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Das klarzellige Nierenzellkarzinom (RCC) ist bei eier Inzidenz von 9 / 100 000 vor allem gekennzeichnet durch seine hohe Mortalität. Die Ursache dafür ist multifaktoriell, eine späte Diagnose, lokal fortgeschrittenes Wachstum, Fernmetastasierung und das Fehlen einer suffizienten Chemo-, bzw. Immunotherapie spielen eine entscheidende Rolle. Der Mangel an therapeutischen Optionen erfordert weitergehende Forschungsmaßnahmen zur Aufklärung der Tumormetastasierungsstrategien und zur Entwicklung antitumoraler Therapien. Migration und Extravasation werden als essentielle Parameter des Metastasierungsprozesses beschrieben. In einem modellhaft geschaffenen Metastasierungsszenario wurde das dynamische Verhalten von Integrinrezeptoren bei der Adhäsion von Tumorzellen am Gefäßendothel oder der Matrix beobachtet. Zu diesem Zweck wurden mehrere Nierentumorzelllinien, teilweise auch unter Blockade- oder Stimulationsbedingungen, diesem Interaktionsprozess ausgesetzt. Die Zellen wurden in biologischen Assays, fluorometrisch, mittels konfokaler Laserscanmikroskopie und mikrobiologisch auf der RNA-, der Protein- und der zellulären Ebene bezüglich Veränderungen von Protoonkogenen, Tumorsuppressoren und Adhäsionsmolekülen untersucht. Der Nachweis auf RNA-Ebene erfolgte mittels PCR, auf der Protein-Ebene mit Hilfe von Western-Hybridisierung und Durchflusszytometrie. Ferner wurden im Rahmen dieser Arbeit funktionelle Adhäsionsstudien und Verdrängungsassays auf Endothelzellen und Matrixproteinen durchgeführt, um mögliche Unterschiede der Malignität in Bezug auf das Migrationsverhalten der Nierentumorzellen aufzuzeigen. Dabei konnte erstmalig eine transiente Integrinrezeptorreduktion auf Nierentumorzellen nach Kontakt zum Endothel mit einer sich anschließenden Re-Expression nachgewiesen werden. Für einen umschriebenen Zeitraum wird die Zell-Zell- und Zell-Matrix-Adhäsion der Tumorzellen reduziert. Dieser Adhäsionsverlust ist verbunden mit einem schnellen und reversiblen Verlust der Integrin-Subtypen α2β1, α3β1 und α5β1. Begleitend wurde eine reduzierte Expression intrazellulärer Signalkaskadenproteine wie PKCδ, PKCε, PKCγ, MEK1, ERK1, p38, p38 phosph., JNKphosph., JNK und RACK1 beobachtet. Zusammen scheinen diese Prozesse in eine dynamische Tumorzell-Migrationsstrategie involviert zu sein. Mutmaßlich spielen die dynamischen und reversiblen Veränderungen des Integrin Rezeptorprofils eine wichtige Rolle im Bereich der Tumorzellinvasion, indem die Zellen von einem adhäsiven Zustand weg, hin zu einem motilen und invasiven Status transformiert werden. Eine einzelne Zelle kann sich so im Sinne einer Metastase aus dem initialen Tumoraggregat loslösen, ein gleiches Phänomen für die Migration der Tumorzellen aus dem Gefäßsystem in das Zielgewebe wird vermutet. Allerdings muss besonders herausgestellt werden, dass die Dynamik der transendothelialen Invasion auch integrin-unabhängige Phasen beinhaltet, die ganz offensichtlich für eine zielgerichtete Motilität verantwortlich ist. Während dieser Interaktion von Tumorzellen mit Zellen des Gefäßsystems konnten außerdem morphologische Veränderungen der Tumorzellen im Sinne eines Entdifferenzierungsprozesses beobachtet werden. Der Auslöser dieses Effektes ist durch weitere Forschungsaktivitäten zu klären. Aufgrund der multifunktionalen Wirkungsweise der Integrinrezeptoren erscheint als therapeutisches Ziel die Wiederherstellung der ursprünglichen, physiologischen Integrinbalance anzustreben. Weniger die Expressionsdichte eines einzelnen Integrintyps, als vielmehr die Balance, respektive Dysbalance mehrerer Integrin-Untereinheiten reguliert Zell-Zell und Zell-Matrix Interaktionen und trägt dadurch zur Prävention der Disseminierung des lokal fortgeschrittenen bzw. metastastasierten Nierenzellkarzinomes bei.
