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Macrophage S1PR1 signaling alters angiogenesis and lymphangiogenesis during skin inflammation
(2019)
The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains unknown. We show that myeloid specific S1P receptor 1 (S1PR1) deletion enhances early inflammation in a mouse model of imiquimod-induced psoriasis, without altering the immune cell infiltrate. Mechanistically, myeloid S1PR1 deletion altered the formation of IL-1β, VEGF-A, and VEGF-C, and their receptors’ expression in psoriatic skin, which subsequently lead to reciprocal regulation of neoangiogenesis and neolymphangiogenesis. Experimental findings were corroborated in human clinical datasets and in knockout macrophages in vitro. Increased blood vessel but reduced lymph vessel density may explain the exacerbated inflammatory phenotype in conditional knockout mice. These findings assign a novel role to macrophage S1PR1 and provide a rationale for therapeutically targeting local S1P during skin inflammation.
The website Sci-Hub enables users to download PDF versions of scholarly articles, including many articles that are paywalled at their journal’s site. Sci-Hub has grown rapidly since its creation in 2011, but the extent of its coverage has been unclear. Here we report that, as of March 2017, Sci-Hub’s database contains 68.9% of the 81.6 million scholarly articles registered with Crossref and 85.1% of articles published in toll access journals. We find that coverage varies by discipline and publisher, and that Sci-Hub preferentially covers popular, paywalled content. For toll access articles, we find that Sci-Hub provides greater coverage than the University of Pennsylvania, a major research university in the United States. Green open access to toll access articles via licit services, on the other hand, remains quite limited. Our interactive browser at https://greenelab.github.io/scihub allows users to explore these findings in more detail. For the first time, nearly all scholarly literature is available gratis to anyone with an Internet connection, suggesting the toll access business model may become unsustainable.
Background: The aim of this study was to assess the knowledge and attitudes towards pregnancy-related issues of Zika virus (ZIKV) infection among general practitioners (GPs), a frontline healthcare worker group, in Indonesia.
Methods: A cross-sectional, online survey assessing knowledge and attitudes towards ZIKV infection on multiple-item scales was sent to GPs in the Sumatra and Java islands of Indonesia. The associations between independent factors and either knowledge or attitude were assessed with logistic regressions. The correlation and association between knowledge and attitude were estimated.
Results: We included 457 (53.7%) out of 850 responses in the analysis. Among these, 304 (66.5%) and 111 (24.2%) respondents had a good knowledge and attitude, respectively. No demographic, workplace, professional development, or experiential characteristics related to ZIKV infection were associated with knowledge. In the multivariate analysis, only contact experience was associated with attitude. There was a significant, positive correlation between knowledge and attitude scores.
Conclusions: Although knowledge of pregnancy-related complications of ZIKV infection is relatively high among GPs in Indonesia, more than 75% of them had a poor attitude towards pregnancy-related issues of Zika. Strategies for enhancing the capacity of GPs to develop positive attitudes and respond to ZIKV infection are needed.
Parabens and sorbic acid are commonly used as food preservatives due to their antimicrobial effect. However, their use in foods for infants and young children is not permitted in the European Union. Previous studies found these compounds in some gel-filled baby teethers, whereby parabens, which are well-known as endocrine disruptors, were identified in the polymer-based chewing surface consisting of ethylene-vinyl acetate (EVA). To assess the exposure of infants and young children to these products, the application of parabens in teethers should be thoroughly investigated. Therefore, the present study aimed to apply a representative migration test procedure combined with an accurate analytical method to examine gel-filled baby teethers without elaborate sample preparation, high costs, and long processing times. Accordingly, solid-phase extraction (SPE), in combination with a stable isotope dilution assay (SIDA) and subsequent gas chromatography–mass spectrometry (GC–MS) for analysis of methyl-, ethyl-, and n-propylparaben (MeP, EtP, and n-PrP), was found to be well-suited, with recoveries ranging from 93 to 99%. The study compared the release of these parabens from intact teether surfaces into water and saliva simulant under real-life conditions, with total amounts of detected parabens found to be in the range of 101–162 µg 100 mL−1 and 57–148 µg 100 mL−1, respectively. Furthermore, as a worst-case scenario, the release into water was examined using a long-term migration study.
Despite the popularity of direct democracy in recent decades, research on the actual output effects of popular decision-making is rare. This is especially true with regard to equality, where there are at least three major research gaps: 1) a lack of cross-national analyses; 2) insufficient investigation of the differential effects of different direct democratic instruments on equality; and 3) a failure to distinguish between different aspects of equality, i.e., socioeconomic, legal and political equality. This article takes a first step to tackle these shortcomings by looking at all national referenda in European democracies between 1990 and 2015, differentiating between mandatory, bottom-up and top-down referenda. We find that a large majority of successful direct democratic bills—regardless of which instrument is employed—are not related to equality issues. Of the remaining ones, there are generally more successful pro-equality bills than contra-equality ones, but the differences are rather marginal. Mandatory referenda tend to produce pro-equality outputs, but no clear patterns emerge for bottom-up and top-down referenda. Our results offer interesting, preliminary insights to the current debate on direct democracy, pointing to the conclusion that popular decision-making via any type of direct democratic instrument is neither curse nor blessing with regard to equality. Instead, it is necessary to look at other factors such as context conditions or possible indirect effects in order to get a clearer picture of the impacts of direct democracy on equality.
Zielsetzung: Ziel dieser Arbeit war es, den Einfluss des neuen, rauschoptimierten virtuell monoenergetischen Rekonstruktionsalgorithmus (VMI+) von abdominellen Dual-Energy CT (DECT) Aufnahmen bei Patienten mit gastrointestinalem Stromatumor (GIST) hinsichtlich der objektiven und subjektiven Bildqualität zu evaluieren sowie die Vorteile dessen im Vergleich zu den bislang verwendeten Algorithmen aufzuzeigen.
Material und Methoden: 45 DECT Datensätze von 21 Patienten mit GIST (12 Männer und 9 Frauen, durchschnittliches Alter: 63.4 ± 9.2 Jahre) wurden sowohl mit einem linear gemischten Algorithmus (M_0.6), mit dem traditionellen virtuell monoenergetischen Algorithmus (VMI) als auch mit dem rauschoptimierten VMI+ Algorithmus in 10 keV Intervallen von 40 bis 100 keV rekonstruiert. Zur objektiven Berechnung des Signal-zu-Rausch Verhältnisses („signal-to-noise ratio“=SNR) sowie des Kontrast-zu-Rausch Verhältnisses („contrast-to-noiseratio“=CNR) wurde die Signalabschwächung der GIST-Läsionen und abdomineller Metastasen in den drei Rekonstruktionsvarianten in Hounsfield Units (HU) gemessen. Die Beurteilung der subjektiven allgemeinen Bildqualität, der Abgrenzbarkeit der Läsionen, der Bildschärfe sowie des Bildrauschens im jeweiligen Rekonstruktionsalgorithmus wurde von drei Radiologen unter Verwendung von Likert-Skalen durchgeführt.
Ergebnisse: Die objektive Bildqualität wies die höchsten Werte in den 40 keV VMI+ Serien auf (SNR: 11.0 ± 4.7; CNR: 9.0 ± 4.1) und war somit signifikant besser als die M_0.6 Serie (SNR: 7.5 ± 2.8; CNR: 5.5 ± 2.7) und alle VMI Serien (bei allen P < 0.001). Bezüglich der subjektiven Bildqualität und der Bildschärfe wurden die 60 keV VMI+ Rekonstruktionen bevorzugt (Median: 5; P ≤ 0.008). Die subjektive Einschätzung bezüglich der Abgrenzbarkeit der GIST Läsionen erzielte die besten Werte in den 40 keV und 50 keV VMI+ Rekonstruktionen (beide Mediane: 4). Das Bildrauschen wurde in den 90 keV und 100 keV VMI und VMI+ Rekonstruktionen als am geringsten beurteilt (alle Mediane: 5).
Schlussfolgerung: Niedrigenergetische VMI+ Rekonstruktionen erhöhen signifikant das Signal-zu-Rausch Verhältnis sowie das Kontrast-zu-Rausch Verhältnis verglichen mit den traditionellen VMI Rekonstruktionen und der linear gemischten M_0.6 Bildserie und verbessern sowohl die objektive als auch die subjektive Bildqualität abdomineller DECT Aufnahmen bei Patienten mit GIST signifikant.
Astrocytes are increasingly perceived as active partners in physiological brain function and behaviour. The structural correlations of the glia–synaptic interaction are the peripheral astrocyte processes (PAPs), where ezrin and radixin, the two astrocytic members of the ezrin-radixin-moesin (ERM) family of proteins are preferentially localised. While the molecular mechanisms of ERM (in)activation appear universal, at least in mammalian cells, and have been studied in great detail, the actual ezrin and radixin kinases, phosphatases and binding partners appear cell type specific and may be multiplexed within a cell. In astrocytes, ezrin is involved in process motility, which can be stimulated by the neurotransmitter glutamate, through activation of the glial metabotropic glutamate receptors (mGluRs) 3 or 5. However, it has remained open how this mGluR stimulus is transduced to ezrin activation. Knowing upstream signals of ezrin activation, ezrin kinase(s), and membrane-bound binding partners of ezrin in astrocytes might open new approaches to the glial role in brain function. Ezrin has also been implicated in invasive behaviour of astrocytomas, and glial activation. Here, we review data pertaining to potential molecular interaction partners of ezrin in astrocytes, with a focus on PKC and GRK2, and in gliomas and other diseases, to stimulate further research on their potential roles in glia-synaptic physiology and pathology.
Purpose: To determine whether machine learning assisted-texture analysis of multi-energy virtual monochromatic image (VMI) datasets from dual-energy CT (DECT) can be used to differentiate metastatic head and neck squamous cell carcinoma (HNSCC) lymph nodes from lymphoma, inflammatory, or normal lymph nodes.
Materials and methods: A retrospective evaluation of 412 cervical nodes from 5 different patient groups (50 patients in total) having undergone DECT of the neck between 2013 and 2015 was performed: (1) HNSCC with pathology proven metastatic adenopathy, (2) HNSCC with pathology proven benign nodes (controls for (1)), (3) lymphoma, (4) inflammatory, and (5) normal nodes (controls for (3) and (4)). Texture analysis was performed with TexRAD® software using two independent sets of contours to assess the impact of inter-rater variation. Two machine learning algorithms (Random Forests (RF) and Gradient Boosting Machine (GBM)) were used with independent training and testing sets and determination of accuracy, sensitivity, specificity, PPV, NPV, and AUC.
Results: In the independent testing (prediction) sets, the accuracy for distinguishing different groups of pathologic nodes or normal nodes ranged between 80 and 95%. The models generated using texture data extracted from the independent contour sets had substantial to almost perfect agreement. The accuracy, sensitivity, specificity, PPV, and NPV for correctly classifying a lymph node as malignant (i.e. metastatic HNSCC or lymphoma) versus benign were 92%, 91%, 93%, 95%, 87%, respectively.
Conclusion: Machine learning assisted-DECT texture analysis can help distinguish different nodal pathology and normal nodes with a high accuracy.
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (KNa1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20–30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519.
Der DNA-Translokator von T. thermophilus HB27, ebenso wie Typ-IV-Pili (T4P), sind Multiproteinkomplexe, die die Membranen und das Periplasma durchspannen. Sie sind ähnlich aufgebaut und enthalten identische Proteine. Der DNA-Translokator vermittelt Transport von DNA in das Zellinnere während der natürlichen Transformation. T4P sind filamentöse Zellorganellen, die an der inneren Membran assembliert werden und bis zu mehrere Mikrometer aus der Zelle hinausragen. Sie dienen der Anhaftung und Fortbewegung der Zellen auf Oberflächen.
Das Ziel dieser Arbeit war es, die Funktionen einzelner Komponenten der Komplexe und ihrer Proteindomänen bei der natürlichen Transformation, der T4P-Assemblierung und den durch T4P vermittelten Funktionen Adhäsion und „twitching motility“ aufzuklären.
