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The Nok Culture of Central Nigeria is known for its sophisticated terracotta figurines initially described in the 1950s by the British archaeologist Bernard Fagg. Since 2009, the Nok Culture has been the subject of research at the Goethe University Frankfurt within the scope of a long-term project funded by the German Research Foundation (DFG). This book is the outcome of a PhD thesis that involved pXRF analysis of features associated with the Nok Culture, namely stone-pot-arrangements and pit features.
Stone-pot-arrangements are considered to be burials, indicated by arranged and modified stones associated with complete pots and, in a few cases, a necklace made of stone beads. However, the absence of bones and other skeletal remains meant that their interpretation as burials was unresolved. The interpretation of pits or pit-like structures, of various shapes and sizes, also remained inconclusive.
Employing pXRF analysis succeeded in revealing traces of a decomposed body, supporting the hypothesis of stone-pot-arrangements being interments. Together with the analysis of pits, new ideas about the formation and use of Nok sites were advanced. These culminated in a 'patchwork model' that assumes a repetitive cycle of utilising land for farming, settlements and burials, followed by abandonment and subsequent re-visiting and re-use of the formerly abandoned land.
Der Sammelband widmet sich dem Verhältnis von Erziehungswissenschaft, Medienpädagogik und Online-Forschung. Den Ausgangspunkt bildet die Frage, welche Bedeutung die umfassende Mediatisierung und Digitalisierung beinahe aller Lebensbereiche für Gesellschaft und Individuen aus einer erziehungswissenschaftlichen Perspektive hat. In den Fokus gerückt werden hier die mit dem digitalen Wandel verbundenen theoretisch-begrifflichen wie empirisch-methodischen Herausforderungen für die (medienpädagogische) Forschung, insbesondere die Online-Forschung.
Die bisherigen erziehungswissenschaftlichen und medienpädagogischen Diskurse zur Forschung im und mit dem Internet können als verstreut und disparat bezeichnet werden. Ziel dieses Bandes ist es daher zum einen, die (medien-) pädagogischen Zugänge zur Online-Forschung zu bündeln, zu diskutieren und zu bilanzieren. Zum anderen werden die Herausforderungen des skizzierten Wandels für die Online-Forschung in theoretisch-methodologischer, methodischer und forschungsthematischer Hinsicht in den Blick genommen.
Die zunehmende Nutzung von Online-Kommunikationskanälen vereinfacht nicht nur den alltäglichen, zwischenmenschlichen Austausch, sondern eröffnet auch der erziehungswissenschaftlichen Forschung neue Möglichkeiten. Gleichzeitig stehen Chancen wie der Reichweitenerhöhung von Forschungsaktivitäten auch Herausforderungen bspw. im Bereich der Validität gegenüber. Vor diesem Hintergrund geht der Beitrag der Frage nach, ob sich diese Nachteile durch die methodologisch fundierte Kombination von Offline- und Online-Umgebungen kompensieren lassen. Anhand eines Forschungsszenarios werden drei verschiedene Designs konzipiert, die auf genau diese Herausforderung eingehen. Dazu wird eine Mixed Methods Perspektive eingenommen, um verschiedene Möglichkeiten aufzuzeigen, die einzelne Schwächen der Methoden adäquat ausgleichen oder sogar Synergieeffekte erzielen.
Die Wettbewerbsfähigkeit der deutschen Wirtschaft steht vor gewaltigen Herausforderungen. Traditionell starke Sektoren wie die Automobilindustrie oder der Maschinenbau befinden sich angesichts disruptiver Veränderungen durch neue Technologien, den Kampf gegen den Klimawandel und veränderte regulatorische Rahmenbedingungen in einer Umbruchphase. Zahlreiche Industriezweige wandeln sich durch den Einsatz von Künstlicher Intelligenz zu „Smart Industries“. Gleichzeitig gewinnt die Kompetenz in Querschnittstechnologien wie Cloud Computing oder Cyber Security an Bedeutung, da diese den effektiven Einsatz von Künstlicher Intelligenz erst ermöglichen. Eine Analyse der Wettbewerbsposition der deutschen Wirtschaft zeigt auf, dass in manchen Zukunftsfeldern ein erheblicher Nachholbedarf besteht.
