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Start Thinking in Systems / Berthold Kracke
Buying into Fraud – German Retail Investors and the Wirecard Scandal / Konstantin Bräuer, Andreas Hackethal, Guido Lenz, Thomas Pauls
Insights from Explainable Interactive Machine Learning in the Age of COVID-19 / Oliver Hinz, Nicolas Pfeuffer, Wolfgang Stammer, Patrick Schramowski, Benjamin M. Abdel-Karim, Andreas Bucher, Christian Hügel, Gernot Rohde, Kristian Kersting
The Customer Determines the Success or Failure of the Company : interview with Philipp Schmitt
The ongoing digitalization of educational resources and the use of the internet lead to a steady increase of potentially available learning media. However, many of the media which are used for educational purposes have not been designed specifically for teaching and learning. Usually, linguistic criteria of readability and comprehensibility as well as content-related criteria are used independently to assess and compare the quality of educational media. This also holds true for educational media used in economics. This article aims to improve the analysis of textual learning media used in economic education by drawing on threshold concepts. Threshold concepts are key terms in knowledge acquisition within a domain. From a linguistic perspective, however, threshold concepts are instances of specialized vocabularies, exhibiting particular linguistic features. In three kinds of (German) resources, namely in textbooks, in newspapers, and on Wikipedia, we investigate the distributive profiles of 63 threshold concepts identified in economics education (which have been collected from threshold concept research). We looked at the threshold concepts' frequency distribution, their compound distribution, and their network structure within the three kinds of resources. The two main findings of our analysis show that firstly, the three kinds of resources can indeed be distinguished in terms of their threshold concepts' profiles. Secondly, Wikipedia definitely shows stronger associative connections between economic threshold concepts than the other sources. We discuss the findings in relation to adequate media use for teaching and learning—not only in economic education.
Introduction Occurrence of inaccurate or delayed diagnoses is a significant concern in patient care, particularly in emergency medicine, where decision making is often constrained by high throughput and inaccurate admission diagnoses. Artificial intelligence-based diagnostic decision support system have been developed to enhance clinical performance by suggesting differential diagnoses to a given case, based on an integrated medical knowledge base and machine learning techniques. The purpose of the study is to evaluate the diagnostic accuracy of Ada, an app-based diagnostic tool and the impact on patient outcome.
Methods and analysis The eRadaR trial is a prospective, double-blinded study with patients presenting to the emergency room (ER) with abdominal pain. At initial contact in the ER, a structured interview will be performed using the Ada-App and both, patients and attending physicians, will be blinded to the proposed diagnosis lists until trial completion. Throughout the study, clinical data relating to diagnostic findings and types of therapy will be obtained and the follow-up until day 90 will comprise occurrence of complications and overall survival of patients. The primary efficacy of the trial is defined by the percentage of correct diagnoses suggested by Ada compared with the final discharge diagnosis. Further, accuracy and timing of diagnosis will be compared with decision making of classical doctor–patient interaction. Secondary objectives are complications, length of hospital stay and overall survival.
Ethics and dissemination Ethical approval was received by the independent ethics committee (IEC) of the Goethe-University Frankfurt on 9 April 2020 including the patient information material and informed consent form. All protocol amendments must be reported to and adapted by the IEC. The results from this study will be submitted to peer-reviewed journals and reported at suitable national and international meetings.
Trial registration number DRKS00019098.
The Kinase Chemogenomic Set (KCGS): an open science resource for kinase vulnerability identification
(2021)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Drawing on the role of teachers for peer ecologies, we investigated whether students favored ethnically homogenous over ethnically diverse relationships, depending on classroom diversity and perceived teacher care. We specifically studied students’ intra- and interethnic relationships in classrooms with different ethnic compositions, accounting for homogeneous subgroups forming on the basis of ethnicity and gender diversity (i.e., ethnic-demographic faultlines). Based on multilevel social network analyses of dyadic networks between 1299 early adolescents in 70 German fourth grade classrooms, the results indicated strong ethnic homophily, particularly driven by German students who favored ethnically homogenous dyads over mixed dyads. As anticipated, the results showed that there was more in-group bias if perceived teacher care was low rather than high. Moreover, stronger faultlines were associated with stronger in-group bias; however, this relation was moderated by teacher care: If students perceived high teacher care, they showed a higher preference for mixed-ethnic dyads, even in classrooms with strong faultlines. These findings highlight the central role of teachers as agents of positive diversity management and the need to consider contextual classroom factors other than ethnic diversity when investigating intergroup relations in schools.
Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
Inflammation is a crucial part of immune responses towards invading pathogens or tissue damage. While inflammatory reactions are aimed at removing the triggering stimulus, it is important that these processes are terminated in a coordinate manner to prevent excessive tissue damage due to the highly reactive inflammatory environment. Initiation of inflammatory responses was proposed to be regulated predominantly at a transcriptional level, whereas post-transcriptional modes of regulation appear to be crucial for resolution of inflammation. The RNA-binding protein tristetraprolin (TTP) interacts with AU-rich elements in the 3′ untranslated region of mRNAs, recruits deadenylase complexes and thereby facilitates degradation of its targets. As TTP regulates the mRNA stability of numerous inflammatory mediators, it was put forward as a crucial post-transcriptional regulator of inflammation. Here, we summarize the current understanding of the function of TTP with a specific focus on its role in adding to resolution of inflammation.