Die Dissertation befasste sich mit der endsteinzeitlichen und früheisenzeitlichen Besiedlungsgeschichte des südwestlichen Tschadbeckens (NO-Nigerias) mit einem Schwerpunkt auf dem Übergang zwischen beiden Perioden. Neben einer Ãœbersicht über die geborgenen Funde und die dokumentierten Befunde aus Grabungsarbeiten an sieben Fundstellen wurde eine Sequenz der Keramikmerkmale vorgelegt. Unter anderem verdeutlichte sie die Gegensätze der endsteinzeitlichen und füheisenzeitlichen Keramiktraditionen im Arbeitsgebiet. Der Schwerpunkt der Studien lag auf der Präsentation von Ergebnissen archäologischer und geophysikalischer Untersuchungen des Fundplatzes Zilum, datiert in die Mitte des ersten Jahrtausends BC. Zilum ist wegen seines Alters, seiner Dimension und seiner strukturellen Komplexität von zentraler Bedeutung für die Archäologie der Region um den Tschadsee und für Afrika südlich der Sahara im Allgemeinen. Zusammen mit jenen Siedlungen, die nach dieser entstanden, bietet der Fundplatz einen guten Ansatz zur Beantwortung der Frage, wie sich der Übergang von der Steinzeit zur Eisenzeit im Untersuchungsraum vollzog. Er gibt zudem einen Einblick in die Entstehung früher, strukturell und sozioökonomisch komplexerer Siedlungsformen in Afrika südlich der Sahara, und so wird seine Bedeutung für die Archäologie und Geschichte eingehender diskutiert. Aus der Kombination vorhandener und neu gesammelter Informationen zur Siedlungs- und Wirtschaftsweise mit bereits verfügbaren Daten zur Entwicklung von Klima und Umwelt im Tschadbecken wurde ein Abriss der endsteinzeitlichen und früheisenzeitlichen Besiedlungsgeschichte im Untersuchungsraum erarbeitet.
The present study consists of two parts: The first part is made up of questions concerning the cognitive underpinnings of auditory verbal hallucinations in schizophrenia. As this thesis framed schizophrenia as a multivariate problem, neural correlates to auditory verbal and visual hallucinations were investigated in the second part. The main finding is that vividness of mental imagery was increased in all putative high-risk groups as well as the patients themselves, compared with low-schizotypy controls. Therefore, it seems that vivid imagery is a trait rather than a state marker, and may be related to the genetic liability to develop schizophrenia. However, no evidence was found for a linear relationship between vividness of mental imagery and predisposition to hallucinate. Self-reported imagery vividness and predisposition to hallucinate did not depend on psychomotor speed or intelligence. In addition, individual psychopathology ratings did not correlate significantly with the mental imagery scores. Furthermore, the analysis of the control orientation and the degree of dysfunctional psychopathological status across the schizophrenia spectrum, showed an independence of control orientation and dysfunctional status from each other, as well as from other markers of schizophrenia or schizophrenic-like individuals. As a conclusion, external control orientation seems to be a symptom or a trait marker of schizophrenia. The results lead to the assumption that, beside schizophrenic individuals, first-degree relatives and schizotypy controls have some impairments and visible signs without suffering from the illness directly. This would lead to the further assumption that the illness schizophrenia is not only genetic but also dependent on environmental factors. In the second part of the study, we investigated anatomical and functional brain abnormalities in the schizophrenia patients compared with first-degree relatives and healthy controls. Here, the results followed the continuum of healthy controls, first-degree relatives and schizophrenic patients in the functional and anatomical data sets, and in the language lateralization. The decrease of lateralisation correlated with the severity of symptoms in the patient group. The investigation of visual hallucinations showed activity in higher visual areas during the experience of visual hallucinations in a schizophrenia patient and in a blindfolded subject. The activity in higher visual areas followed the boundaries of category-selective areas in both subjects. In contrast to the memory-related areas found in the schizophrenic patient experiencing visual hallucinations, we did not observe memory-related areas during visual hallucinations induced by blindfolding. This suggests that the neural mechanisms underlying hallucinations in schizophrenia are at least partly distinct from those operational in cortical deafferentation. It is proposed that individual differences in psychopathology, as well as neuropsychological and psychosocial functioning may provide further means to understand the complex and highly dynamic aspects of hallucinations specifically and schizophrenia in general. The enlargement of the subject sample to high-schizotypy controls and first-degree relatives of patients allowed new insights into the mental imagery debate and the dysfunctional connectivity pattern known to be responsible for psychotic symptoms. Further topics of research are discussed.