Stinginess was yesterday
(2020)
Geiz war gestern
(2020)
In Deutschland ist die Wohneigentumsquote innerhalb der OECD am zweitniedrigsten. Eine wichtige Rolle spielt dabei die Wohnungspolitik, die hierzulande Anreize für das Mieten schafft. Neue Studien zeigen, dass eine veränderte Politik die Wohneigentumsquote erhöhen und die Vermögensungleichheit verringern könnte.
In resource-limited or point-of-care settings, rapid diagnostic tests (RDTs), that aim to simultaneously detect HIV antibodies and p24 capsid (p24CA) antigen with high sensitivity, can pose important alternatives to screen for early infections. We evaluated the performance of the antibody and antigen components of the old and novel version of the Determine™ HIV-1/2 Ag/Ab Combo RDTs in parallel to quantifications in a fourth-generation antigen/antibody immunoassay (4G-EIA), p24CA antigen immunoassay (p24CA-EIA), immunoblots, and nucleic acid quantification. We included plasma samples of acute, treatment-naïve HIV-1 infections (Fiebig stages I–VI, subtypes A1, B, C, F, CRF02_AG, CRF02_AE, URF) or chronic HIV-1 and HIV-2 infections. The tests’ antigen component was evaluated also for a panel of subtype B HIV-1 transmitted/founder (T/F) viruses, HIV-2 strains and HIV-2 primary isolates. Furthermore, we assessed the analytical sensitivity of the RDTs to detect p24CA using a highly purified HIV-1NL4-3 p24CA standard. We found that 77% of plasma samples from acutely infected, immunoblot-negative HIV-1 patients in Fiebig stages II–III were identified by the new RDT, while only 25% scored positive in the old RDT. Both RDTs reacted to all samples from chronically HIV-1-infected and acutely HIV-1-infected patients with positive immunoblots. All specimens from chronically infected HIV-2 patients scored positive in the new RDT. Of note, the sensitivity of the RDTs to detect recombinant p24CA from a subtype B virus ranged between 50 and 200 pg/mL, mirrored also by the detection of HIV-1 T/F viruses only at antigen concentrations tenfold higher than suggested by the manufacturer. The RTD failed to recognize any of the HIV-2 viruses tested. Our results indicate that the new version of the Determine™ HIV-1/2 Ag/Ab Combo displays an increased sensitivity to detect HIV-1 p24CA-positive, immunoblot-negative plasma samples compared to the precursor version. The sensitivity of 4G-EIA and p24CA-EIA to detect the major structural HIV antigen, and thus to diagnose acute infections prior to seroconversion, is still superior.
Vor zwei Monaten traf ich Sascia Bailer, die Künstlerischen Leiterin des M.1 der Arthur Boskamp-Stiftung in Hohenlockstedt, um über ihr Programm "Care" zu sprechen. Seitdem haben die dramatischen Geschehnisse uns gezwungen, die Realität neu zu überdenken. Bailers Konzept hat in der gegenwärtigen Krise nur an Aktualität gewonnen: Wir alle werden uns noch lange erinnern, wie sich die Care-Arbeitenden – Krankenschwestern, Pfleger*innen, Ärzt*innen und Sozialarbeiter*innen – in den Zeiten der höchsten Not, um uns gekümmert haben. Das Programm in der Ausstellungshalle M.1 hat das Ziel, die Unsichtbarkeit der Fürsorge und ihre Überlastung zu thematisieren und dieser entgegenzuwirken. Im Moment sind die Räume des M.1 sowie alle anderen Museen in Deutschland geschlossen, es lohnt sich aber, genau hinzuschauen, wie neue Dialoge in unserer Gemeinschaft hergestellt werden und welche Rolle dabei die Kunst spielen kann.
Household finance
(2020)
Household financial decisions are complex, interdependent, and heterogeneous, and central to the functioning of the financial system. We present an overview of the rapidly expanding literature on household finance (with some important exceptions) and suggest directions for future research. We begin with the theory and empirics of asset market participation and asset allocation over the lifecycle. We then discuss house-hold choices in insurance markets, trading behavior, decisions on retirement saving, and financial choices by retirees. We survey research on liabilities, including mortgage choice, refinancing, and default, and household behavior in unsecured credit markets, including credit cards and payday lending. We then connect the household to its social environment, including peer effects, cultural and hereditary factors, intra-household financial decision making, financial literacy, cognition and educational interventions. We also discuss literature on the provision and consumption of financial advice.
