase velocity variations with temperature and exemplary damage detection results using state-of-the-art signal processing methods that aim to suppress the temperature effect.
AMPA receptors and interacting proteins are importantly involved in mediating stress-dependent plasticity. Previously we reported that GluA1-containing AMPA receptors and their interaction with PDZ-proteins are required for the experience-dependent expression of behavioral despair in the forced swim test. However, it is unclear if the expression of GluA1-containing AMPA receptors is affected by this type of behavior. Here we investigated in wild type mice, whether hippocampal gene or protein levels of GluA1 or associated PDZ proteins is altered following forced swim stress. We show that expression of Dlg4 (the gene coding for PSD-95) was strongly reduced after two days of forced swimming. In contrast, levels of Dlg1, Gria1, and Gria2 (coding for SAP97, GluA1, and GluA2 respectively) were not affected after one or two days of forced swimming. The changes in gene expression largely did not translate to the protein level. These findings indicate a limited acute effect of forced swim stress on the expression of the investigated targets and suggest that the acute involvement of GluA1-containing AMPA receptors tor forced swim behavior is a result of non-genomic mechanisms.
Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.
Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.
Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.
Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and often has a poor prognosis. The present study investigated the role of the low affinity nerve growth factor receptor CD271 as a putative therapy target in HNSCC. Neurotrophins that bind to CD271 also have a high affinity for the tropomyosin receptor kinase family (Trk), consisting of TrkA, TrkB, and TrkC, which must also be considered in addition to CD271. A retrospective study and functional in vitro cell line tests (migration assay and cell sorting) were conducted in order to evaluate the relevance of CD271 expression alone and with regard to Trk expression. CD271 and Trks were heterogeneously expressed in human HNSCC. The vast majority of tumors exhibited CD271 and TrkA, whereas only half of the tumors expressed TrkB and TrkC. High expression of CD271-positive cells predicted a bad clinical outcome of patients with HNSCC and was associated with distant metastases. However, the human carcinomas that also expressed TrkC had a reduced correlation with distant metastases and better survival rates. In vitro, CD271 expression marked a subpopulation with higher proliferation rates, but proliferation was lower in tumor cells that co-expressed CD271 and TrkC. The CD271 inhibitor LM11A 31 suppressed cell motility in vitro. However, neither TrkA nor TrkB expression were linked to prognosis or cell proliferation. We conclude that CD271 is a promising candidate that provides prognostic information for HNSCC and could be a putative target for HNSCC treatment.
Background: Outcomes of catheter ablation of atrial fibrillation (AF) are variable and the predictors of success require further elucidation since the identification of correctable risk factors could help to optimize therapy. We aimed to assess the impact of body mass index (BMI) in the overall safety and efficacy of catheter ablation of AF, with emphasis on the use of cryoballoon ablation and novel oral anticoagulants.
Methods and Results: There were 2497 consecutive patients undergoing catheter ablation of AF in 7 European high volume centers were stratified according to BMI (normal weight <25 kg/m2, pre‐obese 25–30 kg/m2, obesity 30–35 kg/m2, and morbid obesity ≥35 kg/m2) and comparisons of procedural outcomes evaluated. Pre‐obese and obese patients presented more comorbidities (hypertension, diabetes mellitus, and sleep apnea), and had higher rates of non‐paroxysmal AF ablation procedures. The rate of atrial 12‐month arrhythmia relapse increased alongside with BMI (35.2%, 35.7%, 43.6%, and 48.0% P<0.001). During a median follow‐up of 18.8 months (interquartile range 11–28), after adjusting for all baseline differences, BMI was an independent predictor of relapse (hazard ratio=1.01 per kg/m2; 95% CI 1.01–1.02; P=0.002), adding incremental predictive value to obstructive sleep apnea. BMI was not a predictor for any of the reported complications. Using novel oral anticoagulants and cryoballoon ablation was safe and efficacy was comparable with vitamin‐K antagonists and radiofrequency ablation.
Conclusions: Obese patients present with a more adverse comorbidity profile, more advanced forms of AF, and have lower chances of being free from AF relapse after ablation. Use of novel oral anticoagulants and cryoballoon ablation may be an option in this patient group.
In vivo functional diversity of midbrain dopamine neurons within identified axonal projections
(2019)
Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.