In der Sekundärliteratur und in Rezensionen rekurriert man mit regelmäßigem Vergnügen auf Dr. Johnsons berühmtes Verdikt über Tristram Shandy, das der zeitgenössische Biograph James Boswell in seinem Life of Samuel Johnson dem englischen Gelehrten zuschreibt: „Nothing odd will do long. Tristram Shandy did not last." Sieht man davon ab, dass die Anbringung dieses Zitates heute oft mehr dem ironischen Nachweis, dass auch ein eminenter Kritiker sich irren kann, als einem spezifischen Interesse an der Langlebigkeit von Laurence Sternes Hauptwerk geschuldet ist, bleibt dennoch festzuhalten, dass der Satz repräsentativ für einen Großteil der Reaktionen steht, die Tristram Shandy in den vergangenen zweieinhalb Jahrhunderten seit seiner sukzessiven Erstveröffentlichung in neun zwischen 1759 und 1767 erschienenen Bänden hervorgerufen hat. „Sterne ist der grosse Meister der Zweideutigkeit", konstatiert schon Nietzsche: „Der Leser ist verloren zu geben, der jederzeit genau wissen will, was Sterne eigentlich über eine Sache denkt, ob er bei ihr ein ernsthaftes oder ein lächelndes Gesicht macht." Was Nietzsche als den Freigeist des Autors lobte, war für andere Anlass zu moralischer wie auch intellektueller Entrüstung - ein überzeitliches Phänomen, das sich nicht auf sittenstrenge Epochen wie den Viktorianismus eingrenzen lässt. Als Ursache der immer wieder geäußerten Kritik sind ohne große Spekulation der exzentrische, stellenweise derbe Humor sowie die nicht-lineare Erzählstruktur auszumachen, die den Leser daran hindert, den Plot unmittelbar zu erschließen. Noch 1961 sieht sich Bowman Piper in seinem Artikel „Tristram Shandy's Digressive Artistry" veranlasst, die These, dass Tristram seine narrativen Digressionen bewusst und kontrolliert einsetzt, gegen die Ansichten jener zu verteidigen, die die Abschweifungen der Erzählerfigur als Ausdruck von deren kurzer Aufmerksamkeitsspanne oder anderer psychologischer Dispositionen und mentaler Schwächen lesen.
The Na+,K+-ATPase was discovered more than 50 years ago, but even today the pumpcycle and its partial reactions are still not completely understood. In this thesis, Voltage Clamp Fluorometry was used to monitor the conformational changes that are associated with several electrogenic partial reactions of the Na+,K+-ATPase. The conformational dynamics of the ion pump were analyzed at different concentrations of internal Na+ or of external K+ and the influences on the conformational equilibrium were determined. To probe the effect of the internal Na+ concentration on the Na+ branch of the ion pump, oocytes were first depleted of internal Na+ and then loaded with Na+ using the epithelial sodium channel which can be blocked by amiloride. The conformational dynamics of the K+ branch were studied using different external K+ concentrations in the presence and in the absence of external Na+ to yield additional information on the apparent affinity of K+. The results of our Voltage Clamp Fluorometry experiments demonstrate that lowering the intracellular concentration of Na+ has a comparable effect on the conformational equilibrium as increasing the amount of K+ in the external solution. Both of these changes shift the equilibrium towards the E1/E1(P) conformation. Furthermore, it can be shown that the ratio between external Na+ and K+ ions is also a determinant for the position of the conformational equilibrium: in the absence of external Na+, the K+ dependent shift of the equilibrium towards E1 was observed at a much lower K+ concentration than in the presence of Na+. In addition, indications were found that both external K+ and internal Na+ bind within an ion well. Finally, the crucial role of negatively charged glutamate residues in the 2nd extracellular loop for the control of ion-access to the binding sites could be verified.