Es sind neun Proteine bekannt, die eine duale Rolle als Komponenten des DNA-Translokators und des T4P spielen. Eines dieser Proteine ist die Assemblierungs-ATPase PilF, die Hexamere bildet. Diese cytoplasmatischen ATPase-Komplexe stellen die Energie für die Assemblierung der T4P bereit, ebenso wie für die Aufnahme freier DNA. Es ist jedoch bisher nicht geklärt, wie die durch PilF bereitgestellte Energie auf die anderen Komponenten des DNA-Translokators/T4P übertragen wird.
In dieser Arbeit konnte gezeigt werden, dass PilF an das cytoplasmatische Protein PilM des T4P und DNA-Translokators bindet. Zudem konnten Proteinkomplexe bestehend aus den Proteinen PilM, PilN und PilO heterolog produziert und aus Zellmembranen koisoliert werden. PilF interagierte mit diesen PilMNO-Komplexen via PilM. Diese Interaktionen führt zur Stimulierung der ATPase-Aktivität von PilF. Dies deutet an, dass PilM ein Kupplungsprotein ist, welches die Assemblierungs-ATPase PilF physisch und funktionell mit dem T4P/DNA-Translokator über den PilMNO-Komplex verbindet.
Neben PilF standen Präpiline von T. thermophilus im Fokus dieser Arbeit. Präpiline sind Vorläuferproteine, die zu Pilinen prozessiert werden und als solche dann die Untereinheiten der Pilus-Strukturen bilden.
Zusammenfassend konnten die Rollen einzelner Präpilin-ähnlicher Proteine bei T4P-assoziierten Funktionen geklärt werden und es konnten erste Analysen zur Charakterisierung des weitestgehend unbekannten Proteins ComZ durchgeführt werden. Desweiteren liefert diese Arbeit Hinweise darauf, dass die membranassoziierten Proteine PilM, PilN und PilO Kupplungsproteine sind, die PilF mit den periplasmatischen Komponenten des T4P/DNA-Translokators verbinden und dadurch die ATPase-Aktivität von PilF stimulieren. Die Rollen einzelner Proteindomänen von PilF und PilM bei der Protein-Protein-Interaktion und der Bindung von Liganden wurden aufgeklärt, sowie ihre Funktionen bei den T4P-vermittelten Funktionen und der natürlichen Transformation.
Seit dem 28. Juni 2019 ist in der hessischen Landeshauptstadt eine der größten privaten Jugendstil-Sammlungen Europas in einer Dauerausstellung zu sehen. Mit seiner großzügigen Schenkung hat der Kunstsammler Ferdinand Wolfgang Neess bereits vor zwei Jahren 570 Werke seiner in einem halben Jahrhundert zusammengetragenen Sammlung von Inkunabeln des internationalen Jugendstils dem Landesmuseum Wiesbaden vermacht. Seitdem wurde an der Präsentation dieser einmaligen Objekte im Südflügel des Museums gearbeitet, die nun seit knapp zwei Monaten der Öffentlichkeit zugänglich sind. ...
Background: Complications after surgery for esophageal cancer are associated with significant resource utilization. The aim of this study was to analyze the economic burden of two frequently used endoscopic treatments for anastomotic leak management after esophageal surgery: Treatment with a Self-expanding Metal Stent (SEMS) and Endoscopic Vacuum Therapy (EVT).
Materials and methods: Between January 2012 and December 2016, we identified 60 German-Diagnosis Related Group (G-DRG) cases of patients who received a SEMS and / or EVT for esophageal anastomotic leaks. Direct costs per case were analyzed according to the Institute for Remuneration System in Hospitals (InEK) cost-accounting approach by comparing DRG payments on the case level, including all extra fees per DRG catalogue.
Results: In total, 60 DRG cases were identified. Of these, 15 patients were excluded because they received a combination of SEMS and EVT. Another 6 cases could not be included due to incomplete DRG data. Finally, N = 39 DRG cases were analyzed from a profit-center perspective. A further analysis of the most frequent DRG code -G03- including InEK cost accounting, revealed almost twice the deficit for the EVT group (N = 13 cases, € - 9.282 per average case) compared to that for the SEMS group (N = 9 cases, € - 5.156 per average case).
Conclusion: Endoscopic treatments with SEMS and EVT for anastomotic leaks following oncological Ivor Lewis esophagectomies are not cost-efficient for German hospitals. Due to longer hospitalization and insufficient reimbursements, EVT is twice as costly as SEMS treatment. An adequate DRG cost compensation is needed for SEMS and EVT.
This article presents an analysis of the police television series A Touch of Frost (Yorkshire Television, 1992) and the crime novels by Rodney Wingfield upon which it is based.
In order to analyse the way the protagonist, Inspector Jack Frost, is characterised in either version, data is drawn from the pilot episode of the series and Wingfield’s debut novel Frost at Christmas (1984). Wingfield was less than impressed with television’s version of Frost, stating, ‘He just isn’t my Frost’. The rationale for this article is to apply established models in stylistics to investigate the differences between the original and the adaptation. A core motivation for stylistics is to ‘support initial impressions in various extracts’ readings’ and to ‘describe the readers’ response with some precision’ (Gregoriou 2007: 19); this article therefore offers a close linguistic explanation for an author’s dissatisfaction with the adaptation of his own work. The famously reticent Wingfield did not elaborate in detail on why he disapproved of the television version of Frost, although several critics observed that Wingfield felt television had ‘softened’ his creation. This article contends that ‘softness’ is represented in language through politeness strategies adopted by speakers whilst impoliteness represents the ‘tougher’ speech of Wingfield’s original iteration of Jack Frost. In order to demonstrate this contention, this study will analyse pragmatic elements of the dialogue of both novel and television versions of Frost through the analytical framework for impoliteness developed by Culpeper (1996; 2010). This framework will be integrated into the model for analysing the elements of narrative outlined by Simpson and Montgomery (1995), in turn suggesting an elaboration of this model. In investigating whether television’s Jack Frost is ‘softer’ than the character envisaged by Wingfield, free direct speech and accompanying physical behaviour in novel and television adaptation are analysed, focussing on whether the perceived softness of the latter has been partly achieved by making the speech of Frost less impolite on television.
Interleukin (IL)-18 and IL-22 are key components of cytokine networks that play a decisive role in (pathological) inflammation, host defense, and tissue regeneration. Tight regulation of cytokine-driven signaling, inflammation, and immunoactivation is supposed to enable nullification of a given deleterious trigger without mediating overwhelming collateral tissue damage or even activating a cancerous face of regeneration. In fact, feedback regulation by specific cytokine opponents is regarded as a major means by which the immune system is kept in balance. Herein, we shine a light on the interplay between IL-18 and IL-22 and their opponents IL-18 binding protein (IL-18BP) and IL-22BP in order to provide integrated information on their biology, pathophysiological significance, and prospect as targets and/or instruments of therapeutic intervention.
Forschen und Kuratieren sind Kerntätigkeitsbereiche von KunsthistorikerInnen. Genau das tun gerade junge NachwuchswissenschaftlerInnen am Kunstgeschichtlichen Institut der Goethe-Universität. In dem auf zwei Jahre angelegten Forschungs- und Ausstellungsprojekt "Die Porträtsammlung der Frankfurter Patrizierfamilie Holzhausen aus kunst- und kulturhistorischer Sicht" haben Masterstudierende der Kunstgeschichte und des Masterstudiengangs Curatorial Studies die Gelegenheit, am Puls der Forschung mitzuarbeiten. Unter der Leitung von Prof. Dr. Jochen Sander erlernen sie in einer Serie von drei Hauptseminaren, worauf es in der wissenschaftlichen Praxis und beim Ausstellungsmachen ankommt. ...
Endometriosis represents nowadays a real burden for the patients as well as for the physicians, as it requires surgical and/or medical treatment, often long – termed and repeated. Moreover, the high costs necessary to diagnose and treat endometriosis represent a real economic burden, being comparable to other chronic diseases like diabetes or rheumatoid arthritis. Therefore, the physicians dealing with this disease should take into account not only the efficacy of the treatment, but also the economic aspects and patients compliance.
The present paper analyses the efficiency of progestins (lynestrenol and medrogestone) in endometriosis as a cost – effective, but forgotten medical therapy of the disease. Our study underlines the good tolerability of progestins, as they have limited side effects, the compliance of patients being high. They are also low-cost medications, which could represent an effective alternative method in the endometriosis treatment, especially in less – developed countries that cannot afford the higher therapeutic costs.
Die Keksfabrik, das alte Backsteingemäuer, dessen Schornstein hinter der Universitätsbibliothek in die Höhe ragt, beherbergt seit vielen Jahrzehnten das Institut für Kunstpädagogik. Auf besondere Weise hat dieser Ort Arbeit und Lehre beeinflusst; nicht zuletzt durch die Aneignung der Räumlichkeiten als Werkstätten und Ateliers. Doch der Umzug auf den Campus Westend rückt näher und noch bevor die Erinnerung an das markante Gebäude verblasst, soll die Geschichte dieses besonderen Standortes, sowie sein Einfluss auf das Institutsleben in einer Ausstellung beleuchtet werden. Eröffnet wird sie an diesem Donnerstag ab 18 Uhr mit einem Rundgang. ...
Background: Patient Reported Outcomes (PRO) are gaining more and more importance in the context of clinical trials. The assessment of PRO is frequently performed by questionnaires where the multiple items of a questionnaire are usually pooled within summarizing scores. These scores are used as variables to measure subjective aspects of treatments and diseases. In clinical research, the calculation of these scores is mostly kept very simple, e.g. by a simple summation of item values. In the medical literature, there is hardly any guidance for performing a refinements of questionnaires and for deducing adequate scores. In contrast, in psychometric literature, there are plenty of more sophisticated methods, which overcome typical assumptions made in traditional (sum) scores, however to the prize of more complicated algorithms, which might be difficult to communicate. When faced with the practical task to refine an existing questionnaire, there exist a clear gap of guidance for applied medical researchers. By this article we try to fill this important gap between psychometric theory and medical application by illustrating our methodological choices on the example of a clinical PRO questionnaire.
Methods: Based on our experiences with the refinement of the BCTOS, a PRO questionnaire to assess aesthetic and function after breast conserving therapy in breast cancer patients, we present the following general steps that we performed by refining the BCTOS questionnaire and its scores: 1. Refinement of the length of the questionnaire and the (item-factor) structure. 2. Selection of the factor score estimation method. 3. Validation of the refined questionnaire and scores with respect to validity, reliability and structure based on a validation cohort.
Results: Our step-step-step procedure helped us to shorten the current form of the BCTOS and to redefine the factor structure. By this, the compliance of patients can be increased and the interpretation of the results becomes more coherent.
Conclusions: We present a step-by-step procedure to refine an existing medical questionnaire along with its scores illustrated and discussed by the refinement of the BCTOS.
Trial registration: Due to the character of the study (no intervention study), no registration was performed.
Early, non-invasive sensing of sustained hyperglycemia in mice using millimeter-wave spectroscopy
(2019)
Diabetes is a very complex condition affecting millions of people around the world. Its occurrence, always accompanied by sustained hyperglycemia, leads to many medical complications that can be greatly mitigated when the disease is treated in its earliest stage. In this paper, a novel sensing approach for the early non-invasive detection and monitoring of sustained hyperglycemia is presented. The sensing principle is based on millimeter-wave transmission spectroscopy through the skin and subsequent statistical analysis of the amplitude data. A classifier based on functional principal components for sustained hyperglycemia prediction was validated on a sample of twelve mice, correctly classifying the condition in diabetic mice. Using the same classifier, sixteen mice with drug-induced diabetes were studied for two weeks. The proposed sensing approach was capable of assessing the glycemic states at different stages of induced diabetes, providing a clear transition from normoglycemia to hyperglycemia typically associated with diabetes. This is believed to be the first presentation of such evolution studies using non-invasive sensing. The results obtained indicate that gradual glycemic changes associated with diabetes can be accurately detected by non-invasively sensing the metabolism using a millimeter-wave spectral sensor, with an observed temporal resolution of around four days. This unprecedented detection speed and its non-invasive character could open new opportunities for the continuous control and monitoring of diabetics and the evaluation of response to treatments (including new therapies), enabling a much more appropriate control of the condition.