This essay discusses the current Europeanization of national museums in different European countries and considers it against the background of media theories and feminist epistemologies. Taking the example of the European Solidarity Centre Gdansk, the Deutsches Historisches Museum Berlin and the Musée des civilisations de l’Europe et de la Méditerranée Marseille, it suggests two approaches to the dynamics of travel and locatedness in the museum. Firstly, using the concept of what I call “Europoeic media” this essay shows how “Europe” as a travelling memory is shaped by and in media. Secondly, I argue that the locatedness both of memories and the memory researcher are not detrimental but instead produce “situated knowledges”. Thus, in combining media-sensitivity and standpoint-reflexivity, the paper proposes new ways of taking into account the travels and locatedness of both memories and memory research.
Der vorliegende Beitrag diskutiert, wie mithilfe von Unterrichtsvideographien die Reflexionskompetenz angehender Englischlehrkräfte bereits in der ersten Ausbildungsphase angebahnt und geschult werden kann. Er geht von der Annahme aus, dass praktizierenden Lehrkräften häufig die Gelegenheiten oder auch die Kompetenzen zur systematischen Reflexion fehlen (vgl. Kittel & Rollett, 2017) und diese bereits vorher grundgelegt werden müssen. Anhand von zwei Seminarbeispielen aus der Englischdidaktik, welche sich auf die disziplinspezifischen Heterogenitätsdimensionen Mehrsprachigkeit (vgl. u.a. Elsner & Wildemann, 2012; Niesen, 2018) und Transkulturalität (vgl. u.a. Viebrock, 2018; Kreft, 2019a, 2019b) beziehen, werden praktische Umsetzungsmöglichkeiten bzw. die wechselseitige Integration theoretischer Konzepte und unterrichtlicher Handlungen/Interaktionen illustriert. Die vorgestellten Aufgabenformate beziehen sich auf die kasuistische Fallarbeit (nach Lindow & Münch, 2014) sowie auf VierSchritt-Analysen (nach Santagata & Guarino, 2011). Als grundlegende Struktur für die Entwicklung von Reflexionskompetenz in videobasierten Lernsettings wird eine adaptierte Fassung des Modells von Aeppli und Lötscher (2016) mit den Verfahrensschritten „Erleben“, „Erkennen“, „Darstellen“, „Analysieren“ und „Alternative Szenarien entwickeln“ verwendet. Es zeigt sich, dass die gewählte Vorgehensweise Studierende in die Lage versetzt, die konzeptionelle und unterrichtspraktische Bedeutung von sprachlicher und kultureller Heterogenität im Englischunterricht zu erkennen und, in einem weiteren Schritt, Möglichkeiten zur Förderung von transkulturalitäts- bzw. mehrsprachigkeits-sensitivem Handeln zu identifizieren und somit ihre Reflexionskompetenzen zu schulen.
L'osservazione secondo la quale lo scarto come oggetto di ricerca sia allo stesso tempo un effetto della sua ricerca è ciò che l'articolo traccia in tre studi sulla spazzatura: Rubbish! di William Rathje e Cullen Murphy, Un mondo usa e getta di Guido Viale e Das Miill-System di Volker Grassmuck e Christian Unverzagt. Questi tre studi esemplificano tre modi di presentare lo scarto: esplorazione, problema e ricie/aggio. Guardarli come argomenti scientifici ci permette di discutere di ciò che è considerato scarto ponendo domande di presentazione testuale e, allo stesso tempo, di chiedere quali conseguenze abbia la presentazione per il concetto scientifico dello scarto.
This paper offers a description and account of the patterns of 'ex-situ' focus in Dagbani. We show that there are two syntactic strategies for creating 'ex-situ' focus in the language, one involving A’-movement to the left periphery, and the second involving base generation in the left periphery combined with coreference to a resumptive pronoun. Furthermore, we argue that subjects are difficult to move from Spec,TP to Spec,CP in the left-periphery because of 'anti-locality', which creates a tension when trying to focus subjects, which are required to derivationally fill the specifier of both positions. We further show that what looks to be a two-way distinction between the behaviour of subjects and non-subjects in the language is in fact a three-way distinction between subjects that are focussed to a local left-periphery, subjects that are focussed to a non-local left-periphery, and non-subjects. These distinctions arise due to there being two methods for Dagbani to resolve the antilocality problem of subject movement, and so local subjects solve the problem differently to non-local subjects.
