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In this study we investigate which economic ideas were prevalent in the macroprudential discourse post-crises in order to understand the availability of ideas for reform minded agents. We base our analysis on new findings in the field of ideational shifts and regulatory science, which posit that change-agents engage with new ideas pragmatically and strategically in their effort to have their economic ideas institutionalized. We argue that in these epistemic battles over new regulation, scientific backing by academia is the key resource determining the outcome. We show that the present reforms implemented internationally follow this pattern. In our analysis we contrast the entire discourse on systemic risk and macroprudential regulation with Borio’s initial 2003 proposal for a macroprudential framework. We find that mostly cross-sectional measures targeted towards increasing the resilience of the financial system rather than inter-temporal measures dampening the financial cycle have been implemented. We provide evidence for the lacking support of new macroprudential thinking within academia and argue that this is partially responsible for the lack of anti-cyclical macroprudential regulation. Most worryingly, the financial cycle is largely absent in the academic discourse and is only tacitly assumed instead of fully fledged out in technocratic discourses, pointing to the possibility that no anti-cyclical measures will be forthcoming.
Background: Conversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation.
Methods: Biopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids.
Results: At least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively.
Conclusions: This analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy.
Trial registration: ClinicalTrials.gov NCT00154310. Date of registration: September 12, 2005.
Background: Subdural hematoma (SDH) is a common disease associated with high morbidity, which is becoming more prominent due to the increasing incidence. Decision for a surgical evacuation is made depending on the clinical appearance and the volume of SDH, wherefore it is important to have a simple ‘bedside’ method to measure and compare the volume of SDH.
Objective: The aim of the study was to verify the accuracy of the simplified ABC/2 volumetric formula to determine a valuable tool for the clinical practice.
Methods: Preoperative CT-scans of 83 patients with SDHs were used for the computer-assisted volumetric measurement via BrainLab® as well as the ABC/2 volumetric measurement. A = largest length (anterior to posterior) of the SDH; B = maximum width (lateral to midline) 90° to A; C = maximum height (coronal plane or multiplication of slices) of the hematoma. These measurements were performed by two independent clinicians in a blinded fashion. Both volumes were compared by linear regression analysis of Pearson and Bland-Altman regression analysis.
Results: Among 100 SDHs, 53% were under an 47% were over 100cm3 showing a well distribution of the hematoma sizes. There was an excellent correlation between computer-assisted volumetric measurement and ABC/2 (R2 = 0.947, p<0.0001) and no undesirable deviation and trend were detected (p = 0.101; p = 0.777). A 95% tolerance region of the ratios of both methods was [0.805–1.201].
Conclusion: The ABC/2 method is a simple and fast bedside formula for the measurement of SDH volume in a timely manner without limited access through simple adaption, which may replace the computer-assisted volumetric measurement in the clinical and research area. Reason for the good accuracy seems to be the spherical form of SDH, which has a similarity to a half ellipsoid.
Descent of testes from a position near the kidneys into the lower abdomen or into the scrotum is an important developmental process that occurs in all placental mammals, with the exception of five afrotherian lineages. Since soft-tissue structures like testes are not preserved in the fossil record and since key parts of the placental mammal phylogeny remain controversial, it has been debated whether testicular descent is the ancestral or derived condition in placental mammals. To resolve this debate, we used genomic data of 71 mammalian species and analyzed the evolution of two key genes (relaxin/insulin-like family peptide receptor 2 [RXFP2] and insulin-like 3 [INSL3]) that induce the development of the gubernaculum, the ligament that is crucial for testicular descent. We show that both RXFP2 and INSL3 are lost or nonfunctional exclusively in four afrotherians (tenrec, cape elephant shrew, cape golden mole, and manatee) that completely lack testicular descent. The presence of remnants of once functional orthologs of both genes in these afrotherian species shows that these gene losses happened after the split from the placental mammal ancestor. These “molecular vestiges” provide strong evidence that testicular descent is the ancestral condition, irrespective of persisting phylogenetic discrepancies. Furthermore, the absence of shared gene-inactivating mutations and our estimates that the loss of RXFP2 happened at different time points strongly suggest that testicular descent was lost independently in Afrotheria. Our results provide a molecular mechanism that explains the loss of testicular descent in afrotherians and, more generally, highlight how molecular vestiges can provide insights into the evolution of soft-tissue characters.
Since its founding in 1993 the International Long-term Ecological Research Network (ILTER) has gone through pronounced development phases. The current network comprises 44 active member LTER networks representing 700 LTER Sites and ~ 80 LTSER Platforms across all continents, active in the fields of ecosystem, critical zone and socio-ecological research. The critical challenges and most important achievements of the initial phase have now become state-of-the-art in networking for excellent science. At the same time increasing integration, accelerating technology, networking of resources and a strong pull for more socially relevant scientific information have been modifying the mission and goals of ILTER. This article provides a critical review of ILTER's mission, goals, development and impacts. Major characteristics, tools, services, partnerships and selected examples of relative strengths relevant for advancing ILTER are presented. We elaborate on the tradeoffs between the needs of the scientific community and stakeholder expectations. The embedding of ILTER in an increasingly collaborative landscape of global environmental observation and ecological research networks and infrastructures is also reflected by developments of pioneering regional and national LTER networks such as SAEON in South Africa, CERN/CEOBEX in China, TERN in Australia or eLTER RI in Europe. The primary role of ILTER is currently seen as a mechanism to investigate ecosystem structure, function, and services in response to a wide range of environmental forcings using long-term, place-based research. We suggest four main fields of activities and advancements for the next decade through development/delivery of a: (1) Global multi-disciplinary community of researchers and research institutes; (2) Strategic global framework and strong partnerships in ecosystem observation and research; (3) Global Research Infrastructure (GRI); and (4) a scientific knowledge factory for societally relevant information on sustainable use of natural resources.
The marine hydrocarbonoclastic bacterium Alcanivorax borkumensis is well known for its ability to successfully degrade various mixtures of n-alkanes occurring in marine oil spills. For effective growth on these compounds, the bacteria possess the unique capability not only to incorporate but also to modify fatty intermediates derived from the alkane degradation pathway. High efficiency of both these processes provides better competitiveness for a single bacteria species among hydrocarbon degraders. To examine the efficiency of A. borkumensis to cope with different sources of fatty acid intermediates, we studied the growth rates and membrane fatty acid patterns of this bacterium cultivated on diesel, biodiesel and rapeseed oil as carbon and energy source. Obtained results revealed significant differences in both parameters depending on growth substrate. Highest growth rates were observed with biodiesel, while growth rates on rapeseed oil and diesel were lower than on the standard reference compound (hexadecane). The most remarkable observation is that cells grown on rapeseed oil, biodiesel, and diesel showed significant amounts of the two polyunsaturated fatty acids linoleic acid and linolenic acid in their membrane. By direct incorporation of these external fatty acids, the bacteria save energy allowing them to degrade those pollutants in a more efficient way. Such fast adaptation may increase resilience of A. borkumensis and allow them to strive and maintain populations in more complex hydrocarbon degrading microbial communities.
The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.
The photoregulation of nucleic acids by azobenzene photoswitches has recently attracted considerable interest in the context of emerging biotechnological applications. To understand the mechanism of photoinduced isomerisation and conformational control in these complex biological environments, we employ a Quantum Mechanics/Molecular Mechanics (QM/MM) approach in conjunction with nonadiabatic Surface Hopping (SH) dynamics. Two representative RNA–azobenzene complexes are investigated, both of which contain the azobenzene chromophore covalently attached to an RNA double strand via a β-deoxyribose linker. Due to the pronounced constraints of the local RNA environment, it is found that trans-to-cis isomerization is slowed down to a time scale of ∼10–15 picoseconds, in contrast to 500 femtoseconds in vacuo, with a quantum yield reduced by a factor of two. By contrast, cis-to-trans isomerization remains in a sub-picosecond regime. A volume-conserving isomerization mechanism is found, similarly to the pedal-like mechanism previously identified for azobenzene in solution phase. Strikingly, the chiral RNA environment induces opposite right-handed and left-handed helicities of the ground-state cis-azobenzene chromophore in the two RNA–azobenzene complexes, along with an almost completely chirality conserving photochemical pathway for these helical enantiomers.
Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds.
Background: Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific anti-tumor and virus-specific cellular immunity may be applied in this context.
Methods: CIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-γ, anti-CD3, interleukin (IL)-2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities.
Results: Pre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. In vitro cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity.
Discussion: The transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD.
SAFE Newsletter : 2018, Q2
(2018)
Cross-border exchange and comparison of forensic DNA data in the context of the Prüm decision
(2018)
This study, commissioned by the European Parliament’s Policy Department for Citizens’ Rights and Constitutional Affairs at the request of the LIBE Committee, provides an overview of the Prüm regime. It first considers the background of the Prüm Convention and Prüm Decision. The subsequent two chapters summarize the Prüm regime in relation mainly to DNA data looking at value and shortcomings; and ethical, legal and social implications of forensic DNA typing and databasing in relation to the Prüm regime. Finally, based on the analysis, it provides the policy recommendations.
Crystal growth and characterization of cerium- and ytterbium-based quantum critical materials
(2018)
In der Festkörperphysik werden heutzutage Themen wie Supraleitung, Magnetismus und Quantenkritikalität sowohl von experimenteller als auch von theoretischer Seite stark untersucht. Quantenkritikalität und Quantenphasenübergänge können in Systemen erforscht werden, für welche ein Kontroll Parameter existiert, durch den z.B. eine magnetische Ordnung soweit unterdrückt wird, bis der Phasenübergang bei Null Kelvin, bei einem quantenkritischen Punkt (QCP), stattfindet. Vorzugsweise wird quantenkritisches Verhalten an Einkristallen untersucht, da diese in sehr reiner Qualität gezüchtet werden können und da deren gemessenen physikalischen Eigenschaften ausschließlich intrinsisch sind und nicht durch Verunreinigungseffekte überlagert werden. Der Schwerpunkt dieser Arbeit lag auf der Züchtung von Einkristallen und der Charakterisierung von Materialien, die quantenkritische Phänomene aufweisen. Als Ausgangsstoffe dienten dabei Elemente höchstmöglicher Reinheit. Es wurden die Serie YbNi4(P1-xAsx)2 mit einem ferromagnetischen QCP bei x=0,1, die Verbindung YbRh2Si2 mit einem feldinduzierten QCP bei Bcrit = 60mT und die Serie Ce(Ru1-xFex)PO mit einem QCP bei x = 0,86 untersucht. Für alle Verbindungen wurde das Züchtungsverfahren entwickelt, dann wurden Einkristalle gezüchtet und charakterisiert. Die Züchtung wurde zum einen mittels der Bridgman-Methode, zum anderen mit der Czochralski Methode durchgeführt. Neben struktureller und chemischer Charakterisierung der Einkristalle mittels Röntgen-Pulverdiffraktometrie, Laue-Methode und Energie-dispersiver Röntgen-Spektroskopie, wurden auch deren spezifische Wärme, elektrischer Widerstand und Magnetisierung im Temperaturbereich 1,8 – 300 K untersucht. Im weiteren Verlauf wurden die Kristalle in verschiedenen Kooperationen untersucht und bis in den Tieftemperatur- Bereich (20 mK), bei YbRh2Si2 bis in den Submillikelvin-Bereich, charakterisiert. Ausserdem wurden im Rahmen dieser Dissertation Einkristalle weiterer antiferromagnetischer Verbindungen SmRh2Si2, GdRh2Si2, GdIr2Si2, HoRh2Si2 und HoIr2Si2 gezüchtet. Bei diesen Verbindungen stand die Untersuchung elektronischer Oberflächenzustände mittels winkelaufgelöster Photoemissionsspektroskopie im Vordergrund.
Background: Electrical stimulation (ES) has a long history of successful use in the clinical treatment of refractory, non-healing bone fractures and has recently been proposed as an adjunct to bone tissue-engineering treatments to optimize their therapeutic potential. This idea emerged from ES’s demonstrated positive effects on stem cell migration, proliferation, differentiation and adherence to scaffolds, all cell behaviors recognized to be advantageous in Bone Tissue Engineering (BTE). In previous in vitro experiments we demonstrated that direct current ES, administered daily, accelerates Mesenchymal Stem Cell (MSC) osteogenic differentiation. In the present study, we sought to define the optimal ES regimen for maximizing this pro-osteogenic effect.
Methods: Rat bone marrow-derived MSC were exposed to 100 mV/mm, 1 hr/day for three, seven, and 14 days, then osteogenic differentiation was assessed at Day 14 of culture by measuring collagen production, calcium deposition, alkaline phosphatase activity and osteogenic marker gene expression.
Results: We found that exposing MSC to ES for three days had minimal effect, while seven and 14 days resulted in increased osteogenic differentiation, as indicated by significant increases in collagen and calcium deposits, and expression of osteogenic marker genes Col1a1, Osteopontin, Osterix and Calmodulin. We also found that cells treated with ES for seven days, maintained this pro-osteogenic activity long (for at least seven days) after discontinuing ES exposure.