An increased expression and cytoplasmic abundance of the ubiquitous RNA binding protein human antigen R (HuR) is critically implicated in the dysregulated control of post-transcriptional gene expression during colorectal cancer development and is frequently associated with a high grade of malignancy and therapy resistance. Regardless of the fact that HuR elicits a broad cell survival program by increasing the stability of mRNAs coding for prominent anti-apoptotic factors, recent data suggest that HuR is critically involved in the regulation of translation, particularly, in the internal ribosome entry site (IRES) controlled translation of cell death regulatory proteins. Accordingly, data from human colon carcinoma cells revealed that HuR maintains constitutively reduced protein and activity levels of caspase-2 through negative interference with IRES-mediated translation. This review covers recent advances in the understanding of mechanisms underlying HuR’s modulatory activity on IRES-triggered translation. With respect to the unique regulatory features of caspase-2 and its multiple roles (e.g., in DNA-damage-induced apoptosis, cell cycle regulation and maintenance of genomic stability), the pathophysiological consequences of negative caspase-2 regulation by HuR and its impact on therapy resistance of colorectal cancers will be discussed in detail. The negative HuR-caspase-2 axis may offer a novel target for tumor sensitizing therapies.
Background: Congenital duodenal obstruction (CDO) can be complete (CCDO) or incomplete (ICDO). To date there is no outcome analysis available that compares both subtypes.
Aim: To quantify and compare the association between CCDO and ICDO with outcome parameters.
Methods: We retrospectively reviewed all patients who underwent operative repair of CCDO or ICDO in our tertiary care institution between January 2004 and January 2017. The demographics, clinical presentation, preoperative diagnostics and postoperative outcomes of 50 patients were compared between CCDO (n = 27; atresia type 1-3, annular pancreas) and ICDO (n = 23; annular pancreas, web, Ladd´s bands).
Results: In total, 50 patients who underwent CDO repair were enrolled and followed for a median of 5.2 and 3.9 years (CCDO and ICDO, resp.). CCDO was associated with a significantly higher prenatal ultrasonographic detection rate (88% versus 4%; CCDO vs ICDO, P < 0.01), lower gestational age at birth, lower age and weight at operation, higher rate of associated congenital heart disease (CHD), more extensive preoperative radiologic diagnostics, higher morbidity according to Clavien-Dindo classification and comprehensive complication index (all P ≤ 0.01). The subgroup analysis of patients without CHD and prematurity showed a longer time from operation to the initiation of enteral feeds in the CCDO group (P < 0.01).
Conclusion: CCDO and ICDO differ with regard to prenatal detection rate, gestational age, age and weight at operation, rate of associated CHD, preoperative diagnostics and morbidity. The degree of CDO in mature patients without CHD influences the postoperative initiation of enteral feeding.
Electrical stimulation shifts healing/scarring towards regeneration in a rat limb amputation model
(2019)
Different species respond differently to severe injury, such as limb loss. In species that regenerate, limb loss is met with complete restoration of the limbs’ form and function, whereas in mammals the amputated limb’s stump heals and scars. In in vitro studies, electrical stimulation (EStim) has been shown to promote cell migration, and osteo- and chondrogenesis. In in vivo studies, after limb amputation, EStim causes significant new bone, cartilage and vessel growth. Here, in a rat model, the stumps of amputated rat limbs were exposed to EStim, and we measured extracellular matrix (ECM) deposition, macrophage distribution, cell proliferation and gene expression changes at early (3 and 7 days) and later stages (28 days). We found that EStim caused differences in ECM deposition, with less condensed collagen fibrils, and modified macrophage response by changing M1 to M2 macrophage ratio. The number of proliferating cells was increased in EStim treated stumps 7 days after amputation, and transcriptome data strongly supported our histological findings, with activated gene pathways known to play key roles in embryonic development and regeneration. In conclusion, our findings support the hypothesis that EStim shifts injury response from healing/scarring towards regeneration. A better understanding of if and how EStim controls these changes, could lead to strategies that replace scarring with regeneration.
Cheilostome Bryozoa Anoteropora latirostris, a colonial marine invertebrate, constructs its skeleton from calcite and aragonite. This study presents firstly correlated multi-scale electron microscopy, micro-computed tomography, electron backscatter diffraction and NanoSIMS mapping. We show that all primary, coarse-grained platy calcitic lateral walls are covered by fine-grained fibrous aragonite. Vertical lateral walls separating autozooid chambers have aragonite only on their distal side. This type of asymmetric mineralization of lateral walls results from the vertical arrangement of the zooids at the growth margins of the colony and represents a type of biomineralization previously unknown in cheilostome bryozoans. NanoSIMS mapping across the aragonite-calcite interface indicates an organic layer between both mineral phases, likely representing an organic template for biomineralization of aragonite on the calcite layer. Analysis of crystallographic orientations show a moderately strong crystallographic preferred orientation (CPO) for calcite (7.4 times random orientation) and an overall weaker CPO for aragonite (2.4 times random orientation) with a high degree of twinning (45%) of the aragonite grains. The calculated Young’s modulus for the CPO map shows a weak mechanical direction perpendicular to the colony’s upper surface facilitating this organism’s strategy of clonal reproduction by fragmentation along the vertical zooid walls.
Künstliche Intelligenz als Ende des Strafrechts? Zur algorithmischen Transformation der Gesellschaft
(2019)
Does Artificial Intelligence (AI) imply the end of criminal law and justice as we know it? This article submits that AI is a transformative technology that seemingly assumes and optimizes the rationalities of criminal law (the effective prevention of crime; the objective, neutral and coherent application of the law etc.), namely by replacing the counterfactual guarantees of the law with the factual guarantees of technology. As a consequence, AI must not be trivialized by criminal law theory. Likewise, it is not enough to subversively criticize the current weaknesses of AI (e.g. vis-à-vis the “bias in, bias out” problem). Rather, criminal law theory should draw on the highflying promises of AI to reflect upon the foundational premises of criminal law. For a criminal law that is mostly a governance tool in the administrative and/or welfare state, AI applications promise the culmination of the law’s very objectives (like the effective inhibition and prevention of crime, e.g. by means of predictive policing; or the political determination of fuzzy sentencing rationales in sentencing algorithms that ensure equal sentences for comparable crimes). For a criminal law, however, that protects liberal freedoms and rests on inter-personal trust, AI may well lead to the passing of the law’s very ideals (e.g. of the presumption of innocence, which can no longer be upheld once everyone, ordinary citizens and judges alike, is deemed a possible risk). The question about “AI as the end of criminal law?” thus eventually raises the two-pronged question “Which criminal law for which society?”. Indeed, what is the status of freedom (esp. in a surveillance society needed to power Big Data driven algorithms), trust (esp. under the zero trust paradigm that underlies many risk assessment algorithms) and future (esp. when algorithms make predictions based on past data) once AI enters into the administration of criminal justice? These are the questions, or so I respectfully submit, that criminal law theory needs to address today in order to come up with a criminal law that is both (for pragmatic reasons) open to technology as well as (for humane reasons) sensible. In all of this, we must take to heart Joachim Hruschka’s great legacy and remain intellectually honest.
Gegenstand aller natürlichen Sprachen, die Menschen hervorgebracht haben, ist das Sprechen. Die Schrift einer solchen Sprache kann insofern als sekundäre Errungenschaft bezeichnet werden. Sorten und Gattungen der menschlichen Sprachen und Schriften sind historisch wie auch heute von großer Vielfalt und krassen Gegensätzen geprägt: z.B. die indoeuropäischen Sprachen mit flektierendem Grammatikbau versus der vielen sinotibetischen Sprachen mit analytischem Bau oder das lateinische Alphabet versus die logographische chinesische Schrift. In dieser Arbeit wird gezeigt, welche Faktoren die Korrespondenz der schriftlichen Repräsentation auf eine Sprache entscheiden und in welcher Art und Weise die Schrift die sprachlichen Entwicklungen beeinflussen kann.
IL-1 family member IL-33 exerts a variety of immune activating and regulating properties and has recently been proposed as a prognostic biomarker for cancer diseases, although its precise role in tumor immunity is unclear. Here we analyzed in vitro conditions influencing the function of IL-33 as an alarmin and a co-factor for the activity of cytotoxic CD8+ T cells in order to explain the widely discussed promiscuous behavior of IL-33 in vivo. Circulating IL-33 detected in the serum of healthy human volunteers was biologically inactive. Additionally, bioactivity of exogenous recombinant IL-33 was significantly reduced in plasma, suggesting local effects of IL-33, and inactivation in blood. Limited availability of nutrients in tissue causes necrosis and thus favors release of IL-33, which—as described before—leads to a locally high expression of the cytokine. The harsh conditions however influence T cell fitness and their responsiveness to stimuli. Nutrient deprivation and pharmacological inhibition of mTOR mediated a distinctive phenotype characterized by expression of IL-33 receptor ST2L on isolated CD8+ T cells, downregulation of CD8, a transitional CD45RAlowROlow phenotype and high expression of secondary lymphoid organ chemokine receptor CCR7. Under nutrient deprivation, IL-33 inhibited an IL-12 induced increase in granzyme B protein expression and increased expression of GATA3 and FOXP3 mRNA. IL-33 enhanced the TCR-dependent activation of CD8+ T cells and co-stimulated the IL-12/TCR-dependent expression of IFNγ. Respectively, GATA3 and FOXP3 mRNA were not regulated during TCR-dependent activation. TCR-dependent stimulation of PBMC, but not LPS, initiated mRNA expression of soluble IL-33 decoy receptor sST2, a control mechanism limiting IL-33 bioactivity to avoid uncontrolled inflammation. Our findings contribute to the understanding of the compartment-specific activity of IL-33. Furthermore, we newly describe conditions, which promote an IL-33-dependent induction of pro- or anti-inflammatory activity in CD8+ T cells during nutrient deprivation.
Background: The nature of perceptual-cognitive expertise in interactive sports has gained more and more scientific interest over the last two decades. Research to understand how this expertise can be developed has not been addressed profoundly yet. In approaches to study this with interventional designs, only few studies have scrutinized several levels of transfer such as to the field. Therefore, the aim of this study was to examine the efficacy of a generic off-court perceptual-cognitive training in elite volleyball players on three different levels: task-specific, near-transfer, and far-transfer effects. Based on overlapping cognitive processes between training and testing, we hypothesized task-specific improvements as well as positive near- and far-transfer effects after a multiple-object tracking training intervention.
Methods: Twenty-two volleyball experts completed a 8-week three-dimensional (3D) multiple-object tracking (3D-MOT) training intervention. A control group (n = 21; volleyball experts also) participated in regular ball practice only. Before and after training, both groups performed tests on the 3D-MOT, four near-transfer tests in cognitive domains, and a far-transfer, lab-based, and volleyball-specific blocking test.
Results: The results of the 2 × 2 analysis of variance (ANOVA) (group, time) showed significant interaction effects in the 3D-MOT task [F(1,40) = 93.10; p < 0.001; η2p = 0.70] and in two near-transfer tests [sustained attention: F(1,40) = 15.45; p < 0.001; η2p = 0.28; processing speed: F(1,40) = 12.15; p = 0.001; η2p = 0.23]. No significant interaction effects were found in the far-transfer volleyball test.
Conclusions: Our study suggests positive effects in task-specific and two near-transfer tests of a perceptual-cognitive intervention in elite volleyball athletes. This supports a partial overlap in cognitive processing between practice and tests with the result of positive near-transfer. However, there are no significant effects in far-transfer testing. Although these current results are promising, it is still unclear how far-transfer effects of a generic perceptual-cognitive training intervention can be assured.