Intact-cell maldi-tof mass spectrometry for the authentication of drug-adapted cancer cell lines
(2019)
The use of cell lines in research can be affected by cell line misidentification. Short tandem repeat (STR) analysis is an effective method, and the gold standard, for the identification of the genetic origin of a cell line, but methods that allow the discrimination between cell lines of the same genetic origin are lacking. Here, we use intact cell MALDI-ToF mass spectrometry analysis, routinely used for the identification of bacteria in clinical diagnostic procedures, for the authentication of a set of cell lines consisting of three parental neuroblastoma cell lines (IMR-5, IMR-32 and UKF-NB-3) and eleven drug-adapted sublines. Principal component analysis (PCA) of intact-cell MALDI-ToF mass spectrometry data revealed clear differences between most, but not all, of the investigated cell lines. Mass spectrometry whole-cell fingerprints enabled the separation of IMR-32 and its clonal subline IMR-5. Sublines that had been adapted to closely related drugs, for example, the cisplatin- and oxaliplatin-resistant UKF-NB-3 sublines and the vincristine- and vinblastine-adapted IMR-5 sublines, also displayed clearly distinctive patterns. In conclusion, intact whole-cell MALDI-ToF mass spectrometry has the potential to be further developed into an authentication method for mammalian cells of a common genetic origin.
Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (cHL) are lymphomas that contain CD30-expressing tumor cells and have numerous pathological similarities. Whereas ALCL is usually diagnosed at an advanced stage, cHL more frequently presents with localized disease. The aim of the present study was to elucidate the mechanisms underlying the different clinical presentation of ALCL and cHL. Chemokine and chemokine receptor expression were similar in primary ALCL and cHL cases apart from the known overexpression of the chemokines CCL17 and CCL22 in the Hodgkin and Reed-Sternberg (HRS) cells of cHL. Consistent with the overexpression of these chemokines, primary cHL cases encountered a significantly denser T cell microenvironment than ALCL. Additionally to differences in the interaction with their microenvironment, cHL cell lines presented a lower and less efficient intrinsic cell motility than ALCL cell lines, as assessed by time-lapse microscopy in a collagen gel and transwell migration assays. We thus propose that the combination of impaired basal cell motility and differences in the interaction with the microenvironment hamper the dissemination of HRS cells in cHL when compared with the tumor cells of ALCL.
Inflammatory activation of astroglia adds to the pathology of various neurological diseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1α (IL-1α) with enhanced inflammatory signaling. This provokes pro-inflammatory gene expression of, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2 (Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely studied, pathways related to how metabolism modulates inflammatory signaling in astrocytes are underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects inflammatory responses towards IL-1α and tumor necrosis factor α in neonatal rat astrocytes. Blocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect activation of inflammatory signaling by IL-1α, but did elicit differential effects on inflammatory gene mRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1α was consistently up-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted from mRNA stabilization. Mitochondrial inhibitors also increased IL-1α-triggered secretion of eicosanoids, such as prostaglandin E2, prostaglandin F2α, and 6-keto-prostaglandin F1α, as assessed by liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation elevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK). AMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators recapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte inflammatory responses by oxidative metabolism, with relevance towards eicosanoid production.
Background: Receiving a cancer diagnosis can be a major life event which causes distress even years after primary treatment.
Aim: To examine the prevalence of distress in older patients with cancer (OPCs) up until 5 years post-diagnosis, and identify predictors present at time of diagnosis. Results are compared with reference groups of middle-aged patients with cancer (MPCs) and older patients without a cancer diagnosis (OPs).
Design & setting: OPCs, MPCs, and OPs participated in a longitudinal cohort study in Belgium and the Netherlands by filling in questionnaires at designated time points from 2010–2019.
Method: Data from 541 patients were analysed using multivariable logistic regression analyses.
Results: At baseline, 40% of OPCs, 37% of MPCs, and 17% of OPs reported distress. After 5 years, 35% of OPCs, 23% of MPCs, and 25% of OPs reported distress. No significant predictors for long-term distress in OPCs and OPs were found. For MPCs, it was found that baseline distress (odds ratio [OR] 2.94; 95% confidence intervals [CI] = 1.40 to 6.19) and baseline fatigue (OR 4.71; 95% CI = 1.81 to 12.31) predicted long-term distress.
Conclusion: Distress is an important problem for people with cancer, with peaks at different moments after diagnosis. Feelings of distress are present shortly after diagnosis but they decrease quickly for the majority of patients. In the long term, however, OPCs in particular appear to be most at risk for distress. This warrants extra attention from primary healthcare professionals, such as GPs who are often patients’ first medical contact point. More research into risk factors occurring later in an illness trajectory might shed more light on predictors for development of long-term distress.
