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Orthotopic bladder cancer xenografts are essential for testing novel therapies and molecular manipulations of cell lines in vivo. Current xenografts rely on tumor cell inoculation by intravesical instillation or direct injection into the bladder wall. Instillation is limited by the lack of cell lines that are tumorigenic when delivered in this manner. The invasive model inflicts morbidity on the mice by the need for laparotomy and mobilization of the bladder. Furthermore this procedure is complex and time-consuming. Three bladder cancer cell lines (UM-UC1, UM-UC3, UM-UC13) were inoculated into 50 athymic nude mice by percutaneous injection under ultrasound guidance. PBS was first injected between the muscle wall and the mucosa to separate these layers, and tumor cells were subsequently injected into this space. Bioluminescence and ultrasound were used to monitor tumor growth. Contrast-enhanced ultrasound was used to study changes in tumor perfusion after systemic gemcitabine/cisplatin treatment. To demonstrate proof of principle that therapeutic agents can be injected into established xenografts under ultrasound guidance, oncolytic virus (VSV) was injected into UM-UC3 tumors. Xenograft tissue was harvested for immunohistochemistry after 23–37 days. Percutaneous injection of tumor cells into the bladder wall was performed efficiently (mean time: 5.7 min) and without complications in all 50 animals. Ultrasound and bioluminescence confirmed presence of tumor in the anterior bladder wall in all animals 3 days later. The average tumor volumes increased steadily over the study period. UM-UC13 tumors showed a marked decrease in volume and perfusion after chemotherapy. Immunohistochemical staining for VSV-G demonstrated virus uptake in all UM-UC3 tumors after intratumoral injection. We have developed a novel method for creating orthotopic bladder cancer xenograft in a minimally invasive fashion. In our hands this has replaced the traditional model requiring laparotomy, because this model is more time efficient, more precise and associated with less morbidity for the mice.
Natural killer (NK) cells are highly specialized effectors of the innate immune system that hold promise for adoptive cancer immunotherapy. Their cell killing activity is primarily mediated by the pro-apoptotic serine protease granzyme B (GrB), which enters targets cells with the help of the pore-forming protein perforin. We investigated expression of a chimeric GrB fusion protein in NK cells as a means to augment their antitumoral activity. For selective targeting to tumor cells, we fused the epidermal growth factor receptor (EGFR) peptide ligand transforming growth factor α (TGFα) to human pre-pro-GrB. Established human NKL natural killer cells transduced with a lentiviral vector expressed this GrB-TGFα (GrB-T) molecule in amounts comparable to endogenous wildtype GrB. Activation of the genetically modified NK cells by cognate target cells resulted in the release of GrB-T together with endogenous granzymes and perforin, which augmented the effector cells' natural cytotoxicity against NK-sensitive tumor cells. Likewise, GrB-T was released into the extracellular space upon induction of degranulation with PMA and ionomycin. Secreted GrB-T fusion protein displayed specific binding to EGFR-overexpressing tumor cells, enzymatic activity, and selective target cell killing in the presence of an endosomolytic activity. Our data demonstrate that ectopic expression of a targeted GrB fusion protein in NK cells is feasible and can enhance antitumoral activity of the effector cells.
Despite numerous large-scale phylogenomic studies, certain parts of the mammalian tree are extraordinarily difficult to resolve. We used the coding regions from 19 completely sequenced genomes to study the relationships within the super-clade Euarchontoglires (Primates, Rodentia, Lagomorpha, Dermoptera and Scandentia) because the placement of Scandentia within this clade is controversial. The difficulty in resolving this issue is due to the short time spans between the early divergences of Euarchontoglires, which may cause incongruent gene trees. The conflict in the data can be depicted by network analyses and the contentious relationships are best reconstructed by coalescent-based analyses. This method is expected to be superior to analyses of concatenated data in reconstructing a species tree from numerous gene trees. The total concatenated dataset used to study the relationships in this group comprises 5,875 protein-coding genes (9,799,170 nucleotides) from all orders except Dermoptera (flying lemurs). Reconstruction of the species tree from 1,006 gene trees using coalescent models placed Scandentia as sister group to the primates, which is in agreement with maximum likelihood analyses of concatenated nucleotide sequence data. Additionally, both analytical approaches favoured the Tarsier to be sister taxon to Anthropoidea, thus belonging to the Haplorrhine clade. When divergence times are short such as in radiations over periods of a few million years, even genome scale analyses struggle to resolve phylogenetic relationships. On these short branches processes such as incomplete lineage sorting and possibly hybridization occur and make it preferable to base phylogenomic analyses on coalescent methods.