One of the most difficult challenges in clinical hepatology is the diagnosis of a drug-induced liver injury (DILI). The timing of the events, exclusion of alternative causes, and taking into account the clinical context should be systematically assessed and scored in a transparent manner. RUCAM (Roussel Uclaf Causality Assessment Method) is a well-established diagnostic algorithm and scale to assess causality in patients with suspected DILI. First published in 1993 and updated in 2016, RUCAM is now the worldwide most commonly used causality assessment method (CAM) for DILI. The following manuscript highlights the recent implementation of RUCAM around the world, by reviewing the literature for publications that utilized RUCAM, and provides a review of “best practices” for the use of RUCAM in cases of suspected DILI. The worldwide appreciation of RUCAM is substantiated by the current analysis of 46,266 DILI cases, all tested for causality using RUCAM. These cases derived from 31 reports published from 2014 to early 2019. Their first authors came from 10 countries, with China on top, followed by the US, and Germany on the third rank. Importantly, all RUCAM-based DILI reports were published in high profile journals. Many other reports were published earlier from 1993 up to 2013 in support of RUCAM. Although most of the studies were of high quality, the current case analysis revealed shortcomings in few studies, not at the level of RUCAM itself but rather associated with the work of the users. To ensure in future DILI cases a better performance by the users, a list of essential elements is proposed. As an example, all suspected DILI cases should be evaluated 1) by the updated RUCAM to facilitate result comparisons, 2) according to a prospective study protocol to ensure complete data sets, 3) after exclusion of cases with herb induced liver injury (HILI) from a DILI cohort to prevent confounding variables, and 4) according to inclusion of DILI cases with RUCAM-based causality gradings of highly probable or probable, in order to increase the specificity of the results. In conclusion, RUCAM benefits from its high appreciation and performs well provided the users adhere to published recommendations to prevent confounding variability.
Microenvironmental regulation of tumor progression and therapeutic response in brain metastasis
(2019)
Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.
The development of multimodal sensor-based applications designed to support learners with the improvement of their skills is expensive since most of these applications are tailor-made and built from scratch. In this paper, we show how the Presentation Trainer (PT), a multimodal sensor-based application designed to support the development of public speaking skills, can be modularly extended with a Virtual Reality real-time feedback module (VR module), which makes usage of the PT more immersive and comprehensive. The described study consists of a formative evaluation and has two main objectives. Firstly, a technical objective is concerned with the feasibility of extending the PT with an immersive VR Module. Secondly, a user experience objective focuses on the level of satisfaction of interacting with the VR extended PT. To study these objectives, we conducted user tests with 20 participants. Results from our test show the feasibility of modularly extending existing multimodal sensor-based applications, and in terms of learning and user experience, results indicate a positive attitude of the participants towards using the application (PT+VR module).
The quest for new and improved therapies for glioblastoma (GB) has been mostly unsuccessful in more than a decade despite significant efforts. The few exceptions include the optimization of classical alkylating chemotherapy by including lomustine in the first line regimen for GB with a methylated MGMT promoter and tumor treating fields. The GB signaling network has been well-characterized and genetic alterations resulting in activation of receptor tyrosine kinases and especially epidermal growth factor receptor (EGFR) and downstream mammalian target of rapamycin complex 1 (mTORC1) signaling were found in the majority of GBs. ...
Dieses Zitat von Sperone Speroni aus dem "Dialogo d’Amore" (1542) beschreibt eindrücklich die herausragende Stellung des Malers Tizian. Die Hochachtung, die aus diesen Worten hervorgeht, spiegelt sich in der Ausstellung Tizian und die Renaissance in Venedig wieder, die vom 13. Februar bis zum 26. Mai 2019 im Frankfurter Städel Museum zu sehen ist. Die Sonderausstellung mit über 100 Meisterwerken widmet sich nicht nur Tizian, sondern auch anderen wichtigen Vertretern der venezianischen Malerei der Renaissance. So werden unter anderem Gemälde und Zeichnungen von Giovanni Bellini, Jacopo Palma il Vecchio, Sebastiano del Piombo, Lorenzo Lotto, Jacopo Tintoretto, Jacopo Bassano und Paolo Veronese gezeigt. In einer Folge von acht Kapiteln führt die Präsentation dieser Meisterwerke durch ausgewählte Themenfelder, die für die venezianische Malerei im 16. Jahrhundert charakteristisch sind. ...
Background: Obesity impairs a variety of cell types including adipose-derived mesenchymal stem cells (ASCs). ASCs are indispensable for tissue homeostasis/repair, immunomodulation, and cell renewal. It has been demonstrated that obese ASCs are defective in differentiation, motility, immunomodulation, and replication. We have recently reported that some of these defects are linked to impaired primary cilia, which are unable to properly convey and coordinate a variety of signaling pathways. We hypothesized that the rescue of the primary cilium in obese ASCs would restore their functional properties.
Methods: Obese ASCs derived from subcutaneous and visceral adipose tissues were treated with a specific inhibitor against Aurora A or with an inhibitor against extracellular signal-regulated kinase 1/2 (Erk1/2). Multiple molecular and cellular assays were performed to analyze the altered functionalities and their involved pathways.
Results: The treatment with low doses of these inhibitors extended the length of the primary cilium, restored the invasion and migration potential, and improved the differentiation capacity of obese ASCs. Associated with enhanced differentiation ability, the cells displayed an increased expression of self-renewal/stemness-related genes like SOX2, OCT4, and NANOG, mediated by reduced active glycogen synthase kinase 3 β (GSK3β).
Conclusion: This work describes a novel phenomenon whereby the primary cilium of obese ASCs is rescuable by the low-dose inhibition of Aurora A or Erk1/2, restoring functional ASCs with increased stemness. These cells might be able to improve tissue homeostasis in obese patients and thereby ameliorate obesity-associated diseases. Additionally, these functionally restored obese ASCs could be useful for novel autologous mesenchymal stem cell-based therapies.
Die Welt ist im Wandel, der Globalisierungsprozess weit fortgeschritten. Inwiefern spielen dann Kolonialismus und Unterdrückung noch eine Rolle? Sind diese Zeitgeschehnisse nicht wie man so schön sagt "Geschichte"? Dieser Frage gehen der britisch-ghanaische Künstler John Akomfrah und das Black Audio Film Collective im gemeinsamen Werk "Expeditions 1 – Signs of Empire" (1983) nach. Die zweiteilige Videoarbeit zeigt mithilfe dokumentarischer Fotografien, Textfragmenten und Tonaufzeichnungen des British Empire ein Bild, welches die Potenz heutiger nationalstaatlicher Strukturen des Okzidents in der Unterdrückung und Ausbeutung kolonialisierter Länder verortet – und so den Mythos der moralischen Überlegenheit des Westens dekonstruiert. ...
Der technische Fortschritt ermöglicht die Auswertung großer Datenmengen mittels Algorithmen zur Feststellung bislang unbekannter Korrelationen. Schlagwortartig werden solche Analysen unter dem Begriff Big Data zusammengefasst. Häufig sind personenbezogene Daten Gegenstand von Big-Data-Anwendungen, sei es als Grundlage oder Ergebnis einer Auswertung. In diesen Fällen ist das Datenschutzrecht zu beachten.
Der Zweckbindungsgrundsatz fordert die Angabe eines Verarbeitungszwecks bereits bei Erhebung der Daten und eine Bindung des weiteren Datenumgangs an diesen Zweck. Damit besteht ein Spannungsverhältnis zu Big-Data-Anwendungen, die zu Verarbeitungsbeginn den Zweck allenfalls unspezifisch anzugeben vermögen. Auf Grundlage des alten Bundesdatenschutzgesetzes mit einzelnen Ausblicken auf die Datenschutzgrundverordnung untersucht die Arbeit die datenschutzrechtlichen Anforderungen an die Zweckfestlegung und welche Bindungen aus ihr folgen. Zudem nimmt der Autor mögliche Lösungen des Konflikts zwischen Big-Data-Anwendungen und dem Zweckbindungsgrundsatz in den Blick.
The sphingolipid sphingosine-1-phosphate (S1P) is produced by sphingosine kinases to either signal through intracellular targets or to activate a family of specific G-protein-coupled receptors (S1PR). S1P levels are usually low in peripheral tissues compared to the vasculature, forming a gradient that mediates lymphocyte trafficking. However, S1P levels rise during inflammation in peripheral tissues, thereby affecting resident or recruited immune cells, including macrophages. As macrophages orchestrate initiation and resolution of inflammation, the sphingosine kinase/S1P/S1P-receptor axis emerges as an important determinant of macrophage function in the pathogenesis of inflammatory diseases such as cancer, atherosclerosis, and infection. In this review, we therefore summarize the current knowledge how S1P affects macrophage biology.
Canada’s geographic centre lies in the Territory Nunavut. From here the distance to the geographic North Pole is as far as to the US border. Nunavut takes up about 1/5 of the Canadian land mass but has by far the smallest population with currently about 38,000 residents. 85% of its population are Inuit whose culture dramatically changed within the last 70 years.
As a result, the territory is dealing with several generations of Inuit that are traumatized or at least severely affected by cultural and economic changes that started after World War 2 with the resettlement from the land into permanent communities. No matter if we are talking about the actual elders, mid-age adults or pre-teenagers, each of this generation experienced and still experiences various personal and cultural challenges of identity, financial and housing insecurity, food insecurity, substance abuse education, change of social values ranging from inter-generational and gender relationships to the introduction of a foreign political and legal system.
On the other side, a lot of the traditional societal values are still being practiced in Inuit families. Despite all the tragedies that several generations of Inuit have experienced by now, the society keeps generating the strength and cultural pride that allows many Inuit both, as individuals and as a collective under the umbrella of either Inuit Land Claims or not for profit organizations to advocate on behalf of Inuit culture, to fight for more acknowledgement of Inuit culture and to enhance pride in the historic and present day cultural achievements of Nunavut’s indigenous population.
The social issues, inter- and intra-cultural processes described in my thesis are not exclusive to the situation in Nunavut or to Inuit. Studies from other regions, in Canada or from around the world (LaPrairie 1987; Jensen 1986; Nunatsiaq News 6/30/2010) reveal similar challenges.
Though many structural similarities can be identified by comparing these studies with each other, e.g. marginalization of the indigenous local population, colonization, paternalism and resulting issues like personal and cultural identity loss, it is important to have a more in depth look into the single cases to determine which individual events and developments causes and maybe still cause such a devastating social situation as it is found among many indigenous peoples across the world. From my perspective effective improvements of the situation of a group, a respective community or region can only happen when particularities of socialization, communication and philosophy in the single cultural entities are being considered.
That is why my thesis will exclusively focus on developments in Nunavut and use various case studies of communities. The case studies shall help to identify local differences in historic and recent developments and thus provide starting points for explanations of different developments in different Nunavut communities.
The thesis is looking at both, historic and recent root causes for the many issues in Nunavut.
The data that my my thesis is based on are a combination of literature and about 60 formal and informal interviews that I conducted in three Nunavut communities (Iqaluit, Whale Cove, Kugluktuk) during my 18 months of field work between October 2008 and March 2010. Many more spontaneous unstructured conversations between me and community members added to the pool of first-hand information that I gathered.
Since my field work is limited to those three communities it has a very strong qualitative character. The quantitative side, which allows me to confidently apply my research analyses to entire Nunavut, comes from literature research as well as many informal conversations and a few formal interviews that I conducted with people who had some experience in other communities than Iqaluit, Kugluktuk and Whale Cove.
Furthermore, while I was living at the old residence of the Nunavut Arctic College in Iqaluit, I spend time with college students from across Nunavut. Through them, I obtained „case studies “from following communities: Iqaluit, Qikiqtarjuaq, Kimmirut, Pangnirtung, Clyde River, Pond Inlet, Igloolik, Repulse Bay, Cape Dorset, Chesterfield Inlet, Baker Lake, Rankin Inlet, Whale Cove, Arviat, Taloyoak, Kugluktuk.