Wie man weiß, zählt der Sozialstaat der Industrieepoche zu den ganz großen Innovationen in der Institutionengeschichte. Es entsteht ausgehend vom europäischen Norden und Westen und schnell mit kontinentalen und globalen Dimensionen ein hochkomplexes Geflecht aus Organisationen, aus juridischen und nicht-juridischen Normen und aus sozialen Praktiken, das auf die große – für das Schicksal der kapitalistischen Ordnung mitentscheidende – Herausforderung der "sozialen Frage" antwortet. Dabei ist dieses Gefüge nicht strukturell einheitlich, sondern durch erhebliche nationale Variation geprägt. Darüber hinaus entstehen die Institutionen im Rahmen der Einzelstaaten in keiner Weise gleichzeitig, sondern auf einer langgestreckten Zeitachse. Dieser Befund der hochgradigen Varianz kennzeichnet den Sektor der industriellen Beziehungen, in dem kollektive Akteure wesentliche Aufgaben des Sozialstaats "übernehmen", in einer besonders intensiven Weise. Es ist dieser Bereich, auf den wir sogleich näher eingehen. Im Weiteren kommt es auf dem Kontinent mit dem Aufstieg nicht-demokratischer Regime und deren Versionen des Sozialstaats zu einer zusätzlichen Komplizierung. Und schließlich tritt die neue Makrostruktur – ihren genetischen Raum überschreitend – alsbald im globalen Rahmen in Erscheinung. Ihre weltweiten Wirkungen sind immens, wie das 100-jährige Jubiläum der ILO unterstreichen mag. Und die Rückwirkungen und Irritationen vor allem aus neuen dynamischen Zentren des demokratisch verfassten Kapitalismus, zunächst der USA und dann auch Japans, sind es nicht minder. ...
Introduction: An overview of the requirements for the head of a surgical department in Germany should be given.
Materials and methods: A retrospective literature research on surgical professional policy publications of the last 10 years in Germany was conducted.
Results: Surveys show that commercial influences on medical decisions in German hospitals have today become an everyday, predominantly negative, actuality. Nevertheless, in one survey, 82.9% of surgical chief physicians reported being very satisfied with their profession, compared with 61.5% of senior physicians and only 43.4% of hospital specialists. Here, the chief physician is challenged. Only 70% of those surveyed stated that they could rely on their direct superiors when difficulties arose at work, and only 34.1% regarded feedback on the quality of their work as sufficient. The high distress rate in surgery (58.2% for all respondents) has led to a lack in desirability and is reflected in a shortage of qualified applicants for resident positions. In various position papers, surgical residents (only 35% describe their working conditions as good) demand improved working conditions. Chief physicians are being asked to facilitate a suitable work-life balance with regular working hours and a corporate culture with participative management and collegial cooperation. Appreciation of employee performance must also be expressed. An essential factor contributing to dissatisfaction is that residents fill a large part of their daily working hours with non-physician tasks. In surveys, 70% of respondents stated that they spend up to ≥3 h a day on documentation and secretarial work.
Discussion: The chief physician is expected to relieve his medical staff by employing non-physician assistants to take care of non-physician tasks. Transparent and clearly structured training to achieve specialist status is essential. It has been shown that a balanced work-life balance can be achieved for surgeons. Family and career can be reconciled in appropriately organized departments by making use of part-time and shift models that exclude 24-h shifts and making working hours more flexible.
The artworks of the Peruvian artist Carlos Runcie Tanaka, who has his British and Japanese Roots combined in his surname, refer to pre-Columbian ceramics and traditional Peruvian, Japanese and European practices. He represented Peru in ARCOmadrid 2019, the 12th Havana Biennial, the XXVI Sao Paulo Biennial, the 49th Venice Biennale, and the I Bienal Iberoamericana de Lima. In August, we sat down to talk about music, the past, the present, and the future. We discussed how all references of time can be combined into one material.
By studying pre-Columbian ceramics, researchers have developed several interpretations about the lifestyle and cosmovision of the ancient Peruvian people. Many of the techniques and motifs included in these traditional practices are still being passed on to communities throughout the country today. This ancestral knowledge is a fundamental element of identity. Therefore, ceramic is a material that has made the generation of historical discourse and the preservation of cultural memory possible. At the same time, ceramics are connected to aspects of our daily life. As objects of daily use (such as mugs, plates and bowls) they contribute to the fulfillment of basic needs. They are also included in ritual and funerary practices. In conclusion, the use of ceramics can be understood not only in a practical sense, but in an artistic sense as well.
