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Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.
Wie nehmen Sie die Goethe-Universität heute in Zeiten des stärkeren nationalen und internationalen Wettbewerbs der Hochschulen wahr?
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Was wünschen Sie der Goethe-Universität für die nächsten 50 Jahre?
Die Welt des Rechts lässt sich heute nicht mehr so leicht in nationale oder internationale Sphären ordnen. Wo Lawmaker als private Akteure in einer globalisierten Ökonomie die Normen häufig nachhaltiger bestimmen als staatliches Recht, da ändern sich auch die Anforderungen an die Rechtswissenschaft.
Caspase-2 represents the most conserved member of the caspase family, which exhibits features of both initiator and effector caspases. Using ribonucleoprotein (RNP)-immunoprecipitation assay, we identified the proapoptotic caspase-2L encoding mRNA as a novel target of the ubiquitous RNA-binding protein HuR in DLD-1 colon carcinoma cells. Unexpectedly, crosslinking-RNP and RNA probe pull-down experiments revealed that HuR binds exclusively to the caspase-2-5' untranslated region (UTR) despite that the 3' UTR of the mRNA bears several adenylate- and uridylate-rich elements representing the prototypical HuR binding sites. By using RNAi-mediated loss-of-function approach, we observed that HuR regulates the mRNA and in turn the protein levels of caspase-2 in a negative manner. Silencing of HuR did not affect the stability of caspase-2 mRNA but resulted in an increased redistribution of caspase-2 transcripts from RNP particles to translational active polysomes implicating that HuR exerts a direct repressive effect on caspase-2 translation. Consistently, in vitro translation of a luciferase reporter gene under the control of an upstream caspase-2-5'UTR was strongly impaired after the addition of recombinant HuR, whereas translation of caspase-2 coding region without the 5'UTR is not affected by HuR confirming the functional role of the caspase-2-5'UTR. Functionally, an elevation in caspase-2 level by HuR knockdown correlated with an increased sensitivity of cells to apoptosis induced by staurosporine- and pore-forming toxins as implicated by their significant accumulation in the sub G1 phase and an increase in caspase-2, -3 and poly ADP-ribose polymerase cleavage, respectively. Importantly, HuR knockdown cells remained insensitive toward STS-induced apoptosis if cells were additionally transfected with caspase-2-specific siRNAs. Collectively, our findings support the hypothesis that HuR by acting as an endogenous inhibitor of caspase-2-driven apoptosis may essentially contribute to the antiapoptotic program of adenocarcinoma cells by HuR.
Background: The phagocytic enzyme myeloperoxidase (MPO) acts as a front-line defender against microorganisms. However, increased MPO levels have been found to be associated with complex and calcified atherosclerotic lesions and incident cardiovascular disease. Therefore, this study aimed to investigate a predictive role of MPO, a biomarker of inflammation and oxidative stress, for total and cardiovascular mortality in patients referred to coronary angiography.
Methods and results: MPO plasma concentrations along with eight MPO polymorphisms were determined in 3036 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up 7.75 years). MPO concentrations were positively associated with age, diabetes, smoking, markers of systemic inflammation (interleukin-6, fibrinogen, C-reactive protein, serum amyloid A) and vascular damage (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) but negatively associated with HDL-cholesterol and apolipoprotein A-I. After adjustment for cardiovascular risk factors MPO concentrations in the highest versus the lowest quartile were associated with a 1.34-fold risk (95% CI: 1.09–1.67) for total mortality. In the adjusted model the hazard ratio for cardiovascular mortality in the highest MPO quartile was 1.42 (95% CI: 1.07–1.88). Five MPO polymorphisms were positively associated with MPO concentrations but not with mortality. Using Mendelian randomization, we did not obtain evidence for a causal association of MPO with either total or cardiovascular mortality.
Conclusions: MPO concentrations but not genetic variants at the MPO locus are independently associated with risk for total and cardiovascular mortality in coronary artery disease patients.
Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts
(2014)
Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.
Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.
Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.
Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively.
Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
Background: Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032.
Findings: PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines.
Conclusion: PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.
It is common practice to use a 30-year period to derive climatological values, as recommended by the World Meteorological Organization. However this convention relies on important assumptions, of which the validity can be examined by deriving the uncertainty inherent to using a limited time-period for deriving climatological values. In this study a new method, aiming at deriving this uncertainty, has been developed with an application to precipitation for a station in Europe (Westdorpe) and one in Africa (Gulu). The weather generator framework is used to produce synthetic daily precipitation time-series that can also be regarded as alternative climate realizations. The framework consists of an improved Markov model, which shows good performance in reproducing the 5-day precipitation variability. The sub-seasonal, seasonal and the inter-annual signals are introduced in the weather generator framework by including covariates. These covariates are derived from an empirical mode decomposition analysis with an improved stability and significance assessment. Introducing covariates was found to substantially improve the monthly precipitation variability for Gulu. From the weather generator, 1,000 synthetic time-series were produced. The divergence between these time-series demonstrates an uncertainty, inherent to using a 30-year period for mean precipitation, of 11 % for Westdorpe and 15 % for Gulu. The uncertainty for precipitation 10-year return levels was found to be 37 % for both sites.
In this study we show how size-resolved measurements of aerosol particles and cloud condensation nuclei (CCN) can be used to characterize the supersaturation of water vapor in a cloud. The method was developed and applied during the ACRIDICON-Zugspitze campaign (17 September to 4 October 2012) at the high-Alpine research station Schneefernerhaus (German Alps, 2650 m a.s.l.). Number size distributions of total and interstitial aerosol particles were measured with a scanning mobility particle sizer (SMPS), and size-resolved CCN efficiency spectra were recorded with a CCN counter system operated at different supersaturation levels.
During the evolution of a cloud, aerosol particles are exposed to different supersaturation levels. We outline and compare different estimates for the lower and upper bounds (Slow, Shigh) and the average value (Savg) of peak supersaturation encountered by the particles in the cloud. A major advantage of the derivation of Slow and Savg from size-resolved CCN efficiency spectra is that it does not require the specific knowledge or assumptions about aerosol hygroscopicity that are needed to derive estimates of Slow, Shigh, and Savg from aerosol size distribution data. For the investigated cloud event, we derived Slow ≈ 0.07–0.25%, Shigh ≈ 0.86–1.31% and Savg ≈ 0.42–0.68%.
Antigen presentation to cytotoxic T lymphocytes via major histocompatibility complex class I (MHC I) molecules depends on the heterodimeric transporter associated with antigen processing (TAP). For efficient antigen supply to MHC I molecules in the ER, TAP assembles a macromolecular peptide-loading complex (PLC) by recruiting tapasin. In evolution, TAP appeared together with effector cells of adaptive immunity at the transition from jawless to jawed vertebrates and diversified further within the jawed vertebrates. Here, we compared TAP function and interaction with tapasin of a range of species within two classes of jawed vertebrates. We found that avian and mammalian TAP1 and TAP2 form heterodimeric complexes across taxa. Moreover, the extra N-terminal domain TMD0 of mammalian TAP1 and TAP2 as well as avian TAP2 recruits tapasin. Strikingly, however, only TAP1 and TAP2 from the same taxon can form a functional heterodimeric translocation complex. These data demonstrate that the dimerization interface between TAP1 and TAP2 and the tapasin docking sites for PLC assembly are conserved in evolution, whereas elements of antigen translocation diverged later in evolution and are thus taxon specific.
This article deals with the topic of dyslexia in adults and its consequences for learning German during university studies; the author explores the extent to which an optimized German text influences understanding. The results of research on dyslexia and psycholinguistic research on text understanding show that depending on the text structure and the simplicity of the linguistic means used, different levels of text understanding may be expected. The main tool of the research is text optimization based on a practical application of the "Hamburg concept of understandability", involving four text properties which make the text understandable to different extents.
