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Models propose an auditory-motor mapping via a left-hemispheric dorsal speech-processing stream, yet its detailed contributions to speech perception and production are unclear. Using fMRI-navigated repetitive transcranial magnetic stimulation (rTMS), we virtually lesioned left dorsal stream components in healthy human subjects and probed the consequences on speech-related facilitation of articulatory motor cortex (M1) excitability, as indexed by increases in motor-evoked potential (MEP) amplitude of a lip muscle, and on speech processing performance in phonological tests. Speech-related MEP facilitation was disrupted by rTMS of the posterior superior temporal sulcus (pSTS), the sylvian parieto-temporal region (SPT), and by double-knock-out but not individual lesioning of pars opercularis of the inferior frontal gyrus (pIFG) and the dorsal premotor cortex (dPMC), and not by rTMS of the ventral speech-processing stream or an occipital control site. RTMS of the dorsal stream but not of the ventral stream or the occipital control site caused deficits specifically in the processing of fast transients of the acoustic speech signal. Performance of syllable and pseudoword repetition correlated with speech-related MEP facilitation, and this relation was abolished with rTMS of pSTS, SPT, and pIFG. Findings provide direct evidence that auditory-motor mapping in the left dorsal stream causes reliable and specific speech-related MEP facilitation in left articulatory M1. The left dorsal stream targets the articulatory M1 through pSTS and SPT constituting essential posterior input regions and parallel via frontal pathways through pIFG and dPMC. Finally, engagement of the left dorsal stream is necessary for processing of fast transients in the auditory signal.
Photorhabdus are highly effective insect pathogenic bacteria that exist in a mutualistic relationship with Heterorhabditid nematodes. Unlike other members of the genus, Photorhabdus asymbiotica can also infect humans. Most Photorhabdus cannot replicate above 34°C, limiting their host-range to poikilothermic invertebrates. In contrast, P. asymbiotica must necessarily be able to replicate at 37°C or above. Many well-studied mammalian pathogens use the elevated temperature of their host as a signal to regulate the necessary changes in gene expression required for infection. Here we use RNA-seq, proteomics and phenotype microarrays to examine temperature dependent differences in transcription, translation and phenotype of P. asymbiotica at 28°C versus 37°C, relevant to the insect or human hosts respectively. Our findings reveal relatively few temperature dependant differences in gene expression. There is however a striking difference in metabolism at 37°C, with a significant reduction in the range of carbon and nitrogen sources that otherwise support respiration at 28°C. We propose that the key adaptation that enables P. asymbiotica to infect humans is to aggressively acquire amino acids, peptides and other nutrients from the human host, employing a so called “nutritional virulence” strategy. This would simultaneously cripple the host immune response while providing nutrients sufficient for reproduction. This might explain the severity of ulcerated lesions observed in clinical cases of Photorhabdosis. Furthermore, while P. asymbiotica can invade mammalian cells they must also resist immediate killing by humoral immunity components in serum. We observed an increase in the production of the insect Phenol-oxidase inhibitor Rhabduscin normally deployed to inhibit the melanisation immune cascade. Crucially we demonstrated this molecule also facilitates protection against killing by the alternative human complement pathway.
Pharmakophore sind ein zentrales Konzept der medizinischen Chemie. Im Liganden-basierten Design abstrahieren sie physikochemische Eigenschaften einer Menge aktiver Liganden und lassen dadurch Rückschlüsse auf die möglichen Interaktionen mit einem Target zu. Umgekehrt werden im Struktur-basierten Design Kristallstrukturen von Proteinen genutzt um zu modellieren, welche Eigenschaften die Bindetasche besitzt und welche Eigenschaften das entsprechende Gegenstück möglicher Liganden habe sollte. Diese Informationen können genutzt werden, um neue Substanzen zu identifizieren, welche die im Pharmakophore-Modell modellierten Interaktionen mit dem Target eingehen können. Durch die Abstraktion können hierbei sowohl Verbindungen mit neuen Grundgerüsten (scaffold) als auch mit veränderten funktionellen Gruppen gefunden werden. Im ersten Fall spricht man dabei von „scaffold hopping“, der letzte Fall ist eng verbunden mit dem Konzept des bioisosteren Ersatzes.
Im Rahmen dieser Arbeit wurden Pharmakophore genutzt, um in drei Studien neue Inhibitoren der Arachidonsäurekaskade zu finden. Die Arachidonsäurekaskade ist ein Stoffwechselweg in der aus Arachidonsäure eine Reihe von Lipidmediatoren synthetisiert wird. Viele dieser Mediatoren spielen eine entscheidende Rolle in Entzündungsprozessen und damit einhergehenden Krankheitsbildern. Es wurde außerdem eine neue Methode zur automatischen Generierung von Pharmakophor-Modellen aus einer Menge bekannter Liganden entwickelt.
In der ersten Studie wurde ein Struktur-basiertes Pharmakophor-Modell der Bindetasche der löslichen Epoxidhydrolase (sEH) erstellt, welches die möglichen, relevanten Interaktionsmöglichkeiten abbilden sollte. Dieses Pharmakophor-Modell wurde zum Screening einer Datenbank kommerziell erhältlicher Verbindungen genutzt und führte zu zwei Verbindungen mit IC50-Werten im niedrigen mikromolaren Bereich sowie einer dritten Verbindung mit einem bisher nicht für Inhibitoren der sEH beschriebenem Chemotyp. Zwar war diese Verbindung in höheren Konzentration unlöslich war, jedoch erreichten Derivate ebenfalls IC50-Werte im niedrigen mikromolaren Bereich und könnten als mögliche Startpunkte für eine neue Substanzklasse von sEH-Inhibitoren dienen.
In einer zweiten Studie wurde ein Liganden-basierter Ansatz gewählt um neue Inhibitoren der Leukotrien-A4 Hydrolase (LTA4H) zu suchen. Im Rahmen dieser Studie wurde außerdem eine neue Methode zur automatischen Generierung von Pharmakophor-Modellen entwickelt, welche auf einem wachsenden neuronalen Gas basiert, einer Methode aus dem Bereich des maschinellen Lernens. Die Methode wurde retrospektiv anhand mehrerer Benchmark-Datensätze validiert. Unter anderem wurde überprüft, inwiefern die Methode in der Lage ist die bioaktive Konformation eines Liganden vorherzusagen. Hierzu wurden, ausgehend von co-kristallisierten Liganden, automatisch Modelle generiert, welche im Anschluss genutzt wurden um Konformations-Datenbanken der Liganden zu durchsuchen. Je näher die beste gefundene Konformation an der co-kristallisierten Konformation lag, desto besser war das erzeugte Modell. Die entwickelte Methode war in nahezu allen Fällen in der Lage ein Modell zu erzeugen, mit welchem die durchschnittliche Abweichung zwischen co-kristallisierter und gefundener Konformation unter 2 Å lag. Im Rahmen der Studie wurde die neu entwickelte Methode auch in einem prospektiven Virtual Screening nach neuen Liganden der LTA4H genutzt. Hierzu wurden basierend auf 24 Kristallstrukturen mehrere Pharmakophor-Modelle für LTA4H-Liganden erstellt. Durch zusätzliche Nutzung des ESshape3D Fingerprints konnte außerdem die Form der Bindetasche der LTA4H erfasst werden. Diese Modelle wurden anschließend eingesetzt um eine Datenbank kommerziell erhältlicher Verbindungen zu durchsuchen und führten zur Identifizierung von zwei Substanzen mit IC50-Werten im unteren mikromolaren Bereich. Des Weiteren war die neue Methode in der Lage, den Bindemodus des genutzten Referenzinhibitors vorherzusagen, welcher durch Röntgenstrukturanalyse bestätigt wurde.
In zwei weiteren Studien wurde versucht, duale Inhibitoren der sEH und der 5-Lipoxygenase (5-LO) zu finden. Die erste dieser beiden Studien nutzte hierfür „duale“ Pharmakophor-Modelle: für beide Targets wurde basierend auf einer Vielzahl publizierter, aktiver Liganden eine Reihe von Pharmakophor-Modellen erstellt. Diese Modelle wurden paarweise miteinander verglichen; Modelle, welche eine ausreichend hohe Überlappung an Features besaßen, dienten als Ausgangspunkt für die Suche nach potentiell dualen Liganden. Durch die Suche in einer Fragment-Datenbank konnten neun Verbindungen identifiziert werden, welche eine Aktivität gegenüber einem der beiden Targets zeigten. Diese Verbindungen besaßen zum Teil noch nicht in der Literatur für sEH- oder 5 LO Inhibitoren beschriebene Strukturmerkmale. Eine der Verbindungen war außerdem in der Lage beide Targets im niedrigen mikromolaren Bereich zu inhibieren und könnte als Ausgangspunkt zur Entwicklung weiterer dualer 5-LO/sEH-Inhibitoren dienen. In der zweiten Studie wurde eine auf selbst-organisierenden Karten (SOM) basierende Methode genutzt um potentiell duale Liganden zu suchen. Hierzu wird je eine SOM mit repräsentativen (Sub-) Strukturen von Liganden beider Targets trainiert. Die DrugBank, eine Datenbank zugelassener Wirkstoffe, dient hierbei als Hintergrundverteilung und stellt den Raum wirkstoffartiger chemischer Strukturen dar. Durch einen automatischen Vergleich der trainierten SOMs können mögliche gemeinsame Substrukturen identifiziert werden. Die Anwendung dieser Methode auf bekannte Inhibitoren der sEH und der 5-LO identifizierte neun Fragmente, die auf einem der beiden Targets, sowie fünf Fragmente welche auf beiden Targets im niedrigen mikromolaren Bereich inhibierend wirken. Eine Substruktursuche nach einem dieser Fragmente in einer internen Datenbank lieferte eine Verbindung, welche beide Targets im nanomolaren Bereich inhibiert und eine vielversprechender Basis als Leitstruktur für die Entwicklung dualer 5-LO/sEH-Inhibitoren darstellt.
Zusammenfassend wurden in dieser Arbeit mehrere Ansätze vorgestellt wie Pharmakophore in der Wirkstoffsuche eingesetzt werden können. Im Rahmen mehrerer Virtual Screenings konnten eine Reihe neuer Inhibitoren gefunden werden, einige mit nicht zuvor beschriebenen Strukturmerkmalen für das jeweilige Target. Es wurde außerdem eine neue Methode zur automatischen Generierung von Pharmakophor-Modellen entwickelt, welche sowohl retrospektiv als auch prospektiv validiert wurde.
We compute the probability distribution P(N) of the net-baryon number at finite temperature and quark-chemical potential, μ, at a physical value of the pion mass in the quark-meson model within the functional renormalization group scheme. For μ/T < 1, the model exhibits the chiral crossover transition which belongs to the universality class of the O(4) spin system in three dimensions. We explore the influence of the chiral crossover transition on the properties of the net baryon number probability distribution, P(N). By considering ratios of P(N) to the Skellam function, with the same mean and variance, we unravel the characteristic features of the distribution that are related to O(4) criticality at the chiral crossover transition. We explore the corresponding ratios for data obtained at RHIC by the STAR Collaboration and discuss their implications. We also examine O(4) criticality in the context of binomial and negative-binomial distributions for the net proton number.
Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.
BACKGROUND: Vermeulen et al. 2014 published a meta-regression analysis of three relevant epidemiological US studies (Steenland et al. 1998, Garshick et al. 2012, Silverman et al. 2012) that estimated the association between occupational diesel engine exhaust (DEE) exposure and lung cancer mortality. The DEE exposure was measured as cumulative exposure to estimated respirable elemental carbon in μg/m(3)-years. Vermeulen et al. 2014 found a statistically significant dose-response association and described elevated lung cancer risks even at very low exposures.
METHODS: We performed an extended re-analysis using different modelling approaches (fixed and random effects regression analyses, Greenland/Longnecker method) and explored the impact of varying input data (modified coefficients of Garshick et al. 2012, results from Crump et al. 2015 replacing Silverman et al. 2012, modified analysis of Moehner et al. 2013).
RESULTS: We reproduced the individual and main meta-analytical results of Vermeulen et al. 2014. However, our analysis demonstrated a heterogeneity of the baseline relative risk levels between the three studies. This heterogeneity was reduced after the coefficients of Garshick et al. 2012 were modified while the dose coefficient dropped by an order of magnitude for this study and was far from being significant (P = 0.6). A (non-significant) threshold estimate for the cumulative DEE exposure was found at 150 μg/m(3)-years when extending the meta-analyses of the three studies by hockey-stick regression modelling (including the modified coefficients for Garshick et al. 2012). The data used by Vermeulen and colleagues led to the highest relative risk estimate across all sensitivity analyses performed. The lowest relative risk estimate was found after exclusion of the explorative study by Steenland et al. 1998 in a meta-regression analysis of Garshick et al. 2012 (modified), Silverman et al. 2012 (modified according to Crump et al. 2015) and Möhner et al. 2013. The meta-coefficient was estimated to be about 10-20 % of the main effect estimate in Vermeulen et al. 2014 in this analysis.
CONCLUSIONS: The findings of Vermeulen et al. 2014 should not be used without reservations in any risk assessments. This is particularly true for the low end of the exposure scale.