Protein ubiquitination is a post-translational modification that typically involves the conjugation of ubiquitin to substrate proteins via a three-enzyme cascade and regulates a wide variety of cellular processes. Recent studies have revealed that SidE family of Legionella effectors such as SdeA catalyzes novel phosphoribosyl-linked ubiquitination (PR-ubiquitination) of serines in host substrate proteins utilizing NAD+, without the need of E2, E3. The catalytic core of SdeA comprises a mono-ADP-ribosyltransferase (mART) domain that functions to ADP-ribosylate ubiquitin, and a phosphodiesterase (PDE) domain that processes ADP-ribosylated ubiquitin and transfers the resulting phosphoribosylated ubiquitin to serines of substrates.
To date, extensive efforts have been made to study the function of SdeA and mechanism of SdeA mediated PR-ubiquitination, however, the cellular effects of this novel ubiquitination and phosphoribosylation of ubiquitin remained poorly understood. In our study, using biochemical and cell biological approaches, we explored the biological effect of phosphoribosylation of ubiquitin caused by SdeA in cells. We found that phosphoribosylated ubiquitin is not available for conventional ubiquitination, thereby phosphoribosylation of ubiquitin impairs numerous classical ubiquitination related cellular processes including mitophagy, TNF-α signaling and proteasomal degradation.
The precise temporal regulation of the functions of bacterial effectors during Legionella infection by other effectors with antagonizing activities has been well studied so far. Not surprisingly, PR-ubiquitination catalyzed by SidE family effecters is tightly controlled as well, it has been long known that effector SidJ counteracts the toxicity of SdeA to yeast cells. Interestingly, in an experiment for verifying the activity of SidJ, we found that Legionella lysate lacking SidJ was still able to remove ubiquitin from PR-ubiquitinated substrates. Using biochemical approach we identified DupA and DupB, two Legionella bacterial effectors that specifically reverse the novel serine PR-ubiquitination catalyzed by SdeA. We found that DupA and DupB possess a highly homologous PDE domain that removes ubiquitin from PR-ubiquitinated substrates by cleaving the phosphodiester bond between the phosphoribosylated-ubiquitin and serines of substrates. Catalytically deficient mutant DupA H67A strongly binds to PR-ubiquitinated proteins but not capable of cleaving PR-ubiquitin, using it as a trapping bait we identified over 180 substrates of PR-ubiquitination, including a number of ER and Golgi proteins.
In particular, we found that exogenously expressed SdeA localizes to the Golgi apparatus via its C-terminal region and disrupts the Golgi. We validated the identified potential substrates of SidE effectors and found that SdeA modifies Golgi tethering proteins GRASP55 and GRASP65. Using mass spectrometry analyses we identified four serine targets (S3, S408, S409, S449) of GRASP55 PR-ubiquitinated by SdeA in vitro. Ubiquitination of GRASP55 serine mutant in cells co-expressing SdeA or infected with Legionella was markedly decreased, compared with that of the wild-type GRASP55. In addition, with co-immunoprecipitation analyses we found that SdeA-catalyzed ubiquitination regulates the function of GRASP55. PR-ubiquitinated GRASP55 exhibited reduced self-interaction compared to unmodified GRASP55, expression of GRASP55 serine mutant in cells in part rescued Golgi damage caused by SdeA. Furthermore, our study reveals that Golgi structure disruption caused by SdeA does not result in the recruitment of Golgi membranes to the Legionella-containing vacuoles. Instead, it affects cellular secretory pathway including cytokine secretion in cells.
Taken all together, this work expands the understanding of this unconventional PR-ubiquitination catalyzed by Legionella effectors and sheds light on the functions of PR-ubiquitination by which Legionella regulates the Golgi function and secretion pathway during bacterial infection.
Ziel der Studie: Eine psychische Komorbidität spielt im Kontext mit weiteren persönlichen, sozialen und beruflichen Faktoren bei der Ermittlung des spezifischen Rehabilitationsbedarfs der Patienten in Deutschland eine immer bedeutendere Rolle. Um die Zuweisung von Patienten zu einer Rehabilitationsform besser ausdifferenzieren zu können, soll im Rahmen dieser retrospektiven Analyse ermittelt werden, von welchem der beiden untersuchten Rehabilitationskonzepte (OR/VMO) Patienten mit psychischer Komorbidität unter Berücksichtigung von Geschlecht, Erwerbsstatus und orthopädischer Hauptdiagnose stärker profitieren.
