111 research outputs found
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
Can multiparticle correlations be described by present analytical QCD calculations?
No full textPrevious experimental studies of various correlation functions in angular intervals and their comparison with QCD calculations are summarized. A good description is only obtained for a globally normalized function (r). The hypothesis of local parton hadron duality (LPHD) seems to be well fulfilled in this case. For all differentially normalized functions, however, several disagreements are observed and the validity of LPHD is in question. It is argued (using Monte Carlo calculations) that LPHD could still be valid also in this case - after improving the perturbative QCD calculations. Only after the inclusion of full energy-momentum conservation in the calculations one will have a better handle to estimate, how far non- perturbative effects are spoiling the agreement with the data. (14 refs)
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:
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
Analysis of a hardware random number generator considering cryptographic capabilities
No full textDie vorliegende Masterarbeit baut auf eine Bachelorarbeit [Ren22a, Ren22b] aus dem Studiengang „Angewandte Elektronik“ auf, in welcher ein Zufallszahlengenerator-Prototyp entwickelt wurde, der im Vergleich zu anderen Zufallszahlengeneratoren ein deutlich besseres Preis-/Leistungs-Verhältnis aufweist. Da Zufallszahlen in der Kryptografie eine essenzielle Rolle für die Datensicherheit z. B. bei Verschlüsselungen übernehmen, ist der Einsatz qualitativ hochwertig Zufallszahlen erforderlich. Andernfalls werden statistische Angriffe, auch gegen den besten Algorithmus, möglich.
Forschungsziel der vorliegenden Arbeit war es, zu beantworten, ob der vorhandene Zufallszahlengenerator die Ansprüche für den Einsatz im kryptografischen Umfeld erfüllt. In dieser Arbeit wurden folglich die getroffenen Designentscheidungen in Bezug auf Effektivität überprüft und es wurde eine Testserie durchgeführt, um die Einsatzbereitschaft des Prototyps sowohl unter Normalbedingungen als auch unter besonderen Umständen zu kontrollieren.
Die Auswertung der erhobenen Daten zeigt, dass der vorgelegte Prototyp im aktuellen Zustand nicht in der Lage ist, echte Zufallszahlen zu erzeugen. Dies ist dem Umstand geschuldet, dass Rauschgeneratoren nicht immer fehlerfrei funktionieren und dass die Güte der produzierten Zufallszahlen von der Umgebungstemperatur beeinflusst werden kann. Zur Behebung der gefundenen (Design-)Mängel wurde eine Liste mit Vorschlägen ausgearbeitet und postuliert.This master’s thesis is based on a bachelor’s thesis [Ren22a, Ren22b] from the course „Applied Electronics“, in which a random number generator prototype with a significantly better price/performance ratio compared to other random number generators was developed. Since random numbers in cryptography play an essential role in data security, for instance, through encryption, the use of high-quality random numbers is essential. Otherwise, statistical attacks, even against the best algorithms, become possible.
This thesis aims to answer whether the present random number generator fulfils the requirements for implementation in a cryptographic environment. Accordingly, the present work reviews the design decisions for their effectiveness and conducts an active test series to verify the operability of the prototype under both normal conditions and special circumstances.
The evaluation of the collected data shows that the prototype is incapable of generating true random numbers in its current condition. This is because not all noise generators function without errors. Furthermore, all noise generators can be influenced by their surroundings temperature in terms of the quality of the random numbers they produce. To remedy the (design) deficiencies found, a list of suggestions is developed and postulated.Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersMasterarbeit Wien, FH Campus Wien 202
Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival
No full textAltres ajuts: This work was supported in part by a grant from [...] and a grant from Celgene Spain. Research in the Buschbeck and Zamora labs is further supported by the following grants: [...] the Deutsche José Carreras Leukämie Stiftung DJCLS 14R/2018 (to MB);[...] and Fundació La Marató de TV3 254/C/2019 (to MB). Research at the IJC is supported by the "La Caixa" Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and[...].Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival
A search for rare B meson decays at the CERN S p anti-p S collider
No full textWe report on a search for the decays B0 --> mu+mu-, B --> mu+mu-X and B(d)0 --> mu+mu-K0*, which are expected to be rare if mediated by flavor changing neutral currents. Using data collected during the 1984-1989 CERN ppBAR Collider runs, the UA1 search was carried out using mu+mu- events with 3.9 mu+mu- of 8.3 x 10(-6), for B --> mu+mu-X of 5.0 x 10(-5), and for B(d)0 --> mu+mu-K0* of 2.3 x 10(-5). Implications for upper limits on the t-quark mass are discussed
Multidimensional HBT correlations in proton-antiproton collisions at root(s) = 630 GeV
No full textPlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected] Vir Teoretiese Fisik
Transverse-longitudinal HBT correlations in p over(p, ̄) collisions at sqrt(s) = 630 GeV
No full textCorrelations of like-sign pion pairs emerging from proton-antiproton collisions are analysed in the two-dimensional ( qL, qT ) decomposition of the three-momentum difference q. While the data cannot be adequately represented by Gaussian, exponential, power-law or Edgeworth parametrisations, more elaborate ones such as Lévy and an exponential with a cross term do better. A two-scale model using a hard cut to separate small and large scales may indicate a core that is more prolate than the halo. Consideration not only of the interference peak at small ( qL, qT ), but also of the shape of the correlation distribution at intermediate momentum differences is crucial to understanding the data. © 2006 Elsevier B.V. All rights reserved.Articl
First observation of the beauty baryon LAMBDA(b) in the decay channel LAMBDA(b) ---> J / psi LAMBDA at the CERN proton - anti-proton collider
No full textWe report on the first observation of the beauty baryon LAMBDA(b) in an exclusive decay channel at the CERN ppBAR collider. Using 4.7 pb-1 of muon data collected in the 1988/89 collider runs we reconstruct 16 +/- 5 LAMBDA(b)'s in the decay mode LAMBA(b) --> J/psi-LAMBDA above a background of 9 +/- 1 events, corresponding to a significance of about five standard deviations. We measure the LAMBDA(b) mass to be m(LAMBDA(b)) = 5640 +/- 50 +/- 30 MeV/c2. Using the beauty cross-section measured by UA1 we deduce for the product of the production fraction and branching ratio f(LAMBDA(b)) Br(LAMBDA(b) --> J/psi-LAMBDA) = (1.8 +/- 1.0) X 10(-3). Our sample contains a three-muon event in which the beauty particle opposite to the LAMBDA(b)BAR is tagged by the third muon. We also observe an indication of a signal in the decay channel B0 --> J/psi-K0* with a significance of three standard deviations
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