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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...