Endlich wird neben vielen wissenschaftlichen Veröffentlichungen ein Werk vorgelegt, das die umfangreichen Daten über Brutbestande und Entwicklungstrends von verschiedenen Vogelarten kurz, einprägsam und übersichtlich präsentiert. Nach kurzer Einführung und Erläuterung der Datengrundlagen werden in anschaulichen Tabellen und Diagrammen ausgewählte Vogelschutzaspekte vorgestellt sowie die Bestandsentwicklung von Vogelarten in verschiedenen Lebensraumen abgehandelt. Die vielen hervorragenden Fotos bereichern die Schrift in besonderer Weise. Einen Glückwunsch an die Autoren.
Background Drought is the major constraint to increase yield in chickpea (Cicer arietinum). Improving drought tolerance is therefore of outmost importance for breeding. However, the complexity of the trait allowed only marginal progress. A solution to the current stagnation is expected from innovative molecular tools such as transcriptome analyses providing insight into stress-related gene activity, which combined with molecular markers and expression (e)QTL mapping, may accelerate knowledge-based breeding. SuperSAGE, an improved version of the serial analysis of gene expression (SAGE) technique, generating genome-wide, high-quality transcription profiles from any eukaryote, has been employed in the present study. The method produces 26 bp long fragments (26 bp tags) from defined positions in cDNAs, providing sufficient sequence information to unambiguously characterize the mRNAs. Further, SuperSAGE tags may be immediately used to produce microarrays and probes for real-time-PCR, thereby overcoming the lack of genomic tools in non-model organisms. Results We applied SuperSAGE to the analysis of gene expression in chickpea roots in response to drought. To this end, we sequenced 80,238 26 bp tags representing 17,493 unique transcripts (UniTags) from drought-stressed and non-stressed control roots. A total of 7,532 (43%) UniTags were more than 2.7-fold differentially expressed, and 880 (5.0%) were regulated more than 8-fold upon stress. Their large size enabled the unambiguous annotation of 3,858 (22%) UniTags to genes or proteins in public data bases and thus to stress-response processes. We designed a microarray carrying 3,000 of these 26 bp tags. The chip data confirmed 79% of the tag-based results, whereas RT-PCR confirmed the SuperSAGE data in all cases. Conclusion This study represents the most comprehensive analysis of the drought-response transcriptome of chickpea available to date. It demonstrates that – inter alias – signal transduction, transcription regulation, osmolyte accumulation, and ROS scavenging undergo strong transcriptional remodelling in chickpea roots already 6 h after drought stress. Certain transcript isoforms characterizing these processes are potential targets for breeding for drought tolerance. We demonstrate that these can be easily accessed by micro-arrays and RT-PCR assays readily produced downstream of SuperSAGE. Our study proves that SuperSAGE owns potential for molecular breeding also in non-model crops.
The syndicated loan market, as a hybrid between public and private debt markets, comprises financial institutions with access to valuable private information about borrowers as a result of close bank-borrower relationships. In this paper, we seek empirical evidence for the costs of these relationships in a sample of UK syndicated loan contracts for the time period 1996 through 2005. Using detailed financial data for both borrowers (private and public companies) and for financial institutions, we find that undercapitalized banks charge higher loan spreads for loans to opaque borrowers using various measures for borrower opaqueness and controlling for bank, borrower and loan characteristics. We further analyze this hold-up effect over the business cycle and find that it only prevails during recessions. In expansion phases, however, we do not find evidence for banks exploiting their information monopoly. This finding is consistent with theories on bank reputation in bank loan commitments. Ambiguity about borrower financial health, which induces the information monopoly in the first place, also gives banks the discretion to exploit or not exploit informational captured borrowers. Our findings are both statistically and economically significant and robust to alternative bank and macroeconomic risk proxies. We address potential concerns about unobserved borrower heterogeneity exploiting the panel data nature of our sample. Using firm-bank fixed effect regressions, we find supporting evidence for our theoretical framework. JEL Classifications: G14, G21, G22, G23, G24 Keywords: Syndicated loans; Hold-up; Lending relationships; Business cycle
The Oryctini (Coleoptera: Scarabaeidae: Dynastinae) is a large tribe of worldwide distribution with approximately 26 genera and 230 species. Fourteen genera and 113 species are found in the Neotropical region. Knowledge of the tribe in the Neotropics is fragmentary, necessitating further studies that address taxonomy, biology, and geographical distribution patterns. This study surveyed the Oryctini of the Brazilian Amazon. The composition of the group in the study area consisted of 7 genera, 18 species and 2 subspecies found in 7 states, 91 municipal districts, and approximately 167 specific localities. States with larger number of species are Amazonas and Pará, with 17 and 13 species respectively. Heterogomphus eteocles Burmeister, Heterogomphus aidoneus (Perty), Heterogomphus telamon Burmeister, Megaceras crassum Prell, and Megaceras laevipenne Prell are reported for the first time from the study area. Megaceras laevipenne is reported for the first time from Brazil. The taxonomy, descriptions, distribution maps, and biological and ecological data are provided for all species. A character analysis is provided as well as an identification key for all oryctine species that occur in the Brazilian Amazon.