Methodik: Mittels der Screening-Fragebögen HADS-A, HADS-D, SIMBO und BPI sowie eines Klinikfragebogens zu Beginn der Rehabilitation wurden Angaben von 913 Probanden (529 m/384 w) ausgewertet. Hiervon wurden 43 % der OR und 57 % der VMO zugewiesen. So wurde die Häufigkeitsverteilung der Faktoren psychische Komorbidität, Geschlecht, Erwerbsstatus und orthopädische Hauptdiagnose festgestellt. Mittels HADS wurde am Ende der Therapie der Benefit durch Vergleich der Scorewert-Mediane ermittelt.
Ergebnisse: Häufigkeitsverteilungen und die Entwicklung der HADS-Scores zeigen, dass die im Vorfeld erfolgte Einteilung gemäß psychischer Komorbidität korrekt war. Frauen waren häufiger von einer psychischen Komorbidität betroffen und erzielten in der VMO größere Erfolge. Bezüglich der orthopädischen Hauptdiagnose ergab sich eine hohe Prävalenz von HWS- und LWS-Beschwerden. Beim Erwerbsstatus (Arbeits(un)fähigkeit, Arbeitslosigkeit, berufliche Problemlage) zeigte sich ein diffuseres Bild, das keine generalisierende Aussage bezüglich der arbeitsweltbezogenen Faktoren zulässt.
Schlussfolgerungen: Das Vorliegen einer psychischen Komorbidität stellt einen zielführenden Indikator dar, der als eines der Hauptzuweisungskriterien zur VMO beizubehalten ist. Auch das weibliche Geschlecht in Verbindung mit dem Vorliegen einer psychischen Komorbidität ist als adäquates Kriterium anzusehen. Bezüglich der orthopädischen Hauptdiagnose können insbesondere HWS-Beschwerden als Zuweisungskriterium geeignet sein. Aufgrund der sehr heterogenen Ergebnisse hinsichtlich der Aspekte des Erwerbsstatus lässt sich festhalten, dass diesbezüglich eine Zuweisung zu einem arbeitsweltbezogenen Therapiekonzept (z. B. MBOR) zielführender erscheint.
The aim of this work was to establish a new way of predicting novel dual active compounds by combining classical fingerprint representation with state-of-the-art machine learning algorithms. Advantages and disadvantages of the applied 2D- and 3D-fingerprints were investigated. Further, the impact of various machine learning algorithms was analyzed. The new method developed in this work was used to predict compounds, which inhibit two different targets (LTA4H and sEH) involved in the same disease pattern (inflammation). The development of multitarget drugs has become more important in recent years. Many widespread diseases like metabolic syndrome, or cancer are of a multifactorial nature, which makes them hard to be treated effectively with a single drug. The new in silico method presented in this work can help to accelerate the design and development of multitarget drugs, saving time and efforts.
The nowadays readily available access to a large number of 3D-structures of biological targets and published activity data of millions of synthesized compounds enabled this study and was used as a starting point for this work. Four different data sets were compiled (crystalized ligands from the PDB, active and inactive compounds from ChEMBL23, newly designed compounds using a combinatorial library). Those data sets were collected and processed using an automated KNIME workflow. This automation has the advantage of allowing easy change and update of compound sources and adapted processing ways.
In a next step, the compounds from the compiled data sets were represented using a variety of well-established 2D- and 3D-fingerprints (PLIF, AtomPair, Morgan, FeatMorgan, MACCS). All those fingerprints share the same underlying bit string scheme but vary in the way they describe the molecular structure. Especially the difference between 2D- and 3D-fingerprints was investigated. 2D-fingerprints are solely based on ligand information. 3D-fingerprints, on the other hand, are based on X-ray structure information of protein-ligand complexes. One major difference between 2D- and 3D-fingerprints usage is the need for a 3D-conformation (pose) of the compound in the targets of interest when using 3D-fingerprints. This additional step is time-consuming and brings further uncertainties to the method.
Based on the calculated fingerprints state-of-the-art machine learning algorithms (SVC, RF, XGB and ADA) were used to predict novel dual active compounds. The models were evaluated by 10-fold cross validation and accuracy as the primary measure of model performance was maximized. Second, individual parameters of the four machine learning algorithms were optimized in a grid search to achieve maximal accuracy using the optimized partitioning scheme. Overall accuracies, regardless of fingerprint and machine learning algorithm, are slightly better for LTA4H than for sEH.
The goal to predict dual active compounds was realized by comparing the set of predicted to be active compounds for LTA4H and sEH. For the 3D-fingerprint PLIF the machine learning algorithm Random Forest was chosen, from which compounds for synthesis and testing were selected. Of 115 predicted to be active compounds, six compounds were cherry picked. Two compounds showed very good/moderate dual inhibitory activity. Of the 2D-fingerprints, the AtomPair fingerprint in combination with the machine learning algorithm Random Forest was chosen from which compounds were selected for synthesis and testing. 116 compounds were predicted to be dual active against LTA4H and sEH. One of those compounds showed good dual inhibitory activity.