The RAF family of kinases constitutes the members A, B and CRAF. They mediate RAS signaling by linking it to the MEK/ERK transduction module, which regulates cellular processes such as cell proliferation, migration, survival and cell death. As the RAS/RAF/MEK/ERK (MAPK) pathway is found to be activated in human cancers, the RAF kinases have been exploited as valuable therapeutic targets and RAF inhibitors show promising results in the clinic, esp. with tumors harboring an activating BRAFV600E mutation. However, RAF inhibitors paradoxically accelerate metastasis in RAS mutant and BRAF wildtype tumors. They also become ineffective over time in BRAFV600E tumors because of reactivation of downstream mitogen-activated protein kinase (MAPK) signaling by promoting RAF dimerization. Aims of the present work were 1) to investigate the role of ARAF kinase in the paradoxical activation of the enzymatic cascade by RAF inhibitors downstream of mutated RAS and 2) to study the consequences of the loss of ARAF function on signal transduction in vitro and in vivo (nude mice). We have engineered several cell lines that would allow the study of basal and RAF inhibitor induced effects on MAPK activation, tumor cell migration and invasion.
In summary, we were able to show that the RAF isoform ARAF has an obligatory role in promoting MAPK activity and tumor cell invasion in a cell type dependent manner. In these cell types, ARAF depletion prevented the activation of MAPK kinase 1 (MEK1) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and led to a significant decrease of protrusions growing out of tumor cell spheroids in a three-dimensional (3D) culture that were otherwise induced by BRAFV600E-specific or BRAF/CRAF inhibitors (GDC-0879 and sorafenib, respectively). RAF inhibitors stimulated homodimerization of ARAF and heteromerization of BRAF with CRAF and the scaffolding protein KSR1. However, induced oligomerization was not sufficient to activate MAPK signaling if ARAF was depleted. By employing full length recombinant kinases, we were able to show for the first time that the three RAF isoforms competed for the binding to MEK1. In cell culture models, the overexpression of dimer-deficient ARAF mutants impaired the interaction between ARAF and endogenous MEK1 and thus prevented the subsequent phosphorylation of MEK1 and ERK1/2. Our findings reveal a new role for ARAF in directly activating the MAPK cascade through homodimerization and thereby promoting tumor cell invasion, suggesting the conserved RAF-dimer interface as a target for RAS- and RAF mediated cancer therapy.
Collectively, we provide evidence for the dual role ARAF plays in controlling MAPK signaling and cancer as loss of ARAF promoted strong lung metastasis formation in nude mice. Preliminary data describing the underlying mechanisms behind ARAF-regulated metastases have been presented and discussed.
Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIFα subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIFα by ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitylases. Here, we show that expression of HIF2α (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2α gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2α transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2α, demonstrating that the HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression through control of E2F1 levels. Our results thus suggest that HIF2α is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling.
In search for the elusive schizophrenia pathway, candidate genes for the disorder from a discovery sample were localized within the energy-delivering and ischemia protection pathway. To test the adult vascular-ischemic (AVIH) and the competing neurodevelopmental hypothesis (NDH), functional genomic analyses of practically all available schizophrenia-associated genes from candidate gene, genome-wide association and postmortem expression studies were performed. Our results indicate a significant overrepresentation of genes involved in vascular function (P<0.001), vasoregulation (that is, perivascular (P<0.001) and shear stress (P<0.01), cerebral ischemia (P<0.001), neurodevelopment (P<0.001) and postischemic repair (P<0.001) among schizophrenia-associated genes from genetic association studies. These findings support both the NDH and the AVIH. The genes from postmortem studies showed an upregulation of vascular-ischemic genes (P=0.020) combined with downregulated synaptic (P=0.005) genes, and ND/repair (P=0.003) genes. Evidence for the AVIH and the NDH is critically discussed. We conclude that schizophrenia is probably a mild adult vascular-ischemic and postischemic repair disorder. Adult postischemic repair involves ND genes for adult neurogenesis, synaptic plasticity, glutamate and increased long-term potentiation of excitatory neurotransmission (i-LTP). Schizophrenia might be caused by the cerebral analog of microvascular angina.
The muscarinic M2 receptor (M2R) acts as a negative feedback regulator in central cholinergic systems. Activation of the M2 receptor limits acetylcholine (ACh) release, especially when ACh levels are increased because acetylcholinesterase (AChE) activity is acutely inhibited. Chronically high ACh levels in the extracellular space, however, were reported to down-regulate M2R to various degrees. In the present study, we used the PRiMA knockout mouse which develops severely reduced AChE activity postnatally to investigate ACh release, and we used microdialysis to investigate whether the function of M2R to reduce ACh release in vivo was impaired in adult PRiMA knockout mice. We first show that striatal and hippocampal ACh levels, while strongly increased, still respond to AChE inhibitors. Infusion or injection of oxotremorine, a muscarinic M2 agonist, reduced ACh levels in wild-type mice but did not significantly affect ACh levels in PRiMA knockout mice or in wild-type mice in which ACh levels were artificially increased by infusion of neostigmine. Scopolamine, a muscarinic antagonist, increased ACh levels in wild-type mice receiving neostigmine, but not in wild-type mice or in PRiMA knockout mice. These results demonstrate that M2R are dysfunctional and do not affect ACh levels in PRiMA knockout mice, likely because of down-regulation and/or loss of receptor-effector coupling. Remarkably, this loss of function does not affect cognitive functions in PRiMA knockout mice. Our results are discussed in the context of AChE inhibitor therapy as used in dementia.
Pharmacology: the pharmacodynamics of nutrients and nutrient interactions in biological functions
(2015)
Epidemiological studies and randomized controlled trials (RCTs) have shown that nutrition and nutritional habits may play a critical role in the optimal functioning of biological systems from conception to old age. Epidemiological studies, due to their methodology, can only provide correlations between consumption of nutrient(s) and biological outcomes, whereas RCTs normally study just one dose of a certain nutrient. Both study types are therefore ill-suited to study the mechanisms by which nutrients exert their benefits. Moreover, the nutrients’ functions may depend on each other. For example, B-vitamins’ functions are known to be interdependent. While the exact mechanisms are unclear, the course and severity of conditions such as obesity, cellular aging, cancer, and neurological disorders can be affected by nutritional approaches. Thus, food and nutrition play an intimate and inextricable role in human health. Despite growing interest in adequate nutrition, the effects of nutrient interaction, the possible varying effects on different organs, and the dependency of such effects on age or health status are complicated topics that deserve careful examination. ...
This article discusses obstacles to overcoming dangerous climate change. It employs an account of dangerous climate change that takes climate change and climate change policy as dangerous if it imposes avoidable costs of poverty prolongation. It then examines plausible accounts of the collective action problems that seem to explain the lack of ambition to mitigate. After criticizing the merits of two proposals to overcome these problems, it discusses the pledge and review process. It argues that pledge and review possesses the virtues of encouraging broad participation and of providing a procedural safeguard for the right of sustainable development. However, given the perceptions of the marginal short term costs of mitigation, pledge and review is unlikely, at least initially, to issue in an agreement to make deep reductions in greenhouse gas emissions. Because there is no rival approach that seems likely to better instantiate the two virtues, pledge and review may be the best available policy for mitigation. Moreover, recent economic research suggests that the co-benefits of mitigation may be greater than previously assumed and that the costs of renewable energy may be less than previously calculated. This would radically undermine claims that the short term mitigation costs necessarily render mitigation irrational and produce collective action problems. Given the circumstances, pledge and review might be our best hope to avoid dangerous climate change.
The upcoming CBM Experiment at FAIR aims at exploring the region of highest net baryonic densities reproducible in energetic heavy ion collisions. Due to the very high beam intensities expected at FAIR, unprecedented data regarding rare observables such as charm quarks and hyperons will be accessible. Open charm mesons are particularly interesting, since they support the reconstruction of the total charm cross-section in order to search for exotic phenomena, e.g. a phase transition towards the quark-gluon plasma which is predicted by several theoretical models. Open charm studies will be performed via secondary vertex reconstruction with a suitable Micro-Vertex Detector (MVD). The CBM-MVD is currently in the development and prototyping phase with primary design goals concentrating on spatial resolution, radiation hardness, material budget, and readout performance. CMOS Monolithic Active Pixel Sensors (MAPS) provide an excellent spatial resolution for the MVD in the order of few um in combination with a low material budget (50 um thickness) and high radiation hardness. The active volume of the devices is formed from the epitaxial layer of standard CMOS wafers. This allows for integration of pixels together with analogue and digital data processing circuits on one single chip. This option was explored with the MIMOSA-26 prototype, which integrates functionalities like pedestal correction, correlated double sampling, discrimination and data sparsification based on zero suppression combined with a small and dense pixel matrix. The pixel array composed of 576 lines of 1152 pixels is read out in a column-parallel rolling shutter mode. One discriminator per column and the digital data processing circuits are located on the same chip in a 3 mm wide area beneath the pixel matrix allowing for binary hit encoding. This area also contains the circuits for pedestal correction and the configuration memory, which is programmed via JTAG. The preprocessed digital data is read out via two 80 Mbit/s LVDS links per sensor, which stream their data continuously based on a low-level protocol.
Within the scope of this thesis, a readout concept of the CBM-MVD is proposed and studied based on the current MIMOSA sensor generation. The backbone of the system is formed by the Readout Controller boards (ROCs) featuring FPGA microchips and optical links. Several ROC prototypes are considered using the synergy with the HADES Experiment. Finally, the TRB3 board is selected as a possible candidate for the initial FAIR experiments. Furthermore, a highly scalable, hardware independent FPGA firmware is implemented in order to steer and read out multiple MIMOSA-26 sensors. The reconfigurable firmware is also designed with the support for future MIMOSA sensor generations. The free-streaming sensor data is deserialized and error-checked, prior to its transmission over a suitable network interface. In order to demonstrate the validity of the concept, a readout network similar to the HADES Data Acquisition (DAQ) system is developed. The ROC is tested on the HADES TRB2 boards and data is acquired using suitable MAPS add-on boards and the TrbNet protocol.
In the context of the CBM-MVD prototype project, a readout network with 12 MIMOSA-26 sensors has been prepared for an in-beam test at the CERN SPS facility. A comprehensive control system is designed comprising customized software tools. The subsequent in-beam test is used to validate the design choices. As a result, the system could be operated synchronously and dead-time free for several days. The readout network behavior in a realistic operating environment has been carefully studied with the outcome the the TrbNet based approach handles the MVD prototype setup without any difficulties. A procedure to keep the sensors synchronous even in case of a data overflow has been pioneered as well. After the beam test, improvements and conceptual changes to the readout systems are being addressed which allow an integration into the global CBM DAQ system.
Background: Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib.
Results: The tozasertib concentration that reduces cell viability by 50 % (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3ABCG2 cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3ABCG2 cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression.
Conclusions: Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds.
The PKCβ inhibitor enzastaurin was tested in parental neuroblastoma and rhabdomyosarcoma cell lines, their vincristine-resistant sub-lines, primary neuroblastoma cells, ABCB1-transduced, ABCG2-transduced, and p53-depleted cells. Enzastaurin IC50s ranged from 3.3 to 9.5 μM in cell lines and primary cells independently of the ABCB1, ABCG2, or p53 status. Enzastaurin 0.3125 μM interfered with ABCB1-mediated drug transport. PKCα and PKCβ may phosphorylate and activate ABCB1 under the control of p53. However, enzastaurin exerted similar effects on ABCB1 in the presence or absence of functional p53. Also, enzastaurin inhibited PKC signalling only in concentrations ≥ 1.25 μM. The investigated cell lines did not express PKCβ. PKCα depletion reduced PKC signalling but did not affect ABCB1 activity. Intracellular levels of the fluorescent ABCB1 substrate rhodamine 123 rapidly decreased after wash-out of extracellular enzastaurin, and enzastaurin induced ABCB1 ATPase activity resembling the ABCB1 substrate verapamil. Computational docking experiments detected a direct interaction of enzastaurin and ABCB1. These data suggest that enzastaurin directly interferes with ABCB1 function. Enzastaurin further inhibited ABCG2-mediated drug transport but by a different mechanism since it reduced ABCG2 ATPase activity. These findings are important for the further development of therapies combining enzastaurin with ABC transporter substrates.
Im Juni spricht der Leipziger Schriftsteller Clemens Meyer im Rahmen der Frankfurter Poetikvorlesungen über den „Untergang der Äkschn GmbH“. Meyers ungewöhnliche Biographie und seine Romane über Leipziger Jugendgangs, Prostituierte und Zuhälter versprechen interessante Vorträge. Wir haben ihm vorab einige Fragen gestellt – seine mitunter forschen Antworten deuten jedenfalls an, dass der Autor sein Publikum bestimmt nicht langweilen wird.
Im Schulunterricht der deutschen Gymnasien hat die Vermittlung poetologischen Wissens im 19. Jahrhundert einen besonderen Platz eingenommen. Dabei wurde das Gebiet der Poetik jedoch sehr unterschiedlich dargestellt. Zum einen war die Poetik, die Lehre der Dichtkunst, seit dem 18. und während des gesamten 19. Jahrhunderts fortlaufend Veränderungen und Repositionierungen unterworfen. Zum anderen formte und entwickelte sich der moderne Deutschunterricht in dieser Zeit, stark beeinflusst durch die zeitgeschichtlichen Tendenzen der Verwissenschaftlichung, der Fächerdifferenzierung und der Nationalideologien. Als Konstante lässt sich jedoch über das gesamte Jahrhundert hinweg eine hohe Wertschätzung der Poetik als Unterrichtsfach erkennen. Daher wurden von Schulbuchverlagen von Beginn des 19. und bis in die 20er Jahre des folgenden Jahrhunderts hinein didaktische Poetiken veröffentlicht, die eine sehr lange und weite schulische Verwendung fanden.
