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Auxiliar-vermittelte Synthese von nicht-natürlichen Aminosäuren als Bausteine für RNA-Liganden (2005)

Verena Ludwig

In den letzten Jahren wurde deutlich, daß mRNAs regulatorische Elemente aufweisen.Ein Beispiel hierfür ist z. B. die Transkription des Human Immunodeficiency Virus Typ1 (HIV-1). Die Arginin-reiche Domäne des Tat-Proteins interagiert hierbei mit einer Bindungstelle innerhalb der Bulge-Region der TAR-RNA. Das Vorliegen des hochkonservierten Tat-TAR-Komplexes ist die Voraussetzung für die effiziente Transkription viraler Gene. Eine kompetitive Bindung synthetischer Liganden an die Bulge-Region sollte daher den viralen Vermehrungszyklus unterbrechen. Hochspezifische Liganden mit inhibitorischem Potential sind somit von größtem Interesse. Für eine hohe Liganden-Affinität sind neben ionischen Wechselwirkungen und HBrücken-Interaktionen vor allem auch Stapelwechselwirkungen (stacking) von entscheidender Bedeutung. Die Ligandensuche wurde auf Tripeptide fokussiert. Da die Anzahl natürlich vorkommender aromatischer Aminosäuren sehr limitiert ist,erfolgte im Rahmen dieser Arbeit zunächst eine stereoselektive Synthese von neuen,nicht-natürlichen Aminosäuren mit heteroaromatischen Seitenketten. Um den generellen Einsatz dieser Bausteine in kombinatorischen Bibliotheken zu demonstrieren,wurden zunächst Tripeptide des Musters Arg-X-Arg hergestellt. Bereits diese Tripeptide zeigten in einem Fluoreszenz-Assay inhibierende Effekte auf den Tat- TAR-Komplex von HIV-1 mit IC50-Werten von 2 - 80 µM. Diese vielversprechenden Liganden wiesen auch in einem Tat-TAR kontrollierten Reportergen-Assay stark inhibierende Wirkung in den Zellkulturen auf. Am Beispiel eines Peptides ließ sich mittels NMR-Spektroskopie eine Komplexkonformation bestimmen, die der des bekannten TAR-Argininamid-Komplexes entspricht. Durch den Einsatz von nichtnatürlichen und Standard-Aminosäuren in kombinatorischen Tripeptidbibliotheken (split and combine-Methode) konnte die Suche von potentiellen Peptid-Liganden um ein Vielfaches erweitert werden. Über ein on-bead-Screening ließen sich weitere vielversprechende TAR-bindende Tripeptide identifizieren. Die RNA-Ligandensuche wurde desweiteren auf die psi-RNA (HIV-1) und auf die mRNA des onkogenen bcr-abl Proteins ausgeweitet. Auch hier konnten einige RNA-bindende Tripeptide isoliert werden.

Cymantren- und Ferrocen-basierte Poly(pyrazol-1-yl)borate : Kation-Pi-Wechselwirkungen und Multidecker-Sandwichkomplexe (2005)

Alireza Haghiri Ilkhechi

Personal rights management (PRM) : enabling privacy rights in digital online media content (2005)

Lothar Fritsch Klaus Kursawe

With ubiquitous use of digital camera devices, especially in mobile phones, privacy is no longer threatened by governments and companies only. The new technology creates a new threat by ordinary people, who now have the means to take and distribute pictures of one’s face at no risk and little cost in any situation in public and private spaces. Fast distribution via web based photo albums, online communities and web pages expose an individual’s private life to the public in unpreceeded ways. Social and legal measures are increasingly taken to deal with this problem. In practice however, they lack efficiency, as they are hard to enforce in practice. In this paper, we discuss a supportive infrastructure aiming for the distribution channel; as soon as the picture is publicly available, the exposed individual has a chance to find it and take proper action.

Algebraic values of Schwarz triangle functions (2005)

Hironori Shiga Jürgen Wolfart

We consider Schwarz maps for triangles whose angles are rather general rational multiples of pi. Under which conditions can they have algebraic values at algebraic arguments? The answer is based mainly on considerations of complex multiplication of certain Prym varieties in Jacobians of hypergeometric curves. The paper can serve as an introduction to transcendence techniques for hypergeometric functions, but contains also new results and examples.