Discussion: This study showed that while three days of ES is insufficient to solicit pro-osteogenic effects, seven and 14 days significantly increases osteogenic differentiation. Importantly, we found that cells treated with ES for only seven days, maintained this pro-osteogenic activity long after discontinuing ES exposure. This sustained positive osteogenic effect is likely due to the enhanced expression of RunX2 and Calmodulin we observed. This prolonged positive osteogenic effect, long after discontinuing ES treatment, if incorporated into BTE treatment protocols, could potentially improve outcomes and in doing so help BTE achieve its full therapeutic potential.
Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger. However, the role of Th17 cells during allo-response driven colitis remains ambiguous due to a series of studies with inconclusive results. Interestingly, we recently identified granulocyte-macrophage colony-stimulating factor (GM-CSF+) T cells to be promoted by interleukin-7 (IL-7) signaling and controlled by the activating protein-1 transcription factor family member basic leucine zipper transcription factor ATF-like (BATF) as critical mediators of intestinal GvHD in mice. Given the dual role of BATF, the contribution of IL-23-mediated signaling within donor T cells and bona fide Th17 cells remains to be delineated from the regulation of GM-CSF+ T cells in the absence of BATF. Here, we found in a complete MHC class I-mismatched model that genetic inactivation of the IL-23 receptor (IL-23R) or the transcription factor retinoic acid-related orphan receptor gamma t (RORγt) within donor T cells similarly ablated Th17 cell formation in vivo but preserved the T cells’ ability to induce intestinal GvHD in a compared to wild-type controls indistinguishable manner. Importantly, RORγt-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF+ T cells as BATF/RORγt double-deficient T cells failed to induce colitis and the antibody-mediated blockage of IL-7/IL-7R interaction and GM-CSF significantly diminished signs of intestinal GvHD elicited by RORγt-deficient donor T cells. Finally, in analogy to our murine studies, colonic RORC expression levels inversely correlated with the presence of GvHD in allo-HSCT patients. Together, this study provides a crucial example of a BATF-dependent, however, IL-23R signaling- and RORγt-, i.e., Th17 fate-independent regulation of a colitogenic T cell population critically impacting the current understanding of intestinal GvHD.
We present an open-source Python package to compute information-theoretical quantities for electroencephalographic data. Electroencephalography (EEG) measures the electrical potential generated by the cerebral cortex and the set of spatial patterns projected by the brain's electrical potential on the scalp surface can be clustered into a set of representative maps called EEG microstates. Microstate time series are obtained by competitively fitting the microstate maps back into the EEG data set, i.e., by substituting the EEG data at a given time with the label of the microstate that has the highest similarity with the actual EEG topography. As microstate sequences consist of non-metric random variables, e.g., the letters A–D, we recently introduced information-theoretical measures to quantify these time series. In wakeful resting state EEG recordings, we found new characteristics of microstate sequences such as periodicities related to EEG frequency bands. The algorithms used are here provided as an open-source package and their use is explained in a tutorial style. The package is self-contained and the programming style is procedural, focusing on code intelligibility and easy portability. Using a sample EEG file, we demonstrate how to perform EEG microstate segmentation using the modified K-means approach, and how to compute and visualize the recently introduced information-theoretical tests and quantities. The time-lagged mutual information function is derived as a discrete symbolic alternative to the autocorrelation function for metric time series and confidence intervals are computed from Markov chain surrogate data. The software package provides an open-source extension to the existing implementations of the microstate transform and is specifically designed to analyze resting state EEG recordings.
This study aims at characterizing the diversity and temporal changes of species richness and composition of fungi in an ecotone of a forest border and a meadow in the Taunus mountain range in Germany. All macroscopically visible, epigeous fungi and vascular plants were sampled monthly over three years, together with climatic variables like humidity and temperature that influence fungal diversity and composition as shown by previous studies. In this mosaic landscape, a total of 855 fungal species were collected and identified based on morphological features, the majority of which belonged to Ascomycota (51 %) and Basidiomycota (45 %). Records of fungal species and plant species (218) for this area yielded a fungus to plant species ratio of 4:1, with a plant species accumulation curve that reached saturation. The three years of monitoring, however, were not sufficient to reveal the total fungal species richness and estimation factors showed that a fungus to plant species ratio of 6:1 may be reached by further sampling efforts. The effect of climatic conditions on fungal species richness differed depending on the taxonomic and ecological group, with temporal patterns of occurrence of Basidiomycota and mycorrhizal fungi being strongly associated with temperature and humidity, whereas the other fungal groups were only weakly related to abiotic conditions. In conclusion, long-term, monthly surveys over several years yield a higher diversity of macroscopically visible fungi than standard samplings of fungi in autumn. The association of environmental variables with the occurrence of specific fungal guilds may help to improve estimators of fungal richness in temperate regions.
Die vorliegende Dissertation beschäftigt sich mit der moderierenden Rolle der Elaboriertheit des sportbezogenen Selbstaspekts auf die Verarbeitung selbstrelevanter Informationen im Sport.
Im ersten Kapitel werden aus einer übergeordneten Perspektive heraus zunächst die beiden im Mittelpunkt der Dissertation stehenden Konstrukte Selbst und Identität in einen historischen Kontext gesetzt und begrifflich umrissen. Im Anschluss werden verschiedene Modelle des Selbst vorgestellt. Dabei wird aufgezeigt, dass insbesondere in der sportpsychologischen Forschung bislang eher Inhalte und weniger Strukturen und Prozesse des Selbstkonzepts im Mittelpunkt standen. In der vorliegenden Dissertation wird das Selbst bzw. die Identität als komplexes, dynamisches System aufgefasst, das sowohl die Informationsverarbeitung beeinflusst als auch durch Prozesse der Informationsverarbeitung beeinflusst wird. Im Anschluss stehen Theorien der Selbstwerterhöhung und der Selbstkonsistenz im Mittelpunkt, deren Vertreter unterschiedliche Vorhersagen für die Verarbeitung konsistenter und von der eigenen Selbsteinschätzung positiv abweichender Rückmeldungen postulieren: Während Selbstwerterhöhungstheorien eine Präferenz für positives Feedback vorhersagen, bevorzugen Personen laut Selbstkonsistenztheorien solches Feedback, das mit ihrer eigenen Selbsteinschätzung übereinstimmt. Anschließend werden mit der Art der Reaktion (affektiv vs. kognitiv) und der Elaboriertheit des betroffenen Selbstaspekts zwei Variablen vorgestellt, die moderieren, ob die Informationsverarbeitung eher konsistenztheoretischen (kognitive Reaktion, hohe Elaboriertheit) oder selbstwerterhöhenden (affektive Reaktion, geringe Elaboriertheit) Vorhersagen folgt.
Ausführlicher werden dann mit dem Exercise Self-Schema und der Exercise Identity zwei sportbezogene Konstrukte vorgestellt, die zur Operationalisierung der Elaboriertheit des entsprechenden Selbstaspekts genutzt werden können. Hierbei wird sowohl auf die Messung als auch auf den empirischen Forschungsstand eingegangen und es wird dargestellt, dass die beiden Konstrukte zwar unterschiedlichen theoretischen Denklinien entstammen, auf operationaler Ebene aber weitgehend austauschbar sind.
Das zweite Kapitel enthält einen Überblick über die drei durchgeführten quantitativen empirischen Studien. Studie 1 (N = 530) beschreibt die Übersetzung und Validierung der Exercise Identity Scale ins Deutsche. Dabei wird neben den beiden in der Literatur diskutierten Ein- und Zwei-Faktor-Modellen auch ein Bifaktor-Modell als mögliche Alternative geprüft. Zusätzlich wird die Invarianz der Skala über die Zeit (Abstand: 14 Tage) mit einer Teilstichprobe, die Invarianz zwischen Männern und Frauen mit der Gesamtstichprobe sowie die konvergente Validität über Korrelationen mit verwandten Konstrukten getestet.
Die Studien 2 und 3 widmen sich der eigentlichen Forschungsfrage nach der moderierenden Wirkung der Elaboriertheit auf die Verarbeitung von sportbezogenem selbstrelevantem Feedback. In Studie 2 (Onlinestudie) wird die Elaboriertheit über das Exercise Self-Schema operationalisiert (N = 472). In dieser Studie zeigt sich, dass Personen – unabhängig davon, ob sie ein Selbstschema im Bereich sportlichen Trainings aufweisen oder nicht – Feedback, das von ihrer eigenen Selbsteinschätzung positiv abweicht, gegenüber mit ihrer Selbsteinschätzung übereinstimmendem (konsistentem) Feedback vorziehen. In Studie 3 (Laborstudie, N = 215) werden einige Limitationen der Onlinestudie adressiert, indem u. a. das fingierte Feedback nach einem objektiveren (physiologischen) Test gegeben und die Elaboriertheit mithilfe der kontinuierlichen Exercise Identity Scale gemessen wird. Auch hier zeigt sich die vermutete moderierende Wirkung der Exercise Identity nicht: Bei der affektiven Reaktion dominiert das Selbstwerterhöhungsmotiv; bei der kognitiven zeigt sich zwar ein kleiner Effekt, der allerdings erwartungswidrig ausfällt (Personen mit geringerer Exercise Identity bevorzugten konsistentes gegenüber positivem Feedback). In beiden Studien zeigt sich darüber hinaus ein moderierender Effekt der Elaboriertheit des sportbezogenen Selbstaspekts hinsichtlich des zur Kontrolle mit in das Versuchsdesign einbezogenen negativen Feedbacks.
Im dritten Kapitel wird eine Gesamtdiskussion der Ergebnisse aus einer übergeordneten Perspektive vorgenommen. Die Befunde werden in den bisherigen empirischen Forschungsstand eingeordnet und es werden Grenzen der durchgeführten Studien diskutiert. Implikationen für zukünftige Forschung werden u. a. im Hinblick auf eine Verbindung zwischen der grundlagenorientierten kognitiv-motivationalen Perspektive der vorliegenden Arbeit und einer eher anwendungsorientierten Perspektive im Sinne der Förderung einer Bindung an sportliche Aktivität diskutiert.
This paper gives an account of the unmaking of Soviet workers at the Vernissage in Armenia. I argue that the unmaking of Soviet workers, first, is the irrelevance of Soviet workers as workers once they lost their jobs after the collapse of the Soviet Union and came to the Vernissage to trade. During the Soviet period, private trade was forbidden, and the Soviet government persecuted people who dared to engage in it. Consequently, many people grew up thinking of trade as a criminal activity that was non-productive and parasitic, as opposed to productive work that facilitated the modernization of the USSR. After the dissolution of the USSR, when trade was liberalized and many former Soviet workers were pushed into trade as they lost their jobs, it still retained its quality of not being “real” work, to borrow Roberman’s (2013) wording. Even 25 years after the dissolution of the USSR, former Soviet workers at the Vernissage still want to be identified with their former Soviet occupations and not with trade. However, now engaged in trade, former Soviet workers came up with a “new” way of establishing identity and hierarchy—through production. I describe this “new” way as “the identification game”; employing it, I demonstrate how former Soviet workers at the Vernissage identify and represent themselves as masters, whose work is productive and intellectual. In doing so, they single out resellers, people who resell the work of other masters, by implying that their work is parasitic and selfish. However, this “identification game” is reified only by the older generation of traders, former Soviet workers. The younger generation of traders at the Vernissage, which does not have any experience of being Soviet workers, is disengaged from it, thus undermining the Soviet view of trade as not “real” work and making it irrelevant in the postsocialist era. Thus, I contend that the unmaking of Soviet workers consists in, first, their irrelevance as workers in a postsocialist period, and second, the irrelevance of their ideas about trade as not “real” work. Furthermore, to support my depiction of a master who engages in “the identification game” and a younger-generation trader who is disengaged from it, I give two ethnographic portraits of traders at the Vernissage. I assert that the disengagement of a younger generation of traders at the Vernissage signals a change in the perception of trade as “real” work and runs parallel to the unmaking of Soviet workers.
Continuous blood glucose monitoring reveals enormous circadian variations in pregnant diabetic rats
(2018)
Aim: Diabetes in pregnancy is a major burden with acute and long-term consequences. Its treatment requires adequate diagnosis and monitoring of therapy. Many experimental research on diabetes during pregnancy has been performed in rats. Recently, continuous blood glucose monitoring of non-pregnant diabetic rats revealed an increased circadian variability of blood glucose that made a single blood glucose measurement per day inappropriate to reflect glycemic status. Continuous blood glucose measurement has never been performed in pregnant rats. We wanted to perform continuous blood glucose monitoring in pregnant rats to decipher the influence of pregnancy on blood glucose in diabetic and normoglycemic status.
Methods: We used the transgenic Tet29 diabetes rat model with an inducible knock down of the insulin receptor via RNA interference upon application of doxycycline (DOX) leading to insulin resistant type II diabetes. All Tet29 rats received a HD-XG telemetry implant (Data Sciences International, USA) that measured blood glucose and activity continuously. Rats were divided into four groups and blood glucose was monitored until end of pregnancy or the corresponding period: Tet29 + DOX (diabetic) non-pregnant, Tet29 + DOX (diabetic) pregnant, Tet29 (normoglycemic) non-pregnant, Tet29 (normoglycemic) pregnant.