Therapy of acute myeloid leukemia (AML) is unsatisfactory. Histone deacetylase inhibitors (HDACi) are active against leukemic cells in vitro and in vivo. Clinical data suggest further testing of such epigenetic drugs and to identify mechanisms and markers for their efficacy. Primary and permanent AML cells were screened for viability, replication stress/DNA damage, and regrowth capacities after single exposures to the clinically used pan-HDACi panobinostat (LBH589), the class I HDACi entinostat/romidepsin (MS-275/FK228), the HDAC3 inhibitor RGFP966, the HDAC6 inhibitor marbostat-100, the non-steroidal anti-inflammatory drug (NSAID) indomethacin, and the replication stress inducer hydroxyurea (HU). Immunoblotting was used to test if HDACi modulate the leukemia-associated transcription factors β-catenin, Wilms tumor (WT1), and myelocytomatosis oncogene (MYC). RNAi was used to delineate how these factors interact. We show that LBH589, MS-275, FK228, RGFP966, and HU induce apoptosis, replication stress/DNA damage, and apoptotic fragmentation of β-catenin. Indomethacin destabilizes β-catenin and potentiates anti-proliferative effects of HDACi. HDACi attenuate WT1 and MYC caspase-dependently and -independently. Genetic experiments reveal a cross-regulation between MYC and WT1 and a regulation of β-catenin by WT1. In conclusion, reduced levels of β-catenin, MYC, and WT1 are molecular markers for the efficacy of HDACi. HDAC3 inhibition induces apoptosis and disrupts tumor-associated protein expression.
Web spiders connect silk proteins, so-called spidroins, into fibers of extraordinary toughness. The spidroin N-terminal domain (NTD) plays a pivotal role in this process: it polymerizes spidroins through a complex mechanism of dimerization. Here we analyze sequences of spidroin NTDs and find an unusually high content of the amino acid methionine. We simultaneously mutate all methionines present in the hydrophobic core of a spidroin NTD from a nursery web spider’s dragline silk to leucine. The mutated NTD is strongly stabilized and folds at the theoretical speed limit. The structure of the mutant is preserved, yet its ability to dimerize is substantially impaired. We find that side chains of core methionines serve to mobilize the fold, which can thereby access various conformations and adapt the association interface for tight binding. Methionine in a hydrophobic core equips a protein with the capacity to dynamically change shape and thus to optimize its function.
Purpose: The aim of this study is to record material- and surface-dependent heat dissipation during the process of inserting implants into native animal bone. Materials and Methods: Implants made of titanium and zirconium that were identical in macrodesign were inserted under controlled conditions into a bovine rib tempered to 37 °C. The resulting surface temperature was measured on two bone windows by an infrared camera. The results of the six experimental groups, ceramic machined (1), sandblasted (2), and sandblasted and acid-etched surfaces (3) versus titanium implants with the corresponding surfaces (4, 5, and 6) were statistically tested. Results: The average temperature increase, 3 mm subcrestally at ceramic implants, differed with high statistical significance (p = 7.163 × 10−9, resulting from group-adjusted linear mixed-effects model) from titanium. The surface texture of ceramic implants shows a statistical difference between group 3 (15.44 ± 3.63 °C) and group 1 (19.94 ± 3.28 °C) or group 2 (19.39 ± 5.73 °C) surfaces. Within the titanium implants, the temperature changes were similar for all surfaces. Conclusion: Within the limits of an in vitro study, the high temperature rises at ceramic versus titanium implants should be limited by a very slow insertion velocity.
The group of neurodegenerative diseases, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) all exhibit inclusions containing amyloid-type α-synuclein (α-syn) aggregates within degenerating brain cells. α-syn also exists as soluble oligomeric species that are hypothesized to represent intermediates between its native and aggregated states. These oligomers are present in brain extracts from patients suffering from synucleinopathies and hold great potential as biomarkers. Although easily prepared in vitro, oligomers are metastable and dissociate over time, thereby complicating α-syn oligomer research. Using the small amine-reactive cross-linker, formaldehyde (FA), we successfully stabilized α-syn oligomers without affecting their size, overall structure or antigenicity towards aggregate-conformation specific α-syn antibodies FILA and MJFR-14-6-4-2. Further, cross-linked α-syn oligomers show resistance towards denaturant like urea and SDS treatment and remain fully functional as internal standard in an aggregation-specific enzyme-linked immunosorbent assay (ELISA) despite prior incubation with urea. We propose that FA cross-linked α-syn oligomers could serve as important calibrators to facilitate comparative and standardized α-syn biomarker studies going forward.
Narratives 2.0 : a multi-dimensional approach to semi-public storytelling in WhatsApp voice messages
(2019)
Based on a corpus of voice message narratives in German WhatsApp group chats, the present study contributes to research on social media storytelling in that it focusses on stories of personal experience which are embedded in a communication platform which favours a continuous dialogic exchange, narrated to well-defined non-anonymous publics and multimodal (comprised of visual and audible posting types). To capture the characteristics of this type of social media storytelling, the paper argues that Ochs and Capps’ (2001) dimensional model originally developed for conversational narratives (including the dimensions of tellability, tellership, embeddedness, linearity, moral stance) should be expanded by the dimensions of publicness, multimodality and sequencing. The prototype of storytelling in WhatsApp group chats is based on recent personal experiences; it is related by a single teller as an initial, sequentially non-embedded and linearly organised “big package” story (in a single voice message sometimes introduced by a text message containing an abstract); other group members routinely document their evaluative stances in rather conventionalised text message responses in the semi-public group space.
