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The nuclear modification factor, RAA, of the prompt charmed mesons D0, D+ and D∗+, and their antiparticles, was measured with the ALICE detector in Pb-Pb collisions at a centre-of-mass energy sNN−−−√=2.76 TeV in two transverse momentum intervals, 5<pT<8 GeV/c and 8<pT<16 GeV/c, and in six collision centrality classes. The RAA shows a maximum suppression of a factor of 5-6 in the 10% most central collisions. The suppression and its centrality dependence are compatible within uncertainties with those of charged pions. A comparison with the RAA of non-prompt J/ψ from B meson decays, measured by the CMS Collaboration, hints at a larger suppression of D mesons in the most central collisions.
Die Sowjetunion unter Stalin war ein Ort, an dem Terror und Gewalt herrschten, in der öffentlichen Propaganda aber wurde sie zeitgleich als Hort der "Brüderlichkeit" und "Völkerfreundschaft" inszeniert. Die Kulturpolitik jener Jahre zielte auf eine sowjetweite Repräsentation der nationalen Kulturen und die Etablierung einer "multinationalen" Sowjetliteratur bzw. Sowjetkultur. Ungeachtet der ideologischen Gleichschaltung war das Arsenal von Figuren des Nationalen keineswegs für alle gleich, sondern hing von den jeweiligen geschichtlichen und (religions-)kulturellen Traditionen der einzelnen Völker ab. Am Beispiel Georgiens lassen sich kulturelle Phänomene - wie etwa die Kolchis, das georgische Pantheon nationaler Heroen oder die Figur des mittelalterlichen Dichters Šota Rust'aveli - als "Figuren des Nationalen im Sowjetimperium" untersuchen. Georgien ist nicht nur deshalb ein interessantes Beispiel, weil Stalins Heimat in den offiziellen Diskursen viel Aufmerksamkeit erhielt. Die georgische Kultur - und damit gleichsam die Sowjetkultur generell - ließ sich auch durch ihre weit in die Vergangenheit zurückreichende kulturelle Tradition als eine besonders alte Kultur inszenieren.
Charged jet production cross sections in p–Pb collisions at √sNN=5.02 TeV measured with the ALICE detector at the LHC are presented. Using the anti-kT algorithm, jets have been reconstructed in the central rapidity region from charged particles with resolution parameters R=0.2 and R=0.4. The reconstructed jets have been corrected for detector effects and the underlying event background. To calculate the nuclear modification factor, RpPb, of charged jets in p–Pb collisions, a pp reference was constructed by scaling previously measured charged jet spectra at s=7 TeV. In the transverse momentum range 20≤pT,chjet≤120 GeV/c, RpPb is found to be consistent with unity, indicating the absence of strong nuclear matter effects on jet production. Major modifications to the radial jet structure are probed via the ratio of jet production cross sections reconstructed with the two different resolution parameters. This ratio is found to be similar to the measurement in pp collisions at √s=7 TeV and to the expectations from PYTHIA pp simulations and NLO pQCD calculations at √sNN=5.02 TeV.
The elliptic flow, v2, of muons from heavy-flavour hadron decays at forward rapidity (2.5<y<4) is measured in Pb–Pb collisions at √sNN=2.76 TeV with the ALICE detector at the LHC. The scalar product, two- and four-particle Q cumulants and Lee–Yang zeros methods are used. The dependence of the v2 of muons from heavy-flavour hadron decays on the collision centrality, in the range 0–40%, and on transverse momentum, pT, is studied in the interval 3<pT<10 GeV/c. A positive v2 is observed with the scalar product and two-particle Q cumulants in semi-central collisions (10–20% and 20–40% centrality classes) for the pT interval from 3 to about 5 GeV/c with a significance larger than 3σ, based on the combination of statistical and systematic uncertainties. The v2 magnitude tends to decrease towards more central collisions and with increasing pT. It becomes compatible with zero in the interval 6<pT<10 GeV/c. The results are compared to models describing the interaction of heavy quarks and open heavy-flavour hadrons with the high-density medium formed in high-energy heavy-ion collisions.
Unraveling the activation mechanism of taspase1 which controls the oncogenic AF4–MLL fusion protein
(2015)
We have recently demonstrated that Taspase1-mediated cleavage of the AF4–MLL oncoprotein results in the formation of a stable multiprotein complex which forms the key event for the onset of acute proB leukemia in mice. Therefore, Taspase1 represents a conditional oncoprotein in the context of t(4;11) leukemia. In this report, we used site-directed mutagenesis to unravel the molecular events by which Taspase1 becomes sequentially activated. Monomeric pro-enzymes form dimers which are autocatalytically processed into the enzymatically active form of Taspase1 (αββα). The active enzyme cleaves only very few target proteins, e.g., MLL, MLL4 and TFIIA at their corresponding consensus cleavage sites (CSTasp1) as well as AF4–MLL in the case of leukemogenic translocation. This knowledge was translated into the design of a dominant-negative mutant of Taspase1 (dnTASP1). As expected, simultaneous expression of the leukemogenic AF4–MLL and dnTASP1 causes the disappearance of the leukemogenic oncoprotein, because the uncleaved AF4–MLL protein (328 kDa) is subject to proteasomal degradation, while the cleaved AF4–MLL forms a stable oncogenic multi-protein complex with a very long half-life. Moreover, coexpression of dnTASP1 with a BFP-CSTasp1-GFP FRET biosensor effectively inhibits cleavage. The impact of our findings on future drug development and potential treatment options for t(4;11) leukemia will be discussed.