My general categorization of “early contact period”, “contact”, “1st generation” and “2nd generation” is very similar to Damas’ terms of “early contact phase”, “contact – traditional”, “resettlement” that he uses to create a timeline that describes the major phases of impact for Inuit society (Damas 2002: 7, 17).
Chapters 2 is meant to provide an inventory of the key aspects of current social issues in Nunavut. In this context I am looking at the four major aspects that in my opinion shape Nunavut’s society:
1) violence and other forms of social dysfunctions
2) the associated services and delivering agencies that try to address those matters
3) Education
4) Inuit cultural particularities in communication and socialization
Those four areas are forming the foundation for the rest of my work. The following chapters will guide the reader through the historic transformation process of Inuit pre-colonial semi-nomadic society to a society that is living in permanent settlements, strongly influenced if not in many ways dominated by Euro-Canadian culture. Each of those chapters will be referring to the social and cultural changes that happened in the different time periods that I labeled with “Pre-settlement, First, Second, and Third Generation”. The relevance of violence and other social dysfunctions, their context and strategies how each generation dealt with those matters will be analyzed while I will be also referring to the impacts that non-Inuit, primarily Euro-Canadians and Euro-Americans had and have on Inuit society.
...
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Die vorliegende Arbeit behandelt einen Rechtsvergleich zwischen dem Neutralitätsgebot in der Bundesrepublik Deutschland und die Laizität in der Türkei aus der Perspektive des Religionsverwaltungsrechts im Referenzgebiet Medienrecht. Der Schwerpunkt liegt in der Darstellung des Türkischen Rechts.
Zu Beginn werden die beiden Begriffe des Neutralitätsgebots und der Laizität als Analyseinstrumente näher erörtert. Insbesondere erfolgt eine historische Begriffsgenese der Laizität im türkischen Rechtssystem in Bezug auf die Verfassungen der Türkei von Kanun-i Esasi 1876 bis hin zur aktuellen Verfassung von 1982. Darüber hinaus wird sowohl in der Rechtsprechung als auch in der Literatur erforscht, welchen Wandel der Laizitätsbegriff seit seiner Aufnahme in die Verfassung erfahren hat.
Es wird festgestellt, dass beide Begriffe einer Begriffskategorie angehören, wobei sie sich überwiegend durch ihre Intensität bei der Trennung vom Sakralem und Säkularem gerade hinsichtlich Kooperationen derselben und der vorherrschenden Koexistenz unterscheiden.
Zusätzlich wird auf die Funktion und die Auswirkungen des Diyanet sowohl auf den Laizitätsbegriff selbst als auch auf das Medienrecht eingegangen.
Im Folgenden wird das Medienrecht in beiden Ländern aus der Perspektive der öffentlichen Medien, insbesondere der Rundfunkanstalten untersucht. Hierbei werden in der Bundesrepublik Deutschland alle öffentlich-rechtlichen Rundfunkanstalten, ihre Organisationsstruktur und Regelungen zur Vertretung der Religionsgemeinschaften behandelt, die gängigen Regelungen diesbezüglich ausführlich erörtert und aktuelle Unterschiede derselben bei der Vertretung der Religionsgemeinschaften im jeweiligen Rundfunkrat mitunter auch tabellarisch aufgezeigt. Durch die Behandlung der Vertretungsregelungen werden Mängel aufgewiesen. Diese ergeben sich beispielsweise in Hessen bei der Auswahl der vertretungsberechtigten Organisationen, da bei den parlamentarischen Überlegungen hierzu möglicherweise nicht hinreichend sachdienliche Gutachten herangezogen wurden. Eine andere Quelle für Fehler wird in der Anwendung von bestimmten Rechtsbegriffen als Parameter für die Eignung der Religionsgemeinschaften zur Vertretung gesehen, die ihrerseits auf christliche Religionsgemeinschaften zugeschnitten sind, jedoch gerade die innerhalb der Bevölkerung am stärksten vertretene Minderheitengruppe, nämlich die Muslime, mangels Körperschaftsstatus, außen vor lässt. Letztendlich werden auch gerade für die Bundesrepublik Deutschland Lösungsansätze herausgearbeitet.
Im türkischen Recht erfolgt eine ebensolche Darstellung, wobei als Besonderheit auch der TMSF als Einlagensicherungsfonds, sowie die These behandelt werden, dass durch die Eingriffe des TMSF öffentlich-rechtliche Printmedien vorhanden seien. Speziell werden die Entstehung und Entwicklung des Medienrechts, der Aufbau und die Kompetenzen der öffentlich-rechtlichen Medien und die Eingriffe auf diese dargestellt.
In der Türkei werden bereits in der verwaltungsrechtlichen Normierung der Kompetenzen einzelner Institutionen und erst Recht in der verwaltungsrechtlichen Praxis gravierende Mängel festgestellt.
Over the last years, many microRNAs (miRNAs) have been identified that regulate the formation of bioactive lipid mediators such as prostanoids and leukotrienes. Many of these miRNAs are involved in complex regulatory circuits necessary for the fine-tuning of biological functions including inflammatory processes or cell growth. A better understanding of these networks will contribute to the development of novel therapeutic strategies for the treatment of inflammatory diseases and cancer. In this review, we provide an overview of the current knowledge of miRNA regulation in eicosanoid pathways with special focus on novel miRNA functions and regulatory circuits of leukotriene and prostaglandin biosynthesis.
The lateralization of neuronal processing underpinning hearing, speech, language, and music is widely studied, vigorously debated, and still not understood in a satisfactory manner. One set of hypotheses focuses on the temporal structure of perceptual experience and links auditory cortex asymmetries to underlying differences in neural populations with differential temporal sensitivity (e.g., ideas advanced by Zatorre et al. (2002) and Poeppel (2003). The Asymmetric Sampling in Time theory (AST) (Poeppel, 2003), builds on cytoarchitectonic differences between auditory cortices and predicts that modulation frequencies within the range of, roughly, the syllable rate, are more accurately tracked by the right hemisphere. To date, this conjecture is reasonably well supported, since – while there is some heterogeneity in the reported findings – the predicted asymmetrical entrainment has been observed in various experimental protocols. Here, we show that under specific processing demands, the rightward dominance disappears. We propose an enriched and modified version of the asymmetric sampling hypothesis in the context of speech. Recent work (Rimmele et al., 2018b) proposes two different mechanisms to underlie the auditory tracking of the speech envelope: one derived from the intrinsic oscillatory properties of auditory regions; the other induced by top-down signals coming from other non-auditory regions of the brain. We propose that under non-speech listening conditions, the intrinsic auditory mechanism dominates and thus, in line with AST, entrainment is rightward lateralized, as is widely observed. However, (i) depending on individual brain structural/functional differences, and/or (ii) in the context of specific speech listening conditions, the relative weight of the top-down mechanism can increase. In this scenario, the typically observed auditory sampling asymmetry (and its rightward dominance) diminishes or vanishes.
The three major autoimmune diseases (ADs) of the liver are primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). All of those diseases show an aggressive immune reaction resulting in the destruction of liver tissue and finally to the development of hepatic fibrosis.
PSC is an autoimmune mediated disease of unknown etiology. It is characterized by inflammation of intra- and extrahepatic bile ducts. The progressive destruction of the bile ducts can lead to liver cirrhosis and finally to liver failure. Clinical signs for PSC are increased alkaline phosphatase (AP) and gamma glutamyltransferase (GGT) levels, presence of perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and bile ducts with characteristic strictures and dilations of the biliary tree as well as onion skin fibrosis surrounding the damaged bile ducts. Currently, there is no established treatment for PSC patients. The administration of ursodeoxycholic acid (UDCA) is being use as a therapy. However, it merely serves a symptomatic treatment to reduce serum AP and GGT as well as the formation of gallstones. In the advanced stage of PSC, liver transplantation is the last therapeutic option. Mdr2-/- mice are an excepted mouse model for human PSC. Such mice show lymphocytes infiltration into the liver, bile duct lesions, as well as the presence of the typical onion skin-like pericholangitis and periductal fibrosis.
AIH is a rare chronic autoimmune disease of the liver that results from the loss of self-tolerance to hepatocytes and leads to destruction of the hepatic parenchyma with the onset of cirrhosis. Clinical signs for AIH are elevated alanine aminotransferase (ALT) and aspartate transaminase (AST) levels, hypergammaglobulinemia and different types of autoantibodies. In addition, interphase hepatitis with lymphocytic and plasmacellular infiltrates in the periportal field are characteristic for AIH. Two different subtypes of AIH exist and depending on their autoantibody profile they can be distinguished into AIH type 1 which is characterized by the presence of anti-nuclear (ANA) and/or anti-smooth muscular (SMA) autoantibodies, and AIH type 2 showing liver/kidney microsomal autoantibodies (LKM-1). LKM-1 recognizes the major autoantigen, the 2D6 isoform of the cytochrome P450 enzyme family (CYP2D6). One mouse model for AIH is the CYP2D6 model in which the injection of Ad-2D6 leads to a breakdown of the immune tolerance by the destruction of hepatocytes.
There are some patients with autoimmune diseases of the liver who have both cholestatic and hepatic liver enzymes and histological features suggestive of two different liver diseases. These patients are diagnosed with an overlap syndrome (OS).
In my thesis I generated an animal model with characteristics of both diseases, which would mimic features of human PSC-AIH OS. Mdr2-/- mice which spontaneously develop PSC were infected with Ad-2D6 to trigger the autoimmune-driven hepatic injury. Pathogenesis of PSC-AIH OS mice was compared to mice with solitary PSC or AIH. Naïve FVB wild type mice have been used as healthy controls. The characterization of the PSC-AIH OS model was done by analyzing serological parameters like ALT, AP, different antibodies like pANCA, LKM-1 like CYP2D6 and total IgG. Additionally, fibrosis and cholangitis were analyzed by immunohistochemistry and Western blotting. Moreover, cellular infiltrations of CD4+ and CD8+ T cells, dendritic cells (DCs), monocytes/macrophages and neutrophils were determined with immunohistochemistry. Finally, the overall immune balance in the liver and the frequency of CYP specific T cells were analyzed via flow cytometry. Our new mouse model indeed represents the characteristics of both PSC and AIH and mimics features of the human PSC-AIH OS. It allows studying the development of a PSC-AIH OS and how the two overlapping diseases are influencing one another. In a second approach I wanted to induce CYP2D6-specific tolerance in AIH mice. Therefore, I tried four different approaches, namely intranasal peptide administration, injection of tolerogenic DCs, antigen-coupled splenocytes, and Ag-coupled nanoparticles (NP) and evaluated their potential to induce CYP2D6 specific Treg with the capacity to prevent AIH in mice. Unfortunately, the intranasal peptide administration and also the injection of tolerogenic DCs did not increase the amount of CYP2D6 specific Treg which would lead to a reduction of the frequency of inflammatory T cells. Surprisingly, the injection of antigen-coupled splenocytes showed the opposite effect characterized by a very strong cytokine secretion in the tolerized mice. The use of NPs led to an increase in CYP2D6 specific Treg as well as in decrease in the frequency of inflammatory T cells and finally has the potential for a therapeutic approach.
In summary, the generated PSC-AIH OS model represents many clinical signs which can also be observed in PSC-AIH OS patients. This model can be used to study the etiology of this overlap syndrome and further to test potential therapeutic approaches. The different immune tolerance induction pathways which I tried in the AIH model show that NPs have to potential to induce immune tolerance but this approach has to be refined and the outcome has to be characterized in more detail.
The paper analyses the linkages from financial developments to public finances. It maps and discusses the transmission channels to fiscal variables. These channels include asset prices, financing conditions, balance sheets of banks, non-banks and central banks and international linkages. The study argues that the fiscal effects via each and all these channels can be very serious in magnitude and can put the sustainability of public finances at risk. However, there is an only limited in-depth analysis of these channels and risks.