Der Beitrag widmet sich einem ausgewählten Bereich öffentlicher Pressesprache, wobei strukturelle, semantische und pragmatische Besonderheiten der sogenannten hölzernen Sprache in der deutschsprachigen Zeitung Neuer Weg (NW) aus Rumänien exemplarisch am Beispiel von Beileidstelegrammen zum Ableben der kommunistischen Führer Josef Wissarionowitsch Stalin und Gheorghe Gheorghiu-Dej (1953 bzw.1965) erfasst werden sollen. Mit der Darstellung von Formulierungspräferenzen in einer ausgewählten Textsorte der öffentlichen schriftlichen Kommunikationspraxis und der Analyse dieses soziokulturell geprägten Sprachgebrauchs hinaus sollen auch die sozial-historischen Bedingungen, die für das Auftauchen der Ausdrucksformen der hölzernen Sprache förderlich waren, eruiert werden.
Neste artigo, pretende-se apontar para uma tensão dialética entre o racional e o irracional, entre o conceito e o não conceitual, atualizando o sentido do não idêntico. Essa atualização configura-se na necessidade de potencializar uma filosofia da educação crítico-formativa com base na perspectivada “expressividade estética”. A questão que se coloca é a seguinte: como podemos compreender o sentido do não idêntico, a partir das necessidades de uma educação crítico-formativa e das condições para efetivá-la no âmbito das reflexões filosófico-educacionais? Desse modo, faz-se uma breve incursão no que consiste o papel da dialética negativa do filósofo Theodor W. Adorno para se pensar o sentido da “razão” (ou das razões) na perspectiva do “não idêntico”. Partindo disso, busca--se apontar as possibilidades da crítica imanente adorniana, cujo escopo manifesta na dialética do sofrimento no âmbito do capitalismo. Por fim, pretende-se assinalar e discutir a potencialidade da “expressividade estética” do não idêntico, articulada com algumas possibilidades para a educação no contexto atual.
Bestände, die von Calamagrostis epigejos dominiert werden, gehören zu den charakteristischen Elementen der Vegetation im östlichen Mitteleuropa. In der Literatur wurden Calamagrostis epigejos-Gesellschaften bisher meist als monoton, artenarm und wenig divers beschrieben. Für den Berliner Raum wurden 54 Vegetationsaufnahmen von Brachflächen und ehemaligen Rieselfeldern ausgewertet, in denen C. epigejos dominant war (Deckung >25 %). Die C. epigejos-Dominanzbestände konnten hauptsächlich zwei Gesellschaften zugeordnet werden: der Calamagrostis epigejos-(Galio-Urticetea)-Gesellschaft und der Calamagrostis epigejos-(Onopordetalia/Agropyretalia)-Gesellschaft. Die Calamagrostis epigejos-(Galio-Urticetea)-Gesellschaft wächst auf nährstoffreichen, frischen bis nassen, zum Teil auch zeitweilig überstauten Flächen. Derartige Standortverhältnisse sind vor allem auf eutrophierten ehemaligen Rieselfeldern zu finden. Die Bestände der Calamagrostis epigejos-(Onopordetalia/Agropyretalia)-Gesellschaft kommen auf nährstoffärmeren und trockeneren Standorten vor. Für die mittleren F- und N-Zeigerwerte ergeben sich jeweils signifikante Unterschiede von 1,4 Stufen zwischen beiden Gesellschaften; für die mittleren R-Zeigerwerte beträgt der Unterschied 0,4 Stufen.
Background: Acute leukemia in early age (EAL) is characterized by acquired genetic alterations such as MLL rearrangements (MLL-r). The aim of this case-controlled study was to investigate whether single nucleotide polymorphisms (SNPs) of IKZF1, ARID5B, and CEBPE could be related to the onset of EAL cases (<24 months-old at diagnosis).