Intrinsically disordered protein (IDP) duplexes composed of two IDP chains cross-linked by bivalent partner proteins form scaffolds for assembly of multiprotein complexes. The N-terminal domain of dynein intermediate chain (N-IC) is one such IDP that forms a bivalent scaffold with multiple dynein light chains including LC8, a hub protein that promotes duplex formation of diverse IDP partners. N-IC also binds a subunit of the dynein regulator, dynactin. Here we characterize interactions of a yeast ortholog of N-IC (N-Pac11) with yeast LC8 (Dyn2) or with the intermediate chain-binding subunit of yeast dynactin (Nip100). Residue level changes in Pac11 structure are monitored by NMR spectroscopy, and binding energetics are monitored by isothermal titration calorimetry (ITC). N-Pac11 is monomeric and primarily disordered except for a single α-helix (SAH) at the N terminus and a short nascent helix, LH, flanked by the two Dyn2 recognition motifs. Upon binding Dyn2, the only Pac11 residues making direct protein-protein interactions are in and immediately flanking the recognition motifs. Dyn2 binding also orders LH residues of Pac11. Upon binding Nip100, only Pac11 SAH residues make direct protein-protein interactions, but LH residues at a distant sequence position and L1 residues in an adjacent linker are also ordered. The long distance, ligand-dependent ordering of residues reveals new elements of dynamic structure within IDP linker regions.
Emerging evidence indicates that protein synthesis and degradation are necessary for the remodeling of synapses. These two processes govern cellular protein turnover, are tightly regulated, and are modulated by neuronal activity in time and space. The anisotropic anatomy of the neurons presents a challenge for the study of protein turnover, but the understanding of protein turnover in neurons and its modulation in response to activity can help us to unravel the fine-tuned changes that occur at synapses in response to activity. Here we review the key experimental evidence demonstrating the role of protein synthesis and degradation in synaptic plasticity, as well as the turnover rates of specific neuronal proteins.
Background: Tumor associated macrophages (TAMs) are known to support tumor progression and their accumulation is generally associated with poor prognosis. The shift from a tumor-attacking to a tumor-supportive macrophage phenotype is based on an educational program that, at least in part, is initiated by apoptotic tumor cells.
Aims: We explored the macrophage phenotype shift during tumor progression by analyzing the macrophage NO-output system and examining potential NO targets.
Methods: Biochemical and Molecular Biology-orientated cell culture experiments, in part using 3d-tumor spheroid models as well as animal experiments were used.
Results: Apoptotic cells polarize macrophages towards a healing, tumor-supportive phenotype. Soluble mediators released from apoptotic cells, among them the lipid sphingosine-1-phosphate (S1P), cause expression of arginase 2 in macrophages, thereby lowering citrulline/NO formation but enhancing ornithine production. Mechanistically, this is achieved via the S1P2 receptor and the CRE (cAMP-response element) binding site in the arginase 2 promoter. Reduced NO-formation is also seen in ex vivo macrophages from a xenograft model allowing restricted vs. unrestricted tumor growth based on tumor-associated S1P-formation. The theoretical ability of NO to target hypoxia-inducible factor-1 (HIF-1) and jumonji histone demethylases (JHDMs) in cells of the tumor microenvironment will be discussed in light of the iNOS/arginase balance. Moreover, data on the importance of HIF-1 in macrophages for their interaction with tumor cells, polarization, and angiogenic potential will be presented.
Conclusions: We hypothesize that apoptotic death of tumor cells and associated macrophage activation facilitates the progression of malignant disease. The macrophage polarization program affects the NO-output system and the capacity of macrophages to support or restrict tumor growth.
Combination chemotherapy with gemcitabine and cisplatin in patients with metastatic urothelial cancer of the bladder frequently results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance could help to identify candidate treatments for an efficient second-line therapy. Six cisplatin- and six gemcitabine-resistant cell lines were established. Cell viability assays were performed to evaluate the sensitivity to 16 different chemotherapeutic substances. The activity of the drug transporter ATP-binding cassette transporter, subfamily B, member 1 (ABCB1, a critical mediator of multidrug resistance in cancer) was evaluated using fluorescent ABCB1 substrates. For functional assessment, cells overexpressing ABCB1 were generated by transduction with a lentiviral vector encoding for ABCB1, while zosuquidar was used for selective inhibition. In this study, 8 of 12 gemcitabine- or cisplatin-resistant cell lines were cross-resistant to carboplatin, 5 to pemetrexed, 4 to methotrexate, 3 to oxaliplatin, 5-fluorouracil, and paclitaxel, and 2 to cabazitaxel, larotaxel, docetaxel, topotecan, doxorubicin, and mitomycin c, and 1 of 12 cell lines was cross-resistant to vinflunine and vinblastine. In one cell line with acquired resistance to gemcitabine (TCC-SUPrGEMCI20), cross-resistance seemed to be mediated by ABCB1 expression. Our model identified the vinca alkaloids vinblastine and vinflunine, in Europe an already approved second-line therapeutic for metastatic bladder cancer, as the most effective compounds in urothelial cancer cells with acquired resistance to gemcitabine or cisplatin. These results demonstrate that this in vitro model can reproduce clinically relevant results and may be suitable to identify novel substances for the treatment of metastatic bladder cancer.
We present an angular thin-lens formula giving the angle of refraction β for arbitrary values of the angle of incidence α. With this formula, we find analytical results for the focal length f of a thin-lens system. The number of lenses n and their focal lengths f1,f2,…,fn are abitrary, as are the mutual distances D12,…,D(n−1)n between the lenses. All these results are exact, i.e. not restricted to small or even paraxial angles. In the literature, the 2-lens and 3-lens versions (the last one without proof or derivation) are known [1]. We present the general result for n lenses and for (the positions of) its principal planes.