In der hier vorgelegten Arbeit werden anhand einer Auswahl dieser Schulpoetiken die Grundargumente des Diskurses über Poetik herausgearbeitet und untersucht, wie sich diese im Laufe des Jahrhunderts veränderten. Dadurch wird eine Grundlage dafür geschaffen, das als gültig wahrgenommene Wissen über Form und Wesen der Literatur zu rekonstruieren, das sowohl die Leser aber auch die Schriftsteller beeinflusst hat, die aus den Schülergenerationen zwischen 1830 und 1920 stammen.
Nach der Landtagswahl in Bremen 2007 haben sich, nach langjähriger SPD/CDU-Partnerschaft (1995-2007), zwei Parteien zu einer Koalition entschlossen, die in ihren Wahlprogrammen eine „Schule für alle“ (Grüne) bzw. eine „Gemeinsame Schule“ (SPD) von 5 bis 10 angekündigt haben. Die Befürworter einer solchen Schule erwarteten, dass den Ankündigungen im Wahlkampf nun auch Taten folgen. So forderte die GEW von SPD und Grünen die als ersten Schritt versprochenen Maßnahmen: Alle Schulen werden verpflichtet, „die aufgenommenen Schülerinnen und Schüler in ihrer Schule zu einem Abschluss zu führen“ (SPD) und alle Abschlüsse der Sekundarstufe I können „an jeder Schule erworben werden“ (Grüne), womit alle Bildungsgänge, das Gymnasium eingeschlossen, bei der Entwicklung eines integrativen Schulsystems einbezogen waren...
In der familienbiographischen Studie „Bürgerliche Lebenswelten im Spiegel eines familiären Briefwechsels“ wird eine bürgerliche, nicht-prominente Familie aus Hamburg über drei Generationen hinweg in der Zeit von 1840 bis 1930 untersucht. Als Quellen wurden knapp 3000 Privatbriefe sowie mehrere Familienchroniken ausgewertet.
Thematisch gehört die Arbeit zum Kontext der deutschsprachigen Bürgertumsforschung und hat eine Schnittmenge mit mehreren thematischen Unterbereichen: Sie legt einen starken Fokus auf geschlechtergeschichtliche Themen und Problemstellungen und weist interdisziplinär Schnittmengen mit der Soziologie auf. Gerade bei der Beschreibung von biographisch hochemotionalen Momenten nähert sie sich bewusst der bislang wenig beachteten ,Gefühlskultur’ bürgerlicher Menschen und ihrer je nach Persönlichkeit sehr individuellen Ausprägung an.
Desde Dialéctica de la Ilustración hasta Dialéctica negativa, el materialismo filosófico llevado adelante por T. W. Adorno ha ubicado en un lugar central de sus reflexiones la problemática de lo corporal, poniéndolo en discusión directa tanto con el psicoanálisis y su teoría de las pulsiones, así como con las diferentes versiones del idealismo. La reflexión acerca de este ámbito, permitirá exponer tanto el carácter represivo de la sociedad; también, la posibilidad de una ética verdaderamente democrática.
The presented work inside this thesis aims to raise the degree of automation in analog circuit design. Therefore, a framework was developed to provide the necessary mechanisms in order to carry out a fully automated analog circuit synthesis, i.e., the construction of an analog circuit fulfilling all previously defined (electrical) specifications. Nowadays, analog circuit design in general is a very time consuming process compared to a digital design flow. Due to its discrete nature, the digital design process is highly automated and thus very efficient compared to analog circuit design. In modern Very-Large-Scale integration (VLSI) circuits the analog parts are mostly just a small portion of the overall chip area. Although this small portion is known to consume a major part of the needed workforce. Paired with product cycles which constantly get shorter, the time needed to develop the analog parts of an integrated circuit (IC) becomes a determinant factor. Apart from this, the ongoing progress in semiconductor processing technologies promises more speed with less power consumption on smaller areas, forcing the IC developers to keep track with the technology nodes in order to maintain competitiveness. Analog circuitry exhibits the inherent property of being hard to reuse, as porting from one technology node to another imposes critical changes for operating conditions (e.g., supply voltage) - mostly leading to a full redesign for most of the analog modules. This productivity gap between digital and analog design resembles the primary motivation for this thesis. Due to the availability of commercial sizing tools, this work deliberately focuses on the construction of circuit topologies in distinction to parameter synthesis, which can be obtained with a dedicated sizing tool. The focus on circuit construction allows the development of a framework which allows a full design space exploration. This thesis describes the needed concepts and methods to realize a deterministic, explorative analog synthesis framework. Despite this, a reference implementation is presented, which demonstrates the applicability in current analog design flows.
This paper provides a theoretical assessment of gestures in the context of authoring image-related hypertexts by example of the museum information system WikiNect. To this end, a first implementation of gestural writing based on image schemata is provided (Lakoff in Women, fire, and dangerous things: what categories reveal about the mind. University of Chicago Press, Chicago, 1987). Gestural writing is defined as a sort of coding in which propositions are only expressed by means of gestures. In this respect, it is shown that image schemata allow for bridging between natural language predicates and gestural manifestations. Further, it is demonstrated that gestural writing primarily focuses on the perceptual level of image descriptions (Hollink et al. in Int J Hum Comput Stud 61(5):601–626, 2004). By exploring the metaphorical potential of image schemata, it is finally illustrated how to extend the expressiveness of gestural writing in order to reach the conceptual level of image descriptions. In this context, the paper paves the way for implementing museum information systems like WikiNect as systems of kinetic hypertext authoring based on full-fledged gestural writing.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
The assumed space : pre-reflective spatiality and doctrinal configurations in juridical experience
(2015)
The purpose of this contribution is to analyse, by means of the legal-historical perspective, the relationship between the pre-reflections of space and the configurations of legal concepts and categories. Three examples of the interplay between doctrinal configurations and the spatial dimension within the context of three different historical periods will be illustrated: given space in the Middle Ages, possible space in the Modern Age and decided space in the Contemporary Age. From this basis, the essay considers the heuristic importance of such an analytical approach – mindful of the profiles of presupposition, such as the space assumption, underlying the conceptualisation of ideas – for a history attentive to the constraints of the theoretical sustainability of legal concepts.
Leaky integrate-and-fire (LIF) network models are commonly used to study how the spiking dynamics of neural networks changes with stimuli, tasks or dynamic network states. However, neurophysiological studies in vivo often rather measure the mass activity of neuronal microcircuits with the local field potential (LFP). Given that LFPs are generated by spatially separated currents across the neuronal membrane, they cannot be computed directly from quantities defined in models of point-like LIF neurons. Here, we explore the best approximation for predicting the LFP based on standard output from point-neuron LIF networks. To search for this best “LFP proxy”, we compared LFP predictions from candidate proxies based on LIF network output (e.g, firing rates, membrane potentials, synaptic currents) with “ground-truth” LFP obtained when the LIF network synaptic input currents were injected into an analogous three-dimensional (3D) network model of multi-compartmental neurons with realistic morphology, spatial distributions of somata and synapses. We found that a specific fixed linear combination of the LIF synaptic currents provided an accurate LFP proxy, accounting for most of the variance of the LFP time course observed in the 3D network for all recording locations. This proxy performed well over a broad set of conditions, including substantial variations of the neuronal morphologies. Our results provide a simple formula for estimating the time course of the LFP from LIF network simulations in cases where a single pyramidal population dominates the LFP generation, and thereby facilitate quantitative comparison between computational models and experimental LFP recordings in vivo.
Para responder a la pregunta: ¿Qué es la literatura?, Sartre propone el concepto de unidad como su característica exclusiva que la relaciona con la sociedad por la vía del compromiso. Se analiza tal exclusividad, así como las objeciones de Adorno a la noción de compromiso, para encontrar, en medio de sus grandes diferencias, algunas afinidades que permitan establecer las relaciones entre la literatura y la sociedad.
This chapter outlines the conditions under which accounting-based smoothing can be beneficial for policyholders who hold with-profit or participating payout life annuities (PLAs). We use a realistically-calibrated model of PLAs to explore how alternative accounting techniques influence policyholder welfare as well as insurer profitability and stability. We find that accounting smoothing of participating life annuities is favorable to consumers and insurers, as it mitigates the impact of short-term volatility and enhances the utility of these long-term annuity contracts.
This paper investigates whether exchanging the Social Security delayed retirement credit, currently paid as an increase in lifetime annuity benefits, for a lump sum would induce later claiming and additional work. We show that people would voluntarily claim about half a year later if the lump sum were paid for claiming any time after the Early Retirement Age, and about two-thirds of a year later if the lump sum were paid only for those claiming after their Full Retirement Age. Overall, people will work one-third to one-half of the additional months, compared to the status quo. Those who would currently claim at the youngest ages are likely to be most responsive to the offer of a lump sum benefit.
The paper discusses an additional reform proposal for enhancing Social Security solvency which reframes the existing debate in a different light. In our research, we focus on incentives to prolong working years and to delay benefits claiming as a way of sustaining Social Security. Specifically, we analyze how the offer of a budget-neutral, actuarially fair lump sum payment - instead of the current delayed retirement credit – would encourage people to delay claiming their OASI benefits and work longer. The results of our research will be useful for policymakers, namely in (1) measuring who would delay claiming benefits if offered a lump sum instead of higher annuity payments, (2) examining how long they would wait, and (3) how much longer, if at all, they would continue working in the interim.
Introduction: The effects of manipulated dental occlusion on body posture has been investigated quite often and discussed controversially in the literature. Far less attention has been paid to the influence of dental occlusion position on human movement. If human movement was analysed, it was mostly while walking and not while running. This study was therefore designed to identify the effect of lower jaw positions on running behaviour according to different dental occlusion positions.
Methods: Twenty healthy young recreational runners (mean age = 33.9±5.8 years) participated in this study. Kinematic data were collected using an eight-camera Vicon motion capture system (VICON Motion Systems, Oxford, UK). Subjects were consecutively prepared with four different dental occlusion conditions in random order and performed five running trials per test condition on a level walkway with their preferred running shoes. Vector based pattern recognition methods, in particular cluster analysis and support vector machines (SVM) were used for movement pattern identification.
Results: Subjects exhibited unique movement patterns leading to 18 clusters for the 20 subjects. No overall classification of the splint condition could be observed. Within individual subjects different running patterns could be identified for the four splint conditions. The splint conditions lead to a more symmetrical running pattern than the control condition.
Discussion: The influence of an occlusal splint on running pattern can be confirmed in this study. Wearing a splint increases the symmetry of the running pattern. A more symmetrical running pattern might help to reduce the risk of injuries or help in performance. The change of the movement pattern between the neutral condition and any of the three splint conditions was significant within subjects but not across subjects. Therefore the dental splint has a measureable influence on the running pattern of subjects, however subjects individuality has to be considered when choosing the optimal splint condition for a specific subject.
Diabetes-assoziierte Fußulzerationen (diabetic foot ulcerations, DFU) repräsentieren eine schwerwiegende klinische Komplikation der Wundheilung. Bislang sind pharmakologische Behandlungsansätze diabetischer Wundheilungsstörung unzureichend und limitiert. Der Erkenntnismangel der zugrundeliegenden zellulären und molekularen Mechanismen gestörter Wundheilung ergänzt die unzufrieden stellende klinische Situation. In den vergangenen Jahren sind vermehrt zelluläre Wundverbände in den klinischen Fokus gerückt. Sie ermöglichen eine individuelle, dynamische Wundbehandlung und haben in den ersten klinischen Studien vielversprechende Ergebnisse gezeigt.
In der vorliegenden Arbeit ist ein zellulärer Wundverband der Firma Boehringer Ingelheim genutzt worden, um die Wundheilung in diabetischen db/db-Tieren zu analysieren. Der Wundverband (BAWD; biological active wound dressing) besteht aus humanen Keratinozyten, die auf einer Hyaluronsäure-haltigen Matrix kultiviert werden.
Nach topischer Anwendung der lebenden Wundauflage war eine Interaktion humaner Keratinozyten mit murinem Wundgewebe zu beobachten. Die gestörte diabetische Wundheilung in der db/db-Maus war nach BAWD-Behandlung in einem um 30 % verbesserten Wundverschluss und dem Aufbau qualitativ neuen Gewebes deutlich verbessert.
Aufgrund der unverändert hohen Expression von Zyto- und Chemokinen in der frühen und späten Heilungsphase wurde eine Dämpfung der Immunantwort ausgeschlossen. Vielmehr war eine BAWD-vermittelte differenzielle Immunzellverteilung festzuhalten. Zudem zeigten Whole-Genom-Sequenzanalysen eine BAWD-induzierte Expression von Genen auf, die regenerative M2-ähnliche M[Phi] charakterisieren.
Außerdem scheint die BAWD-Anwendung nach Auswertung immunhistochemischer Daten und über die signifikant erhöhte CD29-, CD44- und Sca1-mRNA-Expression die Rekrutierung heilungsfördernder MSCs zu begünstigen, denen ein potentiell anti-entzündlicher Charakter zugesprochen wird.
In dieser Arbeit konnte zudem ein neuer Regelkreis kutaner Wundheilung beschrieben werden, der auf Basis der Expression muskelspezifischer Faktoren und der transienten Ausbildung kontraktiler Elemente in der Wunde normal heilender Tiere beruht, die bislang nicht beschrieben wurden. Interessanterweise induzierte eine BAWD-Anwendung die Expression muskelspezifischer Gene und Proteine in der Wundheilung diabetischer Tiere. Möglicherweise stellt die Ausbildung kontraktiler Elemente neben der Differenzierung von Fibroblasten zu Myofibroblasten eine ergänzende Komponente für einen beschleunigten Wundverschluss dar. Diese Befunde eröffnen neue Möglichkeiten zu Verständnis und Therapie diabetischer gestörter Wundheilung im humanen Organismus.