Results: All analyzed rats displayed a circadian variation in blood glucose concentration. Circadian variability was much more pronounced in pregnant diabetic rats than in normoglycemic pregnant rats. Pregnancy ameliorated variation in blood glucose in diabetic situation. Pregnancy continuously decreased blood glucose during normoglycemic pregnancy. Diabetic rats were less active than normoglycemic rats. We performed a calculation showing that application of continuous blood glucose measurement reduces animal numbers needed to detect a given effect in experimental setting by decreasing variability and SD.
Interpretation: Continuous blood glucose monitoring via a telemetry device in pregnant rats provides a more informative picture of the glycemic situation in comparison to single measurements. This could improve diagnosis and therapy of diabetes, decrease animal numbers within experimental settings, and add another physiological parameter (activity) to the analysis that could be helpful in testing therapeutic concepts targeting blood glucose levels and peripheral muscle function. We propose continuous glucose monitoring as a new tool for the evaluation of pregnant diabetic rats.
Spontaneous brain activity is characterized in part by a balanced asynchronous chaotic state. Cortical recordings show that excitatory (E) and inhibitory (I) drivings in the E-I balanced state are substantially larger than the overall input. We show that such a state arises naturally in fully adapting networks which are deterministic, autonomously active and not subject to stochastic external or internal drivings. Temporary imbalances between excitatory and inhibitory inputs lead to large but short-lived activity bursts that stabilize irregular dynamics. We simulate autonomous networks of rate-encoding neurons for which all synaptic weights are plastic and subject to a Hebbian plasticity rule, the flux rule, that can be derived from the stationarity principle of statistical learning. Moreover, the average firing rate is regulated individually via a standard homeostatic adaption of the bias of each neuron’s input-output non-linear function. Additionally, networks with and without short-term plasticity are considered. E-I balance may arise only when the mean excitatory and inhibitory weights are themselves balanced, modulo the overall activity level. We show that synaptic weight balance, which has been considered hitherto as given, naturally arises in autonomous neural networks when the here considered self-limiting Hebbian synaptic plasticity rule is continuously active.
Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
Objective: We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants’ spot sign status.
Results: Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients.
Trial registration: ISRCTN93732214 (http://www.isrctn.com)
Background: Early-life institutional deprivation produces disinhibited social engagement (DSE). Portrayed as a childhood condition, little is known about the persistence of DSE-type behaviours into, presentation during, and their impact on, functioning in adulthood.
Aims: We examine these issues in the young adult follow-up of the English and Romanian Adoptees study.
Method: A total of 122 of the original 165 Romanian adoptees who had spent up to 43 months as children in Ceauşescu's Romanian orphanages and 42 UK adoptees were assessed for DSE behaviours, neurodevelopmental and mental health problems, and impairment between ages 2 and 25 years.
Results: Young adult DSE behaviour was strongly associated with early childhood deprivation, with a sixfold increase for those who spent more than 6 months in institutions. However, although DSE overlapped with autism spectrum disorder and attention-deficit hyperactivity disorder symptoms it was not, in itself, related to broader patterns of mental health problems or impairments in daily functioning in young adulthood.
Conclusions: DSE behaviour remained a prominent, but largely clinically benign, young adult feature of some adoptees who experienced early deprivation.
The mechanistic target of the rapamycin (mTOR) inhibitor, temsirolimus, has significantly improved the outcome of patients with renal cell carcinoma (RCC). However, development of temsirolimus-resistance limits its effect and metastatic progression subsequently recurs. Since integrin α7 (ITGA7) is speculated to promote metastasis, this investigation was designed to investigate whether temsirolimus-resistance is associated with altered ITGA7 expression in RCC cell lines and modified tumor cell adhesion and invasion. Caki-1, KTCTL-26, and A498 RCC cell lines were driven to temsirolimus-resistance by exposing them to temsirolimus over a period of 12 months. Subsequently, adhesion to human umbilical vein endothelial cells, to immobilized fibronectin, or collagen was investigated. Chemotaxis was evaluated with a modified Boyden chamber assay and ITGA7 expression by flow cytometry and western blotting. Chemotaxis significantly decreased in temsirolimus-sensitive cell lines upon exposure to low-dosed temsirolimus, but increased in temsirolimus-resistant tumor cells upon reexposure to the same temsirolimus dose. The increase in chemotaxis was accompanied by elevated ITGA7 at the cell surface membrane with simultaneous reduction of intracellular ITGA7. ITGA7 knock-down significantly diminished motility of temsirolimous-sensitive cells but elevated chemotactic activity of temsirolimus-resistant Caki-1 and KTCTL-26 cells. Therefore, ITGA7 appears closely linked to adhesion and migration regulation in RCC cells. It is postulated that temsirolimus-resistance is associated with translocation of ITGA7 from inside the cell to the outer surface. This switch forces RCC migration forward. Whether ITGA7 can serve as an important target in combatting RCC requires further investigation.
Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting. This review will focus on the antimicrobial properties of NK cells and the current standing and future perspectives of generating and using NK cells as immunotherapy in patients with infectious complications, an approach which is promising and might have an important clinical impact in the future.
Early and adequate restoration of endothelial and tubular renal function is a substantial step during regeneration after ischemia reperfusion (IR) injury, occurring, e.g., in kidney transplantation, renal surgery, and sepsis. While tubular epithelial cell injury has long been of central importance, recent perception includes the renal vascular endothelium. In this regard, the fibrin cleavage product fibrinopeptide Bβ15-42 mitigate IR injury by stabilizing interendothelial junctions through its affinity to VE-cadherin. Therefore, this study focused on the effect of Bβ15-42 on post-acute physiological renal regeneration. For this, adult male C57BL/6 mice were exposed to a 30 min bilateral renal ischemia and reperfusion for 24 h or 48 h. Animals were randomized in a non-operative control group, two operative groups each treated with i.v. administration of either saline or Bβ15-42 (2.4 mg/kg) immediately prior to reperfusion. Endothelial activation and inflammatory response was attenuated in renal tissue homogenates by single application of Bβ15-42. Meanwhile, Bβ15-42 did not affect acute kidney injury markers. Regarding the angiogenetic players VEGF-A, Angiopoietin-1, Angiopoietin-2, however, we observed significant higher expressions at mRNA and trend to higher protein level in Bβ15-42 treated mice, compared to saline treated mice after 48 h of IR, thus pointing toward an increased angiogenetic activity. Similar dynamics were observed for the intermediate filament vimentin, the cytoprotective protein klotho, stathmin and the proliferation cellular nuclear antigen, which were significantly up-regulated at the same points in time. These results suggest a beneficial effect of anatomical contiguously located endothelial cells on tubular regeneration through stabilization of endothelial integrity. Therefore, it seems that Bβ15-42 represents a novel pharmacological approach in the targeted therapy of acute renal failure in everyday clinical practice.
The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein‐coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2) strongly activated MEF2. Using pharmacological and protein‐based inhibitors, we demonstrated that PGE2 regulates MEF2 via the EP3 receptor, the βγ subunit of Gi/o protein and two concomitantly activated downstream pathways. The first consists of Tiam1, Rac1, and its effector p21‐activated kinase 2, the second of protein kinase D. Both pathways converge on and inactivate histone deacetylase 5 (HDAC5) and thereby de‐repress MEF2. In vivo, endotoxemia in MEF2‐reporter mice induced upregulation of PGE2 and MEF2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de‐repression of MEF2 through HDAC5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies.
Recent experiments have demonstrated that visual cortex engages in spatio-temporal sequence learning and prediction. The cellular basis of this learning remains unclear, however. Here we present a spiking neural network model that explains a recent study on sequence learning in the primary visual cortex of rats. The model posits that the sequence learning and prediction abilities of cortical circuits result from the interaction of spike-timing dependent plasticity (STDP) and homeostatic plasticity mechanisms. It also reproduces changes in stimulus-evoked multi-unit activity during learning. Furthermore, it makes precise predictions regarding how training shapes network connectivity to establish its prediction ability. Finally, it predicts that the adapted connectivity gives rise to systematic changes in spontaneous network activity. Taken together, our model establishes a new conceptual bridge between the structure and function of cortical circuits in the context of sequence learning and prediction.
The enzyme acetyl-CoA carboxylase (ACC) plays a fundamental role in the fatty acid metabolism. It regulates the first and rate limiting step in the biosynthesis of fatty acids by catalyzing the carboxylation of acetyl-CoA to malonyl-CoA and exists as two different isoforms, ACC1 and ACC2. In the last few years, ACC has been reported as an attractive drug target for treating different diseases, such as insulin resistance, hepatic steatosis, dyslipidemia, obesity, metabolic syndrome and nonalcoholic fatty liver disease. An altered fatty acid metabolism is also associated with cancer cell proliferation. In general, the inhibition of ACC provides two possibilities to regulate the fatty acid metabolism: It blocks the de novo lipogenesis in lipogenic tissues and stimulates the mitochondrial fatty acid β-oxidation. Surprisingly, the role of ACC in human vascular endothelial cells has been neglected so far. This work aimed to investigate the role of the ACC/fatty acid metabolism in regulating important endothelial cell functions like proliferation, migration and tube formation.
To investigate the function of ACC, the ACC-inhibitor soraphen A as well as an siRNA-based approach were used. This study revealed that ACC1 is the predominant isoform both in human umbilical vein endothelial cells (HUVECs) and in human dermal microvascular endothelial cells (HMECs). Inhibition of ACC via soraphen A resulted in decreased levels of malonyl-CoA and shifted the lipid composition of endothelial cell membranes. Consequently, membrane fluidity, filopodia formation and the migratory capacity were attenuated. Increasing amounts of longer acyl chains within the phospholipid subgroup phosphatidylcholine (PC) were suggested to overcompensate the shift towards shorter acyl chains within phosphatidylglycerol (PG), which resulted in a dominating effect on regulating the membrane fluidity. Most importantly, this work provided a link between changes in the phospholipid composition and altered endothelial cell migration. The antimigratory effect of soraphen A was linked to a reduced amount of PG and to an increased amount of polyunsaturated fatty acids (PUFAs) within the phospholipid cell membrane. This link was unknown in the literature so far. Interestingly, a reduced filopodia formation was observed upon ACC inhibition via soraphen A, which presumably caused the impaired migratory capacity.
This work revealed a relationship between ACC/fatty acid metabolism, membrane lipid composition and endothelial cell migration. The natural compound soraphen A emerged as a valuable chemical tool to analyze the role of ACC/fatty acid metabolism in regulating important endothelial cell functions. Furthermore, regulating endothelial cell migration via ACC inhibition promises beneficial therapeutic perspectives for the treatment of cell migration-related disorders, such as ischemia reperfusion injury, diabetic angiopathy, macular degeneration, rheumatoid arthritis, wound healing defects and cancer.
Quantum chromodynamics (QCD) is the theory of the strong interaction between quarks and gluons. Due to Confinement, at lower energies quarks and gluons are bound into colorless states called hadrons. QCD is also asymptotically free, i.e. at large energies or densities it enters a deconfined state, termed quark-gluon plasma (QGP), where quarks and gluons are quasi-free. This transition occurs at an energy scale around 200 MeV where QCD cannot be treated perturbatively. Instead it can be formulated on a space-time grid. The resulting theory, lattice quantum chromodynamics (LQCD), can be simulated efficiently on high performance parallel-computing clusters. In recent years graphic processing units (GPUs), which outperform CPUs in terms of parallel-computing and memory bandwidth capabilities, became very popular for LQCD computations. In this work the QCD deconfinement transition is studied using CL2QCD, a LQCD application that runs efficiently on GPUs. Furthermore, CL2QCD is extended by a Rational Hybrid Monte Carlo algorithm for Wilson fermions to allow for simulations of an odd number of quark flavors.
Due to the sign-problem LQCD simulations are restricted to zero or very small baryon densities, where, in the limit of infinite quark mass QCD has a first order deconfinement phase transition associated to the breaking of the global centre symmetry. Including dynamical quarks breaks this symmetry explicitly. Lowering their mass weakens the first order transition until it terminates in a second order Z2 point. Beyond this point the transition is merely an analytic crossover. As the lattice spacing is decreased, the reduction of discretization errors causes the region of first order transitions to expand towards lower masses. In this work the deconfinement critical point with 2 and 3 flavors of standard Wilson fermions is studied. To this end several kappa values are simulated on temporal lattice extents 6,8,10 (4) for two flavors (three flavors) and various aspect ratios (spatial lattice extent / temporal lattice extent) so as to extrapolate to the thermodynamic limit, applying finite size scaling. For two flavors an estimate is done if and when a continuum extrapolation is possible.