Im Frühjahr 2018 wurde innerhalb des vom Bundesministerium für Bildung und Forschung geförderten Projektes „QuartierMobil“ eine Haushaltsbefragung im innenstadtnahen Stadtteil Frankfurt-Bornheim durchgeführt (N = 1027). Für die Stichprobenauswahl wurden das Random-Route-Verfahren und die Last-Birthday-Methode angewendet. Der Fragebogen wurde in Abstimmung mit den Projektpartner*innen, dem Referat Mobilitäts- und Verkehrsplanung der Stadt Frankfurt sowie dem Planungsbüro Planersocietät, entwickelt. Ziel der Befragung war es, die Dynamiken und Präferenzen der Bewohnenden des Quartiers hinsichtlich ihrer Alltagsmobilität, Verkehrsmittelnutzung und Einstellungen zu Konfliktsituationen zu erhalten. Der Schwerpunkt der Befragung lag auf dem Parken im urbanen Quartier und möglichen Gestaltungsoptionen des städtischen Parkraummanagements hin zu einer nachhaltigeren Mobilität und einer Erhöhung der Aufenthalts- und Lebensqualität im Quartier.
We present a model for the autonomous and simultaneous learning of active binocular and motion vision. The model is based on the Active Efficient Coding (AEC) framework, a recent generalization of classic efficient coding theories to active perception. The model learns how to efficiently encode the incoming visual signals generated by an object moving in 3-D through sparse coding. Simultaneously, it learns how to produce eye movements that further improve the efficiency of the sensory coding. This learning is driven by an intrinsic motivation to maximize the system's coding efficiency. We test our approach on the humanoid robot iCub using simulations. The model demonstrates self-calibration of accurate object fixation and tracking of moving objects. Our results show that the model keeps improving until it hits physical constraints such as camera or motor resolution, or limits on its internal coding capacity. Furthermore, we show that the emerging sensory tuning properties are in line with results on disparity, motion, and motion-in-depth tuning in the visual cortex of mammals. The model suggests that vergence and tracking eye movements can be viewed as fundamentally having the same objective of maximizing the coding efficiency of the visual system and that they can be learned and calibrated jointly through AEC.
Fährt man in den Urlaub, weiß man eigentlich schon vorab, dass man als Reisende ob der eigenen Unwissenheit mehr bezahlt als die ortskundigen Locals. Man weiß, dass die meisten europäischen Urlaubsorte vom Tourismus leben und drückt im Stillen sein Einverständnis damit aus, indem man überhaupt reist. Gelegentlich aber zahlt man nicht nur etwas mehr, sondern wird beim Rückweg zum Flughafen von einem Taxifahrer, der kein Englisch spricht oder auch nur so tut, um die halbe Insel gefahren, obwohl man vom Beifahrersitz in sein Handy schaut und einem Google Maps einen wesentlich kürzeren Weg angezeigt hat. Man könnte sich aufregen, mit Hand und Fuß mit dem Taxifahrer schimpfen, die Türen des Wagens zuknallen und so dem eigenen Unmut Ausdruck verschaffen. Man kann aber auch ruhig bleiben, dem Taxifahrer thank you for showing us the whole island zurufen, zurückfliegen und eine Ausstellung organisieren, wie Cemile Deniz Alibas, Dominika Bednarsky, Un-Zu Ha-Nul Lee und Lena Stewens es getan haben. ...
Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia.
Causes of maladaptation
(2019)
Evolutionary biologists tend to approach the study of the natural world within a framework of adaptation, inspired perhaps by the power of natural selection to produce fitness advantages that drive population persistence and biological diversity. In contrast, evolution has rarely been studied through the lens of adaptation's complement, maladaptation. This contrast is surprising because maladaptation is a prevalent feature of evolution: population trait values are rarely distributed optimally; local populations often have lower fitness than imported ones; populations decline; and local and global extinctions are common. Yet we lack a general framework for understanding maladaptation; for instance in terms of distribution, severity, and dynamics. Similar uncertainties apply to the causes of maladaptation. We suggest that incorporating maladaptation‐based perspectives into evolutionary biology would facilitate better understanding of the natural world. Approaches within a maladaptation framework might be especially profitable in applied evolution contexts – where reductions in fitness are common. Toward advancing a more balanced study of evolution, here we present a conceptual framework describing causes of maladaptation. As the introductory article for a Special Feature on maladaptation, we also summarize the studies in this Issue, highlighting the causes of maladaptation in each study. We hope that our framework and the papers in this Special Issue will help catalyze the study of maladaptation in applied evolution, supporting greater understanding of evolutionary dynamics in our rapidly changing world.
Multitasking is ubiquitous in our everyday life. Accordingly, situations in which two or more tasks need to be handled concurrently or in close temporal succession have been studied intensely. Different paradigms have been developed in that context (Koch et al., 2018). Over the last decades, the psychological refractory period (PRP) paradigm has dominated dual-task research, because it allows quantitative predictions of reaction time increases coupled to stimulus onset asynchrony. Part of the success of this paradigm is grounded in the fact that most of the studies are run under strict experimental control with very elementary tasks, mostly characterized by a definite start and ending. However, it remains unclear whether these limited settings sufficiently reflect the range of eventualities we find in real life. Rather, there is accumulating evidence that important factors modulating multitask performance are not sufficiently captured by the PRP approach. Here we focus on evidence that motor responses that involve continuous interaction with the environment may engage processes that alter the coordination of concurrently performed tasks in fundamental ways. ...
Among the causality assessment methods used for the diagnosis of drug-induced liver injury (DILI), Roussel Uclaf Causality Assessment Method (RUCAM) remains the most widely used not only for individual cases but also for prospective and retrospective studies worldwide. This first place is justified by the characteristics of the method such as precise definition and classification of the liver injury, which determines the right scale in the scoring system, precise definition of the seven criteria, and the validation approach based on cases with positive rechallenge. RUCAM is used not only for any types of drugs but also for herbal medicines causing herb-induced liver injury, (HILI) and dietary supplements. In 2016, the updated RUCAM provided further specifications of criteria and instructions to improve interobserver variability. Although this method was criticized for criteria such as the age and alcohol consumption, recent consensus meeting of experts has recognized their value and recommended their incorporation into any method. While early studies searching for DILI in large databases especially in electronic medical records were based on codes of diseases or natural language without causality assessment, the recommendation is now to include RUCAM in the search for DILI/HILI. There are still studies on DILI detection or the identification of biomarkers that take into consideration the cases assessed as “possible,” although it is well known that these cases reduce the strength of the association between the cases and the offending compound or the new biomarker to be validated. Attempts to build electronic RUCAM or automatized application of this method were successful despite some weaknesses to be corrected. In the future, more reflections are needed on an expert system to standardize the exclusion of alternative causes according to the clinical context. Education and training on RUCAM should be encouraged to improve the results of the studies and the day-to-day work in pharmacovigilance departments in companies or in regulatory agencies. It is also expected to improve RUCAM with biomarkers or other criteria provided that the validation process replaces expert opinion by robust standards such as those used for the original method.
The lysosomal polypeptide transporter TAPL belongs to the superfamily of ATP-binding cassette transporters. TAPL forms a homodimeric transport complex, which translocates oligo- and polypeptides into the lumen of lysosomes driven by ATP hydrolysis. Although the structure and the function of ABC transporters were intensively studied in the past, details about the single steps of the transport cycle are still elusive. Therefore, we analyzed the coupling of peptide binding, transport and ATP hydrolysis for different substrate sizes. Although longer and shorter peptides bind with the same affinity and are transported with identical Km values, they differ significantly in their transport rates. This difference can be attributed to a higher activation energy for the longer peptide. TAPL shows a basal ATPase activity, which is inhibited in the presence of longer peptides. Uncoupling between ATP hydrolysis and peptide transport increases with peptide length. Remarkably, also the type of nucleotide determines the uncoupling. While GTP is hydrolyzed as good as ATP, peptide transport is significantly reduced. In conclusion, TAPL does not differentiate between transport substrates in the binding process but during the following steps in the transport cycle, whereas, on the other hand, not only the coupling efficiency but also the activation energy varies depending on the size of peptide substrate.
Exercise is a treatment option in peripheral artery disease (PAD) patients to improve their clinical trajectory, at least in part induced by collateral growth. The ligation of the femoral artery (FAL) in mice is an established model to induce arteriogenesis. We intended to develop an animal model to stimulate collateral growth in mice through exercise. The training intensity assessment consisted of comparing two different training regimens in C57BL/6 mice, a treadmill implementing forced exercise and a free-to-access voluntary running wheel. The mice in the latter group covered a much greater distance than the former pre- and postoperatively. C57BL/6 mice and hypercholesterolemic ApoE-deficient (ApoE-/-) mice were subjected to FAL and had either access to a running wheel or were kept in motion-restricting cages (control) and hind limb perfusion was measured pre- and postoperatively at various times. Perfusion recovery in C57BL/6 mice was similar between the groups. In contrast, ApoE-/- mice showed significant differences between training and control 7 d postoperatively with a significant increase in pericollateral macrophages while the collateral diameter did not differ between training and control groups 21 d after surgery. ApoE-/- mice with running wheel training is a suitable model to simulate exercise induced collateral growth in PAD. This experimental set-up may provide a model for investigating molecular training effects.
Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.
Evaluation of INSTAND e.V.’s external quality assessment for C-reactive protein and procalcitonin
(2019)
Background: The purpose of this paper was to analyze the general diagnostic strength and performance of in vitro diagnostics for C-reactive protein and procalcitonin based on the results of external quality assessment schemes (EQAs).
Methods: We analyzed qualitative and quantitative data on both markers collected by the Society for Promotion Quality Assurance in Medical Laboratories (INSTAND e.V.) from 20 EQAs. The C-reactive protein evaluation was method-specific and the procalcitonin evaluation manufacturer-specific (pseudonymized). Coefficients of variation were determined in order to evaluate interlaboratory comparability and the performance of individual laboratories during the analyzed period was examined.
Results: Overall most of our participants were able to correctly distinguish the positive from the negative samples, but we occasionally observed also false-positive results for the immunological detection of C-reactive protein. For the semi-quantitative results of C-reactive protein we observed an overall median difference below 5% except for dry chemistry methods (≤ 21%). For procalcitonin two manufacturer collectives showed a good comparability, while one manufacturer detected up to 42% higher results. The coefficients of variation are promising for both analytes even though they surpass the manufacturer’s indication for some collectives. The performance of individual laboratories during the analyzed period was more stable for C-reactive protein than for procalcitonin.
Conclusion: In-vitro diagnostic testing for C-reactive protein and procalcitonin showed promising results in our EQAs but still further improvements are needed. We recommend stepping up research on reference measurement methods for both parameters to possibly enhancing the accuracy and diagnostic strength of such assays.
kurz und kn@pp news : Nr. 46
(2019)
Mit selbstbewusster Haltung wendet sich der gutaussehende John Taylor in seinem Porträt von William L. Denune und Richard Cooper dem Betrachter zu. Dass der englische Arzt ein gepriesener Okulist und versierter Mann von Welt war, wird in dem Kupferstich zum einen mittels der Inschriften des Sockels unter seinem Porträt betont, die ihn als den Augenarzt des Königs von Großbritannien und als Mitglied mehrerer medizinischer Universitäten betiteln, zum anderen durch die Zurschaustellung seiner wissenschaftlichen Abhandlungen. Sein Biograph George Coats, selbst ein englischer Augenarzt, beschreibt ihn als einen klugen und eleganten Mann, ausgestattet mit einer charismatischen Ausstrahlung, welche jenen imponierte, die außerstande waren, die prahlerische Oberfläche zu durchschauen, unter der s ich ein verlogener, unverfrorener Quacksalber verbarg. Die meisten von Taylors Zeitgenossen kritisierten seine wissenschaftlichen Schriften und Praktiken und er selbst gestand einmal, dass Hunderte von Patienten an den Folgen seiner Operationen erblindeten. Wie konnte es dazu kommen, dass dieser offensichtliche Scharlatan zum Hofokulisten von König George II. ernannt wurde und prominente Persönlichkeiten wie Edward Gibbon sowie Johann Sebastian Bach behandelte? ...