At a site in the Bolivian Chiquitano region composed by a mosaic of pastureland and primary Chiquitano Dry Forest (CDF) we conducted a camera-trapping study to (1) survey the mammals, and (2) compare individual Jaguar numbers with other Chiquitano sites. Therefore, we installed 13 camera stations (450 ha polygon) over a period of six months. On 1,762 camera-days and in 1,654 independent capture events, we recorded 24 mammalian species that represent the native fauna of large and medium-sized mammals including apex-predators (Puma, Jaguar), meso-carnivores (Ocelot, Jaguarundi, Margay), and large herbivores (Tapir, Collared and White lipped Peccary). We identified six adult Jaguars and found indications of successful reproductive activity. Captures of Jaguars were higher in CDF than in altered habitats. In summary, we believe that (1) the mammal species richness, (2) the high capture numbers of indicator species, and (3) the high capture numbers of Jaguar indicate that our study area has a good conservation status. Future efforts should be undertaken to keep this, and monitoring programs in this region are necessary to further evaluate the potential importance of the Chiquitano region as a possible key region for mammals, especially Jaguars, in South America.
URPOSE: Today, the majority of medical graduates in countries such as the UK, the US or Germany are female. This poses a major problem for workforce planning especially in urology. We here use first the first time the previously established Brüggmann Groneberg (BG) index to assess if female academic career options advance in urology.
METHODS: Different operating parameters (student population, urology specialist population, urology chair female:male (f:m) ratio) were collected from the Federal Office of Statistics, the Federal Chamber of Physicians and the medical faculties of 36 German universities. Four time points were monitored (2000, 2005, 2010 and 2015). From these data, female to male (f:m) ratios and the recently established career advancement (BG) index have been calculated.
RESULTS: The German hospital urology specialists' f:m ratios were 0.257 (499 female vs. 1944 male) for 2015, 0.195 for 2010, 0.133 for 2005 and 0.12 for 2000. The career advancement (BG) index was 0.0007 for 2000, 0,0005 for 2005, 0.094 for 2010 and 0.073 for 2015. The decrease from 2010 to 2015 was due to an increase in the f:m ratio of hospital urologists and female medical students.
CONCLUSION: The BG index clearly illustrated that there is an urgent need for special academic career funding programs to counteract gender problems in urology. The BG index has been shown to be an excellent tool to assess female academic career options and will be very helpful to assess and document positive or negative changes in the next decades.
BACKGROUND: Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis.
METHODS: Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study.
RESULTS: CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 μg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant.
CONCLUSIONS: Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects.
TRIAL REGISTRATION: ClinicalTrial.gov, EudraCT, 2015-005550-35. Registered 15 July 2016.
Correction to: Scientifc Reports https://doi.org/10.1038/s41598-019-43857-5, published online 17 May 2019. In the original version of this Article, Jan-Hendrik Trösemeier was incorrectly affiliated with ‘Division of Allergology, Paul Ehrlich Institut, Langen, Germany’. Te correct afliations are listed below...
Biofabrication of SDF-1 functionalized 3D-printed cell-free scaffolds for bone tissue regeneration
(2020)
Large segmental bone defects occurring after trauma, bone tumors, infections or revision surgeries are a challenge for surgeons. The aim of our study was to develop a new biomaterial utilizing simple and cheap 3D-printing techniques. A porous polylactide (PLA) cylinder was printed and functionalized with stromal-derived factor 1 (SDF-1) or bone morphogenetic protein 7 (BMP-7) immobilized in collagen type I. Biomechanical testing proved biomechanical stability and the scaffolds were implanted into a 6 mm critical size defect in rat femur. Bone growth was observed via x-ray and after 8 weeks, bone regeneration was analyzed with µCT and histological staining methods. Development of non-unions was detected in the control group with no implant. Implantation of PLA cylinder alone resulted in a slight but not significant osteoconductive effect, which was more pronounced in the group where the PLA cylinder was loaded with collagen type I. Addition of SDF-1 resulted in an osteoinductive effect, with stronger new bone formation. BMP-7 treatment showed the most distinct effect on bone regeneration. However, histological analyses revealed that newly formed bone in the BMP-7 group displayed a holey structure. Our results confirm the osteoinductive character of this 3D-biofabricated cell-free new biomaterial and raise new options for its application in bone tissue regeneration.
Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC.