This contribution aims to describe privacy, publicness and anonymity as essential analytic dimensions for media linguistic research. The dimensions are not inherent in and predetermined by the technical features and forms of communication provided by mobile devices, but are used by the participants as an orientation grid for shaping their online and offline practices in and with mobile media. Considering both mobile device use in the public realm and the dissemination of increasingly private content in social media (which is said to lead to ‘blurred boundaries’ between the private and the public), the paper provides a brief overview of the main developments in mobile media research: Studies adopting various approaches – e. g. sociological-ethnographic, linguistic and media studies – illustrate how publicness, privacy and anonymity are actively shaped and brought about by mobile media users in face-to-face and remote social encounters. As this shows that publicness, privacy and anonymity are still relevant concepts for users, future media linguistics studies should focus on the dynamic multimodal practices by which they are contextualized and accomplished.
Die peripartale Depression tritt während der Schwangerschaft und in den 12 Monaten nach der Geburt auf. Zusätzlich zu Symptomen einer depressiven Episode ist die peripartale Depression durch schwangerschafts- oder kindbezogene Symptome wie infantizidale Vorstellungen, Gefühlslosigkeit gegenüber dem Kind, Versagensängste oder Insuffizienzgefühle als Mutter gekennzeichnet. Die Prävalenz liegt bei 7 bis 10 % präpartal und 7 bis 20 % postpartal. Folge ist ein erhöhtes Risiko für frühzeitige Wehentätigkeit, geringes Geburtsgewicht, intrauterine Wachstumsstörungen, Verhaltensstörungen und gestörte kognitive Entwicklung des Kindes. Außerdem steigt die Wahrscheinlichkeit für Mutter und Kind, im weiteren Leben erneut an einer Depression zu erkranken. Therapieoptionen stehen insbesondere psychotherapeutische Verfahren wie Interpersonelle Psychotherapie und Kognitive Verhaltenstherapie und eine antidepressive Therapie zur Verfügung.
Ziel der Arbeit war es, die Publikationen zu Depression und Schwangerschaft nach szientometrischen Kriterien zu analysieren und Charakteristika und Tendenzen der Forschung zu erkennen und zu interpretieren.
Nach Definition des Suchbegriffes wurden mithilfe der Datenbank Web of Science bzw. Web of Science Core Collection alle Publikationen zu Depression im Rahmen der Schwangerschaft von 1900 bis 2012 inklusive aller bibliometrischer Daten analysiert. Die Daten wurden nach Bereinigung hinsichtlich qualitativer Gesichtspunkte und szientometrischer Parameter wie Zitierungen, Zitationsrate und modifiziertem h-Index der Publikationen, Autoren, Institutionen und Nationen untersucht. Dabei wurden zusätzlich Genderaspekte und sozioökonomische Faktoren berücksichtigt.
Insgesamt wurden 7.330 Veröffentlichungen zu Pregnancy and Depression analysiert. 95,9 % davon waren in englischer Sprache veröffentlicht. Seit 1982 konnte eine kontinuierliche Zunahme der jährlichen Publikationen verzeichnet werden. Die Zahl der Zitierungen stieg seit 1979 ebenso jährlich an. Dabei sank die Zitationsrate seit 1990. Besonders viele Arbeiten wurden im Journal of Affective Disorders und im Archives of Womens Mental Health veröffentlicht. Unter den Forschungseinrichtungen fielen die Harvard University und St. George’s, University of London durch besonders viele Publikationen auf.
Wichtigste Wissenschaftsstandorte waren die USA, Großbritannien, Australien und Kanada, was sich in den meisten Publikationen, Zitierungen und den höchsten modifizierten h Indizes äußerte, gefolgt von meist europäischen Staaten. Unter Berücksichtigung sozioökonomischer Faktoren ergaben sich mehrere Besonderheiten: Die skandinavischen Staaten Norwegen, Schweden und Finnland finden sich unter den produktivsten Ländern nach Bereinigung um die Bevölkerungszahl. Nationen mit mittlerem und niedrigem Einkommen (Low- and middle income countries = LAMICs) wie Pakistan, Südafrika und Äthiopien leisten einen relevanten Beitrag zur Forschung, berücksichtigt man das Bruttoinlandsprodukt oder die Zahl der Wissenschaftler. Internationale Kooperation dieser Nationen entstanden insbesondere mit Großbritan-nien. Durch diese Zusammenarbeit wurde einerseits auf die höhere Prävalenz von Perinataler Depression in Entwicklungs und Schwellenländern hingewiesen. Andererseits wurde die schwangerschaftsassoziierte Depression als wichtiges Element von Global Mental Health anerkannt.