Biodiversity is unevenly distributed on Earth. Highly diverse biotas are particularly expected in mountain systems, because altitudinal zonation provides a number of habitat alternatives, which could lead to lower extinction rates during climatic changes. Nevertheless, the impact of environmental changes on plant diversification (especially for sub-alpine taxa) in the course of mountain orogenesis remains poorly understood. This is also true for the highest and largest plateau on Earth, the Qinghai-Tibetan Plateau (QTP) and its surrounding areas.In this doctoral thesis, I investigated the impact of environmental changes on plant diversification and the floristic exchange between the QTP region and biodiversity hotspots of Southeast Asia as well as other parts of the world by using the sub-alpine genera Agapetes and Vaccinium (Vaccinieae, Ericaceae) as well as Tripterospermum (Gentianinae, Gentianaceae) as model systems. Furthermore, I examined the role of niche evolution and conservatism in a changing environment over time, and detected possible beneficial morphological traits of plants in the surroundings of the QTP by investigating subtropical Gentianinae (Crawfurdia, Kuepferia, Metagentiana, Sinogentiana, and Tripterospermum; Gentianaceae).
Bei der hier anzuzeigenden Monographie handelt es sich um die Habilitationsschrift von St. F. P(fahl), mit der er 2011 im Fach Alte Geschichte unter besonderer Berücksichtigung der historischen Hilfswissenschaften an der Heinrich-Heine Universität Düsseldorf habilitiert wurde. Die Dissertation und die weiteren Veröffentlichungen weisen den Autor als provinzialrömischen Archäologen aus...
Der im Folgenden anzuzeigende Band ist aus der Tagung „Oratory and Politics in the Roman Republic“ hervorgegangen, die im September 2010 in Oxford veranstaltet wurde. Die Herausgeberinnen stellen in der „Introduction“ (1-7) heraus, dass man politische Reden zwar bislang durchaus untersucht, die Wirkung derselben aber eher vernachlässigt habe. Diesem Aspekt ist der Band gewidmet (2). Ferner stünden diesmal nicht Ciceros Reden im Zentrum der folgenden Artikel. Statt dessen habe man sich bewusst auf die weniger gut belegten orationes anderer Politiker konzentriert. Ein wichtiges, aber kaum überraschendes Ergebnis wird bereits hier verkündet: Zwar habe der römische Redner mit seinem Vortrag politischen Einfluss ausüben wollen, doch sei der Effekt einer Rede nicht immer vorhersehbar gewesen (2). Ein weiteres Resultat erstaunt ebenso wenig: Die Rhetorik habe in der politischen Karriere der römischen Politiker zum Teil ganz unterschiedlichen Zielen gedient. Cicero erscheine dabei in mehrfacher Hinsicht als Ausnahme, „both in his near-exclusive dependence on oratory to fuel his public career, and in the choices he makes about how to use oratory. […] and he exploited to an exceptionally high degree the possibility of preserving his oratory in textual form“ (3). Mit anderen Worten, die Sonderstellung Ciceros als erfolgreicher Redner wird erneut betont. Kurze Zusammenfassungen der insgesamt 19 Beiträge schließen die Einführung ab (4-6). Letzteres macht eine kurze Besprechung sämtlicher Artikel obsolet. Statt dessen sollen im Folgenden einzelne Studien detaillierter besprochen werden...
Eine Monographie zur Geschichte der römischen Provinz Germania Superior existiert bislang nicht, wenngleich zahlreiche Artikel, Einzelstudien und auch Bücher sich mit einzelnen Aspekten oder der Provinz insgesamt beschäftigen. Insofern kann man dem Klappentext des hier besprochenen Buches von M. K(lee) durchaus zustimmen, dass es sich um eine „längst überfällige“ Studie handelt, wobei zugleich ein „neuer Blick“ auf die „Gründung und Entwicklung“ der Provinz versprochen wird...
Rezension zu: Alison E. Cooley, The Cambridge Manual of Latin Epigraphy (Cambridge u.a. 2012)
(2015)
Background: Due to the large amount of data produced by advanced microscopy, automated image analysis is crucial in modern biology. Most applications require reliable cell nuclei segmentation. However, in many biological specimens cell nuclei are densely packed and appear to touch one another in the images. Therefore, a major difficulty of three-dimensional cell nuclei segmentation is the decomposition of cell nuclei that apparently touch each other. Current methods are highly adapted to a certain biological specimen or a specific microscope. They do not ensure similarly accurate segmentation performance, i.e. their robustness for different datasets is not guaranteed. Hence, these methods require elaborate adjustments to each dataset.
Results: We present an advanced three-dimensional cell nuclei segmentation algorithm that is accurate and robust. Our approach combines local adaptive pre-processing with decomposition based on Lines-of-Sight (LoS) to separate apparently touching cell nuclei into approximately convex parts. We demonstrate the superior performance of our algorithm using data from different specimens recorded with different microscopes. The three-dimensional images were recorded with confocal and light sheet-based fluorescence microscopes. The specimens are an early mouse embryo and two different cellular spheroids. We compared the segmentation accuracy of our algorithm with ground truth data for the test images and results from state-of-the-art methods. The analysis shows that our method is accurate throughout all test datasets (mean F-measure: 91%) whereas the other methods each failed for at least one dataset (F-measure≤69%). Furthermore, nuclei volume measurements are improved for LoS decomposition. The state-of-the-art methods required laborious adjustments of parameter values to achieve these results. Our LoS algorithm did not require parameter value adjustments. The accurate performance was achieved with one fixed set of parameter values.
Conclusion: We developed a novel and fully automated three-dimensional cell nuclei segmentation method incorporating LoS decomposition. LoS are easily accessible features that ensure correct splitting of apparently touching cell nuclei independent of their shape, size or intensity. Our method showed superior performance compared to state-of-the-art methods, performing accurately for a variety of test images. Hence, our LoS approach can be readily applied to quantitative evaluation in drug testing, developmental and cell biology.
The standard view suggests that removing barriers to entry and improving judicial enforcement reduces informality and boosts investment and growth. However, a general equilibrium approach shows that this conclusion may hold to a lesser extent in countries with a constrained supply of funds because of, for example, a more concentrated banking sector or lower financial openness. When the formal sector grows larger in those countries, more entrepreneurs become creditworthy, but the higher pressure on the credit market limits further capital accumulation. We show empirical evidence consistent with these predictions.
After the mass-vaccination campaign during the influenza A (H1N1) 2009 pandemic, a significant increase in narcolepsy incidence was observed initially in Scandinavia, later in other European countries and recently also in Canada. Narcolepsy is a sleep disease caused by the loss of hypocretin-producing cells in the hypothalamus. Almost all narcolepsy patients carry the HLA-DQB1*0602 allele, giving a link to an autoimmune-mediated process.
Most of the observed narcolepsy cases were correlated to the vaccination with Pandemrix, the most frequently used vaccine in the EU, and a slight connection to Arepanrix was also detected, which was distributed in Canada. Both vaccines were adjuvanted with AS03, suggesting a possible link between AS03 and narcolepsy. No narcolepsy cases were detected with MF59-adjuvanted or non-adjuvanted influenza vaccines. Recent studies reported differences between Pandemrix and Arepanrix and suggested the vaccine rather than the adjuvant as a suspect for narcolepsy development following vaccination. In addition, in China an increase of narcolepsy cases was reported to occur in absence of vaccination. Possible factors and potential additive effects that may have triggered narcolepsy after the pandemic vaccination are being reviewed in this paper.
Adorno und die Kabbala
(2015)
Im neunten Band der Reihe geht Ansgar Martins kabbalistischen Spuren in der Philosophie Theodor W. Adornos (1903–1969) nach. Der Frankfurter Gesellschaftskritiker griff im Rahmen seines radikalen materialistischen Projekts gleichwohl auch auf "theologische" Deutungsfiguren zurück. Vermittelt durch den gemeinsamen Freund Walter Benjamin (1892–1940) stieß Adorno dabei auf das Werk des Kabbala-Forschers Gershom Scholem (1897–1982). Zwischen Frankfurt und Jerusalem entwickelte sich eine lebenslange Korrespondenz.
Für Adorno erscheint vor dem Hintergrund lückenloser kapitalistischer Vergesellschaftung jede religiöse Sinngebung in der Moderne als unmöglich. Der Tradition der jüdischen Mystik schreibt er hingegen eine innere Affinität zu dieser hoffnungslosen Logik des "Verfalls" zu. Sie scheint ihm zur unumgänglichen Säkularisierung religiöser Gehalte aufzufordern. Adornos kabbalistische Marginalien beziehen einen breiten Horizont jüdisch-messianischer Ideen ein. Er verleugnet dabei nie, dass es ihm um eine sehr diesseite Verwirklichung geoffenbarter Heilsversprechen zu tun ist: Transzendenz sei als erfüllte Immanenz, als verwirklichte Utopie zu denken. In diesem Anliegen sieht Adorno selbst jedoch gerade seine Übereinstimmung mit der Kabbala.
Adornos kabbalistische Motive, die auf Scholems Forschungen zurückgehen, werden hier ausführlich an seinen Schriften und Vorlesungen untersucht. In seinem Verständnis der philosophischen Tradition sowie im Modell der Metaphysischen Erfahrung suchte er etwa explizit Anschluss an Deutungen der Kabbala: Das unerreichbare Urbild der Philosophie sei die Interpretation der geoffenbarten Schrift. Wie säkularisierte heilige Texte wurden Werke von Beethoven, Goethe, Kafka oder Schönberg so zum Anlass für "mystische" Interpretationen. Deren detaillierte Untersuchung erlaubt, das viel beschworene jüdische Erbe von Adornos Philosophie zu konkretisieren und bedenkenswerte Einzelheiten von der Negativen Dialektik zur Ästhetik in den Blick zu nehmen.
Incidence rates of clinically significant tinnitus: 10-year trend from a cohort study in England
(2015)
Objective: To investigate the incidence of tinnitus that burdens the health service in England.
Design: This was an observational study of 4.7 million residents of England under 85 years of age who were at risk for developing clinically significant tinnitus (sigT). SigT was defined by a discharge from hospital with a primary diagnosis of tinnitus, or a primary care recording of tinnitus with subsequent related medical follow-up within 28 days. The database used was the Clinical Practice Research Datalink and individual records were linked to additional data from the Hospital Episode Statistics. The observational period was from January 1, 2002 to December 31, 2011. Age-, gender-, and calendar year-specific incidence rates for and cumulative incidences of sigT were estimated and a projection of new cases of sigT between 2012 and 2021 was performed.
Results: There were 14,303 incident cases of sigT identified among 26.5 million person-years of observation. The incidence rate was 5.4 new cases of sigT per 10,000 person-years (95% confidence interval: 5.3 to 5.5). The incidence rate did not depend on gender but increased with age, peaking at 11.4 per 10,000 in the age group 60 to 69 years. The annual incidence rate of sigT increased from 4.5 per 10,000 person-years in 2002 to 6.6 per 10,000 person-years in 2011. The 10-year cumulative incidence of sigT was 58.4 cases (95% confidence interval: 57.4 to 59.4) per 10,000 residents. Nearly 324,000 new cases of sigT are expected to occur in England between 2012 and 2021.
Conclusions: Tinnitus presents a burden to the health care system that has been rising in recent years. Population-based studies provide crucial underpinning evidence; highlighting the need for further research to address issues around effective diagnosis and clinical management of this heterogeneous condition.
Der Aufsatz schlägt die Verbindung und Erweiterung von Analysen des (neoliberalen) Regierens mit nicht-subjektzentrierten und affekttheoretischen Ansätzen vor. Anhand einer Analyse des sozialpolitischen und sozialarbeiterischen Umgangs mit Wohnungslosen wird nachvollzogen, welcher Gewinn sich aus der Verbindung von gouvernementalen und affekttheoretischen Perspektiven ergeben kann. Aus einer gouvernementalen Perspektive wird zunächst nachgezeichnet, wie Affekte und Emotionen in Räumen des betreuten Wohnens für Wohnungslose zum Gegenstand fürsorglicher Intervention werden. Im betreuten Wohnen kommen Mikrotechniken zum Einsatz, die auf eine "ausgewogene" emotionale Bindung an Wohnräume und ihr Inventar hinarbeiten. Das betreute Wohnen ist von Problematisierungen durchzogen, die Wohnungslosigkeit als emotionale Haltung der Rastlosigkeit und Unruhe, als einen Mangel an Verbundenheit mit Orten und Dingen deuten. Gleichzeitig wird den Untergebrachten häufig auch eine übersteigerte affektive Bindung an Dinge unterstellt, die sogenannte "Horder" und "Messies" an einer sozial unauffälligen Haushaltsführung hindere. Eine gouvernementale Analyse kann die therapeutische Rationalität sichtbar machen, die diesen Problematisierungen zugrunde liegt. Eine gouvernementale Analyse allein bietet gleichwohl keine Möglichkeit, alternative Erzählungen über die Bedeutung affektiver Beziehungen für das Wohnen zu entwickeln. Mithilfe unterschiedlicher affekttheoretischer Ansätze geht der Aufsatz daher auch der Frage nach, wie sich jenseits therapeutisierender Perspektiven über das Wohnen und die Bedeutung von Bindungen an Orte und Dinge nachdenken lässt. Nicht-subjektzentrierte Konzepte von Affektivität ermöglichen solche alternativen Erzählungen und eröffnen neue Fluchtlinien der Kritik: Wohnen wir sichtbar als immer schon "betreut", eingelassen in ein Netz von intersubjektiven und interobjektiven Beziehungen.