Neuronal activity differs between wakefulness and sleep states. In contrast, an attractor state, called self-organized critical (SOC), was proposed to govern brain dynamics because it allows for optimal information coding. But is the human brain SOC for each vigilance state despite the variations in neuronal dynamics? We characterized neuronal avalanches – spatiotemporal waves of enhanced activity - from dense intracranial depth recordings in humans. We showed that avalanche distributions closely follow a power law – the hallmark feature of SOC - for each vigilance state. However, avalanches clearly differ with vigilance states: slow wave sleep (SWS) shows large avalanches, wakefulness intermediate, and rapid eye movement (REM) sleep small ones. Our SOC model, together with the data, suggested first that the differences are mediated by global but tiny changes in synaptic strength, and second, that the changes with vigilance states reflect small deviations from criticality to the subcritical regime, implying that the human brain does not operate at criticality proper but close to SOC. Independent of criticality, the analysis confirms that SWS shows increased correlations between cortical areas, and reveals that REM sleep shows more fragmented cortical dynamics.
Bücher und Zeitschriften, aber auch weitere Materialien wie Zeitungen, Notendrucke, Autographen und anderes gehören seit Jahrhunderten zum Bestand wissenschaftlicher Bibliotheken und sind gleichzeitig Objekte für Lehre und Forschung. Sie zu sammeln, zu erschließen und den Interessierten zugänglich zu machen, war und ist die Aufgabe von Bibliotheken. Nun befinden wir uns heute jedoch in einer Zeit des fundamentalen Wandels. Von Vielen wird er als Paradigma beschrieben, welches dadurch gekennzeichnet ist, dass die Welt der gedruckten Texte und Bilder (Gutenberg-Galaxis) abgelöst wird von einer digitalen Welt (Turing-Galaxis), in der Information nicht mehr an einen und schon gar nicht analogen Träger gebunden ist. In der Folge der Entwicklung des Internets sind in den letzten zwei Jahrzehnten mit Suchmaschinen und "Discovery Systemen", mit elektronischen Zeitschriften und ebensolchen Büchern, mit Hypertexten und dem "Semantic Web" Strukturen entstanden, denen eines gemeinsam ist. Ihre informationellen Inhalte sind nicht mehr an ein physisches Objekt gebunden, sie sind nicht mehr lokalisierbar und von daher im Prinzip von überall her und zu jeder Zeit nutzbar. ...
Paging is one of the prominent problems in the field of on-line algorithms. While in the deterministic setting there exist simple and efficient strongly competitive algorithms, in the randomized setting a tradeoff between competitiveness and memory is still not settled. Bein et al. [4] conjectured that there exist strongly competitive randomized paging algorithms, using o(k) bookmarks, i.e. pages not in cache that the algorithm keeps track of. Also in [4] the first algorithm using O(k) bookmarks (2k more precisely), Equitable2, was introduced, proving in the affirmative a conjecture in [7].
We prove tighter bounds for Equitable2, showing that it requires less than k bookmarks, more precisely ≈ 0.62k. We then give a lower bound for Equitable2 showing that it cannot both be strongly competitive and use o(k) bookmarks. Nonetheless, we show that it can trade competitiveness for space. More precisely, if its competitive ratio is allowed to be (Hk + t), then it requires k/(1 + t) bookmarks.
Our main result proves the conjecture that there exist strongly competitive paging algorithms using o(k) bookmarks. We propose an algorithm, denoted Partition2, which is a variant of the Partition algorithm byMcGeoch and Sleator [13]. While classical Partition is unbounded in its space requirements, Partition2 uses θ(k/ log k) bookmarks. Furthermore, we show that this result is asymptotically tight when the forgiveness steps are deterministic.
Recht und die Vorstellung von dem, was Recht ist, sind nicht allein an Territorien oder Herrschaften gebunden, sondern wandern mit den Menschen mit. Treffen mehrere möglicherweise anwendbare Rechte aufeinander, steht für heutige Gerichte ein Kollisionsrecht wie das Internationale Privatrecht bereit, dass über den Umgang mit diesem Konflikt entscheidet , indem es den Fall einer bestimmten nationalstaatlichen Regelung unterstellt. Andere Lösungen sind jedoch ebenfalls denkbar und wurden in der Vergangenheit auch praktiziert, was heute schwer nachzuvollziehen ist. Um die Denkstruktur und Grenzen der modernen Herangehensweise deutlich werden zu lassen, sollen in diesem Beitrag die Schwierigkeiten erläutert werden, das Konzept des Internationalen Privatrechts auf das Neben- und Miteinander verschiedener rechtlicher Traditionen im hellenistischen Ägypten zu übertragen. Ziel ist es, auch Nichtjuristen damit einen Einstieg und eine Übersicht über die Diskussion innerhalb der antiken Rechtsgeschichte zu ermöglichen.