The chiral and deconfinement phase transitions at zero density for light and heavy quarks, respectively, have analytic continuations to purely imaginary chemical potential, where no sign-problem exists and LQCD simulations can be applied. At some critical value of the imaginary chemical potential, the transitions meet the endpoint of the Roberge-Weiss transition between adjacent Z3 sectors. For light and heavy quarks the transition lines meet in a triple point, while for intermediate masses they meet in a second order point. At the boundary between these regimes the junction is a tricritical point, as shown in studies with two and three flavors of staggered and Wilson quarks on lattices with a temporal lattice extent of 4. Employing finite size scaling the nature of this point as a function of the quark mass is studied in this work for two flavors of Wilson fermions with a temporal lattice extent of 6. Of particular interest is the change of the location of tricritical points compared to an earlier study on lattices with temporal extent of 4.
Based on an original dataset of 100 important pieces of legislation passed during the three presidencies of William J. Clinton, George W. Bush, and Barack H. Obama (1992-2013), this study explores two sets of questions:
(1) How do presidents influence legislators in Congress in the legislative arena, and what factors have an effect on the legislative strategies presidents choose?
(2) How successful are presidents in getting their policy positions enacted into law, and what configurations of institutional and actor-centered conditions determine presidential legislative success?
The analyses show that in an hyper-polarized environment, presidents usually have to fight an uphill-battle in the legislative arena, getting more involved if they face less favorable contexts and the odds are against them.
Moreover, the analyses suggest that there is no silver-bullet approach for presidents' legislative success. Instead, multiple patterns of success exist as presidents - depending on the institutional and public environment - can resort to different combinations of actions in order to see their preferred policy outcomes enacted.
Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
The implementation of HTS (high-throughput sequencing) approaches is rapidly changing our understanding of the lichen symbiosis, by uncovering high bacterial and fungal diversity, which is often host-specific. Recently, HTS methods revealed the presence of multiple photobionts inside a single thallus in several lichen species. This differs from Sanger technology, which typically yields a single, unambiguous algal sequence per individual. Here we compared HTS and Sanger methods for estimating the diversity of green algal symbionts within lichen thalli using 240 lichen individuals belonging to two species of lichen-forming fungi. According to HTS data, Sanger technology consistently yielded the most abundant photobiont sequence in the sample. However, if the second most abundant photobiont exceeded 30% of the total HTS reads in a sample, Sanger sequencing generally failed. Our results suggest that most lichen individuals in the two analyzed species, Lasallia hispanica and L. pustulata, indeed contain a single, predominant green algal photobiont. We conclude that Sanger sequencing is a valid approach to detect the dominant photobionts in lichen individuals and populations. We discuss which research areas in lichen ecology and evolution will continue to benefit from Sanger sequencing, and which areas will profit from HTS approaches to assessing symbiont diversity.
An early identification of sepsis patients likely to progress towards multiple organ failure is crucial in order to initiate targeted therapeutic strategies to decrease mortality. Our recent publication highlighted the greater accuracy of mid-regional proadrenomedullin (MR-proADM) compared with conventional biomarkers and clinical scores in predicting 28-day mortality in patients with initially low (≤7 points; N = 240) or moderate (8–13 points; N = 653) Sepsis-related Organ Failure Assessment (SOFA) scores, thus confirming results from smaller investigations. This additional post hoc analysis aimed to further describe the non-surviving patient population of both subgroups and identify those likely to progress towards sepsis-related multiple organ failure. ...
Background: The ideal biofuel should not only be a regenerative fuel from renewable feedstocks, but should also be compatible with the existing fuel distribution infrastructure and with normal car engines. As the so-called drop-in biofuel, the fatty alcohol 1-octanol has been described as a valuable substitute for diesel and jet fuels and has already been produced fermentatively from sugars in small amounts with engineered bacteria via reduction of thioesterase-mediated premature release of octanoic acid from fatty acid synthase or via a reversal of the β-oxidation pathway.
Results: The previously engineered short-chain acyl-CoA producing yeast Fas1R1834K/Fas2 fatty acid synthase variant was expressed together with carboxylic acid reductase from Mycobacterium marinum and phosphopantetheinyl transferase Sfp from Bacillus subtilis in a Saccharomyces cerevisiae Δfas1 Δfas2 Δfaa2 mutant strain. With the involvement of endogenous thioesterases, alcohol dehydrogenases, and aldehyde reductases, the synthesized octanoyl-CoA was converted to 1-octanol up to a titer of 26.0 mg L−1 in a 72-h fermentation. The additional accumulation of 90 mg L−1 octanoic acid in the medium indicated a bottleneck in 1-octanol production. When octanoic acid was supplied externally to the yeast cells, it could be efficiently converted to 1-octanol indicating that re-uptake of octanoic acid across the plasma membrane is not limiting. Additional overexpression of aldehyde reductase Ahr from Escherichia coli nearly completely prevented accumulation of octanoic acid and increased 1-octanol titers up to 49.5 mg L−1. However, in growth tests concentrations even lower than 50.0 mg L−1 turned out to be inhibitory to yeast growth. In situ extraction in a two-phase fermentation with dodecane as second phase did not improve growth, indicating that 1-octanol acts inhibitive before secretion. Furthermore, 1-octanol production was even reduced, which results from extraction of the intermediate octanoic acid to the organic phase, preventing its re-uptake.
Conclusions: By providing chain length control via an engineered octanoyl-CoA producing fatty acid synthase, we were able to specifically produce 1-octanol with S. cerevisiae. Before metabolic engineering can be used to further increase product titers and yields, strategies must be developed that cope with the toxic effects of 1-octanol on the yeast cells.
Background: Bacterial meningitis is associated with high mortality and long-term neurological sequelae. Increasing the phagocytic activity of microglia could improve the resistance of the CNS against infections. We studied the influence of activin A, a member of the TGF-β family with known immunoregulatory and neuroprotective effects, on the functions of microglial cells in vitro.
Methods: Primary murine microglial cells were treated with activin A (0.13 ng/ml–13 μg/ml) alone or in combination with agonists of TLR2, 4, and 9. Phagocytosis of Escherichia coli K1 as well as release of TNF-α, IL-6, CXCL1, and NO was assessed.
Results: Activin A dose-dependently enhanced the phagocytosis of Escherichia coli K1 by microglial cells activated by agonists of TLR2, 4, and 9 without further increasing NO and proinflammatory cytokine release. Cell viability of microglial cells was not affected by activin A.
Conclusions: Priming of microglial cells with activin A could increase the elimination of bacteria in bacterial CNS infections. This preventive strategy could improve the resistance of the brain to infections, particularly in elderly and immunocompromised patients.
Introduction: For decades, conventional galactography was the only imaging technique capable of showing the mammary ducts. Today, diagnosis is based on a multimodal concept which combines high-resolution ultrasound with magnetic resonance (MR) mammography and ductoscopy/galactoscopy and has a sensitivity and specificity of up to 95%. This study used tomosynthesis in galactography for the first time and compared the synthetic digital 2D full-field mammograms generated with this technique with the images created using the established method of ductal sonography. Both methods should be able to detect invasive breast cancers and their precursors such as ductal carcinoma in situ (DCIS) as well as being able to identify benign findings.
Material and Methods: Five patients with pathological nipple discharge were examined using ductal sonography, contrast-enhanced 3D galactography with tomosynthesis and the synthetic digital 2D full-field mammograms generated with the latter method. Evaluation of the images created with the different imaging modalities was done by three investigators with varying levels of experience with complementary breast diagnostics (1, 5 and 15 years), and their evaluations were compared with the histological findings.
Results: All 3 investigators independently evaluated the images created with ductal sonography, contrast-enhanced 3D galactography with tomosynthesis, and generated synthetic digital 2D full-field mammograms. Their evaluations were compared with the histopathological assessment of the surgical specimens resected from the 5 patients. There was 1 case of invasive breast cancer, 2 cases with ductal carcinoma in situ and 2 cases with benign findings. All 3 investigators made more mistakes when they used the standard imaging technique of ductal sonography to diagnose suspicious lesions than when they used contrast-enhanced galactography with tomosynthesis and the generated synthetic digital 2D full-field mammograms.
Conclusion: This is the first time breast tomosynthesis was used in galactography (galactomosynthesis) to create digital 3-dimensional images of suspicious findings. When used together with the generated synthetic digital 2D full-field mammograms, it could be a useful complementary procedure for the diagnosis of breast anomalies and could herald a renaissance of this method. Compared with high-resolution ductal ultrasound, the investigators achieved better results with contrast-enhanced galactography using tomosynthesis and the generated synthetic digital 2D full-field mammograms, as confirmed by histopathological findings.
Electron transfer in respiratory chains generates the electrochemical potential that serves as energy source for the cell. Prokaryotes can use a wide range of electron donors and acceptors and may have alternative complexes performing the same catalytic reactions as the mitochondrial complexes. This is the case for the alternative complex III (ACIII), a quinol:cytochrome c/HiPIP oxidoreductase. In order to understand the catalytic mechanism of this respiratory enzyme, we determined the structure of ACIII from Rhodothermus marinus at 3.9 Å resolution by single-particle cryo-electron microscopy. ACIII presents a so-far unique structure, for which we establish the arrangement of the cofactors (four iron–sulfur clusters and six c-type hemes) and propose the location of the quinol-binding site and the presence of two putative proton pathways in the membrane. Altogether, this structure provides insights into a mechanism for energy transduction and introduces ACIII as a redox-driven proton pump.
Background: Definite diagnosis and therapeutic management of cholangiocarcinoma (CCA) remains a challenge. The aim of the current study was to investigate feasibility and potential impact on clinical management of targeted sequencing of intraductal biopsies.
Methods: Intraductal biopsies with suspicious findings from 16 patients with CCA in later clinical course were analyzed with targeted sequencing including tumor and control benign tissue (n = 55 samples). A CCA-specific sequencing panel containing 41 genes was designed and a dual strand targeted enrichment was applied.
Results: Sequencing was successfully performed for all samples. In total, 79 mutations were identified and a mean of 1.7 mutations per tumor sample (range 0–4) as well as 2.3 per biopsy (0–6) were detected and potentially therapeutically relevant genes were identified in 6/16 cases. In 14/18 (78%) biopsies with dysplasia or inconclusive findings at least one mutation was detected. The majority of mutations were found in both surgical specimen and biopsy (68%), while 28% were only present in biopsies in contrast to 4% being only present in the surgical tumor specimen.
Conclusion: Targeted sequencing from intraductal biopsies is feasible and potentially improves the diagnostic yield. A profound genetic heterogeneity in biliary dysplasia needs to be considered in clinical management and warrants further investigation.
Translational impact: The current study is the first to demonstrate the feasibility of sequencing of intraductal biopsies which holds the potential to impact diagnostic and therapeutical management of patients with biliary dysplasia and neoplasia.
Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation and accumulation of immature myeloblasts, which impair normal hematopoiesis. While this definition categorizes the disease into a distinctive group, the large number of different genetic and epigenetic alterations actually suggests that AML is not a single disease, but a plethora of malignancies. Still, most AML patients are not treated with targeted medication but rather by uniform approaches such as chemotherapy. The identification of novel treatment options likely requires the identification of cancer cell vulnerabilities that take into account the different genetic and epigenetic make-up of the individual tumors. Here we show that STK3 depletion by knock-down, knock-out or chemical inhibition results in apoptotic cells death in some but not all AML cell lines and primary cells tested. This effect is mediated by a premature activation of cyclin dependent kinase 1 (CDK1) in presence of elevated cyclin B1 levels. The anti-leukemic effects seen in both bulk and progenitor AML cells suggests that STK3 might be a promising target in a subset of AML patients.
Powerful environment perception systems are a fundamental prerequisite for the successful deployment of intelligent vehicles, from advanced driver assistance systems to self-driving cars. Arguably the most essential task of such systems is the reliable detection and localization of obstacles in order to avoid collisions. Two particularly challenging scenarios in this context are represented by small, unexpected obstacles on the road ahead, and by potentially dynamic objects observed from a large distance. Both scenarios become exceedingly critical when the ego-vehicle is traveling at high speed. As a consequence, two major requirements placed on environment perception systems are the capability of (a) high-sensitivity generic object detection and (b) high-accuracy obstacle distance estimation. The present thesis addresses both requirements by proposing novel approaches based on stereo vision for spatial perception.
First, this work presents a novel method for the detection of small, generic obstacles and objects at long range directly from stereo imagery. The detection is based on sound statistical tests using local geometric criteria which are applicable to both static and moving objects. The approach is not limited to predefined sets of semantic object classes and does not rely on restrictive assumptions on the environment, such as oversimplified global ground surface models. Free-space and obstacle hypotheses are evaluated based on a statistical model of the input image data in order to avoid a loss of sensitivity through intermediate processing steps. In addition to the detection result, the algorithm simultaneously yields refined estimates of object distances, originating from an implicit optimization of the geometric obstacle hypothesis models. The proposed detection system provides multiple flexible output representations, ranging from 3D obstacle point clouds to compact mid-level obstacle segments to bounding box representations of object instances suitable for model-based tracking. The core algorithm concept lends itself to massive parallelization and can be implemented efficiently on dedicated hardware. Real-time execution is demonstrated on a test vehicle in real-world traffic. For a thorough quantitative evaluation of the detection performance, two dedicated datasets are employed, covering small and hard-to-detect obstacles in urban environments as well as distant dynamic objects in highway driving scenarios. The proposed system is shown to significantly outperform current general purpose obstacle detection approaches in both setups, providing a considerable increase in detection range while reducing the false positive rate at the same time.