In this work it was possible to show advantages and disadvantages of using 2D- and 3D-fingerprints in combination with machine learning algorithms. Both strategies (2D: ligand-based, 3D: structure-based) lead to the prediction of novel dual active compounds with moderate to very good inhibitory activity. The method developed in this work is able to predict dual active compounds with very good inhibitory activity and novel (previously unknown) scaffolds inhibiting the targets LTA4H and sEH. This contribution to in silico drug design is promising and can be used for the prediction of novel dual active compounds. Those compounds can further be optimized regarding binding affinity, solubility and further pharmacological and physicochemical properties.
Empathie ist ein mehrdimensionales psychologisches Konstrukt, das aus verschiedenen Facetten besteht (Decety & Ickes, 2011). Es ist anzunehmen, dass Empathie ein wichtiger Mechanismus ist, um Menschen miteinander zu verbinden und eine Gruppenkohäsion möglich zu machen (Rameson & Lieberman, 2009). Neben der Fähigkeit die Erlebenswelt des Gegenübers mit eigenen mentalen Repräsentationen nachzuvollziehen, werden dadurch Emotionen ausgelöst, die denen des Gegenübers sehr ähnlich sind. Gleichzeitig unterscheidet sich dieses Gefühlserleben aber beispielsweise von reiner Gefühlsansteckung, da eine Selbst-Andere Differenzierung stattfindet und in einer empathischen Episode immer im Vordergrund steht, dass man sich aufgrund der Gefühle des anderen so fühlt (Altmann, 2015). Hier spielt Imitation eine wichtige Rolle, wenn es darum geht, die Erlebenswelt der anderen Person zu erfassen (Meltzoff & Decety, 2003). Besonders auch bei Lehrkräften zeigt sich eine Wichtigkeit von empathischem Handeln und Verstehen (Tausch & Tausch, 2008). In verschiedenen Studien zeigten sich positive Effekte von Empathie auf die Schülerschaft und die Unterrichtsqualität. Die SchülerInnen trauen sich mehr, es herrscht weniger Angst im Klassenzimmer und die Qualität der Unterrichtsbeiträge steigt (vgl. Tausch & Tausch, 1998). Empathie selbst besteht aus State- und Trait-Anteilen, so dass zumindest Teile davon trainierbar sind (Butters, 2010). Eine potentielle Möglichkeit um Empathie zu fördern scheint das Lehr-Lern-Format Service Learning (SL) darzustellen. Hierbei handelt es sich um ein Veranstaltungskonzept, bei dem ein meist fachlicher, akademischer Inhalt mit einem ehrenamtlichen Engagement außerhalb der Universität verknüpft wird (Reinders, 2016). Forschung aus dem angloamerikanischen Raum weist darauf hin, dass Empathie durch derartige Formate gefördert werden kann (Lundy, 2007; Wilson, 2011). Da die meisten Messverfahren von Empathie auf Selbstauskunft basieren und damit nur indirekt Anteile wie das affektive Mitschwingen abbilden können, war es Teil dieser Arbeit im ersten Schritt einen objektiven, videobasierten Test zu entwickeln, der dann mit anderen Verfahren zur Messung eingesetzt werden sollte. In zwei ExpertInnen-Befragungen wurden aus einem Pool von Videosequenzen mit Unterrichtssituationen insgesamt zehn Videoclips mit jeweils vier Items und zugehörigen Antwortoptionen extrahiert. In einer darauf folgenden Validierung mit Studierenden der Goethe-Universität (N = 112) wurden diese Vignetten mit verschiedenen Verfahren zur Messung von Empathie gemeinsam erhoben und die Zusammenhänge analysiert. Die Reliabilitäten der drei Testscores bewegten sich in den beiden gebildeten Testversionen zwischen Cronbachs α = .53 (Verhaltens-Score der Testversion 1) und α = .76 (Intensitäts-Score der Testversion 2). Es zeigten sich zu allen Fragebögen erwartungskonforme Zusammenhänge von kleinen bis mittleren Effekten. Die Itemschwierigkeiten bei den meisten Items lagen zwischen 50 und 65, die Trennschärfen zwischen .18 und .70.
Im nächsten Entwicklungsschritt wurden die Vignetten in neu zusammengestellten Testversionen nur Lehramtsstudierenden (N = 41) vorgelegt und zusätzlich Videoaufnahmen der Gesichter der ProbandInnen gemacht, um sie mit Face-Reader zu analysieren und die Facette Mitschwingen abzubilden. Die Reliabilitäten der Testversionen lagen mit einem neuen Scoring nun zwischen α = .24 (Emotionserkennungs-Score Prä-Testversion) und
α = .57 (Intensitäts-Score Prä-Testversion) sowie zwischen α = .10 (Emotionserkennungs-Score Post-Testversion) und α = .77 (Intensitäts-Score Post-Testversion). Auch die Schwierigkeiten und Trennschärfen änderten sich nach Adaptieren des Scorings und bewegten sich in beiden Testversionen nun von 30 bis 89 (Schwierigkeit) und von .0 bis .5 (Trennschärfe). Die Face-Reader Analysen zeigten nur in Teilen kongruente Emotionen mit den Selbstauskunftsdaten bzw. den eingeschätzten Intensitäten in den Videosequenzen, dann allerdings mittlere bis große Effekte, so dass in Teilen von einem affektiven Mitschwingen ausgegangen werden kann. Da sich die internen Konsistenzen im Vergleich zur Validierung verschlechterten, wurden die Zusammensetzungen der Testversionen für den Praxiseinsatz wieder auf die Validierungs-Versionen umgestellt.
