Central morphisms and Cuspidal automorphic Representations

Let $F$ be a global field. Let $G$ and $H$ be two connected reductive group defined over $F$ endowed with an $F$-morphism $f: H\rightarrow G$ such that the induced morphism $H_{der}\rightarrow G_{der}$ on the derived groups is a central isogeny. Our main results yield in particular the following theorem: Given any irreducible cuspidal representation $\pi$ of $G(\mathbb A_F)$ its restriction to $H(\mathbb A_F)$ contains a cuspidal representation $\sigma$ of $H(\mathbb A_F)$. Conversely, assuming moreover that $f$ is an injection, any irreducible cuspidal representation $\sigma$ of $H(\mathbb A_F)$ appears in the restriction of some cuspidal representation $\pi$ of $G(\mathbb A_F)$. This theorem has an obvious local analogue

Molecular analysis of the cdk1/CCNB1 complex and characterization of cdk-inhibitors in neuroblastoma

Das Neuroblastom ist der häufigste solide extrakranielle Tumor bei Kindern. Er entwickelt sich aus Vorläuferzellen der Neuralleiste und kann sich entlang des sympathischen Grenzstranges entwickeln. Die Heilungschancen gerade bei Rezidivpatienten sind mit einer 20 % 5-Jahres-Überlebensrate ausgesprochen schlecht insbesondere bei Vorliegen einer MYCN Amplifikation. Deshalb ist es notwendig, neue Therapiemöglichkeiten zu entwickeln oder bestehende zu verbessern. Aus diesem Grunde wurde in dieser Arbeit nach möglichen Targets für weitere Therapieansätze gesucht. Dazu wurden vorhandene Exon-Array-Daten primärer NB reanalysiert und nach Genen gesucht, die mit einem schlechten Überleben der Patienten korrelieren. Bei MYCN handelt es sich um einen Transkriptionsfaktor, der mit einem sehr aggressiven Verlauf der Krankheit verknüpft ist. So wurden als mögliche Zielstrukturen die Zellzyklusregulatoren cdk1 und der dazugehörige Interaktionspartner Cyclin B1 identifiziert und standen hier im Fokus der Untersuchungen. Es konnte gezeigt werden, dass cdk1 und CCNB1 in den getesteten Neuroblastomzelllinien überexprimiert sind. Ein direkter Zusammenhang zwischen dem MYCN-Status und der cdk1 bzw. CCNB1 Expression konnte in den Zelllinien jedoch nicht bestätigt werden. Gerade in den letzten Jahrzehnten wurde massiv an neuen Inhibitoren geforscht, die sich gegen Enzyme des Zellzyklus richten. Zu diesen neu entwickelten Inhibitoren gehört auch der cdk1 spezifische Inhibitor (RO33 06) und der pan cdk-Inhibitor (JNJ-77706621). Die beiden Inhibitoren wurden in dieser Arbeit verwendet, um die cdk1 Aktivität zu hemmen und so cdk1 als potentielles Therapieziel zu validieren. Hierbei konnte ein Zusammenhang zwischen dem Effekt der Inhibitoren und dem p53 Status der Zellen festgestellt werden. Zellen mit einer p53 Mutation bzw. einem geringen p53 Level zeigten sich wesentlich resistenter gegenüber beiden Inhibitoren. Des Weiteren konnte eine Aktivierung des p53 Signalweges durch RO3306 in den p53 wt Zellen nachgewiesen werden. Ebenso konnte gezeigt werden, dass die durch RO3306 ausgelöste Apoptose durch Caspasen vermittelt wird. Weiterhin konnte in dieser Arbeit gezeigt werden, dass die duale Inhibition von cdk1 und dem NB-spezifischen Onkogen ALK unter definierten Bedingungen einen synergistischen Effekt auf die Zellviabilität haben kann. Abschließend lässt sich sagen, dass unter Berücksichtigung des p53 Status die cdk1-Inhibition als Therapieansatz im Neuroblastom denkbar wäre. Um eine endgültige Aussage darüber treffen zu können, müssten die generierten Ergebnisse in „in vivo“ Versuchen validiert werden.Neuroblastoma (NB) is the most solid extracranial tumor of childhood. It originates from precursors of the neural crest and normally arises along the sympathetic trunk in the abdomen or neck. The curing prospects of relapse patients are markedly bad with a 5-year-survival-rate of 20%. Disease recurrence frequently affects patients harboring specific MYCN gene amplification. Therefore it is necessary to develop new therapies or to optimize the old ones. To explore future therapy opportunities Exon Array data of primary NBs were reanalyzed for genes correlating with overall survival. By doing so, we identified master regulators of the cell cycle, cdk1 and the corresponding interaction partner Cyclin B1, as candidate genes. In this thesis it could be shown that cdk1 and CCNB1 were overexpressed in neuroblastoma cell lines. No correlation between cdk1 or CCNB1 expression and MYCN status could be confirmed in these cells. As novel cell cycle inhibitors were developed in recent years, both a cdk1 specific inhibitor (RO3306) as well as a pan cdk-inhibitor (JNJ-7706621) were used in this thesis to inhibit cdk1 activation and to evaluate cdk1 as potential target for NB therapy. Interestingly, sensitivity to inhibitor treatment correlated with the p53 status of the cells. Cells harboring p53 mutations or presenting with lower p53 levels were more resistant to the inhibitors than p53 wt cells. Additionally it was shown that RO3306 activated the p53 signaling pathway as well as caspase mediated apoptosis. Furthermore, it was shown that the dual inhibition of cdk1 and NB-specific oncogene ALK has synergistic effects on cell viability depending on inhibitor concentration and on the order of treatment administration. Taken together cdk1 inhibition warrants further investigations as therapeutic approach in neuroblastoma given that the p53 status is taken into account. These findings deserve validation in “in vivo” experiments