Second, this work considers the high-accuracy estimation of object distances from stereo vision, particularly at long range. Several new methods for optimizing the stereo-based distance estimates of detected objects are proposed and compared to state-of-the-art concepts. A comprehensive statistical evaluation is performed on an extensive dedicated dataset, establishing reference values for the accuracy limits actually achievable in practice. Notably, the refined distance estimates implicitly provided by the proposed obstacle detection system are shown to yield highly accurate results, on par with the top-performing dedicated stereo matching algorithms considered in the analysis.
In the context of Brexit, changes to the regulatory architecture of CCPs that empower the European securities markets regulator are under way to prevent the threat of a regulatory race to the bottom. However, this empowerment currently leaves the national supervision of common European rules within the EU intact. This policy letter argues that supervisory arbitrage is as much a threat within the EU as outside of it, wherefore a common supervision of CCP rules in the EU is called for. The paper traces the origins of the current set-up and criticizes the current regulatory proposal by the EU Commission as too cumbersome while discussing possible ways forward to achieve European supervision. In contrast to the current proposal of the Commission, we call for a unified supervision within ESMA, combined with a European fiscal backstop.
This policy letter provides evidence for the crucial importance of the initial regulatory treatment for the further development of financial innovations by exploring the emergence and initial legal framing of off-balance-sheet leasing in Germany. Due to a missing legal framework, lease contracts occurred as an innovative social practice of off-balance-sheet financing. However, this lacking legal framing impeded the development of this financial innovation as it also created legal uncertainties. This was about to change after the initial legal framing of leasing in the 1970’s which eliminated those legal uncertainties and off-balance-sheet leasing entered into a stunning period of growth while laying the foundation of a regulatory resiliency against efforts that seek to abandon the off-balance-sheet treatment of leases. As the initial legal framing is crucial for the further development of a financial innovation, we propose the French approach for the initial vindication of new financial products in which the principles-based rules are aligned with the capabilities of regulators to intervene, even when a financial innovation complies with the letter of the law. In this way, regulators could regulate the frontier of financial innovations and weed out those which are entirely or mainly driven by regulatory arbitrage considerations while maintaining the beneficial elements of those products.
While the debate about the needs and merits of cryptocurrency regulation is ongoing, the unprecedented price hikes of cryptocurrencies towards the end of 2017 triggered a somewhat unexpected sort of regulation in the form of public statements by governments and financial supervisors. It kicked in rather quickly and turned out to be much more effective than imagined. These interventions can be identified as one of the main factors that drove asset prices down, thereby preventing destabilizing bubbles. The experience of the supervisory response to the cryptocurrency bubble of the past months keeps important insights for any prospective regulation of cryptocurrencies. First, public statements are a highly effective regulatory tool in the short term as they manage market expectations, a fact which is well-known as forward guidance in monetary policy. So far, the legal framework in the EU takes insufficient account of the regulatory role of public statements. Second, regulation needs to keep up with the incredible speed of fintech innovations. Some regulators addressed the challenge by adopting a ‘sandbox’ approach. However, the ‘sandbox’ approach clearly calls for international cooperation. To achieve a balance between safety and innovation, international cooperation should emulate the experimental character of sandboxes. One could conceive of a ‘sandbox for regulators’, an arrangement which would facilitate the exchange of information on regulatory initiatives among authorities but also the coordination of communication and forward guidance.
To estimate demand for labor, we use a combination of detailed employment data and the outcomes of procurement auctions, and compare the employment of the winner of an auction with the employment of the second ranked firm (i.e. the runner-up firm). Assuming similar ex-ante winning probabilities for both firms, we may view winning an auction as an exogenous shock to a firm’s production and its demand for labor. We utilize daily data from almost 900 construction firms and about 3,000 auctions in Austria in the time period 2006 until 2009. Our main results show that the winning firm significantly increases labor demand in the weeks following an auction but only in the years before the recent economic crisis. It employs about 80 workers more after the auction than the runner-up firm. Most of the adjustment takes place within one month after the demand shock. Winners predominantly fire fewer workers after winning than runner-up firms. In the crisis, however, firms do not employ more workers than their competitors after winning an auction. We discuss explanations like labor hoarding and productivity improvements induced by the crisis as well discuss implications for fiscal and stimulus policy in the crisis.
Departing from the principle of absolute priority, CoCo bonds are particularly exposed to bank losses despite not having ownership rights. This paper shows the link between adverse CoCo design and their yields, confirming the existence of market monitoring in designated bail-in debt. Specifically, focusing on the write-down feature as loss absorption mechanism in CoCo debt, I do find a yield premium on this feature relative to equity-conversion CoCo bonds as predicted by theoretical models. Moreover, and consistent with theories on moral hazard, I find this premium to be largest when existing incentives for opportunistic behavior are largest, while this premium is non-existent if moral hazard is perceived to be small. The findings show that write-down CoCo bonds introduce a moral hazard problem in the banks. At the same time, they support the idea of CoCo investors acting as monitors, which is a prerequisite for a meaningful role of CoCo debt in banks' regulatory capital mix.
Bargaining with a bank
(2018)
This paper examines bargaining as a mechanism to resolve information problems. To guide the analysis, I develop a parsimonious model of a credit negotiation between a bank and firms with varying levels of impatience. In equilibrium, impatient firms accept the bank’s offer immediately, while patient firms wait and negotiate price adjustments. I test the empirical predictions using a hand-collected dataset on credit line negotiations. Firms signing the bank’s offer right away draw down their line of credit after origination and default more than late signers. Late signers negotiate price adjustments more frequently, and, consistent with the model, these adjustments predict better ex post performance.
We show that time-varying volatility of volatility is a significant risk factor which affects the cross-section and the time-series of index and VIX option returns, beyond volatility risk itself. Volatility and volatility-of-volatility measures, identified model-free from the option price data as the VIX and VVIX indices, respectively, are only weakly related to each other. Delta-hedged index and VIX option returns are negative on average, and are more negative for strategies which are more exposed to volatility and volatility-of-volatility risks. Volatility and volatility of volatility significantly and negatively predict future delta-hedged option payoffs. The evidence is consistent with a no-arbitrage model featuring time-varying market volatility and volatility-of-volatility factors, both of which have negative market price of risk.
This paper studies the distributional consequences of a systematic variation in expenditure shares and prices. Using European Union Household Budget Surveys and Harmonized Index of Consumer Prices data, we construct household-specific price indices and reveal the existence of a pro-rich inflation in Europe. Particularly, over the period 2001-15, the consumption bundles of the poorest deciles in 25 European countries have, on average, become 10.5 percentage points more expensive than those of the richest decile. We find that ignoring the differential inflation across the distribution underestimates the change in the Gini (based on consumption expenditure) by up to 0.03 points. Cross-country heterogeneity in this change is large enough to alter the inequality ranking of numerous countries. The average inflation effect we detect is almost as large as the change in the standard Gini measure over the period of interest.
The paper analyses the contagion channels of the European financial system through the stochastic block model (SBM). The model groups homogeneous connectivity patterns among the financial institutions and describes the shock transmission mechanisms of the financial networks in a compact way. We analyse the global financial crisis and European sovereign debt crisis and show that the network exhibits a strong community structure with two main blocks acting as shock spreader and receiver, respectively. Moreover, we provide evidence of the prominent role played by insurances in the spread of systemic risk in both crises. Finally, we demonstrate that policy interventions focused on institutions with inter-community linkages (community bridges) are more effective than the ones based on the classical connectedness measures and represents consequently, a better early warning indicator in predicting future financial losses.
The increase in alternative working arrangements has sparked a debate over the positive impact of increased flexibility against the negative impact of decreased financial security. We study the prevalence and determinants of intermediated work in order to document the relative importance of the arguments for and against this recent labor market trend. We link data on individual participation and losses from a Federal Trade Commission settlement with a Multi-Level Marketing firm with detailed county-level information. Participation is greater in middle-income areas and in areas where female labor market non-participation is higher, suggesting that flexibility offers real benefits. However, losses from MLM participation are higher in areas with lower education levels and higher income inequality, suggesting that the downsides of alternative work are particularly high in certain demographics. Our results illustrate that the advantages and disadvantages of alternative work arrangements accrue to different groups.
We develop a simple theoretical model to motivate testable hypotheses about how peer-to-peer (P2P) platforms compete with banks for loans. The model predicts that (i) P2P lending grows when some banks are faced with exogenously higher regulatory costs; (ii) P2P loans are riskier than bank loans; and (iii) the risk-adjusted interest rates on P2P loans are lower than those on bank loans. We confront these predictions with data on P2P lending and the consumer bank credit market in Germany and find empirical support. Overall, our analysis indicates the P2P lenders are bottom fishing when regulatory shocks create a competitive disadvantage for some banks.
In contrast to the popularity of financial education interventions worldwide, studies on the economic effects of those interventions report mixed results. With a focus on the effect on disadvantaged groups, we review both the theoretical and empirical findings in order to understand why this discrepancy exists. The survey first highlights that it is necessary to distinguish between the concepts of, and the relationships between, financial education, financial literacy and financial behavior to identify the true effects of financial education. The review addresses possible biases caused by third factors such as numeracy. Next, we review theories on financial literacy which make clear that the effect of financial education interventions is heterogeneous across the population. Last, we look closely at main empirical studies on financial education targeted at the migrants/immigrants, the low-income earners and the young, and compare their methodologies. There seems to be a positive effect on short-term financial knowledge and awareness of the young, but there is no proven evidence on long-term behavior after being grown up. Studies on financial behavior of migrants and immigrants show almost no effect of financial education.
This paper investigates the effect of the conventional and unconventional (e.g. Quantitative Easing - QE) monetary policy intervention on the insurance industry. We first analyze the impact on the stock performances of 166 (re)insurers from the last QE programme launched by the European Central Bank (ECB) by constructing an event study around the announcement date. Then we enlarge the scope by looking at the monetary policy surprise effects on the same sample of (re)insurers over a timeframe of 12 years, also extending the analysis to the Credit Default Swaps (CDS) market. In the second part of the paper by building a set of balance sheet-based indices, we identify the characteristics of (re)insurers that determine sensitivity to monetary policy actions. Our evidences suggest that a single intervention extrapolated from the comprehensive strategy cannot be utilized to estimate the effect of monetary policy intervention on the market. With respect to the impact of monetary policies, we show how the effect of interventions changes over time. Expansionary monetary policy interventions, when generating an instantaneous reduction of interest rates, generated movement in stock prices in the same direction till September 2010. This effect turned positive during the European sovereign debt crisis. However, the effect faded away in 2014-2015. The pattern is confirmed by the impact on the CDS market. With regard to the determinants of these effects, our analysis suggests that sensitivity is mainly driven by asset allocation and in particular by exposure to fixed income assets.
his paper studies heterogeneity in the reaction to rank feedback. In a laboratory experiment, individuals take part in a series of dynamic real-effort contests with intermediate feedback. To solve the identification problem in estimating the causal effect of rank feedback on subsequent effort provision we implement a random multiplier in the first round of each contest. The realization of this multiplier then serves as a valid instrument for rank feedback. While rank feedback has a robust effect on subsequent effort provision on average, an explicit analysis of between-subject heterogeneity reveals that a substantial fraction of participants in fact react entirely opposite than the aggregated results indicate. We further show that this heterogeneity has consequences for overall outcomes, thereby arguing that heterogeneous sensitivities to rank feedback could have implications for the design of various policies in education and organizations.
Purpose: Anastomotic leakage is a major surgical complication following esophagectomy and gastric pull-up. Specific risk factors such as celiac trunk (TC) stenosis and high calcification score of the aorta have been identified, but no data are available on their relative prognostic values. This retrospective study aimed to compare and evaluate calcification score versus stenosis quantification with regards to prognostic impact on anastomotic leakage.
Patients and methods: Preoperative contrast-enhanced computed tomography scans of 164 consecutive patients with primary esophageal cancer were evaluated by two radiologists to apply a calcification score (0–3 scale) assessing the aorta, the celiac axis and the right and left postceliac arteries. Concurrently, the presence and degree of stenosis of TC and superior mesenteric artery were recorded for stenosis quantification.
Results: Anastomotic leakage was noted in 14/164 patients and 12/14 showed stenosis of TC (n=11). The presence of TC stenosis was found to have a significant impact on anastomotic healing (p=0.004). The odds ratio for the prediction of anastomotic leakage by the degree of stenosis was 1.04 (95% CI, 1.02–1.07). Ten of 14 patients had aortic calcification scores of 1 or 2, but calcification scores of the aorta, the celiac axis and the right and left postceliac arteries did not correlate with the corresponding TC stenosis values and showed no influence on patient outcome as defined by the occurrence of anastomotic insufficiency (p=0.565, 0.855, 0.518 and 1.000, respectively). Inter-reader reliability of computed tomography analysis and absolute agreement on calcium scoring was mostly over 90%. No significant differences in preoperative comorbidities and patient characteristics were found between those with and without anastomotic leakage.