Im Praxiseinsatz wurden Lehramtsstudierende in SL und Non-SL-Veranstaltungen rekrutiert und miteinander verglichen. Insgesamt nahmen N = 68 Personen an drei Messzeitpunkten teil (n = 30 in SL und n = 38 in Non-SL-Seminaren). Die Analysen zeigten, dass es zwischen den Gruppen keine signifikanten Unterschiede in den genutzten Instrumenten gab. Auch über die Zeit gab es nach der Bonferroni-Korrektur nur einen signifikanten Effekt (F (2,52) = 6.57, p = .003, η2 = .20). Es ist anzunehmen, dass diese Ergebnisse vor allem auf methodische Einschränkungen und Verbesserungsmöglichkeiten des entwickelten Testverfahrens zurückzuführen sind. Weitere Möglichkeiten werden diskutiert.
The authors embed human capital-based endogenous growth into a New-Keynesian model with search and matching frictions in the labor market and skill obsolescence from long-term unemployment. The model can account for key features of the Great Recession: a decline in productivity growth, the relative stability of inflation despite a pronounced fall in output (the "missing disinflation puzzle"), and a permanent gap between output and the pre-crisis trend output.
In the model, lower aggregate demand raises unemployment and the training costs associated with skill obsolescence. Lower employment hinders learning-by-doing, which slows down human capital accumulation, feeding back into even fewer vacancies than justified by the demand shock alone. These feedback channels mitigate the disinflationary effect of the demand shock while amplifying its contractionary effect on output. The temporary growth slowdown translates into output hysteresis (permanently lower output and labor productivity).
Occasionally binding constraints have become an important part of economic modelling, especially since western central banks see themselves (again) constraint by the so-called zero lower bound (ZLB) of the nominal interest rate. A binding ZLB constraint poses a major problem for a quantitative-structural analysis: Linear solution methods do no work in the presence of a non-linearity such as the ZLB and existing alternatives tend to be computationally demanding. The urge to study macroeconomic questions related to the Great Recession and the Covid-19 crisis in a quantitative-structural framework requires algorithms that are not only accurate, but that are also robust, fast, and computationally efficient.
A particularly important application where efficient and fast methods for occasionally binding constraints (OBCs) are needed is the Bayesian estimation of macroeconomic models. This paper shows that a linear dynamic rational expectations system with OBCs, depending on the expected duration of the constraint, can be represented in closed form. Combined with a set of simple equilibrium conditions, this can be exploited to avoid matrix inversions and simulations at runtime for signifcant gains in computational speed.
Central banks sometimes evaluate their own policies. To assess the inherent conflict of interest, the authors compare the research findings of central bank researchers and academic economists regarding the macroeconomic effects of quantitative easing (QE). They find that central bank papers report larger effects of QE on output and inflation. Central bankers are also more likely to report significant effects of QE on output and to use more positive language in the abstract. Central bankers who report larger QE effects on output experience more favorable career outcomes. A survey of central banks reveals substantial involvement of bank management in research production.
Empirical estimates of equilibrium real interest rates are so far mostly limited to advanced economies, since no statistical procedure suitable for a large set of countries is available. This is surprising, as equilibrium rates have strong policy implications in emerging markets and developing economies as well; current estimates of the global equilibrium rate rely on only a few countries; and estimates for a more diverse set of countries can improve understanding of the drivers. The authors propose a model and estimation strategy that decompose ex ante real interest rates into a permanent and transitory component even with short samples and high volatility. This is done with an unobserved component local level stochastic volatility model, which is used to estimate equilibrium rates for 50 countries with Bayesian methods.
Equilibrium rates were lower in emerging markets and developing economies than in advanced economies in the 1980s, similar in the 1990s, and have been higher since 2000. In line with economic integration and rising global capital markets, synchronization has been rising over time and is higher among advanced economies. Equilibrium rates of countries with stronger trade linkages and similar demographic and economic trends are more synchronized.
With the second wave of the Covid-19 pandemic in full swing, banks face a challenging environment. They will need to address disappointing results and adverse balance sheet restatements, the intensity of which depends on the evolution of the euro area economies. At the same time, vulnerable banks reinforce real economy deficiencies. The contribution of this paper is to provide a comparative assessment of the various policy responses to address a looming banking crisis. Such a crisis will fully materialize when non-performing assets drag down banks simultaneously, raising the specter of a full-blown systemic crisis. The policy responses available range from forbearance, recapitalization (with public or private resources), asset separation (bad banks, at national or EU level), to debt conversion schemes. We evaluate these responses according to a set of five criteria that define the efficacy of each. These responses are not mutually exclusive, in practice, as they have never been. They may also go hand in hand with other restructuring initiatives, including potential consolidation in the banking sector. Although we do not make a specific recommendation, we provide a framework for policymakers to guide them in their decision making.