Reconstructions of biomass burning from sediment charcoal records to improve data–model comparisons
(2015)
The location, timing, spatial extent, and frequency of wildfires are changing rapidly in many parts of the world, producing substantial impacts on ecosystems, people, and potentially climate. Paleofire records based on charcoal accumulation in sediments enable modern changes in biomass burning to be considered in their long-term context. Paleofire records also provide insights into the causes and impacts of past wildfires and emissions when analyzed in conjunction with other paleoenvironmental data and with fire models. Here we present new 1000-year and 22 000-year trends and gridded biomass burning reconstructions based on the Global Charcoal Database version 3 (GCDv3), which includes 736 charcoal records (57 more than in version 2). The new gridded reconstructions reveal the spatial patterns underlying the temporal trends in the data, allowing insights into likely controls on biomass burning at regional to global scales. In the most recent few decades, biomass burning has sharply increased in both hemispheres but especially in the north, where charcoal fluxes are now higher than at any other time during the past 22 000 years. We also discuss methodological issues relevant to data–model comparisons and identify areas for future research. Spatially gridded versions of the global data set from GCDv3 are provided to facilitate comparison with and validation of global fire simulations.
Die Sulfonyl-Gruppe (-SO2-) ist ein weit verbreitetes Strukturmotiv in der organischen Chemie und Bestandteil vieler biologisch aktiver Moleküle, insbesondere Arzneistoffen. Zwei der am häufigsten auftretenden Gruppen sind Sulfone und Sulfonamide, die in über 100 zugelassenen Medikamenten und 10% der meistverkauften Medikamente sind. Insofern kommt der Entwicklung neuer Synthesemethoden eine große Bedeutung zu. Dabei stehen besonders einfache, wirtschaftliche und zeitsparende Vorgehensweisen im Vordergrund, die eine große Bandbreite an neuen Substanzen generieren können. Ein Ansatz hierfür sind Multikomponenten- oder Eintopfreaktionen.
Aufgrund der Wichtigkeit dieser zwei Strukturklassen, sollen im Rahmen der hier vorliegenden Doktorarbeit neue Syntheserouten für Sulfone und Sulfonamide entwickelt werden. Besonderes Augenmerk wird auf die die Einführung der SO2-Einheit während der Reaktionsführung gelegt. Im Vergleich zu bereits existierenden Verfahren ist dies ein enormer Fortschritt, da die Mehrheit der bekannten Routen auf Schwefel- oder Schwefeldioxid-haltige Startmaterialien zurückgreift.
In der vorliegenden Arbeit gelang es, einen synthetischen Zugang zu Arylsulfonen basierend auf von Natrium-, Lithium-, Magnesium- und Zinksulfinaten zu finden. Diese Reaktion besitzt eine sehr große Anwendungsbandbreite und setzt sowohl Aryl- als auch Alkylsulfinate effizient um. Außerdem weisen Reaktionen mit unsymmetrischen Diaryliodoniumsalzen hohe Chemoselektivitäten auf.
Auf der Grundlage auf der Reaktion zwischen Natriumsulfinaten und Iodoniumsalzen wurde eine simple Route zur Synthese von Diarylsulfonen abgeleitet, jedoch war hierbei die Sulfonylgruppe noch Bestandteil eines der Edukte. Um die SO2-Einheit während der Reaktion einführen zu können, wurde ein praktisches Eintopf-Protokoll entwickelt, welches die direkte Umsetzung von (hetero)aromatischen und alkylischen Halogeniden zu Arylsulfonen gestattet. Diese innovative Methode besteht aus folgenden vier Schritten: (1) Generierung des Organometallreagenzes via Halogen-Metall-Austausch, direkte Metallinsertion oder Deprotonierung; (2) Reaktion des Organometallreagenzes mit SO2 zum Sulfinat; (3) Entfernen des SO2-Überschusses und flüchtiger Komponenten und (4) Umsetzung des nicht aufgereinigten Sulfinates mit einem Iodoniumsalz.
Desweiteren wird in dieser Arbeit ein neuartiger Übergangsmetall-katalysierter Ansatz zur Darstellung von Diarylsulfonen ausgehend von Arylhalogeniden und Sulfinaten diskutiert. Erste Experimente deuten auf Nickel-Katalysatoren als gute Wahl für die Reaktion. Optimierungsreaktionen zeigten eine starke Abhängigkeit der Ausbeute in Hinsicht auf die Bisswinkel der an das zentrale Nickelatom koordinierten Liganden. Da die bis dato besten Ergebnisse mit dem Komplex [o-tol-Ni(PPh2Me)2Cl] erzielt wurden, wird der [o-tol-Ni(PMe3)2Cl]-Komplex momentan in unserem Labor weiteren Studien unterzogen. Bislang ist davon auszugehen, dass dieser Katalysator hervorragende Ergebnisse liefert und zu einer allgemein gültigen Methode führt.
In weiteren Kapiteln wird die Anwendbarkeit von SO2-Surrogaten, Metabisulfiten „S2O52-„ oder DABSO; untersucht; mit dem Ziel eine Eintopf- oder Multikomponentenreaktion zu entwickeln.
Zum einen wird die Entwicklung einer Ein-Topf-Reaktion von Alkylhalogeniden mit Metabisulfiten und Organozinkreagenzien zur Darstellung von Alkylarylsulfonen vorgestellt. Darüber hinaus wird eine Übergangsmetall-katalysierte Multikomponenten Reaktion zur Synthese von Sulfonsäureamiden vorgestellt. Eine Reaktion zwischen Aminen, Arylhalogeniden und DABSO als SO2-Quelle wurde in Form einer Palladium-katalysierten Aminosulfonylierung entwickelt.
Asymmetric conflicts in which rule is contested by non-state actors are often interpreted as a destabilization of order. This also holds true for the case of IS. Indeed, it cannot be denied that its transnational “jihad” has contributed to destabilizing a whole region. On the other hand, it has been repeatedly noted that IS has – within the territory it controls – established an alternative order offering stability. At least for those who fit in the worldview of the wannabe-caliphate. As reported by inhabitants of its powerhouse Raqqa, IS does not only create obedience by force but also by providing administration, workplaces and public services. Or as Benham T. Said put it, some few Arabs “associate an Islamic state with notions of justice, stability and prosperity”...
Detectors of modern high-energy physics experiments generate huge data rates during operation. The efficient read-out of this data from the front-end electronics is a sophisticated task, the main challenges, however, may vary from experiment to experiment. The Compressed Baryonic Matter (CBM) experiment that is currently under construction at the Facility for Antiproton and Ion Research (FAIR) in Darmstadt/Germany foresees a novel approach for data acquisition.
Unlike previous comparable experiments that organize data read-out based on global, hierarchical trigger decisions, CBM is based on free-running and self-triggered front-end electronics. Data is pushed to the next stage of the read-out chain rather than pulled from the buffers of the previous stage. This new paradigm requires a completely new development of read-out electronics.
As one part of this thesis, a firmware for a read-out controller to interface such a free-running and self-triggered front-end ASIC, the GET4 chip, was implemented. The firmware in question was developed to run on a Field Programmable Gate Array (FPGA). An FPGA is an integrated circuit whose behavior can be reconfigured "in the field" which offers a lot of flexibility, bugs can be fixed and also completely new features can be added, even after the hardware has already been installed. Due to these general advantages, the usage of FPGAs is desired for the final experiment. However, there is also a drawback to the usage of FPGAs. The only affordable FPGAs today are based on either SRAM or Flash technology and both cannot easily be operated in a radiation environment.
SRAM-based devices suffer severely from Single Event Upsets (SEUs) and Flash-based FPGAs deteriorate too fast from Total Ionizing Dose (TID) effects.
Several radiation mitigation techniques exist for SRAM-based FPGAs, but careful evaluation for each use case is required. For CBM it is not clear if the higher resource consumption of added redundancy, that more or less directly translates in to additional cost, outweighs the advantaged of using FPGAs. In addition, it is even not clear if radiation mitigation techniques (e.g. scrubbing) that were already successfully put into operation in space applications also work as efficiently at the much higher particle rates expected at CBM.
In this thesis, existing radiation mitigation techniques have been analyzed and eligible techniques have been implemented for the above-mentioned read-out controller. To minimize additional costs, redundancy was only implemented for selected parts of the design.
Finally, the radiation mitigated read-out controller was tested by mounting the device directly into a particle beam at Forschungszentrum Jülich. The tests show that the radiation mitigation effect of the implemented techniques remains sound, even at a very high particle flux and with only part of the design protected by costly redundancy.
The promising results of the in-beam tests suggest to use FPGAs in the read-out chain of the CBM-ToF detector.
Background: Acquired resistance to standard chemotherapy causes treatment failure in patients with metastatic bladder cancer. Overexpression of pro-survival Bcl-2 family proteins has been associated with a poor chemotherapeutic response, suggesting that Bcl-2-targeted therapy may be a feasible strategy in patients with these tumors. The small-molecule pan-Bcl-2 inhibitor (−)-gossypol (AT-101) is known to induce apoptotic cell death, but can also induce autophagy through release of the pro-autophagic BH3 only protein Beclin-1 from Bcl-2. The potential therapeutic effects of (−)-gossypol in chemoresistant bladder cancer and the role of autophagy in this context are hitherto unknown.
Methods: Cisplatin (5637rCDDP1000, RT4rCDDP1000) and gemcitabine (5637rGEMCI20, RT4rGEMCI20) chemoresistant sub-lines of the chemo-sensitive bladder cancer cell lines 5637 and RT4 were established for the investigation of acquired resistance mechanisms. Cell lines carrying a stable lentiviral knockdown of the core autophagy regulator ATG5 were created from chemosensitive 5637 and chemoresistant 5637rGEMCI20 and 5637rCDDP1000 cell lines. Cell death and autophagy were quantified by FACS analysis of propidium iodide, Annexin and Lysotracker staining, as well as LC3 translocation.
Results: Here we demonstrate that (−)-gossypol induces an apoptotic type of cell death in 5637 and RT4 cells which is partially inhibited by the pan-caspase inhibitor z-VAD. Cisplatin- and gemcitabine-resistant bladder cancer cells exhibit enhanced basal and drug-induced autophagosome formation and lysosomal activity which is accompanied by an attenuated apoptotic cell death after treatment with both (−)-gossypol and ABT-737, a Bcl-2 inhibitor which spares Mcl-1, in comparison to parental cells. Knockdown of ATG5 and inhibition of autophagy by 3-MA had no discernible effect on apoptotic cell death induced by (−)-gossypol and ABT-737 in parental 5637 cells, but evoked a significant increase in early apoptosis and overall cell death in BH3 mimetic-treated 5637rGEMCI20 and 5637rCDDP1000 cells.
Conclusions: Our findings show for the first time that (−)-gossypol concomitantly triggers apoptosis and a cytoprotective type of autophagy in bladder cancer and support the notion that enhanced autophagy may underlie the chemoresistant phenotype of these tumors. Simultaneous targeting of Bcl-2 proteins and the autophagy pathway may be an efficient new strategy to overcome their "autophagy addiction" and acquired resistance to current therapy.
Members of the Sm protein family are important for the cellular RNA metabolism in all three domains of life. The family includes archaeal and eukaryotic Lsm proteins, eukaryotic Sm proteins and archaeal and bacterial Hfq proteins. While several studies concerning the bacterial and eukaryotic family members have been published, little is known about the archaeal Lsm proteins. Although structures for several archaeal Lsm proteins have been solved already more than ten years ago, we still do not know much about their biological function, however one can confidently propose that the archaeal Lsm proteins will also be involved in RNA metabolism. Therefore, we investigated this protein in the halophilic archaeon Haloferax volcanii. The Haloferax genome encodes a single Lsm protein, the lsm gene overlaps and is co-transcribed with the gene for the ribosomal L37.eR protein. Here, we show that the reading frame of the lsm gene contains a promoter which regulates expression of the overlapping rpl37R gene. This rpl37R specific promoter ensures high expression of the rpl37R gene in exponential growth phase. To investigate the biological function of the Lsm protein we generated a lsm deletion mutant that had the coding sequence for the Sm1 motif removed but still contained the internal promoter for the downstream rpl37R gene. The transcriptome of this deletion mutant was compared to the wild type transcriptome, revealing that several genes are down-regulated and many genes are up-regulated in the deletion strain. Northern blot analyses confirmed down-regulation of two genes. In addition, the deletion strain showed a gain of function in swarming, in congruence with the up-regulation of transcripts encoding proteins required for motility.
A data-driven method was applied to Au+Au collisions at √sNN = 200 GeV made with the STAR detector at RHIC to isolate pseudorapidity distance η-dependent and η-independent correlations by using two- and four-particle azimuthal cumulant measurements. We identified a η-independent component of the correlation, which is dominated by anisotropic flow and flow fluctuations. It was also found to be independent of η within the measured range of pseudorapidity |η| < 1. In 20–30% central Au+Au collisions, the relative flow fluctuation was found to be 34%±2%(stat.)±3%(sys.) for particles with transverse momentum pT less than 2 GeV/c. The η-dependent part, attributed to nonflow correlations, is found to be 5% ± 2%(sys.) relative to the flow of the measured second harmonic cumulant at |η| > 0.7.
Background. There is growing public and scientific concern about the occurrence of anthropogenic chemicals in the aquatic environment. Surface and groundwater serve as main drinking water resource. Especially in metropolitan areas these water reservoirs are impacted by organic pollutants predominantly originating from wastewater treatment plant (WWTP) effluents. The impact of wastewater derived anthropogenic chemicals is therefore related to environmental and human health concerns. In order to lower the potential environmental and human health risk from wastewater associated pollutants, strategies for enhanced pollutant removal are applicable in a medium-term perspective. Ozonation and powdered activated carbon treatment are the two advanced wastewater treatment technologies, which are technically mature as well as economically feasible for the application in large-scale wastewater treatment plants. While powdered activated carbon removes substances by adsorption, ozonation degrades a parent compound into oxidation products. Most of the available research has been done at lab-scale while onsite ecotoxicity tests and chemical analyses are rare.