Background. Extracts from Viscum album L. (VE) are used in the complementary cancer therapy in Europe for decades. VE contain several compounds like the mistletoe lectins (MLs) 1-3 and viscotoxins and also several minor ingredients. Since mistletoe lectin 1 (ML-1) has been described as the main component of VE harboring antitumor activity, purified native or recombinant ML-1 has been recently used in clinical trials. MLs stimulate the immune system, induce cytotoxicity, are able to modify the expression of cancer-associated genes, and influence the proliferation and motility of tumor cells.
Objective. In this study our goal was to determine anticancer effects of the VE ISCADOR Qu, of recombinant ML-1 (Aviscumine), and of native ML-1 in the treatment of glioblastoma (GBM), the most common and highly malignant brain tumor in adults. Additionally we were interested whether these drugs, used in combination with a temozolomide-(TMZ)-based radio-chemotherapy, provide synergistic effects.
Methods. Cell culture assays, ex vivo murine hippocampal brain slice cultures, human GBM cryosections, and a xenograft orthotopic glioblastoma mouse model were used.
Results. In cells, the expression of the ML receptor CD75s, which is also expressed in GBM specimen, but not in normal brain, correlates with the drug-induced cytotoxicity. In GBM cells, the drugs induce cell death in a concentration-dependent manner and reduce cell growth by inducing cell cycle arrest in the G2/M phase. The cell cycle arrest was paralleled by modifications in the expression of cell cycle regulating genes. ML containing drugs, if combined with glioma standard therapy, provide synergistic and additive anticancer effects. Despite not reaching statistical significance, a single intratumoral application of Aviscumine prolonged the median survival of GBM mice longer than tumor irradiation. Moreover, intratumorally applied Aviscumine prolonged the survival of GBM-bearing mice if used in combination with irradiation and TMZ for further 6.5 days compared to the radio-chemotherapy.
Conclusion. Our results suggest that an adjuvant treatment of glioma patients with ML-containing drugs might be beneficial.
Diagnosing and treating acute severe and recurrent antivenom-related anaphylaxis (ARA) is challenging and reported experience is limited. Herein, we describe our experience of severe ARA in patients with neurotoxic snakebite envenoming in Nepal. Patients were enrolled in a randomised, double-blind trial of high vs. low dose antivenom, given by intravenous (IV) push, followed by infusion. Training in ARA management emphasised stopping antivenom and giving intramuscular (IM) adrenaline, IV hydrocortisone, and IV chlorphenamine at the first sign/s of ARA. Later, IV adrenaline infusion (IVAI) was introduced for patients with antecedent ARA requiring additional antivenom infusions. Preantivenom subcutaneous adrenaline (SCAd) was introduced in the second study year (2012). Of 155 envenomed patients who received ≥ 1 antivenom dose, 13 (8.4%), three children (aged 5−11 years) and 10 adults (18−52 years), developed clinical features consistent with severe ARA, including six with overlapping signs of severe envenoming. Four and nine patients received low and high dose antivenom, respectively, and six had received SCAd. Principal signs of severe ARA were dyspnoea alone (n=5 patients), dyspnoea with wheezing (n=3), hypotension (n=3), shock (n=3), restlessness (n=3), respiratory/cardiorespiratory arrest (n=7), and early (n=1) and late laryngeal oedema (n=1); rash was associated with severe ARA in 10 patients. Four patients were given IVAI. Of the 8 (5.1%) deaths, three occurred in transit to hospital. Severe ARA was common and recurrent and had overlapping signs with severe neurotoxic envenoming. Optimising the management of ARA at different healthy system levels needs more research. This trial is registered with NCT01284855.
According to a popular stereotype, women are better at multitasking than men, but empirical evidence for gender differences in multitasking performance is mixed. Previous work has focused on specific aspects of multitasking or has not considered gender differences in abilities contributing to multitasking performance. We therefore tested gender differences (N = 96, 50% female) in sequential (i.e., task switching) and concurrent (i.e., dual tasking) multitasking, while controlling for possible gender differences in working memory, processing speed, spatial abilities, and fluid intelligence. Applying two standard experimental paradigms allowed us to test multitasking abilities across five different empirical indices (i.e., performance costs) for both reaction time (RT) and accuracy measures, respectively. Multitasking resulted in substantial performance costs across all experimental conditions without a single significant gender difference in any of these ten measures, even when controlling for gender differences in underlying cognitive abilities. Thus, our results do not confirm the widespread stereotype that women are better at multitasking than men at least in the popular sequential and concurrent multitasking settings used in the present study.
Die vorliegende Dissertation untersucht die Nichtgleichgewichtsdynamik von relativistischen Schwerionenkollisionen ausgehend von der anfänglichen Produktion von Teilchen durch den Zerfall von Strings, der Bildung eines Quark-Gluon-Plasmas (QGP), dessen kinetische und chemische Äquilibrierung als Funktion der Zeit sowie seine Transporteigenschaften im Gleichgewicht bei endlicher Temperatur und endlichem chemischen Potential. Ein Verständnis der frühen Phase der Schwerionenkollisionen ist insbesondere von großen Interesse, da letztere eine Verbindung zwischen den ersten Nukleon-Nukleon Kollisionen und der Quark-Gluon-Plasma Phase herstellen, die zu einem späteren Zeitpunkt ein gewisses Maß an Thermalisierung zeigt. Allerdings können nur Nichtgleichgewichts-Theorien eine Verbindung zwischen dem anfänglichen QGP und seiner - zumindest partiellen - Thermalisierung herstellen. Um die Dynamik eines stark wechselwirkenden Mediums wie des Quark-Gluon-Plasmas zu beschreiben, reichen übliche Transportgleichungen (basierend auf der Boltzmann-Gleichung) nicht aus und es müssen komplexere Theorien, die auch für stark korrelierte Medien geeignet sind, angewendet werden. Hier kommen hydrodynamische Simulationen oder Transportrechnungen - basierend auf verallgemeinerten Transportgleichungen - zum Einsatz. Solche verallgemeinerte Transportgleichungen, wie die Kadanoff-Baym-Gleichungen, ergeben sich aus der quantenmechanischen Nichtgleichgewichts-Vielteilchentheorie, in der Green’s- Funktionen in Minkowski Raum-Zeit die interessierenden Größen sind, um die Dynamik des betrachteten Mediums zu beschreiben. Mit geeigneten Näherungen kann man so kinetische Transportgleichungen erhalten, die eine einheitliche Behandlung von stabilen und instabilen Teilchen auch außerhalb des Gleichgewichts ermöglichen. Diese Bestandteile bilden die Basis des Transportmodells Parton-Hadron-String Dynamics (PHSD), welches daher ein geeignetes ’Instrument’ ist um die verschiedenen Phasen einer Schwerionenkollision zu analysieren, egal ob die verschiedenen Formen der Materie im Gleichgewicht sind oder nicht.
In dieser Arbeit wird zunächst die Quantenchromodynamik (QCD) vorgestellt und erklärt, wie diese Theorie im Laufe der Jahre entwickelt wurde um ein wichtiger Bestandteil des Standardmodells der Teilchenphysik zu werden. Wir werden weiterhin die verbleibenden Herausforderungen in unserem Verständnis der QCD vorstellen, die sich primär auf das Phasendiagramm der stark wechselwirkenden Materie konzentrieren.
Im zweiten Kapitel untersuchen wir die Nichtgleichgewichts-Feldtheorie und die damit verbundenen Techniken - wie die Keldysh-Kontur - zur Beschreibung der Green’schen Funktionen als wesentlichen Freiheitsgrade. Wir leiten die Evolutionsgleichung für die Green’schen Funktionen her, d. h. die Kadanoff Baym-Gleichungen am Beispiel einer skalaren Feldtheorie.
Im nächsten Kapitel wird das Transportmodell Parton-Hadron-String Dynamics (PHSD), welches die Anwendung der verallgemeinerten Transportgleichungen zur Beschreibung relativistischer Schwerionenkollisionen darstellt, vorgestellt.
Wir beginnen im Kapitel 4 mit der Untersuchung der Nichtgleichgewichtseigenschaften des Quark-Gluon-Plasmas, welches bei relativistischen Schwerionenkollisionen erzeugt wird. Zu diesem Zweck vergleichen wir die Quark-Gluon-Plasmaentwicklung aus dem PHSD mit einem viskosen hydrodynamischen Modell, bei dem ein lokales kinetisches und chemisches Gleichgewicht angenommen wird.
Im Kapitel 5 konzentrieren wir uns auf das frühe Vorgleichgewichtsstadium ultra-relativistischer Schwerionenkollisionen und insbesondere auf die Freiheitsgrade der QGP-Phase in diesem Stadium. Wir untersuchen die Auswirkungen eines QGP, welches anfänglich entweder aus einem System aus massiven Gluonen (Szenario I) oder alternativ aus Quarks und Antiquarks (Szenario II) besteht. Das nächste Kapitel wird ebenfalls die Produktion von Teilchen im Frühstadium von Schwerionenkollisionen behandeln, jedoch bei niedrigeren Kollisionsenergien. Hier wird eine mikroskopische Beschreibung des K+/pi+-Verhältnisses im Vordergrund stehen, d. h. die Erklärung des Maximums in diesem Verhältnis bei etwa 30 A GeV ("Horn") in zentralen Au+Au (oder Pb+Pb) Kollisionen. Insbesonders werden wir die Modifikation des String-Fragmentierungsprozesses (über den Schwinger-Mechanismus) in einer Umgebung mit hoher hadronischer Dichte aufgrund der teilweisen Wiederherstellung der chiralen Symmetrie untersuchen.
In Kapitel 7 erweitern wir das Parton-Hadron-String Dynamics (PHSD)-Transportmodell im partonischen Sektor, indem wir explizit die totalen und differentiellen partonischen Streuungsquerschnitte als Funktion der Temperatur T und des baryochemischen Potentials μB berechnen auf der Basis der effektiven Propagatoren und Kopplungen des Dynamical QuasiParticle Models (DQPM), welches auch die generelle Zeitentwicklung der partonischen Freiheitsgrade beschreibt. Wir finden nur eine sehr bescheidene Änderung von n/s mit dem baryonchemischen Potential μB in Abhängigkeit von der skalierten Temperatur T/Tc(μB). Dies gilt auch für eine Vielzahl von hadronischen Observablen aus zentralen A+A Kollisionen im Energiebereich von 5 GeV < vsNN < 200 GeV bei der Implementierung der differentiellen Querschnitte in das PHSD-Modell. Da wir in Schwerionen-Observablen nur kleine Spuren einer μB-Abhängigkeit finden - obwohl die effektiven Partonenmassen und Kollisionsbreiten sowie deren Partonenquerschnitte eindeutig von μB abhängen - impliziert dies, dass man eine beträchtliche Partonendichte und ein großes Raum-Zeit-QGP-Volumen zur Untersuchung der Dynamik in der partonischen Phase benötigt. Diese Bedingungen sind nur bei hohen Kollisionsenergien erfüllt, bei denen μB jedoch eher niedrig ist. Wenn andererseits die Kollisionsenergie verringert und somit μB erhöht wird, wird die hadronische Phase dominant und dementsprechend wird es zunehmend schwieriger, Signale aus der Partonendynamik auf der Basis von "Bulk"-Observablen zu extrahieren.