This thesis presents various algorithms which have been developed for on-line event reconstruction in the CBM experiment at GSI, Darmstadt and the ALICE experiment at CERN, Geneve. Despite the fact that the experiments are different — CBM is a fixed target experiment with forward geometry, while ALICE has a typical collider geometry — they share common aspects when reconstruction is concerned.
The thesis describes:
— general modifications to the Kalman filter method, which allows one to accelerate, to improve, and to simplify existing fit algorithms;
— developed algorithms for track fit in CBM and ALICE experiment, including a new method for track extrapolation in non-homogeneous magnetic field.
— developed algorithms for primary and secondary vertex fit in the both experiments. In particular, a new method of reconstruction of decayed particles is presented.
— developed parallel algorithm for the on-line tracking in the CBM experiment.
— developed parallel algorithm for the on-line tracking in High Level Trigger of the ALICE experiment.
— the realisation of the track finders on modern hardware, such as SIMD CPU registers and GPU accelerators.
All the presented methods have been developed by or with the direct participation of the author.
2008 konnte erstmals in der Erft ein überwinterndes Vorkommen von Pistia stratiotes beobachtet werden, das sich seitdem immer weiter ausbreitet, in der Erft und in angrenzenden Gewässern dichte Massenbestände ausbildet und die Gewässeroberfläche teilweise vollständig bedeckt. Die Bestände blühen reichlich von Juni bis in den November hinein und bilden viele Samen aus, die eine hohe Keimungsrate aufweisen. Aufgrund der bereits bestehenden Problematik der Beschattung ganzer Nebengewässer und Seitenarme und des durch die Verdriftung von Pflanzen und Samen in den Rhein bestehenden hohen Ausbreitungspotenzials der Art für den Rhein und angrenzende Gewässer erscheint ein Management der Art notwendig.
The way we perceive the visual world depends crucially on the state of the observer. In the present study we show that what we are holding in working memory (WM) can bias the way we perceive ambiguous structure from motion stimuli. Holding in memory the percept of an unambiguously rotating sphere influenced the perceived direction of motion of an ambiguously rotating sphere presented shortly thereafter. In particular, we found a systematic difference between congruent dominance periods where the perceived direction of the ambiguous stimulus corresponded to the direction of the unambiguous one and incongruent dominance periods. Congruent dominance periods were more frequent when participants memorized the speed of the unambiguous sphere for delayed discrimination than when they performed an immediate judgment on a change in its speed. The analysis of dominance time-course showed that a sustained tendency to perceive the same direction of motion as the prior stimulus emerged only in the WM condition, whereas in the attention condition perceptual dominance dropped to chance levels at the end of the trial. The results are explained in terms of a direct involvement of early visual areas in the active representation of visual motion in WM.
Language and transnationalism : language discourse in transnational Salsa communities of practice
(2013)
Language ideologies in contemporary Western societies are characterised by a strong influence of the idea that one language ‘pertains’ to one culture. Yet, cultural developments of globalisation, such as migration, the construction of transnational networks or global mass media, question national frameworks of culture and language.
In this thesis, after reviewing the field of language ideology and discussing historical examples of the development of national language discourse, language ideologies in a transnational context are examined. Using ethnographic research methods and a discursive approach to interview data, concepts and ideas revolving around language of transnational Communities of Practice constituted through Salsa dancing are analysed. Due to its connections to the Latin American cultural space, the practice of Salsa dancing in non-Latin contexts intrinsically constructs transnational ties. Different Salsa Communities of Practice are studied in Sydney, Australia, and Frankfurt, Germany. Interestingly, different local communities show very different ideologies concerning the role of language, multilingualism, concepts of authenticity or influences of capitalist discourse. The cross-national approach allows studying the influence of different national discourses on the formation of local ideologies in transnational contexts.
Thus, next to scrutinising the traditional concept of a ‘language’ and its relevance in a transnational age, the theoretical aim of this study is to analyse the interaction of discourses from different realms – local, regional, national, transnational – in the formation of contemporary discourses on language. These construct new symbolic meanings of language that co-exist next to the national concept of the relationship of language and culture, so that a multiplication of language boundaries can be considered to be a characteristic trait of contemporary language discourse.