A note on boundary components of arithmetic quotients of the group SL2 over an algebraic number field

Given an algebraic number field k, we consider quotients XG/Γ associated with arithmetic subgroups Γ of the special linear algebraic k-group G = SL2. The group G is k-simple, of k-rank one, and split over k. The Lie group G∞ of real points of the Q-group Resk/Q(G), obtained by restriction of scalars, is the finite direct product G∞ = ∏v∈Vk,∞ = SL2(R)s × SL2(C)t, where the product ranges over the set Vk,∞ of all archimedean places of k, and s (resp. t) denotes the number of real (resp. complex) places of k. The corresponding symmetric space is denoted by XG. Using reduction theory, one can construct an open subset YΓ ⊂ XG/Γ such that its closure YΓ is a compact manifold with boundary ∂YΓ, and the inclusion YΓ → XG/Γ is a homotopy equivalence. The connected components Y[P] of the boundary ∂YΓ are in one-to-one correspondence with the finite set of Γ-conjugacy classes of minimal parabolic k-subgroups of G. We are concerned with the geometric structure of the boundary components. Each component carries the natural structure of a fibre bundle. We prove that the basis of this bundle is homeomorphic to the torus Ts+t-1 of dimension s + t - 1, has the compact fibre Tm of dimension m = s + 2t = [k : Q], and its structure group is SLm(Z). Finally, we determine the cohomology of Y[P]

A stochastic simulation model to determine the sample size of repeated national surveys to document freedom from bovine herpesvirus 1 (BoHV-1) infection

<p>Abstract</p> <p>Background</p> <p>International trade regulations require that countries document their livestock's sanitary status in general and freedom from specific infective agents in detail provided that import restrictions should be applied. The latter is generally achieved by large national serological surveys and risk assessments. The paper describes the basic structure and application of a generic stochastic model for risk-based sample size calculation of consecutive national surveys to document freedom from contagious disease agents in livestock.</p> <p>Methods</p> <p>In the model, disease spread during the time period between two consecutive surveys was considered, either from undetected infections within the domestic population or from imported infected animals. The @Risk model consists of the domestic spread in-between two national surveys; the infection of domestic herds from animals imported from countries with a sanitary status comparable to Switzerland or lower sanitary status and the summary sheet which summed up the numbers of resulting infected herds of all infection pathways to derive the pre-survey prevalence in the domestic population. Thereof the pre-survey probability of freedom from infection and required survey sample sizes were calculated. A scenario for detection of infected herds by general surveillance was included optionally.</p> <p>Results</p> <p>The model highlights the importance of residual domestic infection spread and characteristics of different import pathways. The sensitivity analysis revealed that number of infected, but undetected domestic herds and the multiplicative between-survey-spread factor were most correlated with the pre-survey probability of freedom from infection and the resulting sample size, respectively. Compared to the deterministic pre-cursor model, the stochastic model was therefore more sensitive to the previous survey's results. Undetected spread of infection in the domestic population between two surveys gained more importance than infection through animals of either import pathway.</p> <p>Conclusion</p> <p>The model estimated the pre-survey probability of freedom from infection accurately as was shown in the case of infectious bovine rhinotracheitis (IBR). With this model, a generic tool becomes available which can be adapted to changing conditions related to either importing or exporting countries.</p

Emil Artin und Helmut Hasse: Die Korrespondenz 1923–1934 Edited by Günther Frei and Peter Roquette, with contributions of Franz Lemmermeyer. Göttingen (Universitätsverlag Göttingen). 2008. ISBN 978-3-940344-50-2. 499 pp.

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