Kaonen-Produktion in C+C und Si+Si Kollisionen bei 40A und 158A GeV (2005)

Michael Kliemant

In dieser Arbeit wurde die Produktion geladener Kaonen in C+C und Si+Si- Kollisionen bei Strahlenergien von 40A und 158A GeV untersucht, die verwendeten Daten stammen vom CERN Experiment NA49. Die Kaonen wurden über den mittleren Energieverlust in den TPCs identifiziert, was die Messung der Phasenraumverteilung in einem großen Bereich möglich machte. Die Analyse basiert auf der dE/dx Auswertung aller NA49 TPCs (globale Analyse). Es wurde herausgefunden, dass bei den C+C und Si+Si Datensätzen die MTPC dE/dx Information unvollständig auf den DSTs gespeichert wurde. Da die Auflösung bei der Bestimmung des mittleren Energieverlusts beschränkt ist, ist die Teilchenidentifikation nur über statistische Methoden möglich. Im Kapitel 4 wird diese von Marco van Leeuwen mitentwickelte Methode beschrieben. Für die endgültigen Werte der Phasenraumverteilung der Teilchen müssen die identifizierten Kaonen noch auf Effekte korrigiert werden, die durch den Aufbau des Detektors und die verwendete Analysesoftware hervorgerufen werden. Die Korrekturen werden im Kapitel 5.4 beschrieben und angewandt, dies sind unter anderem geometrische Korrekturen, Akzeptanz und Zerfallskorrekturen. Die Ergebnisse bei 158A GeV wurden mit C.Höhnes Ergebnissen verglichen und stimmen im Rahmen der Fehler überein. Zur Übersicht wurden die Daten mit den anderen NA49-Daten zusammengefasst. Dabei ist zu erkennen dass die Verhältnisse < K+ > / < NW >, < K+ > / < + >, < K > / < NW > und < K > / < > im Bereich zwischen p+p und Si+Si schnell ansteigen und im weiterem Verlauf bis Pb+Pb kaum weiter ansteigen. Im Rahmen des Statistical Model of the Early Stage sind dies Anzeichen für einen Übergang in das Quark-Gluon-Plasma bei 40A GeV in Si+Si Kollisionen. Für eine Bestätigung dieser Vermutung sind jedoch weitere Messungen bei unterschiedlichen Energien und Systemen notwendig.

Hematopoietic chimerism after allogeneic stem cell transplantation: a comparison of quantitative analysis by automated DNA sizing and fluorescent in situ hybridization (2005)

Justyna Jólkowska Anna Pieczonka Tomasz Strabel Dariusz Boruczkowski Jacek Wachowiak Peter Bader Michal Witt

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed mainly in patients with high-risk or advanced hematologic malignancies and congenital or acquired aplastic anemias. In the context of the significant risk of graft failure after allo-HSCT from alternative donors and the risk of relapse in recipients transplanted for malignancy, the precise monitoring of posttransplant hematopoietic chimerism is of utmost interest. Useful molecular methods for chimerism quantification after allogeneic transplantation, aimed at distinguishing precisely between donor's and recipient's cells, are PCR-based analyses of polymorphic DNA markers. Such analyses can be performed regardless of donor's and recipient's sex. Additionally, in patients after sex-mismatched allo-HSCT, fluorescent in situ hybridization (FISH) can be applied. Methods: We compared different techniques for analysis of posttransplant chimerism, namely FISH and PCR-based molecular methods with automated detection of fluorescent products in an ALFExpress DNA Sequencer (Pharmacia) or ABI 310 Genetic Analyzer (PE). We used Spearman correlation test. Results: We have found high correlation between results obtained from the PCR/ALF Express and PCR/ABI 310 Genetic Analyzer. Lower, but still positive correlations were found between results of FISH technique and results obtained using automated DNA sizing technology. Conclusions: All the methods applied enable a rapid and accurate detection of post-HSCT chimerism.