Die in diesem Aufsatz entfaltete Analyse der kurzen Passage aus Vitruvs Traktat (VI, praef., 1), die eine erbauliche Anekdote über schiffbrüchigen Philosophen Aristippus darstellt und dabei eine sinngeladene plastisch-symbolische Bildlichkeit in sich verhüllt, erlaubt festzustellen, dass ein die klassisch-antiken ästhetischen Äußerungen bestimmendes Prinzip der Statuarität auch dort seine entscheidende Rolle spielt.
Bibliotheken sind im Erwerbungsalltag mit einer Vielzahl unterschiedlichster Lizenzverträge für die Beschaffung von elektronischen Medien konfrontiert. Dabei nimmt die Komplexität durch das Anwachsen der Zahl der Marktteilnehmer aus Buchhandel und Agenturen, Verlagen und auch der verschiedenen Konsortien sowohl auf nationaler als auch auf internationaler Ebene wie durch die immer größer werdende Vielzahl der Produkte und Lizenzmodelle ständig zu. Die Transaktionskosten bei der Lizenzierung neuer Produkte, aber auch die Aktivitäten zur Verlängerung bestehender Lizenzverträge, steigen proportional mit der Zunahme der Bedeutung und Gewichtung, die elektronische Medienangebote einnehmen. Geschäftsgangmodelle, die ein Verfahren ohne Reibungsverluste garantieren, sind nicht vorhanden - wenn denn ein entsprechendes Problembewusstsein für die Bedeutung und den Wirkungsgrad bestimmter Lizenzvertragsklauseln existiert. Aufgrund der prinzipiell vorhandenen Vertragsfreiheit steht es den Partnern im Grunde frei, einen Vertrag entsprechend den Wünschen und Vorstellungen auszuhandeln. Dies wird in bestimmten Fällen von Vorteil sein, wenn es sich z.B. um Verträge von Konsortien mit Produkteanbietern handelt. Wie aber verhält es sich mit individuell abzuschließenden Lizenzverträgen einzelner Institutionen, z.B. beim Nachkauf von E-Books oder Ergänzungen von weiteren Datenbankprodukten des gleichen Anbieters. In vielen Fällen ist jedesmal ein Lizenzvertrag neu abzuschließen, wobei die minutiöse Lektüre aller Klauseln dringend angeraten sei. Hier würde sich anbieten, den Geschäftsverkehr der Vertragspartner zu vereinfachen, wenn nur schon die Vertragstexte soweit standardisiert wären, dass einheitliche Definitionen und Formulierungen für die einzelnen Regelungspunkte Verwendung fänden und lediglich Sonderabsprachen oder -vereinbarungen als Addenda beizufügen wären.
Vascular endothelial growth factors (VEGFs), initially thought to act specifically on the vascular system, exert trophic effects on neural cells during development and adulthood. Therefore, the VEGF system serves as a promising therapeutic target for brain pathologies, but its simultaneous action on vascular cells paves the way for harmful side effects. To circumvent these deleterious effects, many studies have aimed to clarify whether VEGFs directly affect neural cells or if the effects are mediated secondarily via other cell types, like vascular cells. A great number of reports have shown the expression and function of VEGF receptors (VEGFRs), mainly VEGFR-1 and -2, in neural cells, where VEGFR-2 has been described as the major mediator of VEGF-A signals. This review aims to summarize and compare the divergent roles of VEGFR-1 and -2 during CNS development and homeostasis.
"PULS." – a blog-based online-magazine for students of medicine of the Goethe University Frankfurt
(2013)
In the context of nationwide protests 2009 also students of the faculty of medicine/dentistry at Goethe-University in Frankfurt demanded more transparency and communication. To satisfy these demands, a web 2.0-tool offered an innovative solution: A blog-based online-magazine for students and other faculty-members. The online-magazine "PULS." is realized with the share-ware blog-software (wordpress version 3.1.3) and is conceived and written by an online-journalist. "PULS." is available from https://newsmagazin.puls.med.uni-frankfurt.de/wp/. The articles are generated from own investigations and from ideas of different groups of the faculty– deanship, students and lecturers. A user-analysis is conducted with the open-source software Piwik and considers the data security. Additionally, every year an anonymous online-user-survey (Survey Monkey) is conducted. "PULS." is continuously online since 14.02.2010 and has published 806 articles (state: 27.11.2012) and has about 2400 readers monthly. The content focuses on the needs of Frankfurt medical students. The close cooperation with different groups of the faculty - deanship, students and lecturers - furthermore guarantees themes relevant to the academic faculty. "PULS." flanks complex projects and decisions with background-information and communicates them understandable. The user-evaluation shows a growing number of readers and a high acceptance for the online-magazine, its themes and its style. The web 2.0-tool "Blog" and the web-specific language comply with media habits of the main target group, the students of the faculty medicine/dentistry. Thus, "PULS." has proven as a suitable and strategic instrument. It pushes towards a higher transparency, more communication and a stronger identification of the students with their faculty.