Conclusion: Measurement of TC stenosis in preoperative contrast-enhanced computed tomography scans proved to be more reliable than calcification scores in predicting anastomotic leakage and should, therefore, be used in the risk assessment of patients undergoing esophagectomy and gastric pull-up.
Purpose: All-ceramic restorations required extensive tooth preparation. The purpose of this in vitro study was to investigate a minimally invasive preparation and thickness of monolithic zirconia crowns, which would provide sufficient mechanical endurance and strength.
Materials and methods: Crowns with thickness of 0.2 mm (group 0.2, n=32) or of 0.5 mm (group 0.5, n=32) were milled from zirconia and fixed with resin-based adhesives (groups 0.2A, 0.5A) or zinc phosphate cements (groups 0.2C, 0.5C). Half of the samples in each subgroup (n=8) underwent thermal cycling and mechanical loading (TCML)(TC: 5℃ and 55℃, 2×3,000 cycles, 2 min/cycle; ML: 50 N, 1.2×106 cycles), while the other samples were stored in water (37℃/24 h). Survival rates were compared (Kaplan-Maier). The specimens surviving TCML were loaded to fracture and the maximal fracture force was determined (ANOVA; Bonferroni; α=.05). The fracture mode was analyzed.
Results: In both 0.5 groups, all crowns survived TCML, and the comparison of fracture strength among crowns with and without TCML showed no significant difference (P=.628). Four crowns in group 0.2A and all of the crowns in group 0.2C failed during TCML. The fracture strength after 24 hours of the cemented 0.2 mm-thick crowns was significantly lower than that of adhesive bonded crowns. All cemented crowns provided fracture in the crown, while about 80% of the adhesively bonded crowns fractured through crown and die.
Conclusion: 0.5 mm thick monolithic crowns possessed sufficient strength to endure physiologic performance, regardless of the type of cementation. Fracture strength of the 0.2 mm cemented crowns was too low for clinical application.
With a notional amount outstanding of more than USD 500 trillion, the market for OTC derivatives is of vital importance for global financial stability. A growing proportion of these contracts are cleared via central counterparties (CCPs), which means that CCPs are gaining in importance as critical financial market infrastructures. At the same time, there is growing concern that a new "too big to fail" problem could arise, as the CCP industry is highly concentrated due to economies of scale. From a European perspective, it should be noted that the clearing of euro-denominated OTC derivatives mainly takes place in London, hence outside the EU in the foreseeable future. For some time there has been a controversial discussion as to whether this can remain the case post Brexit.
CCPs, which clear a significant proportion of euro OTC derivatives and are systemically relevant from an EU perspective, should be subject to direct supervision by EU authorities and should be established in the EU. This would represent an important building block for a future Capital Markets Union in Europe, as regulatory or supervisory arbitrage in favour of systemically important third- ountry CCPs could be prevented. In addition, if a systemically relevant CCP handling a considerable portion of the euro OTC derivatives business were to run into serious difficulties, this may impact ECB monetary policy. This applies both to demand for central bank money and to the transmission of monetary policy measures, which can be significantly impaired, particularly in the event that the repo market or payment systems are disrupted. It is therefore essential for the ECB to be closely involved in the supervision of CCPs. Against this background, the draft amendment of EMIR (European Market Infrastructure Regulation) presented on 13 June 2017 is a step in the right direction. In addition, there is an urgent need to introduce a recovery and resolution mechanism for CCPs in the EU to complement the existing single resolution mechanism (SRM) for banks in the eurozone. Only then can the diverse interdependencies between banks and CCPs be adequately taken into account in the recovery and resolution programmes required in a financial crisis.
Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes
(2018)
Previous identification of the inducible nitric oxide synthase (NOS2) gene as a risk allele for psoriasis (Ps) and psoriatic arthritis (PsA) suggests a possible pathogenic role of nitric oxide (NO). Using a mouse model of mannan-induced Ps and PsA (MIP), where macrophages play a regulatory role by releasing reactive oxygen species (ROS), we found that NO was detectable before disease onset in mice, independent of a functional nicotinamide adenine dinucleotide phosphate oxidase 2 complex. MIP was suppressed by either deletion of Nos2 or inhibition of NO synthases with NG-nitro-L-arginine methyl ester, demonstrating that Nos2-derived NO is pathogenic. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-γ–stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1α (IL-1α) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS.
Selective BRAF inhibitors such as vemurafenib have become a treatment option in patients with Langerhans cell Histiocytosis (LCH). To date, only 14 patients receiving vemurafenib for LCH have been reported. Although vemurafenib can stabilize the clinical condition of these patients, it does not seem to cure the patients, and it is unknown, when and how to stop vemurafenib treatment. We present a girl with severe multisystem LCH who responded only to vemurafenib. After 8 months of treatment, vemurafenib was tapered and replaced by prednisone and vinblastine, a strategy which has not been described to date. Despite chemotherapy, early relapse occurred, but remission was achieved by re-institution of vemurafenib. Further investigation needs to address the optimal duration of vemurafenib therapy in LCH and whether and which chemotherapeutic regimen may prevent disease relapse after cessation of vemurafenib.
Human papilloma virus (HPV) infection is linked to cervical cancer, which represents the world's fourth most common cancer in women. So far, no detailed map of the worldwide HPV research architecture has been constructed. Hence, this study focuses on the chronological development and geographical distribution of the global HPV-specific publications and evaluates citation-based parameters as well as socioeconomic features of the publishing countries.
In total, 29,330 HPV-related publications were identified. The US was the leading country with 12,270 publications. Only high-income-countries were found in the ranking of the fifteen most active countries with Germany, France, and Japan among the top five. Analysis of HPV research activity in relation to the economic strength demonstrated a lead position of Finland and Sweden with an average of 2248.78 and 1924.67 HPV-related publications per GDP in 1000 bn US-$, respectively. The most active upper-middle-income country was Mexico (416.78 HPV-related publications per GDP in 1000 bn US-$). India as lower-middle-income country reached a value of 279.78 HPV-related publications per GDP in 1000 bn US-$. Collaboration analysis pointed to the US as the center of the 4517 international HPV collaborations.
The worldwide HPV-research landscape is dominated by North American and Western European countries. By contrast, a high prevalence of HPV-related cervical cancer is documented for low-income countries. Hence, HPV-related public health interventions and prevention research specifically tailored to these countries needs to be fostered by monetary support and international collaborations.
Background: Sphingolipids are versatile signaling molecules derived from membrane lipids of eukaryotic cells. Ceramides regulate cellular processes such as proliferation, differentiation and apoptosis and are involved in cellular stress responses. Experimental evidence suggests a pivotal role of sphingolipids in the pathogenesis of cardiovascular diseases, including ischemic stroke. A neuroprotective effect has been shown for beta-adrenergic antagonists in rodent stroke models and supported by observational clinical data. However, the exact underlying pathophysiological mechanisms are still under investigation. We aimed to examine the influence of propranolol on the ceramide metabolism in the stroke-affected brain.
Methods: Mice were subjected to 60 or 180 min transient middle cerebral artery occlusion (tMCAO) and infarct size, functional neurological deficits, glucose tolerance, and brain ceramide levels were assessed after 12, 24, and 72 h to evaluate whether the latter two processes occur in a similar time frame. Next, we assessed the effects of propranolol (10 mg/kg bw) at 0, 4 and 8 h after tMCAO and FTY720 (fingolimod; 1 mg/kg) on infarct size, functional outcome, immune cell counts and brain ceramide levels at 24 h after 60 min tMCAO.
Results: We found a temporal coincidence between stroke-associated impaired glucose tolerance and brain ceramide accumulation. Whereas propranolol reduced ischemic lesion size, improved functional outcome and reduced brain ceramide accumulation without an effect on circulating immune cells, FTY720 showed the known neuroprotective effect and strong reduction of circulating immune cells without affecting brain ceramide accumulation.
Conclusions: Propranolol ameliorates both stroke-associated impairment of glucose tolerance and brain ceramide accumulation which are temporally linked, strengthening the evidence for a role of the sympathetic nervous system in regulating post-stroke glucose metabolism and its metabolic consequences in the brain.
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK). Both, AICAR and AMPK were reported to attenuate inflammation. However, AICAR is known for many AMPK-independent effects, although the mechanisms remain incompletely understood. Here we report a potent suppression of lipopolysaccharide (LPS)-induced inflammatory gene expression by AICAR in primary human macrophages, which occurred independently of its conversion to AMPK-activating 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - κB (NFκB) by LPS, it prevented the recruitment of NFκB and RNA polymerase II to target gene promoters. AICAR also inhibited signal transducer and activator of transcription 3 (STAT3)-dependent induction of interleukin (IL) IL-6 and IL-10 targets, while leaving STAT6 and HIF1α-dependent gene expression in IL-4 and dimethyloxalylgylcine-treated macrophages intact. This points to a transcription factor-specific mode of action. Attenuated gene expression correlated with impaired NFκB and STAT3, but not HIF-binding in electrophoretic mobility shift assays in vitro. Conclusively, AICAR interferes with DNA binding of NFκB and STAT3 to modulate inflammatory responses.
Inducible gene expression is an important tool in molecular biology research to study protein function. Most frequently, the antibiotic doxycycline is used for regulation of so-called tetracycline (Tet)-inducible systems. In contrast to stable gene overexpression, these systems allow investigation of acute and reversible effects of cellular protein induction. Recent reports have already called for caution when using Tet-inducible systems as the employed antibiotics can disturb mitochondrial function and alter cellular metabolism by interfering with mitochondrial translation. Reprogramming of energy metabolism has lately been recognized as an important emerging hallmark of cancer and is a central focus of cancer research. Therefore, the scope of this study was to systematically analyze dose-dependent metabolic effects of doxycycline on a panel of glioma cell lines with concomitant monitoring of gene expression from Tet-inducible systems. We report that doxycycline doses commonly used with inducible expression systems (0.01–1 µg/mL) substantially alter cellular metabolism: Mitochondrial protein synthesis was inhibited accompanied by reduced oxygen and increased glucose consumption. Furthermore, doxycycline protected human glioma cells from hypoxia-induced cell death. An impairment of cell growth was only detectable with higher doxycycline doses (10 µg/mL). Our findings describe settings where doxycycline exerts effects on eukaryotic cellular metabolism, limiting the employment of Tet-inducible systems.
Sphingosine kinase (SK) catalyses the formation of sphingosine 1-phosphate (S1P), which acts as a key regulator of inflammatory and fibrotic reactions, mainly via S1P receptor activation. Here, we show that in the human renal proximal tubular epithelial cell line HK2, the profibrotic mediator transforming growth factor β (TGFβ) induces SK-1 mRNA and protein expression, and in parallel, it also upregulates the expression of the fibrotic markers connective tissue growth factor (CTGF) and fibronectin. Stable downregulation of SK-1 by RNAi resulted in the increased expression of CTGF, suggesting a suppressive effect of SK-1-derived intracellular S1P in the fibrotic process, which is lost when SK-1 is downregulated. In a further approach, the S1P transporter Spns2, which is known to export S1P and thereby reduces intracellular S1P levels, was stably downregulated in HK2 cells by RNAi. This treatment decreased TGFβ-induced CTGF and fibronectin expression, and it abolished the strong induction of the monocyte chemotactic protein 1 (MCP-1) by the pro-inflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β. Moreover, it enhanced the expression of aquaporin 1, which is an important water channel that is expressed in the proximal tubules, and reverted aquaporin 1 downregulation induced by IL-1β/TNFα. On the other hand, overexpression of a Spns2-GFP construct increased S1P secretion and it resulted in enhanced TGFβ-induced CTGF expression. In summary, our data demonstrate that in human renal proximal tubular epithelial cells, SK-1 downregulation accelerates an inflammatory and fibrotic reaction, whereas Spns2 downregulation has an opposite effect. We conclude that Spns2 represents a promising new target for the treatment of tubulointerstitial inflammation and fibrosis.
Due to its remote and isolated location, Antarctica is home to a unique diversity of species. The harsh conditions have shaped a primarily highly adapted endemic fauna. This includes the notothenioid family Channichthyidae. Their exceptional physiological adaptations have made this family of icefish the focus of many studies. However, studies on their ecology, especially on their parasite fauna, are comparatively rare. Parasites, directly linked to the food chain, can function as biological indicators and provide valuable information on host ecology (e.g., trophic interactions) even in remote habitats with limited accessibility, such as the Southern Ocean. In the present study, channichthyid fish (Champsocephalus gunnari: n = 25, Chaenodraco wilsoni: n = 33, Neopagetopsis ionah: n = 3, Pagetopsis macropterus: n = 4, Pseudochaenichthys georgianus: n = 15) were collected off South Shetland Island, Elephant Island, and the tip of the Antarctic Peninsula (CCAML statistical subarea 48.1). The parasite fauna consisted of 14 genera and 15 species, belonging to the six taxonomic groups including Digenea (four species), Nematoda (four), Cestoda (two), Acanthocephala (one), Hirudinea (three), and Copepoda (one). The stomach contents were less diverse with only Crustacea (Euphausiacea, Amphipoda) recovered from all examined fishes. Overall, 15 new parasite-host records could be established, and possibly a undescribed genotype or even species might exist among the nematodes.