Seit 1992 veröffentlichen pro Jahr mehr Frauen als Männer zu Peripartaler Depression. Die weibliche Autorenschaft liegt bei 63 %. Unter den produktivsten Wissenschaftlern sind 8 Autorinnen und 6 Autoren. Die produktivsten Autoren sind die US Amerikanerin K.L. Wisner und die Britin L. Murray. Letztere wurde am häufigsten zitiert und führt die Liste der modifizierten h Indizes mit einem Wert von 68 an. Für den britischen Autor und Begründer des Screening-Instruments Edinburgh Postnatal Depression Scale (EPDS) J.L. Cox wurde die höchste Zitationsrate berechnet.
Im Gegensatz zu Veröffentlichungen in gynäkologischen Fachzeitschriften oder szientometrischen Arbeiten zu psychiatrischen Erkrankungen wie Schizophrenie ist der Frauenanteil in allen untersuchten Teilbereichen dem Männeranteil überlegen. Einzige Ausnahme ist die Letztautorenschaft. Diese Ergebnisse stellen eine Besonderheit dar, da eine weibliche Dominanz der Wissenschaft im Schnittbereich zwischen Psychiatrie, Psychosomatik, Psychologie und Frauenheilkunde bisher nicht beschrieben ist.
Comprehensive landscape of active deubiquitinating enzymes profiled by advanced chemoproteomics
(2019)
Enzymes that bind and process ubiquitin, a small 76-amino-acid protein, have been recognized as pharmacological targets in oncology, immunological disorders, and neurodegeneration. Mass spectrometry technology has now reached the capacity to cover the proteome with enough depth to interrogate entire biochemical pathways including those that contain DUBs and E3 ligase substrates. We have recently characterized the breast cancer cell (MCF7) deep proteome by detecting and quantifying ~10,000 proteins, and within this data set, we can detect endogenous expression of 65 deubiquitylating enzymes (DUBs), whereas matching transcriptomics detected 78 DUB mRNAs. Since enzyme activity provides another meaningful layer of information in addition to the expression levels, we have combined advanced mass spectrometry technology, pre-fractionation, and more potent/selective ubiquitin active-site probes with propargylic-based electrophiles to profile 74 DUBs including distinguishable isoforms for 5 DUBs in MCF7 crude extract material. Competition experiments with cysteine alkylating agents and pan-DUB inhibitors combined with probe labeling revealed the proportion of active cellular DUBs directly engaged with probes by label-free quantitative (LFQ) mass spectrometry. This demonstrated that USP13, 39, and 40 are non-reactive to probe, indicating restricted enzymatic activity under these cellular conditions. Our extended chemoproteomics workflow increases depth of covering the active DUBome, including isoform-specific resolution, and provides the framework for more comprehensive cell-based small-molecule DUB selectivity profiling.
Age Related Macular Degeneration (AMD) is the first cause of social blindness in people aged over 65 leading to atrophy of retinal pigment epithelial cells (RPE), photoreceptors and choroids, eventually associated with choroidal neovascularization. Accumulation of undigested cellular debris within RPE cells or under the RPE (Drusen), oxidative stress and inflammatory mediators contribute to the RPE cell death. The major risk to develop AMD is the Y402H polymorphism of complement factor H (CFH). CFH interacting with oxidized phospholipids on the RPE membrane modulates the functions of these cells, but the exact role of CFH in RPE cell death and survival remain poorly understood. The aim of this study was to analyze the potential protective mechanism of CFH on RPE cells submitted to oxidative stress. Upon exposure to oxidized lipids 4-HNE (4-hydroxy-2-nonenal) derived from photoreceptors, both the human RPE cell line ARPE-19 and RPE cells derived from human induced pluripotent stem cells were protected from death only in the presence of the full length human recombinant CFH in the culture medium. This protective effect was independent from the membrane attack complex (MAC) formation. CFH maintained RPE cells tight junctions’ structure and regulated the caspase dependent apoptosis process. These results demonstrated the CFH anti-oxidative stress functions independently of its capacity to inhibit MAC formation.
Critique, and especially radical critique of reason, is under pressure from two opponents. Whereas the proponents of "post-critical" or "acritical" thinking denounce critique as an empty and self-righteous repetition of debunking, the decriers of "post-truth" accuse critique of having helped to bring about our current "post-truth" politics. Both advocate realism as a limit critique must respect, but Vogelmann defends the claim that we urgently need radical critiques of reason because they offer a more precise diagnosis of the untruths in politics the two opponents of critique are rightfully worried about. Radical critiques of reason are possible, he argues, if we turn our attention to the practices of criticizing, if we refrain from a sovereign epistemology, and if we pluralize reason without trivializing it. In order to demonstrate the diagnostic advantage of radical critiques of reason, he briefly analyzes the political and epistemic strategy at work in two exemplary untruths in politics.