Objectives. For a comparative evaluation of advanced wastewater treatments' potential to alter toxicity, a broad spectrum of ecotoxicological data need to be collected. The focus has been set on three major objectives: A) Evaluation of the endocrine activity; B) Evaluation of the unspecific toxicity; C) Evaluation of genotoxicity and mutagenicity.
Methods. The advanced treatment methods, ozonation and powdered activated carbon treatment of secondary wastewater effluents, – each equipped with subsequent sand filtration as additional post treatment step – were ecotoxico-logically characterized at a pilot-scale WWTP. For process control the elimination of 35 selected pharmaceuticals was identified by chemical analyses using HPLC-MS/MS.
The endocrine activity ((anti-)estrogenic, (anti-)androgenic, dioxin-like activity)) was characterized by yeast-based in vitro bioassays and cytotoxicity by cell based assays. Genotoxicity and mutagenicity was assessed using umuC'assay and Ames assay, respectively. All in vitro assays were performed using extracts of the wastewater samples. In vivo toxicity was assessed with the fish early life stage test with rainbow trout (Oncorhynchus mykiss). Ozonation was additionally assessed at a full-scale WWTP with in-vitro tests on endocrine activity and cytotoxicity and in vivo toxicity tests using five aquatic model organisms: Lemna minor, Daphnia magna, Chironomus riparius, Lumbriculus variegatus, Potamopyrgus antipodarum.
Results. In conventional activated sludge treated effluents the residual estrogenicity, antiandrogenicity, aryl hydrocarbon receptor agonistic activity and cytotoxicity were considerably reduced while antiestrogenicity was increased by both advanced treatment technologies. Ozonation led to an increase in genotoxic effects detected with Ames assay and with single cell gel electrophoresis of rainbow trout erythrocytes. Furthermore, mortality of rainbow trout was increased and reproduction of L. variegatus was decreased. Sand filtration lessened the genotoxic effects and adjusted reproduction of L. variegatus and mortality of rainbow trout to a similar level as conventional treatment.
Conclusions. This work demonstrates that conventional activated sludge treatment induces in vitro and in vivo toxicity. Advanced wastewater treatment combined with subsequent sand filtration can reduce in vitro and in vivo toxicity. An observed increase of endocrine activity after advanced wastewater treatment is an indication for different removal efficiencies of chemicals causing agonistic or antagonistic activity, respectively. Ozonation of wastewater generates ecotoxicity, which is largely removed by subsequent sand filtration. After a comprehensive investigation and after assurance of the removal of adverse effects, advanced treatment technologies could have beneficial effects on the ecological quality of the receiving water.
Le genre des questions-et-réponses dans la littérature grecque chrétienne se laisse mieux comprendre si l'on le définit comme une série de questions-et-réponses, présentées comme telles (et non comme des lettres ou des dialogues, par exemple) abordant des sujets variés et qui ne se réduisent pas à une seule catégorie de contenu (exégèse biblique ou explications scientifiques, par exemple). Ainsi restreint, le genre des questions-et-réponses dans la littérature grecque chrétienne connaît sa période la plus faste aux Ve-VIIIe s. dans des milieux monastiques ouverts sur les problèmes et les interrogations du monde. Ce genre, d'une grande souplesse et d'une grande vitalité, permet de traiter des questions d'une façon plus accessible et plus libre qu'il ne serait possible de le faire dans une homélie ou un traité théologique.
Repeated Quaternary glaciations have significantly shaped the present distribution and diversity of several European species in aquatic and terrestrial habitats. To study the phylogeography of freshwater invertebrates, patterns of intraspecific variation have been examined primarily using mitochondrial DNA markers that may yield results unrepresentative of the true species history. Here, population genetic parameters were inferred for a montane aquatic caddisfly, T hremma gallicum , by sequencing a 658‐bp fragment of the mitochondrial CO 1 gene, and 12,514 nuclear RAD loci. T . gallicum has a highly disjunct distribution in southern and central Europe, with known populations in the Cantabrian Mountains, Pyrenees, Massif Central, and Black Forest. Both datasets represented rangewide sampling of T. gallicum . For the CO 1 dataset, this included 352 specimens from 26 populations, and for the RAD dataset, 17 specimens from eight populations. We tested 20 competing phylogeographic scenarios using approximate Bayesian computation (ABC ) and estimated genetic diversity patterns. Support for phylogeographic scenarios and diversity estimates differed between datasets with the RAD data favouring a southern origin of extant populations and indicating the Cantabrian Mountains and Massif Central populations to represent highly diverse populations as compared with the Pyrenees and Black Forest populations. The CO 1 data supported a vicariance scenario (north–south) and yielded inconsistent diversity estimates. Permutation tests suggest that a few hundred polymorphic RAD SNP s are necessary for reliable parameter estimates. Our results highlight the potential of RAD and ABC‐based hypothesis testing to complement phylogeographic studies on non‐model species.
The stable isotope geochemistry of pedogenic and lacustrine carbonate and fossil herbivore tooth enamel is a powerful tool to study the evolution of terrestrial paleoenvironments. This thesis aims to reconstruct Neogene ecosystems in the Karonga Basin in the southern part the East African Rift (EAR) and the Central Anatolian Plateau (CAP).
Karonga Basin: Understanding the development of East African savanna biomes is crucial for reconstructing the evolution, migration and dietary behaviors of early hominins. These rift ecosystems range from closed woodland to open grassland savanna and vary widely in fraction of woody cover. Here I present Plio-Pleistocene carbon (δ13C) and oxygen (δ18O) records from pedogenic carbonate and fossil herbivore tooth enamel collected from the Malawi Rift. This is the first southern hemisphere long-term record in the East African Rift.
The studied ca. 4.3 Ma to 0.6 Ma deposits of the Chiwondo Beds (Karonga Basin) are home to two hominin fossil finds, a maxillary fragment of Paranthropus boisei and a mandible of Homo rudolfensis, both dated to ca. 2.4 Ma. The study site is situated between the well-known hominin-bearing localities of eastern and southern Africa and hence fills an important geographical gap for early hominin research.
The δ13C values of pedogenic carbonate (n = 321) and of enamel from 14 different large-bodied herbivorous mammal taxa (suid, equid, bovid, elephant an hippopotamus; n = 122) permit assessment of the evolutionary history of C3 and C4 biomass, which is closely linked to climate patterns. The reconstruction of C4-grassland development offers insights into the retreat of tree cover and the distribution and seasonality of precipitation. δ18O values reflect hydrological patterns, and we supplement the data of fossil proxy material with analyses of modern meteoric water to evaluate influences of seasonality and evaporation.
Consistent δ13C values around -9‰ and δ18O values of ca. 24‰ of the pedogenic carbonate from 14 sections spanning the last 4.3 Ma indicate a relatively mesic and persistent climate with C3-dominated woodland savannas in the Karonga Basin. The data from tooth enamel of suid, elephant, and hippo taxa complement these findings with constantly low δ13C and δ18O values, demonstrating intake of mainly C3 biomass and water from sources which are only very limited affected by evaporation.
In contrast, Karonga Basin equid and bovid taxa reflect much more complex dietary patterns, ranging from mixed C3/C4-feeders to strongly C4-influenced diets. Intra-tooth δ18O values also show large variations, indicating water intake from resources that differ in their isotopic composition and therefore experienced different hydrological settings.
Overall, the stable isotope data reflect a mostly C3-dominated mesic paleoecosystem, which comprises patches of more open C4-grasslands within the range of migrating mammals. Supplementary analyses of δ18O values of modern meteoric water (precipitation, lake, river and groundwater; n = 111) show a similar magnitude to the fossil herbivore oxygen isotopic values. Expected 18O values of the drinking water calculated from herbivore enamel of animals with a mixed- or C3-diet indicate water intake from barely evaporated sources. Specialized feeders with a high C4-consumtion, however, reflect s|||||||||||||||||||||values of 16O-depleted reservoirs, similar in δ18O |||||||||||| to modern evaporated lakes.
The absence of long-term trends towards more positive δ13C and δ18O values in the Karonga Basin contrasts the increasing role of C4-grasslands since ca. 2.5 Ma in the Eastern Rift. Our data hence point to regional differences in climate and vegetation dynamics during the Plio-Pleistocene. Therefore, regions that are home to early hominins such as H. rudolfensis and P. boisei may have had a different environmental history when compared to the Eastern Rift. This suggests that hominin adaptation is not necessarily directly linked to the emergence of open landscapes.
Central Anatolian Plateau: The development of relief and climate patterns in the Central Anatolian Plateau is long-standing debate in modern paleoecological studies. This thesis presents long-term δ13C and δ18O records on five lacustrine successions, which are widely distributed across the CAP. Also, new 40Ar/39Ar geochronological data from volcanic ashes are established in addition to existing biostratigraphic and paleomagnetic data.
Field relationships combined with stable isotope data of 230 lacustrine carbonates indicate a Late Oligocene environment that was characterized by large, temporally open freshwater lakes in a relatively humid subtropic climate. In the middle Aquitanian, an increase in lake δ18O values reflects more arid settings and an overall increasing dominance of closed saline lakes. This time was probably characterized by frequent climatic fluctuations, recording the influence of seasonality, topography and the waxing and waning of aridity.
Background: It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels.
Methods: Cold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 - 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit.
Results: CPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively.
Conclusions: The localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 - 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data.
Ausländische Pflegekräfte in deutschen Privathaushalten : ein Interview mit Prof. Dr. Helma Lutz
(2015)
Helma Lutz ist Professorin am Fachbereich Gesellschaftswissenschaften der Goethe-Universität Frankfurt am Main. Seit 15 Jahren beschäftigt sie sich in ihrer Forschung mit "neuen Dienstmädchen" – Migrantinnen, die Haus-, Erziehungs- und Versorgungsarbeit ("Care-Arbeit") in deutschen Haushalten verrichten. Die Redaktion von focus Migration hat sie zu diesem Thema befragt.
Linking mathematics with reality is not new. It is also not new to use outdoor activities to learn mathematics. It seems to be new, to combine such mathematical outdoor activities with mobile technology, like the geocache community which makes use of GPS technology to guide their members to special places and points of interest. The use of mobile technologies to learn at any time and any location is known as “mobile learning”. This type of learning can be seen as an extension of eLearning. Considering the definition of O’Malley one notices that this definition does not exactly match with the idea of the MathCityMap-Project (MCM), because the learning environment in the MCM-Project is predetermined. Combined with the math trail method the project enables mobile learning within math trails with latest technology.In the MCM-Project students experience mathematics at real places and within real situations in out-of-school activities,with help of GPS-enabled smartphones and special math problems. In contrast to the paper versions of math trails we are able to give direct feedback on the solutions by using “mobile devices” such as smartphones or tablets. If the user has difficulties in solving the modeling task, stepped hints can be provided. The teacher is able to use the MCM-Portal to upload tasks developed by himself or by his students and he is also able to build a personal math trail for his students.
In the nineties, Habermas redirected his political writings to the post-national constellation (global and European) and the possibilities of a society politically integrated through transnational democracy (or post-national democracy). This thematic reorientation took place on two fronts. The first one is the global transnational democracy, which includes the impacts of the economic globalization on national democracies, as well the proposal for a political Constitution for a pluralistic world society, based on a constitutionalization of international law. The second one is the European transnational democracy, which includes the redefinition of the political profile of European welfare state for an economic liberal profile, as well the paradox of democratic technocracy operated by European institutions and the proposal to overcome the decoupled technocratic policy model. This paper will address only this last topic, describing the reasons of the democratic deficit and the consequent delay of European political Union. Despite numerous reforms, the technocratic policies have not eliminated the discrepancy between centralization and democratization, and mistakenly indicate another direction further reinforcing the problem of European undemocratic institutions. In contrast, Habermas argues that the democratic deficit could only be overcome replacing the technocratic approach by a deeper democratization of European institutions.
Abstract: Fine-scale temporal organization of cortical activity in the gamma range (∼25–80Hz) may play a significant role in information processing, for example by neural grouping ('binding') and phase coding. Recent experimental studies have shown that the precise frequency of gamma oscillations varies with input drive (e.g. visual contrast) and that it can differ among nearby cortical locations. This has challenged theories assuming widespread gamma synchronization at a fixed common frequency. In the present study, we investigated which principles govern gamma synchronization in the presence of input-dependent frequency modulations and whether they are detrimental for meaningful input-dependent gamma-mediated temporal organization. To this aim, we constructed a biophysically realistic excitatory-inhibitory network able to express different oscillation frequencies at nearby spatial locations. Similarly to cortical networks, the model was topographically organized with spatially local connectivity and spatially-varying input drive. We analyzed gamma synchronization with respect to phase-locking, phase-relations and frequency differences, and quantified the stimulus-related information represented by gamma phase and frequency. By stepwise simplification of our models, we found that the gamma-mediated temporal organization could be reduced to basic synchronization principles of weakly coupled oscillators, where input drive determines the intrinsic (natural) frequency of oscillators. The gamma phase-locking, the precise phase relation and the emergent (measurable) frequencies were determined by two principal factors: the detuning (intrinsic frequency difference, i.e. local input difference) and the coupling strength. In addition to frequency coding, gamma phase contained complementary stimulus information. Crucially, the phase code reflected input differences, but not the absolute input level. This property of relative input-to-phase conversion, contrasting with latency codes or slower oscillation phase codes, may resolve conflicting experimental observations on gamma phase coding. Our modeling results offer clear testable experimental predictions. We conclude that input-dependency of gamma frequencies could be essential rather than detrimental for meaningful gamma-mediated temporal organization of cortical activity.