Occupational risk of tuberculosis transmission in a low incidence area (2005)

Roland Diel Andreas Seidler Albert Nienhaus Sabine Rüsch-Gerdes Stefan Niemann

Background: To investigate the occupational risk of tuberculosis (TB) infection in a low-incidence setting, data from a prospective study of patients with culture-confirmed TB conducted in Hamburg, Germany, from 1997 to 2002 were evaluated. Methods: M. tuberculosis isolates were genotyped by IS6110 RFLP analysis. Results of contact tracing and additional patient interviews were used for further epidemiological analyses. Results: Out of 848 cases included in the cluster analysis, 286 (33.7%) were classified into 76 clusters comprising 2 to 39 patients. In total, two patients in the non-cluster and eight patients in the cluster group were health-care workers. Logistic regression analysis confirmed work in the health-care sector as the strongest predictor for clustering (OR 17.9). However, only two of the eight transmission links among the eight clusters involving health-care workers had been detected previously. Overall, conventional contact tracing performed before genotyping had identified only 26 (25.2%) of the 103 contact persons with the disease among the clustered cases whose transmission links were epidemiologically verified. Conclusion: Recent transmission was found to be strongly associated with health-care work in a setting with low incidence of TB. Conventional contact tracing alone was shown to be insufficient to discover recent transmission chains. The data presented also indicate the need for establishing improved TB control strategies in health-care settings.

Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas (2005)

Gunter von Minckwitz Sebastian Harder Sascha Hövelmann Elke Jäger Salah-Eddin Al-Batran Sibylle Loibl Akin Atmaca Christian Cimpoiasu Antje Neumann Aklil Abera Alexander Knuth Manfred Kaufmann Dirk Jäger Alexander B. Maurer Winfried S. Wels

Introduction: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients. Methods: We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 μg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks. Results: No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses ≥ 10 μg/kg). Disease progression occurred in 11 of the patients. Conclusion: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development.

The role of cGMP and PKG-I in spinal nociceptive processing (2005)

Achim Schmidtko Irmgard Tegeder Ellen Niederberger Franz Hofmann Peter Ruth Gerd Geisslinger

First paragraph (this article has no abstract) Persistent stimulation of nociceptors results in sensitization of nociceptive sensory neurons, which is associated with hyperalgesia and allodynia. The release of NO and subsequent synthesis of cGMP in the spinal cord are involved in this process. cGMP-dependent protein kinase I (PKG-I) has been suggested to act as a downstream target of cGMP, but its exact role in nociception hadn't been characterized yet. To further evaluate the NO/cGMP/PKG-I pathway in nociception we assessed the effects of PKG-I inhibiton and activaton in the rat formalin assay and analyzed the nociceptive behavior of PKG-I-/- mice. Open access article.

Opisthobranchia (Mollusca, Gastropoda) – more than just slimy slugs. Shell reduction and its implications on defence and foraging (2005)

Heike Wägele Annette Klussmann-Kolb

Background: In general shell-less slugs are considered to be slimy animals with a rather dull appearance and a pest to garden plants. But marine slugs usually are beautifully coloured animals belonging to the less-known Opisthobranchia. They are characterized by a large array of interesting biological phenomena, usually related to foraging and/or defence. In this paper our knowledge of shell reduction, correlated with the evolution of different defensive and foraging strategies is reviewed, and new results on histology of different glandular systems are included. Results: Based on a phylogeny obtained by morphological and histological data, the parallel reduction of the shell within the different groups is outlined. Major food sources are given and glandular structures are described as possible defensive structures in the external epithelia, and as internal glands. Conclusion: According to phylogenetic analyses, the reduction of the shell correlates with the evolution of defensive strategies. Many different kinds of defence structures, like cleptocnides, mantle dermal formations (MDFs), and acid glands, are only present in shell-less slugs. In several cases, it is not clear whether the defensive devices were a prerequisite for the reduction of the shell, or reduction occurred before. Reduction of the shell and acquisition of different defensive structures had an implication on exploration of new food sources and therefore likely enhanced adaptive radiation of several groups. © 2005 Wägele and Klussmann-Kolb; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited: http://www.frontiersinzoology.com/content/2/1/3/

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