Critique, and especially radical critique of reason, is under pressure from two opponents. Whereas the proponents of "post-critical" or "acritical" thinking denounce critique as an empty and self-righteous repetition of debunking, the decriers of "post-truth" accuse critique of having helped to bring about our current "post-truth" politics. Both advocate realism as a limit critique must respect, but I will defend the claim that we urgently need radical critiques of reason because they offer a more precise diagnosis of the untruths in politics the two opponents of critique are rightfully worried about. Radical critiques of reason are possible, I argue, if we turn our attention to the practices of criticizing, if we refrain from a sovereign epistemology, and if we pluralize reason without trivializing it. In order to demonstrate the diagnostic advantage of radical critiques of reason, I briefly analyze the political and epistemic strategy at work in two exemplary untruths in politics.
Background and Aims: Vitamin D has an inhibitory role in the inflammatory signaling pathways and supports the integrity of the intestinal barrier. Due to its immunomodulatory effect, vitamin D plays a role in chronic inflammatory bowel disease (IBD) and a deficiency is associated with an increased risk for a flare. We aimed to investigate to what extent the 25-hydroxyvitamin D (25(OH)D3) level correlates with disease activity and whether a cut-off value can be defined that discriminates between active disease and remission. Methods: Patients with IBD, treated at the University Hospital Frankfurt were analyzed retrospectively. The 25(OH)D3 levels were correlated with clinical activity indices and laboratory chemical activity parameters. A deficiency was defined as 25(OH)D3 levels <30 ng/mL. Results: A total of 470 (257 female) patients with IBD were included, 272 (57.9%) with Crohn’s disease (CD), 198 (42.1%) with ulcerative colitis (UC). The median age of the patients was 41 (18–84). In 283 patients (60.2%), a vitamin D deficiency was detected. 245 (53.6%) patients received oral vitamin D supplementation, and supplemented patients had significantly higher vitamin D levels (p < 0.0001). Remission, vitamin D substitution, and male gender were independently associated with the 25(OH)D3 serum concentration in our cohort in regression analysis. A 25(OH)D3 serum concentration of 27.5 ng/mL was the optimal cut-off value. Conclusion: Vitamin D deficiency is common in IBD patients and appears to be associated with increased disease activity. In our study, vitamin D levels were inversely associated with disease activity. Thus, close monitoring should be established, and optimized supplementation should take place.
The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy
(2019)
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.
Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT.
Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset.
Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses.
Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.
Introduction: Our aim was to highlight the characteristics of pediatric Meckel's diverticulum with a special focus on its complications.
Methods: We report a group of seven patients with Meckel's diverticulum and its resection from the Department of Pediatric Surgery between 2012 and 2017. We reviewed all patient records, clinical presentation, and intraoperative findings. The diagnosis was confirmed by surgery and pathology. For a systematic literature review, we used PubMed, Medline and Google Scholar search engines to locate articles containing terms such as Meckel's diverticulum, children, pediatric, complications and symptomatic. We included article reporting on case series in English and German on pediatric patients only.
Results: All included patients (n = 7) were symptomatic. Some patients showed isolated symptoms, and others presented with a combination of symptoms that consisted of abdominal pain, bloody stool or vomiting. The median age of our seven cases was 3.5 years, including 4 male and 3 female patients. Intestinal obstruction was the most common complication; it was seen in 5 out of 7 patients (intussusception in 4 cases, volvulus in 1 case). Ectopic gastric tissue was identified in 3 cases, and inclusion of pancreatic tissue was observed in 1 case. The literature review identified 8 articles for a total of 641 patients aged between 1 day and 17 years and a male:female ratio of 2.6:1. From this group, 528 patients showed clinical symptoms related to Meckel's diverticulum. The most common symptom was abdominal pain and bloody stool. The most common surgical finding in symptomatic patients was intestinal obstruction (41%), followed by intestinal hemorrhage (34%). Complications such as perforation (10%) and diverticulitis (13%) were less frequently reported. Heterotopic tissue was confirmed on histopathology in 53% of all patients enclosing gastric, pancreatic, and both gastric and pancreatic mucosae. In one case, large intestine tissue could be found. Overall, one death was reported.
Conclusion: The presented case series and literature review found similar clinical presentations and complications of Meckel's diverticulum in children. Intestinal obstruction and bleeding are more frequent than inflammation in pediatric Meckel's diverticulum. Bowel obstruction is the leading cause for complicated Meckel's diverticulum in patients younger than 12 years.