Author Summary: Almost 350 years ago the physicist and polymath Christiaan Huygens first observed the synchronization between two pendulum clocks attached to a common support. Since then synchronization has been recognized as a universal phenomenon from astronomy to biology. The phase-locking (synchrony) and the phase-relation between the two pendulums are determined by two principal forces: the synchronization force exerted over the connection and the tendency to desynchronize due to frequency (speed) differences. We propose that gamma synchronization (25–80Hz) among oscillating cortical neurons in the brain can be understood according to the same principles—like a field of many connected pendula—with the critical addition that input changes the frequency of gamma oscillations, as shown by recent experimental studies. It has been assumed that input-dependent changes in oscillation frequency are detrimental for a meaningful role of gamma synchronization in neural processing. To the contrary, our theoretical analysis demonstrates that because input can change the frequency of the oscillation, phase-locking and phase-relations among neurons relate systematically to input. By analogy, it is because a local push to a pendulum will change its frequency, that resulting changes in phase-locking and phase-relation among the pendula can be used to derive the external force applied.
What happened to the tremendous legacy of juridical knowledge left behind in Italy in the 6th century? Into what labyrinth did it plunge only to re-emerge after the silent age of the early Middle Ages into the light of day, and effectively come to shape the renewal of the jurisprudence at the beginning of the 12th century? One-and-a-half centuries after the fanciful writings of Hermann Fitting, legal historians are still looking for the answers to these questions. Considering the new information we have (especially coming from the paleographical research), this paper re-examines the existence as well as the activities of the school of Rome both during the Justinian Age and in the two centuries thereafter. The aim of this essay is to verify whether Rome, during the very early Middle Ages, continued to represent a centre of juridical culture. According to the hypothesis developed in this contribution, Rome – at that time – not only played a very important role with regard to the material conservation of the Justinian’s libri legales, but also in the initial establishment of the new (i. e., Justinian) imperial law in the West and creation of its image as a significant juridical centre. The absence of such a centre as well as its wide-spread image would truly make the Bolognese renovatio appear "miraculous" and very difficult to explain.
After Justinian, the 7th and 8th centuries can truly be characterised as "silent" in the history of Roman law in the West. However, by studying the medieval manuscript tradition, in particular, that of the Institutiones and the Novellae, we can gather together a series of elements helping us to clarify the situation. Also quite useful is an examination of the manuscript tradition of the Collatio legum Mosaicarum et Romanarum. Through the spread and use of these Late Antique works, we can see how – in conjunction with the actions of the papacy – Rome, toward the end of the 8th century, returned to being a centre of world politics and – given that law follows politics – of the legal culture.
WE DECOMPOSE INDIVIDUAL INVESTORS’ PORTFOLIO RETURNS INTO PASSIVE BENCHMARK RETURNS, ACTIVE SECURITY SELECTION RETURNS, AND ACTIVE MARKET TIMING RETURNS. FOR THE AVERAGE INVESTOR IN OUR SAMPLE, PASSIVE BENCHMARK RETURNS EXPLAIN SOME 40% OF VARIATION IN LONGITUDINAL PORTFOLIO RETURNS, SECURITY SELECTION EXPLAINS AN ADDITIONAL 50%, AND MARKET TIMING PLAYS ONLY A MINOR ROLE. THIS STANDS IN STARK CONTRAST TO EARLIER RESULTS ON INSTITUTIONAL INVESTORS WHERE PASSIVE BENCHMARK RETURNS (REFLECTING DIFFERENT ASSET ALLOCATION STRATEGIES) EXPLAIN OVER 90%. THE PREDOMINANCE OF SECURITY SELECTION COMES AT A COST FOR INDIVIDUAL INVESTORS: INVESTORS FROM THE HIGHEST QUINTILE IN TERMS OF SECURITY SELECTION ACTIVITY UNDERPERFORM THEIR PEERS FROM THE LOWEST QUINTILE BY MORE THAN 10 PERCENTAGE POINTS PER YEAR. TRANSACTION COSTS EXPLAIN ONLY PART OF THIS UNDERPERFORMANCE. THE LESS INVESTORS DIVERSIFY, THE WORSE THEY DO.
In diesem Jahr hat sich die Paul Ehrlich-Stiftung für zwei Preisträger entschieden, die sich den mit 100.000 Euro dotierten Paul Ehrlich- und Ludwig Darmstaedter-Preis teilen. Am 14.03.2015 überreichte Professor Harald zur Hausen, der Vorsitzende des Stiftungsrates, in der Frankfurter Paulskirche den Preis an Professor James P. Allison vom MD Anderson Cancer Center in Houston (Foto Mitte) und an Professor Carl H. June von der Universität Pennsylvania in Philadelphia (r.). Professor Raja Atreya vom Universitätsklinikum in Erlangen (l.) erhielt den Paul Ehrlich- und Ludwig Darmstaedter-Nachwuchspreis.
Background: The objective measurement of the mechanical component and its role in chronic ankle instability is still a matter of scientific debate. We analyzed known group and diagnostic validity of our ankle arthrometer. Additionally, functional aspects of chronic ankle instability were evaluated in relation to anterior talar drawer.
Methods: By manual stress testing, 41 functionally unstable ankles were divided as mechanically stable (n = 15) or mechanically unstable (n = 26). Ankle laxity was quantified using an ankle arthrometer. Stiffness values from the load displacement curves were calculated between 40 and 60 N. Known group validity and eta2 were established by comparing manual and arthrometer testing results. Diagnostic validity for the ankle arthrometer was determined by a 2 × 2 contingency table. The functional ankle instability severity was quantified by the German version of the Foot and Ankle Ability Measure (FAAM-G). Stiffness (40–60 N) and FAAM-G values were correlated.
Results: Mechanically unstable ankles had lower 40–60 N stiffness values than mechanically stable ankles (p = 0.006 and <0.001). Eta for the relation between manual and arthrometer anterior talar drawer testing was 0.628. With 5.1 N/mm as cut-off value, accuracy, sensitivity, and specificity were 85%, 81%, and 93%, respectively. The correlation between individual 40–60 N arthrometer stiffness values and FAAM-G scores was r = 0.286 and 0.316 (p = 0.07 and 0.04).
Conclusions: In this investigation, the ankle arthrometer demonstrated a high diagnostic validity for the determination of mechanical ankle instability. A clear interaction between mechanical (ankle arthrometer) and functional (FAAM-G) measures could not be demonstrated.
Dies ist der zehnte Artikel unseres Blogfokus „Salafismus in Deutschland“.
Was macht salafistisches Denken in religiöser Hinsicht aus? Was hat Salafismus mit Wahhabismus zu tun? Was hat Dschihadismus mit Salafismus zu tun? Alles Fragen, auf die es keine einfachen Antworten gibt. Trotzdem lohnt der Versuch, eine Antwort zu geben, da die religiösen Vorstellungen zentral für die Identität des Salafismus sind. Es geht hier „nur“ um die religiösen Ideen, die immer wieder in salafistischen Diskussionen auftreten. Freilich ist die innersalafistische Debatte vielgestaltig, so dass sich kein „Katechismus“ aufstellen lässt, der ausweist, woran ein/e SalafistIn glaubt. Deshalb werden im Folgenden entlang einzelner Stränge des salafistischen Diskurses ausgewählte religiöse Ideen beleuchtet....
n the EU there are longstanding and ongoing pressures towards a tax that is levied on the EU level to substitute for national contributions. We discuss conditions under which such a transition can make sense, starting from what we call a "decentralization theorem of taxation" that is analogous to Oates (1972) famous result that in the absence of spill-over effects and economies of scale decentralized public good provision weakly dominates central provision. We then drop assumptions that turn out to be unnecessary for this results. While spill-over effects of taxation may call for central rules for taxation, as long as spill-over effects do not depend on the intra-regional distribution of the tax burden, decentralized taxation plus tax coordination is found superior to a union-wide tax.
Background. Bile leakage testing may help to detect and reduce the incidence of biliary leakage after hepatic resection. This review was performed to investigate the value of the White-test in identifying intraoperative biliary leakage and avoiding postoperative leakage.
Material and methods. A systematic review and meta-analysis was performed. Two researchers performed literature research. Primary outcome measure was the incidence of post-hepatectomy biliary leakage; secondary outcome measure was the ability of detecting intraoperative biliary leakage with the help of the White-test.
Results. A total of 4 publications (including original data from our center) were included in the analysis. Evidence levels of the included studies had medium quality of 2b (individual cohort studies including low quality randomized controlled trials). Use of the White-test led to a significant reduction of post-operative biliary leakage [OR: 0.3 (95% CI: 0.14, 0.63), p = 0.002] and led to a significant higher intraoperative detection of biliary leakages [OR: 0.03 (95%CI: 0.02, 0.07), p < 0.00001].
Conclusion. Existing evidence implicates the use of the White-test after hepatic resection to identify bile leaks intraoperatively and thus reduce incidence of post-operative biliary leakage. Nonetheless, there is a requirement for a high-quality randomized controlled trial with adequately powered sample-size to confirm findings from the above described studies and further increase evidence in this field.
Second mitochondria-derived activator of caspase (Smac) mimetics are considered as promising anticancer therapeutics that are currently under investigation in early clinical trials. They induce apoptosis by antagonizing inhibitor of apoptosis proteins, which are frequently overexpressed in cancer. We previously reported that Smac mimetics, such as BV6, additionally exert non-apoptotic functions in glioblastoma (GBM) cells by stimulating migration and invasion in a nuclear factor kappa B (NF-κB)-dependent manner. Because NF-κB target genes mediating these effects are largely unknown, we performed whole-genome expression analyses. Here, we identify chemokine (C-C motif) ligand 2 (CCL2) as the top-listed NF-κB-regulated gene being upregulated upon BV6 treatment in GBM cells. BV6-induced upregulation and secretion of CCL2 are required for migration and invasion of GBM cells because knockdown of CCL2 in GBM cells abolishes these effects. Co-culture experiments of GBM cells with non-malignant astroglial cells reveal that BV6-stimulated secretion of CCL2 by GBM cells into the supernatant triggers migration of astroglial cells toward GBM cells because CCL2 knockdown in BV6-treated GBM cells impedes BV6-stimulated migration of astroglial cells. In conclusion, we identify CCL2 as a BV6-induced NF-κB target gene that triggers migration and invasion of GBM cells and exerts paracrine effects on the GBM's microenvironment by stimulating migration of astroglial cells. These findings provide novel insights into the biological functions of Smac mimetics with important implications for the development of Smac mimetics as cancer therapeutics.
Wasserbedarfsprognosen sind für Wasserversorger eine wichtige Entscheidungsgrundlage für zukünftige Maßnahmen in der wirtschaftlichen und technischen Betriebsführung sowie beim Ressourcenmanagement. In den letzten zwei Jahrzehnten sanken in Deutschland die spezifischen Wasserbedarfe aufgrund von Technik- und Verhaltensinnovationen. Für Regionen mit Wirtschafts- und Bevölkerungswachstum ist aber das Zusammenspiel dieser für den zukünftigen Bedarf konträren Entwicklungen von besonderem Interesse. Auch die Metropolregion Hamburg ist von diesen Entwicklungen betroffen.
Im Auftrag des Wasserversorgers HAMBURG WASSER aktualisierte das ISOE (Forschungsschwerpunkt Wasserressourcen und Landnutzung) in Kooperation mit dem ifo Institut München seine mittel- und langfristige Wasserbedarfsprognose aus dem Jahr 2007 für das Versorgungsgebiet des Auftraggebers. In einem innovativen Konzept wurden dafür Forschungsmethoden aus Natur-, Wirtschafts-, Planungs- und Sozialwissenschaften kombiniert. Mit dem gewählten transdisziplinären Forschungsmodus war das Projekt darauf angelegt, im laufenden Forschungsprozess gemeinsam mit den wissenschaftlichen und außerwissenschaftlichen Projektpartnern das Prognosekonzept weiterzuentwickeln. Der vorliegende Studientext basiert auf dem Projektbericht an HAMBURG WASSER und fasst Prognosekonzept, Modellentwicklung, Prognoseergebnissen und Schlussfolgerungen zusammen.
Rain- and floodwater harvesting (RFWH) technologies and water reuse are ideal and generalpurpose technologies to improve water security and to contribute to climate adaptation – in particular for semi-arid regions. These technologies are part of a multi-resources mix within an integrated water resources management (IWRM). They create capacities to buffer water fluctuations and alleviate water scarcity. In this way, they reduce the pressure on existing resources, and can stimulate local economies. However, in order to be sustainable, these technologies need to be adapted to the local context – through suitable design, adapted operation requirements, and a back-up by training users and operators accordingly.
Background: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.
Methods: Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.
Results: In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.
