422 research outputs found
Bose-Einstein Correlations in e+e- Annihilation
No full textContains fulltext :
53734_bosecoine.pdf (Publisher’s version ) (Open Access)
Contains fulltext :
71953.pdf (Publisher’s version ) (Open Access)Radboud Universiteit, Experimental High Energy Physics, 04 september 2008Promotores : Kittel, E.W., Csorgo, T. Co-promotores : Metzger, W.J., Jong, S.J. de, Buschbeck, B., Wolf, E.A. deIV, 135 p
Untersuchungen zur Regulierung und Funktion der Mitogen-aktivierten Proteinkinase ERK5 = Regulation and Function of the Mitogen-activated Protein Kinase ERK5
No full textMitogen activated protein kinases (MAPKs) are found in all eukaryotic cells and represent crucial elements in the signal transduction from the plasma membrane to the nucleus. Although a broad variety of extracellular stimuli activate MAPKs, they evoke very distinct cellular responses. The amplitude and duration of MAPK activation determine signal identity and ultimately cell fate. A tight and finely tuned regulation is therefore critical for a specific cellular response. The role and the regulation of extracellular signal-regulated kinase 5 (ERK5), a MAPK with a large and unique C-terminal tail, were studied in different cellular systems. The study highlights two aspects of ERK5 regulation: control of the phosphorylation state and regulated protein stability. In analogy to other MAPKs ERK5 is activated by dual phosphorylation of threonine and tyrosine residues in its activation motif. A first part of the study concentrates on whether and how the protein tyrosine phosphatase PTP-SL is involved in the downregulation of the ERK5 signal. The direct interaction of both proteins is shown to result in mutual modulation of their enzymatic activities. PTP-SL is a substrate of ERK5 and, independent of its phosphorylation, binding to the kinase enhances its catalytic phosphatase activity. On the other hand, interaction with PTP-SL does not only downregulate enzymatic ERK5 activity but also effectively impedes its translocation to the nucleus. The second part of this study focuses on the interaction of ERK5 with c-Abl and its oncogenic variants Bcr/Abl and v-Abl. In this study these tyrosine kinases are demonstrated to regulate ERK5 by two mechanisms: first, by induction of kinase activity and secondly, by stabilisation of the ERK5 protein. Stabilisation involves the direct interaction of unique ERK5 domains with Abl kinases and is independent of MAPK cascade activation. The level of ERK5 and its intrinsic basal activity – rather than its activation – are essential for v-Abl-induced transformation as well as for survival of Bcr/Abl-positive leukaemia cells. Stabilisation of ERK5 thus contributes to cell survival and should therefore be considered as an additional aspect in therapy of chronic myeloid leukaemia. Taken together, the results obtained in this study demonstrate that diverse pathways regulate ERK5 signalling by affecting kinase activity, localisation and protein stability. While the phosphatase PTP-SL is involved in negative regulation of ERK5, Abl kinases potently activate ERK5 and increase its half-life. Protein stabilisation thus is presented as a novel mechanism in the regulation of MAPKs.Mitogen-aktivierte Proteinkinasen (MAPKn) werden in allen eukaryontischen Zellen exprimiert und spielen eine bedeutende Rolle in der Weiterleitung von Signalen von der Plasmamembran zum Zellkern. Obwohl eine Vielzahl von unterschiedlichsten Stimulanzien MAPKn aktiveren, rufen diese doch sehr spezifische und vor allem adequate Reaktionen der Zelle hervor. Die molekularen Grundlagen für dieses Pradoxon sind weitgehend unbekannt. Es ist allerdings klar, daß die Amplitude und die Dauer der MAPKn-Aktivierung zwei entscheidende Parameter sind, die den weiteren Signalweg definieren und somit das Schicksal der Zelle festlegen. Daher müssen MAPKn einer sehr stringenten und fein regulierbaren Kontrolle unterliegen. In der vorliegenden Arbeit wurde die Funktion und die Regulierung der durch extrazelluläre Signale regulierten Kinase 5 (ERK5), einer MAPK mit einem außergewöhnlich langen und strukturell einzigartigen C-Terminus, in unterschiedlichen Zellsystemen untersucht. Zwei Aspekte der Regulierung von ERK5 werden insbesonders hervorgehoben: die Kontrolle des Phosphorilierungsstatus und die beeinflußbare Proteinstabilität. In Analogie