About 200 years ago, legal concepts based on the idea of formal equality prevailed. Over the last 150 years, however, the law has tried on a large scale to establish substantive equality, or at least to alleviate social and economic imbalances. To this day, the law which has undertaken this task has grown in scope and become increasingly differentiated. It has become one of the most important components of modern legal systems and has a history with its own distinctive contours. The terms used to summarise the corresponding legal materials are manifold: law of the welfare state, law of the provident state (état providence) (François Ewald), social law, social welfare law, etc. ...
The use of contractual engineering to create channels of credit intermediation outside of the realm of banking regulation has been a recurring activity in Western financial systems over the last 50 years. After the financial crisis of 2007 and 2008, this phenomenon, at that time commonly referred to as ‘shadow banking’, evoked a large-scale regulatory backlash, including several specific regulatory constraints being placed on non-bank financial institutions (NBFI). This paper proposes a different avenue for regulators to keep regulatory arbitrage under control and preserve sufficient space for efficient financial innovation. Rather than engaging in the proverbial race between hare and hedgehog that is emerging with increasingly specific regulation of particular contractual arrangements, this paper argues for a normative approach to supervision. We outline this approach in detail by showing that regulators should primarily analyse the allocation of tail risk inherent in the respective contractual arrangements. Our paper proposes to assign regulatory burdens equivalent to prudential banking regulation, in case these arrangements become only viable through indirect or direct access to an (ad hoc) public backstop. In order to make the pivotal assessment, regulators will need information about recent contractual innovations and their risk-allocating characteristics. According to the scholarship on regulatory networks serving as communities of interpretation, we suggest in particular how regulators should structure their relationships with semi-public gatekeepers such as lawyers, auditors and consultants to keep abreast of the real-world implications of evolving transactional structures. This paper then uses the rise of credit funds as a non-bank entities economically engaged in credit intermediation to apply this normative framework, pointing to recent contractual innovations that call for more regulatory scrutiny in a multipolar regulatory dialogue.
The article analyses how the decrees of the Council of Trent regarding marriage were used by the Church of Rome as a tool to contrast mixed marriages in Early Modern Europe. It investigates how these decrees were evaded by local churches in order to administer a practice of confessional coexistence impossible to eradicate, and how they were manipulated by actors – even Protestants – to put an end to undesirable unions. It also presents the interpretation that the Church of Rome made of the Tametsi to resolve the age-old issue of mixed marriages in the Low Countries, issuing the Benedictine Declaration, later applied to other contexts with a strong Protestant presence – above all out-side Europe. Although the Council of Trent claimed to have fixed a homogeneous and flawless nuptial ritual, the various local practices did not always adapt to it. Indeed, they bypassed it; sometimes refused it. This led parish priests and missionaries to turn to Rome for the resolution of concrete cases. The decisions taken for individual cases became a normative reference point. It was produced by the continuous interaction and negotiation with local churches and went on in fact to profoundly influence the sacramental rituality of marriages, which Tametsi had claimed were fixed and immutable.
Worldwide, academics and practitioners are developing ‘planning-oriented’ approaches to reduce the negative impacts of car traffic for more sustainable urban and transport development. One such example is the design of car-reduced neighborhoods, although these are controversial issues in the hegemonic ‘system’ of automobility. Despite the reduction of emissions and frequent recognition as ‘best practice examples’, ‘planning-critical’ research questions the underlying objectives and narratives of such sustainable developments. Our study contributes to this research perspective by improving the understanding of narratives that emerge along with car-reduced housing developments. For this purpose, we analyze two car-reduced neighborhoods in the City of Darmstadt (Germany) by conducting interviews with different actors involved in the planning and implementation processes. Our investigation reveals that the development of car-reduced neighborhoods (i) is consciously embedded in the context of sustainability, (ii) is characterized by power relations, (iii) follows normative indicators, and (iv) does not always correspond to lived realities. Altogether, the traced narratives of car-reduced neighborhoods are embedded in the overarching debate on sustainability, while at the same time revealing the dependence of society on the automobile. Thus, the hegemonic ‘system’ of automobility—although it is beginning to crack—continues to exist.
The 100th anniversary of the Weimar Constitution’s promulgation has brought a number of new stimuli to a historiography that has for a long time focused largely on the Weimar Republic’s failure. Two prominent recent publications – Udo Di Fabio’s study and a collective volume edited by Horst Dreier und Christian Waldhoff – are reviewed in this issue by the Brazilian constitutional historian Marcelo Neves. His review and the last months’ public debate on the merits and flaws of the Weimar Constitution in Germany, which was framed by current concerns about the state of Western democracies, show to what extent constitutional history is always also a conversation about the present. ...