Methods: The SNPs (IKZF1 rs11978267, ARID5B rs10821936 and rs10994982, CEBPE rs2239633) were genotyped in 265 cases [169 acute lymphoblastic leukemia (ALL) and 96 acute myeloid leukaemia (AML)] and 505 controls by Taqman allelic discrimination assay. Logistic regression was used to evaluate the association between SNPs of cases and controls, adjusted on skin color and/or age. The risk was determined by calculating odds ratios (ORs) with 95% confidence interval (CI).
Results: Children with the IKZF1 SNP had an increased risk of developing MLL-germline ALL in white children. The heterozygous/mutant genotype in ARID5B rs10994982 significantly increased the risk for MLL-germline leukemia in white and non-white children (OR 2.60, 95% CI: 1.09-6.18 and OR 3.55, 95% CI: 1.57-8.68, respectively). The heterozygous genotype in ARID5B rs10821936 increased the risk for MLL-r leukemia in both white and non-white (OR 2.06, 95% CI: 1.12-3.79 and OR 2.36, 95% CI: 1.09-5.10, respectively). Furthermore, ARID5B rs10821936 conferred increased risk for MLL-MLLT3 positive cases (OR 7.10, 95% CI:1.54-32.68). Our data do not show evidence that CEBPE rs2239633 confers increased genetic susceptibility to EAL.
Conclusions: IKZF1 and CEBPE variants seem to play a minor role in genetic susceptibility to EAL, while ARID5B rs10821936 increased the risk of MLL-MLLT3. This result shows that genetic susceptibility could be associated with the differences regarding MLL breakpoints and partner genes.
Many studies about endocrine pollution in the aquatic environment reveal changes in the reproduction system of biota. We analysed endocrine activities in two rivers in Southern Germany using three approaches: (1) chemical analyses, (2) in vitro bioassays, and (3) in vivo investigations in fish and snails. Chemical analyses were based on gas chromatography coupled with mass spectrometry. For in vitro analyses of endocrine potentials in water, sediment, and waste water samples, we used the E-screen assay (human breast cancer cells MCF-7) and reporter gene assays (human cell line HeLa-9903 and MDA-kb2). In addition, we performed reproduction tests with the freshwater mudsnail Potamopyrgus antipodarum to analyse water and sediment samples. We exposed juvenile brown trout (Salmo trutta f. fario) to water downstream of a wastewater outfall (Schussen River) or to water from a reference site (Argen River) to investigate the vitellogenin production. Furthermore, two feral fish species, chub (Leuciscus cephalus) and spirlin (Alburnoides bipunctatus), were caught in both rivers to determine their gonadal maturity and the gonadosomatic index. Chemical analyses provided only little information about endocrine active substances, whereas the in vitro assays revealed endocrine potentials in most of the samples. In addition to endocrine potentials, we also observed toxic potentials (E-screen/reproduction test) in waste water samples, which could interfere with and camouflage endocrine effects. The results of our in vivo tests were mostly in line with the results of the in vitro assays and revealed a consistent reproduction-disrupting (reproduction tests) and an occasional endocrine action (vitellogenin levels) in both investigated rivers, with more pronounced effects for the Schussen river (e.g. a lower gonadosomatic index). We were able to show that biological in vitro assays for endocrine potentials in natural stream water reasonably reflect reproduction and endocrine disruption observed in snails and field-exposed fish, respectively.
Background: Cichlid fishes show considerable diversity in swim bladder morphology. In members of the subfamily Etroplinae, the connection between anterior swim bladder extensions and the inner ears enhances sound transmission and translates into an improved hearing ability. We tested the hypothesis that those swim bladder modifications coincide with differences in inner ear morphology and thus compared Steatocranus tinanti (vestigial swim bladder), Hemichromis guttatus (large swim bladder without extensions), and Etroplus maculatus (intimate connection between swim bladder and inner ears).