zu anderen MAPKs wird ERK5 durch die Phosphorilierung eines Threonin und eines Tyrosinrestes aktiviert. Der erste Teil dieser Studie konzentriert sich auf die Frage ob und wie die Phosphatase PTP-SL und der Regulierung der ERK5 beteiligt sein könnte. Es konnte gezeigt werden, daß die direkte Interaktion dieser beiden Proteine zur gegenseitigen Beeinflussung ihrer enzymatischen Aktivitäten führt. PTP-SL ist nicht nur ein Substrat für die ERK5 sondern besitzt auch im Komplex mit ERK5 eine höhere Aktivität. Andererseits ist PTP-SL in der Lage, die Aktivität von ERK5 runterzuregulieren und darüber hinaus auch die Translokation von ERK5 in den Nucleus zu inhibieren. Der zweite Scherpunkt dieser Arbeit liegt auf der Wechselwirkung von ERK5 mit der Tyrosinkinasen c-Abl und ihren onkogenen Varianten Bcr/Abl und v-Abl. Es konnte gezeigt werden, daß diese Tyrosinkinasen ERK5 in zweierlei Weise beeinflussen: Erstens führen sie zur klassischen Aktivierung von ERK5 und zweitens stabilisieren sie das ERK5-Protein. Die Bedeutung der Proteinstabilisierung wurde durch die Untersuchung der Funktion von ERK5 bei von Abl-Kinase vermittelten Prozessen veranschaulicht. Sowohl für die Vestärkung Transformierung von Nagerfibroblasten durch v-Abl als auch für das Überleben von Bcr/Abl-positiven Leukämiezellen waren die Proteinmenge und die Basalaktivität und nicht etwa die Aktivierung von ERK5 ausschlaggebend. Zusammengenommen zeigen die Ergebnisse dieser Arbeit, daß die ERK5-vermittelte Signale durch Beeinflussung der Kinaseaktivität, der zellulären Lokalisation und der Proteinstabilität von ERK5 reguliert werden können. Während die Phosphatase PTP-SL an der Negativregulierung der ERK5 beteiligt ist, verstärken Abl-Kinasen ihre Aktivität und verlängern darüberhinaus die Halbwertszeit des Proteines in der Zelle. Proteinstabilisierung stellt somit einen neuen Aspekt in der Kontrolle von MAPKn dar
Barcelona conference on epigenetics and cancer 2016 – beyond cancer genomes
No full textThe Barcelona Conference on Epigenetics and Cancer (BCEC) entitled “Beyond Cancer Genomes” took place October 13th and 14th 2016 in Barcelona. The 2016 BCEC was the fourth edition of a series of annual conferences coordinated by Marcus Buschbeck and subsequently organized by leading research centers in Barcelona together with B•DEBATE, a joint initiative of BIOCAT and “La Caixa” Foundation. Salvador Aznar-Benitah, Eduard Batlle, and Raúl Méndez from the Institute for Research in Biomedicine in Barcelona selected the 2016 BCEC panel of speakers. As the title indicates, this year's conference expanded the epigenetic focus to include additional cancer-relevant topics, such as tumor heterogeneity and RNA regulation. Methods to develop therapeutic approaches on the basis of novel insights have been discussed in great detail. The conference has attracted 217 participants from 11 countries
The consequences of cohesin mutations in myeloid malignancies
No full textThe author(s) declare financial support was received for the research, authorship, and/or publication of this article. SB and ED are funded by the Marie Skłodowska Curie Training network 'INTERCEPT-MDS' H2020-MSCA-ITN-2020-953407. Research in the Buschbeck lab is further supported by the following grants: the national grant PID 2021-126907NB-I00 from FEDER/Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación, AGAUR 2021-SGR-260, Fundació La Marató de TV3 257/C/2019 and PRYGN222668BUSC from the Fundación AECC. Research at the IJC is supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya.Recurrent somatic mutations in the genes encoding the chromatin-regulatory cohesin complex and its modulators occur in a wide range of human malignancies including a high frequency in myeloid neoplasms. The cohesin complex has a ring-like structure which can enclose two strands of DNA. A first function for the complex was described in sister chromatid cohesion during metaphase avoiding defects in chromosome segregation. Later studies identified additional functions of the cohesin complex functions in DNA replication, DNA damage response, 3D genome organisation, and transcriptional regulation through chromatin looping. In this review, we will focus on STAG2 which is the most frequently mutated cohesin subunit in myeloid malignancies. STAG2 loss of function mutations are not associated with chromosomal aneuploidies or genomic instability. We hypothesize that this points to changes in gene expression as disease-promoting mechanism and summarize the current state of knowledge on affected genes and pathways. Finally, we discuss potential strategies for targeting cohesion-deficient disease cells