Biological invasions have been associated with niche changes; however, their occurrence is still debated. We assess whether climatic niches between native and non-native ranges have changed during the invasion process using two globally spread mosquitoes as model species, Aedes albopictus and Aedes aegypti. Considering the different time spans since their invasions (>300 vs. 30–40 years), niche changes were expected to be more likely for Ae. aegypti than for Ae. albopictus. We used temperature and precipitation variables as descriptors for the realized climatic niches and different niche metrics to detect niche dynamics in the native and non-native ranges. High niche stability, therefore, no niche expansion but niche conservatism was revealed for both species. High niche unfilling for Ae. albopictus indicates a great potential for further expansion. Highest niche occupancies in non-native ranges occurred either under more temperate (North America, Europe) or tropical conditions (South America, Africa). Aedes aegypti has been able to fill its native climatic niche in the non-native ranges, with very low unfilling. Our results challenge the assumption of rapid evolutionary change of climatic niches as a requirement for global invasions but support the use of native range-based niche models to project future invasion risk on a large scale.
Borrelia burgdorferi sensu lato (Bbsl), the causative agent of Lyme disease, establishes an initial infection in the host’s skin following a tick bite, and then disseminates to distant organs, leading to multisystem manifestations. Tick-to-vertebrate host transmission requires that Bbsl survives during blood feeding. Complement is an important innate host defense in blood and interstitial fluid. Bbsl produces a polymorphic surface protein, CspA, that binds to a complement regulator, Factor H (FH) to block complement activation in vitro. However, the role that CspA plays in the Bbsl enzootic cycle remains unclear. In this study, we demonstrated that different CspA variants promote spirochete binding to FH to inactivate complement and promote serum resistance in a host-specific manner. Utilizing a tick-to-mouse transmission model, we observed that a cspA-knockout B. burgdorferi is eliminated from nymphal ticks in the first 24 hours of feeding and is unable to be transmitted to naïve mice. Conversely, ectopically producing CspA derived from B. burgdorferi or B. afzelii, but not B. garinii in a cspA-knockout strain restored spirochete survival in fed nymphs and tick-to-mouse transmission. Furthermore, a CspA point mutant, CspA-L246D that was defective in FH-binding, failed to survive in fed nymphs and at the inoculation site or bloodstream in mice. We also allowed those spirochete-infected nymphs to feed on C3-/- mice that lacked functional complement. The cspA-knockout B. burgdorferi or this mutant strain complemented with cspA variants or cspA-L246D was found at similar levels as wild type B. burgdorferi in the fed nymphs and mouse tissues. These novel findings suggest that the FH-binding activity of CspA protects spirochetes from complement-mediated killing in fed nymphal ticks, which ultimately allows Bbsl transmission to mammalian hosts.
SAFE Newsletter : 2018, Q1
(2018)
Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas.
We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed.
Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis.
In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.
The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent ApcMin/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.
Division of labor and task specialization explain the success of human and insect societies. Social insect colonies are characterized by division of labor, with workers specializing in brood care early and foraging later in life. Theory posits that this task switching requires shifts in responsiveness to task-related cues, yet experimental evidence is weak. Here, we show that a Vitellogenin (Vg) ortholog identified in an RNAseq study on the ant T. longispinosus is involved in this process: using phylogenetic analyses of Vg and Vg-like genes, we firstly show that this candidate gene does not cluster with the intensively studied honey bee Vg but falls into a separate Vg-like A cluster. Secondly, an experimental knockdown of Vg-like A in the fat body caused a reduction in brood care and an increase in nestmate care in young ant workers. Nestmate care is normally exhibited by older workers. We demonstrate experimentally that this task switch is at least partly based on Vg-like A–associated shifts in responsiveness from brood to worker cues. We thus reveal a novel mechanism leading to early behavioral maturation via changes in social cue responsiveness mediated by Vg-like A and associated pathways, which proximately play a role in regulating division of labor.
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Purpose: Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed brain metastases with high local control rates. However, data about local re-irradiation in case of local failure after SRS (re-SRS) are rare. We evaluated the feasibility, efficacy and patient selection characteristics in treating locally recurrent metastases with a second course of SRS.
Methods: We retrospectively evaluated patients with brain metastases treated with re-SRS for local tumor progression between 2011 and 2017. Patient and treatment characteristics as well as rates of tumor control, survival and toxicity were analyzed.
Results: Overall, 32 locally recurrent brain metastases in 31 patients were irradiated with re-SRS. Median age at re-SRS was 64.9 years. The primary histology was breast cancer and non-small-cellular lung cancer (NSCLC) in respectively 10 cases (31.3%), in 5 cases malignant melanoma (15.6%). In the first SRS-course 19 metastases (59.4%) and in the re-SRS-course 29 metastases (90.6%) were treated with CyberKnife® and the others with Gamma Knife. Median planning target volume (PTV) for re-SRS was 2.5 cm3 (range, 0.1–37.5 cm3) and median dose prescribed to the PTV was 19 Gy (range, 12–28 Gy) in 1–5 fractions to the median 69% isodose (range, 53–80%). The 1-year overall survival rate was 61.7% and the 1-year local control rate was 79.5%. The overall rate of radiological radio-necrosis was 16.1% and four patients (12.9%) experienced grade ≥ 3 toxicities.
Conclusions: A second course of SRS for locally recurrent brain metastases after prior local SRS appears to be feasible with acceptable toxicity and can be considered as salvage treatment option for selected patients with high performance status. Furthermore, this is the first study utilizing robotic radiosurgery for this indication, as an additional option for frameless fractionated treatment.
Indication for combined cardiac surgery and orthotopic liver transplantation is rare and patients are at high risks. Individual surgical strategy must be developed since a general standard of such procedure does not exist. We report the case of a 45-year-old woman who underwent simultaneously modified Bentall procedure and orthotopic liver transplantation. Underlying diseases were end-stage polycystic liver, aneurysm of the ascending aorta, and severe aortic regurgitation. To avoid prolonged bypass times, both teams worked simultaneously. During cardiac reperfusion, time inferior vena cava stayed ligated while the cyst liver was explanted.
Background. The placement of an implant in a previously infected site is an important etiologic factor contributing to implant failure. The aim of this case report is to present the management of retrograde peri-implantitis (RPI) in a first maxillary molar site, 2 years after the implant placement. The RPI was treated using an air-abrasive device, Er,Cr:YSGG laser, and guided bone regeneration (GBR).
Case Description. A 65-year-old Caucasian male presented with a draining fistula associated with an implant at tooth #3. Tooth #3 revealed periapical radiolucency two years before the implant placement. Tooth #3 was extracted, and a ridge preservation procedure was performed followed by implant rehabilitation. A periapical radiograph (PA) showed lack of bone density around the implant apex. The site was decontaminated with an air-abrasive device and Er,Cr:YSGG laser, and GBR was performed. The patient was seen every two weeks until suture removal, followed by monthly visits for 12 months. The periapical X-rays, from 6 to 13 months postoperatively, showed increased bone density around the implant apex, with no signs of residual clinical or radiographic pathology and probing depths ≤4 mm.
Conclusions. The etiology of RPI in this case was the placement of an implant in a previously infected site. The use of an air-abrasive device, Er,Cr:YSGG, and GBR was utilized to treat this case of RPI. The site was monitored for 13 months, and increased radiographic bone density was noted.
Learning, memory consolidation, and retrieval are processes known to be modulated by the circadian (circa: about; dies: day) system. The circadian regulation of memory performance is evolutionarily conserved, independent of the type and complexity of the learning paradigm tested, and not specific to crepuscular, nocturnal, or diurnal organisms. In mammals, long-term memory (LTM) formation is tightly coupled to de novo gene expression of plasticity-related proteins and posttranslational modifications and relies on intact cAMP/protein kinase A (PKA)/protein kinase C (PKC)/mitogen-activated protein kinase (MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling. These memory-essential signaling components cycle rhythmically in the hippocampus across the day and night and are clearly molded by an intricate interplay between the circadian system and memory. Important components of the circadian timing mechanism and its plasticity are members of the Period clock gene family (Per1, Per2). Interestingly, Per1 is rhythmically expressed in mouse hippocampus. Observations suggest important and largely unexplored roles of the clock gene protein PER1 in synaptic plasticity and in the daytime-dependent modulation of learning and memory. Here, we review the latest findings on the role of the clock gene Period 1 (Per1) as a candidate molecular and mechanistic blueprint for gating the daytime dependency of memory processing.
Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.
The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = −0.142/−0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
The tumor vasculature differs from normal blood vessels in morphology, composition and stability. Here, we describe a novel tumor vessel-disrupting mechanism. In an HT1080/mouse xenograft tumor model rhodocetin-αβ was highly effective in disrupting the tumor endothelial barrier. Mechanistically, rhodocetin-αβ triggered MET signaling via neuropilin-1. As both neuropilin-1 and MET were only lumen-exposed in a subset of abnormal tumor vessels, but not in normal vessels, the prime target of rhodocetin-αβ were these abnormal tumor vessels. Consequently, cells lining such tumor vessels became increasingly motile which compromised the vessel wall tightness. After this initial leakage, rhodocetin-αβ could leave the bloodstream and reach the as yet inaccessible neuropilin-1 on the basolateral side of endothelial cells and thus disrupt nearby vessels. Due to the specific neuropilin-1/MET co-distribution on cells lining such abnormal tumor vessels in contrast to normal endothelial cells, rhodocetin-αβ formed the necessary trimeric signaling complex of rhodocetin-αβ-MET-neuropilin-1 only in these abnormal tumor vessels. This selective attack of tumor vessels, sparing endothelial cell-lined vessels of normal tissues, suggests that the neuropilin-1-MET signaling axis may be a promising drugable target for anti-tumor therapy, and that rhodocetin-αβ may serve as a lead structure to develop novel anti-tumor drugs that target such vessels.
The etiology of many diseases results from the dysregulation of inflammation. Understanding the molecular mechanisms controlling the inflammatory response is essential to formulate therapeutic strategies for the treatment of inflammatory conditions. In fact, substantial research has unveiled important aspects of the inflammatory machinery, both at the cellular and molecular levels. Recently, sphingolipids (Sph) have emerged as signaling molecules that regulate many cell functions, and ample evidence emphasizes their role in the regulation of inflammatory responses. ...
B lymphocytes are key players in humoral immunity, expressing diverse surface immunoglobulin receptors directed against specific antigenic epitopes. The development and profile of distinct subpopulations have gained awareness in the setting of primary immunodeficiency disorders, primary or secondary autoimmunity and as therapeutic targets of specific antibodies in various diseases. The major B cell subpopulations in peripheral blood include naïve (CD19+ or CD20+IgD+CD27−), non-switched memory (CD19+ or CD20+IgD+CD27+) and switched memory B cells (CD19+ or CD20+IgD−CD27+). Furthermore, less common B cell subpopulations have also been described as having a role in the suppressive capacity of B cells to maintain self-tolerance. Data on reference values for B cell subpopulations are limited and only available for older age groups, neglecting the continuous process of human B cell development in children and adolescents. This study was designed to establish an exponential regression model to produce continuous reference values for main B cell subpopulations to reflect the dynamic maturation of the human immune system in healthy children.
An iridium(III/IV/V) redox series featuring a terminal imido complex with triplet ground state
(2018)
The iridium(III/IV/V) imido redox series [Ir(NtBu){N(CHCHPtBu2)2}]0/+/2+ was synthesized and examined spectroscopically, magnetically, crystallographically and computationally. The monocationic iridium(IV) imide exhibits an electronic doublet ground state with considerable ‘imidyl’ character as a result of covalent Ir–NtBu bonding. Reduction gives the neutral imide [Ir(NtBu){N(CHCHPtBu2)2}] as the first example of an iridium complex with a triplet ground state. Its reactivity with respect to nitrene transfer to selected electrophiles (CO2) and nucleophiles (PMe3), respectively, is reported.
Organoboranes are among the most versatile and widely used reagents in synthetic chemistry. A significant further expansion of their application spectrum would be achievable if boron-containing reactive intermediates capable of inserting into C–H bonds or performing nucleophilic substitution reactions were readily available. However, current progress in the field is still hampered by a lack of universal design concepts and mechanistic understanding. Herein we report that the doubly arylene-bridged diborane(6) 1H2 and its B[double bond, length as m-dash]B-bonded formal deprotonation product Li2[1] can activate the particularly inert C(sp3)–H bonds of added H3CLi and H3CCl, respectively. The first case involves the attack of [H3C]− on a Lewis-acidic boron center, whereas the second case follows a polarity-inverted pathway with nucleophilic attack of the B[double bond, length as m-dash]B double bond on H3CCl. Mechanistic details were elucidated by means of deuterium-labeled reagents, a radical clock, α,ω-dihaloalkane substrates, the experimental identification of key intermediates, and quantum-chemical calculations. It turned out that both systems, H3CLi/1H2 and H3CCl/Li2[1], ultimately funnel into the same reaction pathway, which likely proceeds past a borylene-type intermediate and requires the cooperative interaction of both boron atoms.