Some anaerobic bacteria use biotin-dependent Na+-translocating decarboxylases (Bdc) of β-keto acids or their thioester analogs as key enzymes in their energy metabolism. Glutaconyl-CoA decarboxylase (Gcd), a member of this protein family, drives the endergonic translocation of Na+ across the membrane with the exergonic decarboxylation of glutaconyl-CoA (ΔG0’ ≈−30 kJ/mol) to crotonyl-CoA. Here, we report on the molecular characterization of Gcd from Clostridium symbiosum based on native PAGE, size exclusion chromatography (SEC) and laser-induced liquid bead ion desorption mass spectrometry (LILBID-MS). The obtained molecular mass of ca. 400 kDa fits to the DNA sequence-derived mass of 379 kDa with a subunit composition of 4 GcdA (65 kDa), 2 GcdB (35 kDa), GcdC1 (15 kDa), GcdC2 (14 kDa), and 2 GcdD (10 kDa). Low-resolution structural information was achieved from preliminary electron microscopic (EM) measurements, which resulted in a 3D reconstruction model based on negative-stained particles. The Gcd structure is built up of a membrane-spanning base primarily composed of the GcdB dimer and a solvent-exposed head with the GcdA tetramer as major component. Both globular parts are bridged by a linker presumably built up of segments of GcdC1, GcdC2 and the 2 GcdDs. The structure of the highly mobile Gcd complex represents a template for the global architecture of the Bdc family.
Requirements analysis and specification for a molecular tumor board platform based on cBioPortal
(2020)
Clinicians in molecular tumor boards (MTB) are confronted with a growing amount of genetic high-throughput sequencing data. Today, at German university hospitals, these data are usually handled in complex spreadsheets from which clinicians have to obtain the necessary information. The aim of this work was to gather a comprehensive list of requirements to be met by cBioPortal to support processes in MTBs according to clinical needs. Therefore, oncology experts at nine German university hospitals were surveyed in two rounds of interviews. To generate an interview guideline a scoping review was conducted. For visual support in the second round, screenshot mockups illustrating the requirements from the first round were created. Requirements that cBioPortal already meets were skipped during the second round. In the end, 24 requirements with sometimes several conceivable options were identified and 54 screenshot mockups were created. Some of the identified requirements have already been suggested to the community by other users or are currently being implemented in cBioPortal. This shows, that the results are in line with the needs expressed by various disciplines. According to our findings, cBioPortal has the potential to significantly improve the processes and analyses of an MTB after the implementation of the identified requirements.
Introduction: Reliable and cost-effective diagnostics for hepatitis E virus (HEV) infection are necessary. The aim of our study was to investigate which diagnostic test is most accurate to detect HEV infection in immunocompetent and immunosuppressed patients in a real world setting. Patients and Methods: We performed a retrospective analysis of 1165 patients tested for HEV antibodies and HEV PCR at the same time point. Clinical, laboratory and virological data were taken from patient charts. HEV IgA was measured in a subgroup of 185 patients. Results: HEV RNA was detectable in 61 patients (5.2%); most of them (n = 49, 80.3%/n = 43, 70.5%) were HEV IgM+ and IgG+; however, 12 patients (19.6%) were HEV RNA positive/HEV IgM negative and 17 patients (27.8%) were HEV RNA positive/HEV IgG negative. Ten HEV RNA positive patients (16.4%) had neither HEV IgG nor IgM antibodies. Importantly, all of them were immunosuppressed. HEV IgA testing was less sensitive than HEV IgM for HEV diagnosis. Conclusions: HEV infection can be overlooked in patients without HEV specific antibodies. Performing PCR is necessary to diagnose or exclude HEV infection in immunocompromised hosts. In immunocompetent patients, a screening based on HEV antibodies (IgG/IgM) is sufficient.
The efficacy of cisplatin-based chemotherapy in ovarian cancer is often limited by the development of drug resistance. In most ovarian cancer cells, cisplatin activates extracellular signal-regulated kinase1/2 (ERK1/2) signalling. Phosphoprotein enriched in astrocytes (PEA-15) is a ubiquitously expressed protein, capable of sequestering ERK1/2 in the cytoplasm and inhibiting cell proliferation. This and other functions of PEA-15 are regulated by its phosphorylation status. In this study, the relevance of PEA-15 phosphorylation state for cisplatin sensitivity of ovarian carcinoma cells was examined. The results of MTT-assays indicated that overexpression of PEA-15AA (a non-phosphorylatable variant) sensitised SKOV-3 cells to cisplatin. Phosphomimetic PEA-15DD did not affect cell sensitivity to the drug. While PEA-15DD facilitates nuclear translocation of activated ERK1/2, PEA-15AA acts to sequester the kinase in the cytoplasm as shown by Western blot. Microarray data indicated deregulation of thirteen genes in PEA-15AA-transfected cells compared to non-transfected or PEA-15DD-transfected variants. Data derived from The Cancer Genome Atlas (TCGA) showed that the expression of seven of these genes including EGR1 (early growth response protein 1) and FLNA (filamin A) significantly correlated with the therapy outcome in cisplatin-treated cancer patients. Further analysis indicated the relevance of nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signalling for the favourable effect of PEA-15AA on cisplatin sensitivity. The results warrant further evaluation of the PEA-15 phosphorylation status as a potential candidate biomarker of response to cisplatin-based chemotherapy.