Wer im mittelalterlichen Frankfurt von "Hibbdebach" nach "Dribbdebach" wollte, also von Sachsenhausen in die Innenstadt, der war auf die Alte Brücke angewiesen – denn eine andere Möglichkeit den Main zu überqueren gab es bis 1868 nicht. Die Verbindung der Mainufer war bereits seit dem 11. Jahrhundert ein wichtiges Wegkreuz zwischen Nord und Süd und trug wohl dazu bei, dass sich Frankfurt nicht nur zum Krönungsort von Königen und Kaisern entwickelte, sondern auch zur Messestadt; es ist also keinesfalls übertrieben die Alte Brücke Ausgangspunkt der Frankfurter Stadtentwicklung zu nennen. ...
Das Museum Giersch scheint manchmal weit ab vom Schuss, gerät es doch im Schatten der großen Frankfurter Galerien ein ums andere Mal in Vergessenheit. Umso wichtiger ist es, diesem Umstand entgegenzuwirken – denn derzeit präsentiert das Ausstellungshaus am Museumsufer mit der Schau Frobenius – Die Kunst des Forschens ein Stück Frankfurts kultureller Identität. Konträr zum vielbesuchten Städel, erwartet das villenartige Museum den Besucher mit gedimmtem Licht und warmem Holz: Eine ruhige Stimmung breitet sich aus, die nicht nur der Konzentration beim Lesen der ausführlichen Erklärtexte, sondern der Wirkung von mehr als 200 gezeigten Werken zuträglich ist. ...
Autophagy, meaning “self-eating”, is an important cellular waste disposal mechanism. Thereby, damaged proteins, lipids and organelles are enclosed by autophagosomes and subsequently transported to the lysosomes for degradation into basic, cellular building blocks. Under basal conditions autophagy prevents the accumulation of defective and harmful material and generally promotes cell survival. However, several studies reported that hyperactivated autophagy, e.g. during developmental processes in lower eukaryotes, or during chemotherapeutic treatment of cancer cells, can also trigger cell death.
In recent years, autophagic cell death (ACD) has been considered as an alternative cell death pathway for tumor therapy, especially for solid tumors with high apoptosis resistance such as glioblastoma. Glioblastoma (GBM) is a very aggressive, malignant primary brain tumor with a median survival of ~ 15 months despite surgery and chemoradiotherapy. Accordingly, there is a great interest in improving GBM therapy through alternative cell death mechanisms. Interestingly, it has been shown that various substances, e.g. AT 101, cannabinoids and the combination of imipramine and ticlopidine (IM+TIC), induce ACD in GBM cells.
The aim of this project was to identify the underlying mechanisms of stress- and drug-induced ACD and its therapeutic potential for glioblastoma treatment. For detailed investigation of ACD, a CRISPR/Cas9-based approach was used to generate ATG5 and ATG7 knockouts as genetic models of autophagy deficiency. In a previous study of our lab it was demonstrated that administration of AT 101 triggers ACD in glioblastoma cells, which was associated with early mitochondrial fragmentation but no signs of apoptosis. Since mitochondrial fragmentation often precedes mitophagy, the first part of this thesis explored the potential role of mitophagy in AT 101-induced cell death.
ATG5-depleted cells confirmed that AT 101 induces ACD. In addition, treatment with AT 101 resulted in a pronounced mitochondrial depolarization, which was at least partly caused by the opening of the mitochondrial permeability pore. Global proteome analysis of AT 101-treated GBM cells revealed a robust decrease in mitochondrial protein clusters as well as a strong increase in the enzyme heme oxygenase-1 (HMOX1). Subsequent experiments for detailed investigation of mitophagy following AT 101 treatment (western blot, flow cytometric MTG and mt-mKeima, qRT-PCR of mitochondrial vs nuclear DNA) consistently indicated strong mitophagy induction by AT 101, which could be reduced by genetic or pharmacological inhibition of autophagy. Furthermore, siRNA-mediated knockdown experiments revealed that the selective mitophagy receptors BNIP3 and BNIP3L and the HMOX1 enzyme play an essential role in AT 101-induced mitophagy and subsequent cell death. Taken together, these data demonstrate that AT 101-induced mitochondrial dysfunction and HMOX1 induction synergize to promote excessive mitophagy with a lethal outcome in glioma cells.
The second part of this thesis focused on the identification of new substances that cause ACD and the investigation of the underlying cell death pathways. Using a cell death screen of the ENZO Screen-Well™ autophagy library in MZ-54 wild-type vs ATG5 and ATG7-depleted cells, loperamide, pimozide, and STF-62247 were identified as ACD-inducing agents. The increase of the autophagic flux and the induction of ACD by these substances was confirmed by using different ATG5 and ATG7 knockout cell lines and the already established positive control IM+TIC.
In contrast to AT 101, IM+TIC, STF-62247, loperamide and pimozide produced neither mitochondrial dysfunction nor mitophagy. Interestingly, it has been described that imipramine, loperamide and pimozide inhibit the lysosomal enzyme acid sphingomyelinase, which is associated with impaired lipid transport. Global proteome analysis and cholesterol staining confirmed that all four substances, but especially loperamide and pimozide, inhibit cellular lipid transport, leading to massive lipid accumulation in the lysosomes. In the further course of the experiments, the connection between defective lipid transport and autophagy was investigated in more detail. On the one hand, the defective lipid transport contributed to the induction of autophagy, on the other hand the massive accumulation of lipids led to lysosomal membrane damage, inhibition of lysosomal degradation at later time points and finally to a lysosomal cell death. Remarkably, it has been shown that hyperactivated autophagy by IM+TIC, loperamide and pimozide massively promotes lysosomal membrane damage. This result highlights the difficulties of a clear distinction between autophagic and lysosomal cell death.
In summary, two new signaling pathways that induce autophagic cell death in GBM cells and may be relevant for glioblastoma therapy were investigated in this study.
Die französische Künstlerin Bettina Rheims zeigte im Château de Vincennes bei Paris unter dem Ausstellungstitel DÉTENUES über sechzig Fotografien von in Frankreich inhaftierten Frauen. Détenues, so heißen die weiblichen Häftlinge auf Französisch. Mit der Themenwahl schließt Rheims an frühere Fotografieprojekte an. In den 1990er Jahren wurde die Fotografin aufgrund einfühlsamer Portraits bekannt, die sie von Prostituierten am legendären Place Pigalle machte. Auch in ihrem Projekt DÉTENUES beweist Rheims eine solche Einfühlsamkeit. Sie nähert sich ihren Modellen in erster Linie als Frauen, die ein Gesicht, einen Körper und Augen haben, die Geschichten erzählen. Erst in zweiter Linie zeigt Rheims inhaftierte Verbrecherinnen, in deren Vergangenheit ein Mord, ein Raub, Drogenmissbrauch oder eine andere Straftat stand. ...
Depressed demand and supply
(2019)
We investigate the implications of experienced-based learning on consumption-saving and labor supply, two fundamental decisions in business cycle models. Using the Dutch Household Survey, we find that individuals who have experienced higher national unemployment rates over their lifetime save more, borrow less, and work less, after controlling for aggregate shocks, income, wealth, and demographics. Possibly explaining these behavioral responses, these individuals find it more important to save for retirement and to cover unexpected expenses, are more worried about losing their job, and dislike their job more. These results have implications for business cycle models and stabilization policies.
In early July 2019, Christian Sewing, the CEO of Deutsche Bank, proclaimed a fundamental shift of the bank’s strategy after finally obtaining the approval of the Supervisory Board, which the management seems to have requested for quite some time. The essential point of the reorientation is a deep cut into the bank’s investment banking activities. At the same time, those parts of the bank’s activity portfolio that had been the mainstay of Deutsche Bank’s business 20 to 25 years ago, in particular lending to large and mid-sized German and European corporate clients, shall be strengthened in spite of a simultaneous reduction of the bank’s staff by 18,000 FTEs over the next three years.
The bank’s CEO, who has only been in office since about one year, was reported to have called this shift of strategy a “return to the roots of Deutsche Bank” at the press conference at which it was announced, without, however, making it clear to which roots he was referring: those of some 40 years ago, when Deutsche Bank was essentially a Germany-focused commercial bank, or even those from the late 19th century, when the bank had been founded with the mission to become an international bank with a strong capital market-orientation. In any event, the press was impressed and keeps repeating these words, that deserve to be taken seriously and irrespective of their vagueness may be justified. If it were successfully implemented, this change of strategy would indeed be fundamental and imply undoing what Deutsche Bank’s former management teams had aspired to do in the last 20 or 25 years.
The newly announced strategy shift raises two questions. Can it be successful, and what does it mean for the bank itself and its shareholders, for its staff and for its clients? And what does it imply for the German financial system? This note focuses on the latter question. What makes it interesting is the fact that the last fundamental change of Deutsche Bank’s strategy of two decades ago, which aimed at transforming Deutsche Bank from a Germany-centered commercial bank into a leading international investment bank, had a profound – and in my view clearly negative - effect on the entire German financial system.
Die Europäische Zentral Bank hat am 6. Juni 2019 beschlossen, die Nullzinspolitik bis Mitte 2020 beizubehalten, obwohl mit dieser das Inflationsziel von 2% seit Jahren, in Japan seit Jahrzehnten, verfehlt wird. Nach dem Neo-Fisher-Effekt sollte, gegeben dieses Ziel, der Zins nicht gesenkt, sondern gehoben werden, weil die Inflationsrate der Differenz von Nominal- und langfristig stabilem Realzins entspricht. Zwar senken rasche Zinserhöhungen Nachfrage und Preise, aber daraus folgt nicht notwendig, dass niedrige Zinsen die Nachfrage anregen. Gemäß neueren Untersuchungen werden langsam durchgeführte Zinserhöhungen bei rationalen Erwartungen dagegen das Preisniveau heben. Der Aufsatz untersucht die begleitenden Verteilungswirkungen und stützt die These mit Überlegungen aus dem 19. Jahrhundert, wonach die gestiegenen Preise durch die Erhöhung der Zinskosten erklärt werden können.
The financial crisis of 2007-08 has stressed the importance of a sound financial system. Unlike other studies weighing the pros and cons of market versus bank-based systems, this paper investigates whether the main elements of the German financial system can be regarded as complementary and consistent. This assessment refers to the idea that there is a potential for positive interaction between different elements in the system that is actually used to make it more valuable to economy and society and more robust to crises. It is shown that the old German bank-based system, where the risk of long-term lending by large private commercial banks was limited by the membership in supervisory boards and strong personal ties between all stakeholders, was a consistent system of well-adjusted complementary elements. After reunification, a hybrid system has emerged where, on the one hand, public savings banks and cooperative banks maintain their role as lenders, but on the other, large private banks have withdrawn from their former dominant role in financing and corporate governance. It is argued that this transition to stronger capital-market and, accordingly, shareholder value orientations has occurred at the expense of consistency.
This paper aspires to provide an overview of the issue of diversity of banking and financial systems and its development over time from a positive and a normative perspective. In other word: how different are banks within a given country and how much do banking systems and entire financial systems differ between countries and regions, and do in-country diversity and between-country diversity change over time, as one would be inclined to expect as a consequence of globalization and increasingly global standards of regulation?
As the first part of this paper shows, the general answer to these questions is that there is still today a surprisingly high level of diversity in finance. This raises the two questions addressed in the second part of the paper: How can the persistence of diversity be explained, and how can it be assessed? In contrast to prevailing views, the author argues that persistent diversity should be regarded as valuable in a context in which there is no clear answer to the question of which structures of banking and financial systems are optimal from an economic perspective
It has been documented that vertical customer-supplier links between industries are the basis for strong cross-sectional stock return predictability (Menzly and Ozbas (2010)). We show that robust predictability also arises from horizontal links between industries, i.e., from the fact that industries are competitors or offer products, which are substitutes for each other. These horizontally linked industries exhibit positively correlated fundamentals. The signal derived from this type of connectedness is the basis for significant alpha in sorted portfolio strategies, and informed investors take the related information into account when they form their portfolios. We thus provide evidence of return predictability based on a new type of economic links between industries not captured in previous studies.