"PULS." - Ein Blog als Online-Magazin für Medizinstudierende der Goethe-Universität Frankfurt
(2013)
Im Herbst 2009 forderten Studierende im Rahmen landesweiter Proteste auch am Fachbereich Medizin/Zahnmedizin der Goethe-Universität Frankfurt mehr Transparenz und Kommunikation zu Angelegenheiten ihres Studiums. Einen innovativen Lösungsansatz, um diesen Forderungen nachzukommen, bietet eines der Web 2.0 Werkzeuge: ein auf einer Blog-Software basierendes Online-Magazin für Studierende und andere Mitglieder des Fachbereichs.
Das öffentlich zugängliche Online-Magazin "PULS." (https://newsmagazin.puls.med.uni-frankfurt.de/wp/) wird mit einer freien Blog-Software (wordpress Version 3.1.3.) realisiert und von einer Online-Redakteurin konzipiert und geschrieben. Die Beiträge entstehen nach eigenen Recherchen sowie aus Anregungen und Gesprächen mit verschiedenen Personengruppen des Fachbereichs. Die datenschutzkonforme Auswertung der Zugriffe erfolgt über eine open-source Webanalyse-Software (Piwik). Zusätzlich werden jährlich mit dem Online-Umfrage-Tool Survey Monkey die Nutzer anonym befragt.
"PULS." ist seit dem 14.02.2010 ununterbrochen online und hat seitdem 806 Beiträge (Stand: 27.11.2012) publiziert und wird von ca. 2400 Besuchern monatlich gelesen. Das Themenspektrum ist zentriert auf die Anliegen der Frankfurter Medizin- und Zahnmedizinstudierenden. Die enge Zusammenarbeit mit verschiedenen Gruppierungen des Fachbereichs – Dekanat, Studierende und Lehrende – garantiert darüber hinaus ein fachbereichs-relevantes Themenspektrum. Das Online-Magazin begleitet komplexe Projekte und Entscheidungen mit Hintergrundinformationen und kommuniziert sie verständlich. Eine jährliche Nutzer-Evaluierung zeigt eine wachsende Leserzahl und eine sehr hohe Zustimmung für das Online-Magazin, seine Inhalte und seinen Stil. Das Web 2.0-Medium "Blog" und seine web-typische Sprache entsprechen dem Medienverhalten der Zielgruppe, d.h. den Studierenden des Fachbereichs Medizin.
"PULS." hat sich als ein geeignetes und strategisches Instrument erwiesen, um größere Transparenz, mehr Kommunikation und letztendlich eine stärkere Identifikation der Studierenden mit ihrem Fachbereich voranzutreiben.
he Influence of trehalose-based glycolipids in the virulence of Mycobacterium tuberculosis (Mtb) is recognised; however, the actual role of these cell-wall glycolipids in latent infection is unknown. As an initial approach, we determined by two-dimensional thin-layer chromatography the sulfolipid (SL) and diacyltrehalose/polyacyltrehalose (DAT/PAT) profile of the cell wall of hypoxic Mtb. Then, qRT-PCR was extensively conducted to determine the transcription profile of genes involved in the biosynthesis of these glycolipids in non-replicating persistent 1 (NRP1) and anaerobiosis (NRP2) models of hypoxia (Wayne model), and murine models of chronic and progressive pulmonary tuberculosis. A diminished content of SL and increased amounts of glycolipids with chromatographic profile similar to DAT were detected in Mtb grown in the NRP2 stage. A striking decrease in the transcription of mmpL8 and mmpL10 transporter genes and increased transcription of the pks (polyketidesynthase) genes involved in SL and DAT biosynthesis were detected in both the NRP2 stage and the murine model of chronic infection. All genes were found to be up-regulated in the progressive disease. These results suggest that SL production is diminished during latent infection and the DAT/PAT precursors can be accumulated inside tubercle bacilli and are possibly used in reactivation processes.