Short linear motifs (SLiMs) located in disordered regions of multidomain proteins are important for the organization of protein–protein interaction networks. By dynamic association with their binding partners, SLiMs enable assembly of multiprotein complexes, pivotal for the regulation of various aspects of cell biology in higher organisms. Despite their importance, there is a paucity of molecular tools to study SLiMs of endogenous proteins in live cells. LC3 interacting regions (LIRs), being quintessential for orchestrating diverse stages of autophagy, are a prominent example of SLiMs and mediate binding to the ubiquitin-like LC3/GABARAP family of proteins. The role of LIRs ranges from the posttranslational processing of their binding partners at early stages of autophagy to the binding of selective autophagy receptors (SARs) to the autophagosome. In order to generate tools to study LIRs in cells, we engineered high affinity binders of LIR motifs of three archetypical SARs: OPTN, p62, and NDP52. In an array of in vitro and cellular assays, the engineered binders were shown to have greatly improved affinity and specificity when compared with the endogenous LC3/GABARAP family of proteins, thus providing a unique possibility for modulating LIR interactions in living systems. We exploited these novel tools to study the impact of LIR inhibition on the fitness and the responsiveness to cytarabine treatment of THP-1 cells – a model for studying acute myeloid leukemia (AML). Our results demonstrate that inhibition of LIR of a single autophagy receptor is insufficient to sensitize the cells to cytarabine, while simultaneous inhibition of three LIR motifs in three distinct SARs reduces the IC50 of the chemotherapeutic.
Background and Aims: Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear.
Methods: Hepatic CC-chemokine ligand 2 (CCL2) expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl4 for 7 weeks). Next, hepatic RNA levels of CCL2 were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension.
Results: In this mouse model of fibrotic hepatitis, hepatic expression of CCL2 (P = 0.009) and the amount of F4/80 positive cells in the liver (P < 0.001) significantly increased after induction of hepatitis by CCl4 compared to control animals. Moreover, strong correlation of hepatic CCL2 expression and F4/80 positive cells were seen (P = 0.023). Furthermore, in human liver explants, hepatic transcription levels of CCL2 correlated with the MELD score of the patients, and thus disease severity (P = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (P = 0.028) and correlation of hepatic CCL2 expression (R = 0.69, P = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte CCL2 expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (P = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (P = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both P = 0.039).
Conclusion: Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.
Background: Previously, we used inhibitors blocking BET bromodomain binding proteins (BRDs) in Ewing sarcoma (EwS) and observed that long term treatment resulted in the development of resistance. Here, we analyze the possible interaction of BRD4 with cyclin-dependent kinase (CDK) 9. Methods: Co-immunoprecipitation experiments (CoIP) to characterize BRD4 interaction and functional consequences of inhibiting transcriptional elongation were assessed using drugs targeting of BRD4 or CDK9, either alone or in combination. Results: CoIP revealed an interaction of BRD4 with EWS-FLI1 and CDK9 in EwS. Treatment of EwS cells with CDKI-73, a specific CDK9 inhibitor (CDK9i), induced a rapid downregulation of EWS-FLI1 expression and block of contact-dependent growth. CDKI-73 induced apoptosis in EwS, as depicted by cleavage of Caspase 7 (CASP7), PARP and increased CASP3 activity, similar to JQ1. Microarray analysis following CDKI-73 treatment uncovered a transcriptional program that was only partially comparable to BRD inhibition. Strikingly, combined treatment of EwS with BRD- and CDK9-inhibitors re-sensitized cells, and was overall more effective than individual drugs not only in vitro but also in a preclinical mouse model in vivo. Conclusion: Treatment with BRD inhibitors in combination with CDK9i offers a new treatment option that significantly blocks the pathognomonic EWS-ETS transcriptional program and malignant phenotype of EwS.