Conclusions: Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
Patienten mit einer BCR/ABL positiven (Ph+) akuten lymphatischen Leukämie (ALL) bilden die größte genetisch definierte Untergruppe der ALL und gelten wegen ihrer schlechten Prognose als Höchstrisiko ALL. Die bisherigen Therapieergebnisse werden durch die Kombination von Tyrosin-Kinase-Inhibitoren (TKI) wie Imatinib und Chemotherapeutika verbessert, sind aber durch das Auftreten von Resistenzen gegen TKI in ihrer langfristigen Wirkung limitiert. Die derzeitige Forschung fokussiert sich weitestgehend auf konstitutive aktive Kinasen, die für die leukämische Transformation verantwortlich sind. Allerdings kann die Deregulation von Phosphatasen, die als Gegenspieler von Kinasen fungieren, durch eine verminderte Inaktivierung dieser Kinasen, ebenso zur Leukämogenese beitragen, indem ihre physiologische Funktion vermindert wird. Im Vorfeld konnte bereits gezeigt werden, dass die deregulierte Protein Tyrosin Phosphatase 1B (PTP1B) bei Ph+ Leukämien eine partielle Resistenz gegenüber TKI vermitteln kann.1 Darüber hinaus zeigen von Juric et al. (2007)2 publizierte Microarrays von 54 Ph+ ALL Patienten eine transkriptionelle Hochregulierung der Phosphatase „Supressor of T-Cell receptor Signalling 1“ (STS-1).2 STS-1 (TULA-2) gehört zusammen mit STS-2 (TULA-1) zur Familie der STS/TULA Proteine, von denen keine weiteren Mitglieder bekannt sind. STS-1 dephosphoryliert diverse Rezeptor-Tyrosin-Kinasen wie z.B. den T-Cell Receptor (TCR) und den Epidermal-Growth-Factor Receptor (EGFR) und verhindert somit deren Internalisierung und proteosomalen Abbau.3 Weitere durch STS-1 dephosphorylierte Substrate sind die Proteintyrosinkinase Syk, die eine wichtige Rolle bei der Signalweiterleitung des B-Cell-Receptors (BCR) spielt sowie andere SRC-Kinasen (z.B. FYN).4 Aufgrund der oben beschriebenen Zusammenhänge zwischen STS-1 und der Ph+ ALL ist die Untersuchung einer möglichen funktionellen Bedeutung von STS-1 bei der Entwicklung einer mutationsunabhängigen Resistenz von Ph+ ALL Inhalt dieser Arbeit. Als Modellsystem dienen in der hier vorliegenden Arbeit aus der BCR/ABL Zelllinie Sup B15 abgeleitete TKI resistente Zellen (Sup B15 RT). Imatinib ist in diesen immer noch in der Lage BCR/ABL zu binden und führt zu einer Verschiebung der Dosiswirkungskurve ohne Apoptose zu induzieren. Mutationen in der Tyrosinkinase Domäne von BCR/ABL konnten als zugrunde liegender Resistenzmechanismus durch Sequenzanalysen ausgeschlossen werden, ebenso wie zusätzliche Translokationen oder genomischen Amplifikationen von BCR/ABL. Eine Analyse der STS-1 Expression zeigte sowohl transkriptionell als auch auf Proteinebene eine deutliche Herunterregulierung von STS-1 in Sup B15 RT Zellen. Die Interaktion zwischen STS-1 und BCR/ABL wurde in verschiedenen Zellmodellen gezeigt. Dabei konnten bezüglich der Interaktion keine Unterschiede zwischen dem p210BCR/ABL und p185BCR/ABL Fusionsprotein festgestellt werden. Auch die „Gatekeeper“ Mutation T315I hatte keinen Einfluss auf die Interaktion. Die Unabhängigkeit der Bindung von STS-1 und BCR/ABL von einer aktiven BCR/ABL Kinase wurde durch die Zugabe von Imatinib gezeigt. Lediglich auf endogenem Level konnte eine Imatinib vermittelte Reduktion der Interaktion nachgewiesen werden. Durch die Verwendung unterschiedlich trunkierter BCR/ABL Proteine wurde gezeigt, dass STS-1 sowohl mit c-ABL als auch mit dem ABL-Anteil von BCR/ABL interagiert und dass eine Oligomerisierung für diese Interaktion nicht notwendig ist. Als Folge der Interaktion kommt es zu einer Dephosphorylierung von BCR/ABL durch STS-1, wobei vor allem die im ABL Anteil lokalisierten und für die Autophosphorylierung wichtigen Tyrosine 245 und 412 dephosphoryliert werden. Mittels eines Proliferations-Kompetitions-Assay konnte gezeigt werden, dass STS-1 sowohl die Proliferationsrate reduziert als auch erheblich die Sensitivität von SupB15 RT Zellen gegenüber Imatinib steigert. Dieser Befund steht im Einklang mit der Annahme, dass diese Sensitivitätssteigerung durch eine gegenüber den sensitiven Sup B15 WT deutlich verminderte STS-1 Expression bedingt ist. Dexamethason in klinisch relevanten Konzentrationen (10-6 M - 10-9 M) konnte sowohl in SupB15 WT als auch in SupB15 RT Zellen die STS-1 Expression um ein Vielfaches steigern und führte in Kombination mit 1 μM Imatinib sogar in den resistenten Zellen zu einer hoch signifikanten Inhibition der Proliferation sowie einer gesteigerten Apoptose. Die Resultate dieser Arbeit rücken Phosphatasen und im speziellen STS-1 in einen stärkeren Fokus, wenn es um die Bildung von Resistenzen geht. Dadurch können sich eine Vielzahl neuer Behandlungsstrategien sowie neue Ansätze für die klinische Wirkstoffforschung ergeben.
This paper investigates the effect of a change in informational environment of borrowers on the organizational design of bank lending. We use micro-data from a large multinational bank and exploit the sudden introduction of a credit registry, an information-sharing mechanism across banks, for a subset of borrowers. Using within borrower and loan officer variation in a difference-in-difference empirical design, we show that expansion of credit registry led to an improvement in allocation of credit to affected
borrowers. There was a concurrent change in the organizational structure of the bank that involved a dramatic increase in delegation of lending decisions of affected borrowers to loan officers. We also find a significant expansion in scope of activities of loan officers who deal primarily with affected borrowers, as well as of their superiors. There is suggestive evidence that larger banks in the economy were better able to implement similar changes as our bank. We argue that these patterns can be understood within the framework of incentive-based and information cost processing theories. Our findings could help rationalize why improvements in the information environment of borrowers may be altering the landscape of lending by moving decisions outside the boundaries of financial intermediaries.
Unusual Deep Water sponge assemblage in South China - witness of the end-Ordovician mass extinction
(2015)
There are few sponges known from the end-Ordovician to early-Silurian strata all over the world, and no records of sponge fossils have been found yet in China during this interval. Here we report a unique sponge assemblage spanning the interval of the end-Ordovician mass extinction from the Kaochiapien Formation (Upper Ordovician-Lower Silurian) in South China. This assemblage contains a variety of well-preserved siliceous sponges, including both Burgess Shale-type and modern type taxa. It is clear that this assemblage developed in deep water, low energy ecosystem with less competitors and more vacant niches. Its explosion may be related to the euxinic and anoxic condition as well as the noticeable transgression during the end-Ordovician mass extinction. The excellent preservation of this assemblage is probably due to the rapid burial by mud turbidites. This unusual sponge assemblage provides a link between the Burgess Shale-type deep water sponges and the modern forms. It gives an excellent insight into the deep sea palaeoecology and the macroevolution of Phanerozoic sponges, and opens a new window to investigate the marine ecosystem before and after the end-Ordovician mass extinction. It also offers potential to search for exceptional fossil biota across the Ordovician-Silurian boundary interval in China.
Understanding how to achieve efficient transduction of hematopoietic stem and progenitor cells (HSPCs), while preserving their long-term ability to self-reproduce, is key for applying lentiviral-based gene engineering methods. SAMHD1 is an HIV-1 restriction factor in myeloid and resting CD4+ T cells that interferes with reverse transcription by decreasing the nucleotide pools or by its RNase activity. Here we show that SAMHD1 is expressed at high levels in HSPCs cultured in a medium enriched with cytokines. Thus, we hypothesized that degrading SAMHD1 in HSPCs would result in more efficient lentiviral transduction rates. We used viral like particles (VLPs) containing Vpx, shRNA against SAMHD1, or provided an excess of dNTPs or dNs to study this question. Regardless of the method applied, we saw no increase in the lentiviral transduction rate. The result was different when we used viruses (HR-GFP-Vpx+) which carry Vpx and encode GFP. These viruses allow assessment of the effects of Vpx specifically in the transduced cells. Using HR-GFP-Vpx+ viruses, we observed a modest but significant increase in the transduction efficiency. These data suggest that SAMHD1 has some limited efficacy in blocking reverse transcription but the major barrier for efficient lentiviral transduction occurs before reverse transcription.
Wild plant species are important nutritious supplements to otherwise nutrient poor diets of rural populations in West Africa. Consequently, a decline of wild food species has a direct negative impact on the nutritional status of local households. In this study, we firstly investigated the preferred wild food species in south-east Burkina Faso, their perceived change in abundance as well as their contribution to wild food income. Secondly, we studied how these species might be substituted in times of species shortfall. Thirdly, we investigated the impact of socio-economic variables on the substitution choice. We conducted 155 household interviews in two villages and found 21 wild food species. With a contribution of almost 70% to wild food income, Vitellaria paradoxa and Parkia biglobosa were economically most important. All species were considered declining to some degree. The wide range of cited substitutes for the ten most important wild food species indicates a great knowledge on alternative plant species in the area. For the majority, the substitution choice did not depend on socio-economic characteristics. Cited as surrogate for several important wild food species, the native tree Balanites aegyptiaca was the most important substitute species. Many valued wild food species were substituted with other highly valued wild food species and therefore the decline of one species can lead to a shortfall of another substitute. Thus, even though our results suggest that people are able to counteract the decrease or absence of wild food species, growing decline of one species would concurrently increase the pressure on other native food species.
Rpn13 is an intrinsic ubiquitin receptor of the 26S proteasome regulatory subunit that facilitates substrate capture prior to degradation. Here we show that the C-terminal region of Rpn13 binds to the tetratricopeptide repeat (TPR) domain of SGTA, a cytosolic factor implicated in the quality control of mislocalised membrane proteins (MLPs). The overexpression of SGTA results in a substantial increase in steady-state MLP levels, consistent with an effect on proteasomal degradation. However, this effect is strongly dependent upon the interaction of SGTA with the proteasomal component Rpn13. Hence, overexpression of the SGTA-binding region of Rpn13 or point mutations within the SGTA TPR domain both inhibit SGTA binding to the proteasome and substantially reduce MLP levels. These findings suggest that SGTA can regulate the access of MLPs to the proteolytic core of the proteasome, implying that a protein quality control cycle that involves SGTA and the BAG6 complex can operate at the 19S regulatory particle. We speculate that the binding of SGTA to Rpn13 enables specific polypeptides to escape proteasomal degradation and/or selectively modulates substrate degradation.
Der Jahrgang 2014 des Masterstudiengangs Curatorial Studies wurde von der KW Institute for Contemporary Art in Berlin eingeladen, eine Ausstellungsserie für den kleinen Raum »3 ½« zu konzipieren und eigenständig durchzuführen. Inhaltliche Vorgaben gab es dafür keine. Eine große Chance, aber auch eine Herausforderung, schließlich haben alle verschiedene Vorstellungen davon, was eine Ausstellung ausmacht.
Background: Lithium has proven suicide preventing effects in the long-term treatment of patients with affective disorders. Clinical evidence from case reports indicate that this effect may occur early on at the beginning of lithium treatment. The impact of lithium treatment on acute suicidal thoughts and/or behavior has not been systematically studied in a controlled trial. The primary objective of this confirmatory study is to determine the association between lithium therapy and acute suicidal ideation and/or suicidal behavior in inpatients with a major depressive episode (MDE, unipolar and bipolar disorder according to DSM IV criteria). The specific aim is to test the hypothesis that lithium plus treatment as usual (TAU), compared to placebo plus TAU, results in a significantly greater decrease in suicidal ideation and/or behavior over 5 weeks in inpatients with MDE.
Methods/Design: We initiated a randomized, placebo-controlled multicenter trial. Patients with the diagnosis of a moderate to severe depressive episode and suicidal thoughts and/or suicidal behavior measured with the Sheehan-Suicidality-Tracking Scale (S-STS) will be randomly allocated to add lithium or placebo to their treatment as usual. Change in the clinician administered S-STS from the initial to the final visit will be the primary outcome.
Discussion: There is an urgent need to identify treatments that will acutely decrease suicidal ideation and/or suicidal behavior. The results of this study will demonstrate whether lithium reduces suicidal ideation and behavior within the first 5 weeks of treatment.
Intrinsic covariation of brain activity has been studied across many levels of brain organization. Between visual areas, neuronal activity covaries primarily among portions with similar retinotopic selectivity. We hypothesized that spontaneous inter-areal co-activation is subserved by neuronal synchronization. We performed simultaneous high-density electrocorticographic recordings across several visual areas in awake monkeys to investigate spatial patterns of local and inter-areal synchronization. We show that stimulation-induced patterns of inter-areal co-activation were reactivated in the absence of stimulation. Reactivation occurred through both, inter-areal co-fluctuation of local activity and inter-areal phase synchronization. Furthermore, the trial-by-trial covariance of the induced responses recapitulated the pattern of inter-areal coupling observed during stimulation, i.e. the signal correlation. Reactivation-related synchronization showed distinct peaks in the theta, alpha and gamma frequency bands. During passive states, this rhythmic reactivation was augmented by specific patterns of arrhythmic correspondence. These results suggest that networks of intrinsic covariation observed at multiple levels and with several recording techniques are related to synchronization and that behavioral state may affect the structure of intrinsic dynamics.
Als sich am 16. Mai 1891 die Drehkreuze zur Internationalen Elektrotechnischen Ausstellung vor dem Frankfurter Bahnhof öffneten, gab es unter den Besuchern kaum noch Zweifel: Elektrizität und künstliche Helligkeit werden die westliche Zivilisation und ihre urbanen Lebenswelten geradezu revolutionär verändern. Das sollte sich bewahrheiten!