Quercetin is a flavonoid that is ubiquitously found in vegetables and fruits. Like other flavonoids, it is active in balancing cellular reactive oxygen species (ROS) levels and has a cyto-protective function. Previously, a link between ROS balancing, aging, and the activity of O-methyltransferases was reported in different organisms including the aging model Podospora anserina. Here we describe a role of the S-adenosylmethionine-dependent O-methyltransferase PaMTH1 in quercetin-induced lifespan extension. We found that effects of quercetin treatment depend on the methylation state of the flavonoid. Specifically, we observed that quercetin treatment increases the lifespan of the wild type but not of the PaMth1 deletion mutant. The lifespan increasing effect is not associated with effects of quercetin on mitochondrial respiration or ROS levels but linked to the induction of the PaMth1 gene. Overall, our data demonstrate a novel role of O-methyltransferase in quercetin-induced longevity and identify the underlying pathway as part of a network of longevity assurance pathways with the perspective to intervene into mechanisms of biological aging.
Purpose: DINO and DACOTA were prospective, noninterventional studies assessing the health status and quality of life of patients with COPD newly treated with roflumilast 500 µg once-daily add-on therapy.
Patients and methods: Patients were evaluated over 6 months. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores were recorded at baseline and after 3 and 6 months. In DACOTA, post-bronchodilator FEV1 was recorded at each time point.
Results: Of 5,462 and 3,645 patients recruited into DINO and DACOTA, respectively, 3,274 patients in DINO and 916 patients in DACOTA completed the 6-month visit. Almost all patients had severe or very severe airway obstruction; mean baseline CCQ total score was 3.9 in DINO and 3.7 in DACOTA. Overall, 33.8% of patients in DACOTA and 30.6% in DINO discontinued treatment prematurely. Significant and clinically relevant improvements in CCQ total scores were observed in both studies (mean change from baseline of 1.36 in DINO and 0.91 in DACOTA at Month 6 [all P<0.001]). Changes in CAT total score from baseline to Month 6 indicated that the average clinical impact of COPD was reduced from a severe (score: 21–30) to a moderate (score: 11–20) impairment. In DACOTA, mean change in post-bronchodilator FEV1 was 202 mL (P<0.001). Diarrhea, nausea, and weight decrease were the most frequently reported adverse drug reactions.
Conclusion: In real-life clinical practice, roflumilast treatment as an add-on therapy is associated with clinically relevant improvements in health status and quality of life.
In this thesis we introduce the imaginary projection of (multivariate) polynomials as the projection of their variety onto its imaginary part, I(f) = { Im(z_1, ... , z_n) : f(z_1, ... , z_n) = 0 }. This induces a geometric viewpoint to stability, since a polynomial f is stable if and only if its imaginary projection does not intersect the positive orthant. Accordingly, the thesis is mainly motivated by the theory of stable polynomials.
Interested in the number and structure of components of the complement of imaginary projections, we show as a key result that there are only finitely many components which are all convex. This offers a connection to the theory of amoebas and coamoebas as well as to the theory of hyperbolic polynomials.
For hyperbolic polynomials, we show that hyperbolicity cones coincide with components of the complement of imaginary projections, which provides a strong structural relationship between these two sets. Based on this, we prove a tight upper bound for the number of hyperbolicity cones and, respectively, for the number of components of the complement in the case of homogeneous polynomials. Beside this, we investigate various aspects of imaginary projections and compute imaginary projections of several classes explicitly.
Finally, we initiate the study of a conic generalization of stability by considering polynomials whose roots have no imaginary part in the interior of a given real, n-dimensional, proper cone K. This appears to be very natural, since many statements known for univariate and multivariate stable polynomials can be transferred to the conic situation, like the Hermite-Biehler Theorem and the Hermite-Kakeya-Obreschkoff Theorem. When considering K to be the cone of positive semidefinite matrices, we prove a criterion for conic stability of determinantal polynomials.
The endoplasmic-reticulum-associated protein degradation pathway ensures quality control of newly synthesized soluble and membrane proteins of the secretory pathway. Proteins failing to fold into their native structure are processed in a multistep process and finally ubiquitinated and degraded by the proteasome in order to protect the cell from proteotoxic stress. My thesis covers structural as well as functional studies of various protein components that constitute the protein complexes that are responsible for this process.
One sub-project addressed the mechanism of glycan recognition by Yos9 as part of the ERAD substrate selection. NMR solution structures of the mannose-6-phosphate homology (MRH) domain of Yos9 both in a free and glycan bound conformation reveal a gripping movement of loop regions upon binding of correctly processed glycan structures.
The main projects focused on revealing the mechanism of efficient ubiquitin chain assembly by the ERAD ubiquitination machinery. This included the investigation of the role of the ERAD components Cue1 and Ubc7 in processive ubiquitin chain formation, how ubiquitin chain conformations change during elongation, how the conformation of a chain is impacted by interacting proteins and finally understand the activity regulation of the ERAD E2 enzyme Ubc7 by its cognate RING E3 ligases. Nuclear magnetic resonance (NMR) analysis and fluorescence-based ubiquitination assays show that the CUE domain of Cue1 contributes with its proximal binding preference as well as with its position dependent accelerating effect to efficient ubiquitin chain formation. This is required to efficiently drive degradation of substrates. Specific ubiquitin binding events dictate and coordinate the spatial arrangement of the E2 enzyme relative to the distal tip of a chain. This process can be further accelerated by RING E3 ligases that promote Ubc7 activity by more than ~20 fold via inducing allosteric changes around the catalytic cysteine. My results additionally suggest a model where Ubc7 dimerization results in proximity induced activation of the E2. This data ensures rapid diubiquitin formation that is followed by a CUE domain assisted chain elongation mechanism where Cue1 acts in an E4 like fashion.
How ubiquitin binding events can modulate the conformations of a ubiquitin chain were investigated by pulsed electron-electron double resonance (PELDOR) spectroscopy combined with molecular modeling. This shows that K48-linked diubiquitin samples a broad conformational space which can be modulated in distinct ways. The CUE domain of Cue1 uses conformational selection of pre-populated open conformations to support ubiquitin chain elongation. In contrast, deubiquitinating enzymes shift the conformational distribution to weakly or even non-populated conformations to allow cleavage of the isopeptide bond that connects adjacent ubiquitins. Ubiquitin chain elongation increases the sampled conformational space and suggests that this high conformational flexibility might contribute to efficient proteasomal recognition.
Background: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC).
Methods: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test.
Results: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3–367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04).
Conclusions: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.
Consistent individual differences in behavioral tendencies (animal personality) can affect individual mate choice decisions. We asked whether personality traits affect male and female mate choice decisions similarly and whether potential personality effects are consistent across different mate choice situations. Using western mosquitofish (Gambusia affinis) as our study organism, we characterized focal individuals (males and females) twice for boldness, activity, and sociability/shoaling and found high and significant behavioral repeatability. Additionally, each focal individual was tested in two different dichotomous mate choice tests in which it could choose between computer-animated stimulus fish of the opposite sex that differed in body size and activity levels, respectively. Personality had different effects on female and male mate choice: females that were larger than average showed stronger preferences for large-bodied males with increasing levels of boldness/activity (i.e., towards more proactive personality types). Males that were larger than average and had higher shoaling tendencies showed stronger preferences for actively swimming females. Size-dependent effects of personality on the strength of preferences for distinct phenotypes of potential mating partners may reflect effects of age/experience (especially in females) and social dominance (especially in males). Previous studies found evidence for assortative mate choice based on personality types or hypothesized the existence of behavioral syndromes of individuals’ choosiness across mate choice criteria, possibly including other personality traits. Our present study exemplifies that far more complex patterns of personality-dependent mate choice can emerge in natural systems.
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.
Understanding the spatial and temporal dynamics of species assemblages is a main challenge in ecology. The mechanisms that shape species assemblages and their temporal fluctuations along tropical elevational gradients are particularly poorly understood. Here, we examined the spatio-temporal dynamics of bird assemblages along an elevational gradient in Ecuador. We conducted bird point counts at three elevations (1000, 2000 and 3000 m) on 18 1-ha plots and repeated the sampling eight times over two years (216 hours in total). For each plot, we obtained data of monthly temperatures and precipitation and recorded the overall resource availability (i.e., the sum of flower, fruit, and invertebrate resources). As expected, bird richness decreased from low to high elevations. Moreover, we found a significant decrease in bird abundance and richness and an increase in evenness between the most and least humid season at each of the three elevations. Climatic factors were more closely related to these temporal fluctuations than local resource availability. While temperature had significant positive effects on the abundance of birds at mid and high elevations, precipitation negatively affected bird abundance at low and mid elevations. Our study highlights that bird assemblages along tropical elevational gradients can show pronounced seasonal fluctuations. In particular, low temperatures and high precipitation seem to impose important constraints on birds. We conclude that potential changes in climate, due to global warming, are likely to affect the spatio-temporal dynamics of bird assemblages along tropical elevational gradients.
Background: Glaucoma is a neurodegenerative disease, leading to thinning of the retinal nerve fibre layer (RNFL). The exact influence of ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFL thickness (RNFLT) is unknown and was analysed in a subgroup of the Gutenberg Health Study (GHS).
Methods: Global peripapillary RNFLT was measured in 3224 eyes of 1973 subjects (49% female) using spectral-domain optical coherence tomography (SD-OCT). The association of age, sex, ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFLT was analysed using Pearson correlation coefficient and fitting a linear mixed model.
Results: In the univariable analysis highest correlations were found for axial length (r = -0.27), spherical equivalent (r = 0.24), and glaucoma (r = -0.15) (p<0.0001, respectively). Other significant correlations with RNFLT were found for age, sex, intraocular pressure, systemic hypertension and systolic blood pressure, previous eye surgery, cholesterol, homocysteine, history of coronary artery disease, history of myocardial infarction, apnoea, diabetes and alcohol intake, p<0.05, respectively. Body length, body weight, BMI, diastolic blood pressure, blood glucose, HbA1c, history of apoplexy, cognitive function, peripheral artery disease, tinnitus, migraine, nicotine intake, central corneal thickness, and pseudophakia were not significantly correlated with RNFLT. The regression model revealed a significant relationship between RNFLT and age in decades (p<0.02), spherical equivalent (p<0.0001), axial length (p<0.0001), glaucoma (p<0.0001), tinnitus (p = 0.04), apnoea (p = 0.047), homocysteine (p = 0.05) and alcohol intake >10g/d for women and >20g/d for men (p = 0.02). Glaucoma, apnoea, higher homocysteine, higher alcohol intake and higher axial length as well as age were related to decreased RNFLT while higher spherical equivalent or history for tinnitus were related to thicker RNFL.
Conclusion: RNFLT is related to age, ocular parameters and lifestyle factors. Considering these parameters in normative databases could improve the evaluation of peripapillary RNFLT. It is necessary to evaluate if a reduction of alcohol intake as well as the therapy of apnea or high homocysteine levels could positively influence RNFLT.
Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infection in early childhood. Underlying pathomechanisms of elevated pulmonary morbidity in later infancy are largely unknown. We found that RSV‐infected H441 cells showed increased mRNA expression of connective tissue growth factor (CTGF), a key factor in airway remodeling. Additional dexamethasone treatment led to further elevated mRNA levels, indicating additive effects. Caffeine treatment prevented RSV‐mediated increase in CTGF mRNA. RSV may be involved in airway remodeling processes by increasing CTGF mRNA expression. Caffeine might abrogate these negative effects and thereby help to restore lung homeostasis.
Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. In this study, we aimed to further characterize the role of macrophage-derived EVs in immune responses against hepatitis C virus (HCV) and the potential of polyunsaturated fatty acids (PUFAs) to modulate this modality of innate immunity. To this end, EVs were isolated from interferon-stimulated macrophage cultures or from serum of patients with acute or chronic hepatitis C. EVs were characterized by electron microscopy, flow cytometry, RNA-sequencing, and Western blot analysis. The effect of EVs on replication of HCV was assessed in coculture models. Functional analyses were performed to assess the impact of PUFAs on EV-mediated antiviral immunity. We found that macrophages secreted various cytokines shortly after stimulation with type I and II IFN, which orchestrated a fast but short-lasting antiviral state. This rapid innate immune answer was followed by the production of macrophage-derived EVs, which induced a late, but long-lasting inhibitory effect on HCV replication. Of note, exposure of macrophages to PUFAs, which are important regulators of immune responses, dampened EV-mediated antiviral immune responses. Finally, EVs from patients with hepatitis C exhibited long-lasting antiviral activities during IFN therapy as well. The antiviral effect of EVs from Caucasian and Japanese patients differed, which may be explained by different nutritional uptake of PUFAs. In conclusion, our data indicate that macrophage-derived EVs mediate long-lasting inhibitory effects on HCV replication, which may bridge the time until efficient adaptive immune responses are established, and which can be blunted by PUFAs.
Background/Aims: Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear.
Methods: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA.
Results: Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors). In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors.
Conclusion: Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.