This policy white paper shows, using data on European Commission (EC) lobby meetings, that financial institutions and finance trade associations have substantial access to EC policymakers. While lobbying could transfer policy-relevant information and expertise to policymakers, it could also result in the capture of policymakers by the industry, which could harm consumers and taxpayers. How could policymakers prevent regulatory capture, but retain the benefits of the sector expertise in policy decisions? Awareness of regulatory capture by policymakers is one of the most important remedies. This paper provides an overview of the origins of the regulatory capture theory and recent academic evidence. The paper shows that regulatory capture could emerge in a variety of institutions and policy areas but is not ubiquitous and depends on the incentives of policymakers and the policy environment. Subsequently, the paper discusses various measures to prevent regulatory capture, such as more transparency, diverse expert groups, and cooling-off periods.
The genetic background of pain is becoming increasingly well understood, which opens up possibilities for predicting the individual risk of persistent pain and the use of tailored therapies adapted to the variant pattern of the patient’s pain-relevant genes. The individual variant pattern of pain-relevant genes is accessible via next-generation sequencing, although the analysis of all “pain genes” would be expensive. Here, we report on the development of a cost-effective next generation sequencing-based pain-genotyping assay comprising the development of a customized AmpliSeq™ panel and bioinformatics approaches that condensate the genetic information of pain by identifying the most representative genes. The panel includes 29 key genes that have been shown to cover 70% of the biological functions exerted by a list of 540 so-called “pain genes” derived from transgenic mice experiments. These were supplemented by 43 additional genes that had been independently proposed as relevant for persistent pain. The functional genomics covered by the resulting 72 genes is particularly represented by mitogen-activated protein kinase of extracellular signal-regulated kinase and cytokine production and secretion. The present genotyping assay was established in 61 subjects of Caucasian ethnicity and investigates the functional role of the selected genes in the context of the known genetic architecture of pain without seeking functional associations for pain. The assay identified a total of 691 genetic variants, of which many have reports for a clinical relevance for pain or in another context. The assay is applicable for small to large-scale experimental setups at contemporary genotyping costs.
In den letzen 30 bis 40 Jahren sind Kommunen verstärkt dazu übergegangen die in ihrem Besitz befindlichen Flächen zu verkaufen und so ihre kommunalen Gestaltungsspielräume zu verlieren. Diese Privatisierungspolitik der „unternehmerischen Stadt“ hat verkannt, dass Boden für Kommunen ein endliches und essentielles Gut ist, welches nicht vermehrt werden kann.
Gerade in den lokalen Räumen der Kommunen wird der Kampf um den begrenzten Boden besonders sichtbar. Das Alltagsleben der Menschen wird dadurch bestimmt, ob Boden im Privateigentum ist und vorrangig der Kapitalvermehrung dient oder ob Boden ein gesellschaftliches Gemeingut ist. Die Privatisierung neoliberaler Kommunalpolitik hat – entgegen der Erwartungen – weder das Leben in den Städten besser noch günstiger gemacht. Die Kosten für Mieten und die privatisierten Leistungen aus Daseinsvorsorge sind in den letzten Jahrzehnten extrem gestiegen. Letztere wurden z. T. auch verkleinert oder vollkommen aufgegeben, wie z. B. der öffentliche Nahverkehr in ländlichen Räumen oder die Schließungen von Kultureinrichtungen, Jugendzentren oder Schwimmbädern.
Auf diese Phase neoliberaler Bodenpolitik ist zunehmend eine polanyische Gegenbewegung zu beobachten, die für den sozial-ökologischen Schutz eintritt. Die Menschen in den Kommunen wollen und können diese Entwicklung nicht weiter hinnehmen. Und auch die Lokalpolitik schwenkt z. T. um, indem sie Forderungen der Rekommunaliserung und sozialverträglicher Mieten unterstützt.
Trotz dieser progressiven Entwicklungen ist gerade die Vergabe von Gewerbeflächen nach wie vor durch ein neoliberales Paradigma der Standortkonkurrenz und Austerität geprägt. In diesem Sinne muss die Vergabe von Boden zuallererst ökonomisch sinnvoll sein. Andere Aspekte werden oft ausgeklammert, da sie unter Finanzierungsvorbehalt stehen. Diese Vergabepraxis ist quasi alternativlos und damit postpolitisch. Obwohl diese Entscheidungen die Kommunen langfristig prägen, werden soziale und ökologische Aspekte der ökonomischen Frage untergeordnet. Die Berücksichtigung von Gemeinwohlaspekten, die sich in einem Kriterienkatalog zur Gewerbeflächenvergabe wiederfinden können, bietet Kommunen die Möglichkeit, eine andere – gemeinwohlorientierte – Handlungsrationalität einzunehmen. Die Entscheidungsgrundlage für die Gewerbeflächenvergabe würden mit solchen Kriterien grundlegend neu justiert werden, da sie nicht mehr auf rein ökonomischen, sondern auf sozialen und ökologischen Werten beruht.