Methodology and results: We applied immunostaining together with confocal imaging and scanning electron microscopy for the investigation of sensory epithelia, and high-resolution, contrast-enhanced microCT imaging for characterizing inner ears in 3D, and evaluated otolith dimensions. Compared to S. tinanti and H. guttatus, inner ears of E. maculatus showed an enlargement of all three maculae, and a particularly large lacinia of the macula utriculi. While our analysis of orientation patterns of ciliary bundles on the three macula types using artificially flattened maculae uncovered rather similar orientation patterns of ciliary bundles, interspecific differences became apparent when illustrating the orientation patterns on the 3D models of the maculae: differences in the shape and curvature of the lacinia of the macula utriculi, and the anterior arm of the macula lagenae resulted in an altered arrangement of ciliary bundles.
Conclusions: Our results imply that improved audition in E. maculatus is associated not only with swim bladder modifications but also with altered inner ear morphology. However, not all modifications in E. maculatus could be connected to enhanced auditory abilities, and so a potential improvement of the vestibular sense, among others, also needs to be considered. Our study highlights the value of analyzing orientation patterns of ciliary bundles in their intact 3D context in studies of inner ear morphology and physiology.
The World Wide Web is the largest information repository available today. However, this information is very volatile and Web archiving is essential to preserve it for the future. Existing approaches to Web archiving are based on simple definitions of the scope of Web pages to crawl and are limited to basic interactions with Web servers. The aim of the ARCOMEM project is to overcome these limitations and to provide flexible, adaptive and intelligent content acquisition, relying on social media to create topical Web archives. In this article, we focus on ARCOMEM’s crawling architecture. We introduce the overall architecture and we describe its modules, such as the online analysis module, which computes a priority for the Web pages to be crawled, and the Application-Aware Helper which takes into account the type of Web sites and applications to extract structure from crawled content. We also describe a large-scale distributed crawler that has been developed, as well as the modifications we have implemented to adapt Heritrix, an open source crawler, to the needs of the project. Our experimental results from real crawls show that ARCOMEM’s crawling architecture is effective in acquiring focused information about a topic and leveraging the information from social media.
Architektur und Albtraum : Erkundungen zu Horrorhäusern, Geisterstädten und metaphysischen Türmen
(2014)
Auf seiner Flucht aus dem Schreckenshaus seiner Ahnen träumt Clifford Pincheon (aus Nathaniel Hawthornes Roman The House of the Seven Gables von 1851) in der Eisenbahn von einem modernen Nomadentum, das einen vom Schicksal befreien könne: Statt sich zum "Gefangenen von Mauern, Backstein" zu machen, wird der Mensch der Zukunft "nirgends - oder besser - überall […] wohnen". Die Vision, sich vom konkreten Ort, von Geschichte zu befreien und gleichsam in der Zeit sesshaft zu werden, verwirklichte sich nicht allein in den silbernen, stromlinienförmigen Home-Trailern und Mobile Homes. Sie verwirklichte sich auf höherer Stufenleiter in den glänzend geschlossenen Spiegelglas-Türmen, die in den Machtzentren des Kapitals heute zunehmend dominieren. Die dunkel oder metallisch spiegelnden Türme wirken wie in heiliges Öl getaucht, rituell gesalbt, dabei jedoch nicht erhaben, sondern verführerisch, bezaubernd: Die fugenlos glatte, glitzernde Hülle aus Spiegelglas und Metall macht die Bauwerke zu Fetischen, phallischen Signifikanten, zu unsterblichen Ikonen einer Macht, deren innerstes Prinzip eine Ökonomie der Zeit ist. Das Kapital träumt seit je davon, sich vom irdischen Raum der Menschen zu befreien: Mit den Türmen - einer artifiziellen Raum-Enklave - gewinnt der Traum strahlend Gestalt. Hierin verdichtet sich gesellschaftlich und technologisch höchste Mobilität, erstarrt in reiner Gegenwart, der Zeitform der global players. Diese arbeiten an einem Schicksal, das jede Bindung an konkreten, irdischen Raum, an Familien und Völker, an vergangene Geschichte verloren hat. Das ist zweifellos unheimlich, doch auf ganz andere Art als das klassische Horrorhaus.