Measurement of the rate of b anti-b b anti-b events in hadronic Z decays and the extraction of the gluon splitting into b anti-b
No full textThe rate was measured using about hadronic decays collected by the DELPHI experiment in 1994 and 1995. Events were forced into 3-jets with and a b-tag was required for every jet. The rate was measured to be: where the invariant mass of every system is above twice the b quark mass. Using the value of the probability of secondary production of a pair from a gluon per hadronic decay, , was extracted and found to be:
Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency
No full textInduced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming “boosters” also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency
In goldenen Lettern. Gebetete Inschriftlichkeit im Spätmittelalter
No full textDer „Liber specialis gratiae“, der ab ungefähr 1290 im Zisterzienserinnenkloster Helfta als Sammlung der Visionen und Offenbarungen Mechthilds von Hackeborn verfasst wurde, berichtet im 42. Kapitel seines ersten Buches von einer wundersamen Inschriftenerscheinung.1 Denn Mechthild, so erzählt der Text, habe sich während einer Marienmesse mit dem innigen Wunsch an die Heilige Jungfrau gewandt, sie doch mit einem Gruß anrufen zu können, quam unquam humanum cor excogitavit (Liber, S. 126). Gleichsam als Erhörung dieser Bitte um übermenschliche Perfektion im Gebet sei ihr daraufhin Maria erschienen, auf deren Brust in goldenen Buchstaben die gewünschten Worte prangten: habens in pectore scriptam aureis litteris Angelicam salutationem (Liber, S. 126.)
Study of gluon fragmentation and colour octet neutralization in DELPHI
No full textUsing the full statistics of the DELPHI experiment at 3-jet events are selected and gluon respectively quark jet enriched subsamples are defined. The leading systems of the two kinds of jets are determined using rapidity gaps. The sum of charges of the leading systems is studied. It is found that for gluon-jets there is a significant excess of leading systems with total charge zero when compared to Monte Carlo simulations with JETSET. The corresponding leading systems of quark-jets do not exhibit such an excess. The mass spectra of the leading systems with total charge zero are studied.Using the full statistics of the DELPHI experiment at 3-jet events are selected and gluon respectively quark jet enriched subsamples are defined. The leading systems of the two kinds of jets are determined using rapidity gaps. The sum of charges of the leading systems is studied. It is found that for gluon-jets there is a significant excess of leading systems with total charge zero when compared to Monte Carlo simulations with JETSET. The corresponding leading systems of quark-jets do not exhibit such an excess. The mass spectra of the leading systems with total charge zero are studied
Internal Cumulants for Femtoscopy with Fixed Charged Multiplicity
No full textA detailed understanding of all effects and influences on higher-order correlations is essential. At low charged multiplicity, the effect of a non-Poissonian multiplicity distribution can significantly distort correlations. Evidently, the reference samples with respect to which correlations are measured should yield a null result in the absence of correlations. We show how the careful specification of desired properties necessarily leads to an average-of-multinomials reference sample. The resulting internal cumulants and their averaging over several multiplicities fulfill all requirements of correctly taking into account non-Poissonian multiplicity distributions as well as yielding a null result for uncorrelated fixed-N samples. Various correction factors are shown to be approximations at best. Careful rederivation of statistical variances and covariances within the frequentist approach yields errors for cumulants that differ from those used so far. We finally briefly discuss the implementation of the analysis through a multiple event buffer algorithm
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