Die vorliegende Arbeit beschäftigt sich mit der Frage, wie eine gemeinwohlorientierte Gewerbeflächenvergabe gestaltet werden kann, indem sie die kommunalen Handlungsspielräume erweitert und so einen Beitrag für eine sozial-ökologische Gegenbewegung zur neoliberalen Kommunalpolitik leistet. Sie kommt zu dem Ergebnis, dass für eine kommunale sozial-ökologische Transformation die Wirtschaft wieder stärker in die Gesellschaft eingebettet werden muss (Polanyi 1944). Eine dementsprechende Gewerbeflächenvergabe setzt daher auf die Dekommodifizierung der Flächen, d. h. sie fördert öffentliche und kollektive Eigentumsformen. Außerdem fördert sie kollektive sozial-ökologische Nutzungsformen der Flächen, die dem Gemeinwohl der Bewohner*innen in der Region dienen. Zur Umsetzung könnten Kommunen Gemeinwohl-Kriterien zur Gewerbeflächenvergabe aufstellen. In der vorliegenden Arbeit wird hierzu ein möglicher Kriterienkatalog entwickelt.
Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with <nCR after first ASCT were assigned tandem ASCT in both trials. In patients with <nCR and tandem ASCT (LEN: n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.
The working paper reflects on the status that "sciences" have held at different points in time, and on the normative orders found in scientific works, as well as on the normative orders imposed by the sciences of a particular place and time on their environment. The latter is also suggested by recent developments concerning the influence (or lack thereof) of scientists on daily life and politics. The paper touches on several fundamental issues in the history of science as a discipline that have been or are still being intensely debated.
The Mediterranean realm, comprising the Mediterranean and Macaronesian regions, has long been recognized as one of the world’s biodiversity hotspots, owing to its remarkable species richness and endemism. Several hypotheses on biotic and abiotic drivers of species diversification in the region have been often proposed but rarely tested in an explicit phylogenetic framework. Here, we investigate the impact of both species-intrinsic and -extrinsic factors on diversification in the species-rich, cosmopolitan Limonium, an angiosperm genus with center of diversity in the Mediterranean. First, we infer and time-calibrate the largest Limonium phylogeny to date. We then estimate ancestral ranges and diversification dynamics at both global and regional scales. At the global scale, we test whether the identified shifts in diversification rates are linked to specific geological and/or climatic events in the Mediterranean area and/or asexual reproduction (apomixis). Our results support a late Paleogene origin in the proto-Mediterranean area for Limonium, followed by extensive in situ diversification in the Mediterranean region during the late Miocene, Pliocene, and Pleistocene. We found significant increases of diversification rates in the “Mediterranean lineage” associated with the Messinian Salinity Crisis, onset of Mediterranean climate, Plio-Pleistocene sea-level fluctuations, and apomixis. Additionally, the Euro-Mediterranean area acted as the major source of species dispersals to the surrounding areas. At the regional scale, we infer the biogeographic origins of insular endemics in the oceanic archipelagos of Macaronesia, and test whether woodiness in the Canarian Nobiles clade is a derived trait linked to insular life and a biotic driver of diversification. We find that Limonium species diversity on the Canary Islands and Cape Verde archipelagos is the product of multiple colonization events followed by in situ diversification, and that woodiness of the Canarian endemics is indeed a derived trait but is not associated with a significant shift to higher diversification rates. Our study expands knowledge on how the interaction between abiotic and biotic drivers shape the uneven distribution of species diversity across taxonomic and geographical scales.
Chronic myeloid leukemia (CML) has been a “model disease” with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage.
Long non-coding RNA aerrie controls DNA damage repair via YBX1 to maintain endothelial cell function
(2021)
Aging is accompanied by many physiological changes. These changes can progressively lead to many types of cardiovascular diseases. During this process blood vessels lose their ability to maintain vascular homeostasis, ultimately resulting in hypertension, stroke, or myocardial infarction. Increase in DNA damage is one of the hallmarks of aging and can be repaired by the DNA signaling and repair system. In our study we show that long non-coding RNA Aerrie (linc01013) contributes to the DNA signaling and repair mechanism. Silencing of Aerrie in endothelial cells impairs angiogenesis, migration, and barrier function. Aerrie associates with YBX1 and together they act as important factors in DNA damage signaling and repair. This study identifies Aerrie as a novel factor in genomic stability and as a binding partner of YBX1 in responding to DNA damage.
This article provides a comprehensive overview of the contribution of linguistic research on Portuguese as a heritage language in Germany to the general understanding of heritage language development. From 1955 to 1973, nearly 166,000 Portuguese migrants found work in Germany as so-called ‘guest workers’ (Gastarbeiter). Because the aim of many Portuguese migrant families was to return to Portugal, their children met relatively good conditions for the acquisition of their heritage language. Nonetheless, second-generation heritage speakers (HSs) show some linguistic particularities in comparison to monolingual Portuguese speakers in Portugal. Based on the results of previous research, we show that the following factors shape the linguistic knowledge of this group of bilinguals: (1) Restricted exposure to the heritage language may cause a delay in the development of certain linguistic structures, (2) deviations from the standard norm may be related to the lack of formal education and the primacy of the colloquial register and (3) heritage bilinguals may accelerate ongoing diachronic development. We argue that apparent effects of influence from the environmental language can often have alternative explanations.
Repeated search studies are a hallmark in the investigation of the interplay between memory and attention. Due to a usually employed averaging, a substantial decrease in response times occurring between the first and second search through the same search environment is rarely discussed. This search initiation effect is often the most dramatic decrease in search times in a series of sequential searches. The nature of this initial lack of search efficiency has thus far remained unexplored. We tested the hypothesis that the activation of spatial priors leads to this search efficiency profile. Before searching repeatedly through scenes in VR, participants either (1) previewed the scene, (2) saw an interrupted preview, or (3) started searching immediately. The search initiation effect was present in the latter condition but in neither of the preview conditions. Eye movement metrics revealed that the locus of this effect lies in search guidance instead of search initiation or decision time, and was beyond effects of object learning or incidental memory. Our study suggests that upon visual processing of an environment, a process of activating spatial priors to enable orientation is initiated, which takes a toll on search time at first, but once activated it can be used to guide subsequent searches.
Astrocytes contribute to many higher brain functions. A key mechanism in glia-to-neuron signalling is vesicular exocytosis; however, the identity of exocytosis organelles remains a matter of debate. Since vesicles derived from the trans-Golgi network (TGN) are not considered in this context, we studied the astrocyte TGN by immunocytochemistry applying anti-Rab6A. In mouse brain, Rab6A immunostaining is found to be unexpectedly massive, diffuse in all regions, and is detected preferentially and abundantly in the peripheral astrocyte processes, which is hardly evident without glial fibrillary acid protein (GFAP) co-staining. All cells positive for the astrocytic markers glutamine synthetase (GS), GFAP, aldehyde dehydrogenase 1 family member L1 (Aldh1L1), or SRY (sex determining region Y)-box 9 (SOX9) were Rab6A+. Rab6A is excluded from microglia, oligodendrocytes, and NG2 cells using cell type-specific markers. In human cortex, Rab6A labelling is very similar and associated with GFAP+ astrocytes. The mouse data also confirm the specific astrocytic labelling by Aldh1L1 or SOX9; the astrocyte-specific labelling by GS sometimes debated is replicated again. In mouse and human brain, individual astrocytes display high variability in Rab6A+ structures, suggesting dynamic regulation of the glial TGN. In summary, Rab6A expression is an additional, global descriptor of astrocyte identity. Rab6A might constitute an organelle system with a potential role of Rab6A in neuropathological and physiological processes.
PKCζ and PKCι/λ form the atypical protein kinase C subgroup, characterised by a lack of regulation by calcium and the neutral lipid diacylglycerol. To better understand the regulation of these kinases, we systematically explored their interactions with various purified phospholipids using the lipid overlay assays, followed by kinase activity assays to evaluate the lipid effects on their enzymatic activity. We observed that both PKCζ and PKCι interact with phosphatidic acid and phosphatidylserine. Conversely, PKCι is unique in binding also to phosphatidylinositol-monophosphates (e.g., phosphatidylinositol 3-phosphate, 4-phosphate, and 5-phosphate). Moreover, we observed that phosphatidylinositol 4-phosphate specifically activates PKCι, while both isoforms are responsive to phosphatidic acid and phosphatidylserine. Overall, our results suggest that atypical Protein kinase C (PKC) localisation and activity are regulated by membrane lipids distinct from those involved in conventional PKCs and unveil a specific regulation of PKCι by phosphatidylinositol-monophosphates.
Objective: In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited.
Methods: A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons).
Results: Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98%), the state of health before admission (96%), SOFA-score (85%) and patient age (69%). Interestingly, other principles of allocation, such as a treatment of “youngest first” (61%) and members of the healthcare sector (50%) were also noted. While these were the most accepted parameters affecting the triage of patients, a “first-come, first-served” principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team.
Conclusions: The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU.
“Right to Buy” (RTB), a large-scale natural experiment by which incumbent tenants in public housing could buy properties at heavily-subsidised prices, increased the UK homeownership rate by over 10 percentage points between 1980 and the late 1990s. This paper studies its impact on crime, showing that RTB generated significant reductions in property and violent crime that persist up to today. The behavioural changes of incumbent tenants and the renovation of public properties were the main drivers of the crime reduction. This is evidence of a novel means by which subsidised homeownership and housing policy may contribute to reduce criminality.
Functional coupling of Slack channels and P2X3 receptors contributes to neuropathic pain processing
(2021)
The sodium-activated potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (IKNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated IKNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated IKNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.