Ideale universelle Nucleosid-Analoga könnten im Hinblick auf therapeutische Oligonucleotide einen Fortschritt in der Entwicklung darstellen. Zudem bieten solche Nucleosidanaloga auch aus synthetischer Sicht Vorteile: Durch ihre Struktur sind chemische Modifikationen – wie beispielsweise Modifizierungen an der Zuckereinheit – leichter zugänglich, als bei den natürlichen Nucleosiden. Ein Ziel der vorliegenden Doktorarbeit bestand darin, bereits bekannte universelle Nucleosidbausteine solchermaßen zu modifizieren, das bei ihrer Anwendung in Oligonucleotiden ihre Vorteile besser zum Tragen kommen. Vor diesem Hintergrund besaßen vor allem protonierbare 2´-O-Modifikationsmotive eine besondere Relevanz. Im Vergleich zur bereits bekannten 2´-O-Aminoethyl-Modifikation des 4,6-Difluorbenzimidazol-Nucleosidbausteins konnte eine um eine Methyleneinheit längere 2´-O-Aminopropylfunktion des Nucleosids hergestellt werden. Dabei wurde eine Syntheseroute eingeschlagen, mit der diese Modifikation in hohen Ausbeuten und hoher Reinheit aus dem 3´-,5´-Markiewicz-geschützten Nucleosid eingeführt werden konnte. Grundlage dieser Modifizierungsmethode ist eine Michael-Addition von Acrylnitril an die 2´-OH-Funktion unter basischen Bedingungen. Damit konnte ein 2´-O-Cyanoethylrest an das Nucleosid geknüpft werden; dieser wurde als Modifikationsmotiv beibehalten und es konnte das entsprechende 3´-Phosphoramidit hergestellt werden. Außerdem lässt sich ein 2´-O-Cyanoethylrest mittels Raney-Nickel-katalysierter Hydrierung in das primäre Amin überführen. Durch diese Michael-Addition-Reduktionssequenz konnte die erwähnte 2´-O-Aminopropylmodifikation in nur zwei Stufen mit einer Gesamtausbeute von über 80 % an das Difluorbenzimidazolnucleosid geknüpft werden. Die 2´-O-Aminopropylfunktion wurde zudem als Ausgangspunkt zur Kupplung weiterer erfolgsversprechender Modifikationsmotiven verwendet: In diesem Ansatz wurden mittels standardisierter Peptidkupplungschemie Carbonsäurederivate an die freie Aminofunktion gekuppelt. Hierdurch waren neuartige 2´-O-Modifizierungen, wie z.B. Lysin- oder auch Laurinsäurekonjugate zugänglich; diese waren über den Propylamidlinker mit dem Nucleosid verbunden. Im Hinblick einer polykationischen Modifizierung konnte auch ein Sperminderivat an die Aminopropylfunktion gekuppelt werden. Sämtliche dieser Konjugate konnten ebenfalls nach mehrstufigen Synthesen in das 3´-Phosphoramidit überführt werden und wurden schließlich erfolgreich in RNA-Oligonucleotide eingebaut. Für den Einbau der 2´-modifizierten universellen Nucleosidanaloga in RNA-Oligonucleotide wurden zunächst kurze 12mer-Sequenzen gewählt, die sich bereits als gute Testsysteme für spektroskopische Untersuchungen herausgestellt haben. Hernach konnten mit diesen Duplexen spektroskopische Untersuchungen wie UV-Schmelzkurvenanalysen und CD-Spektroskopie durchgeführt werden. Zudem stand die biologische Testung dieser Modifikationen in synthetisch zugänglichen siRNA-Oligonucleotiden im Fokus dieser Arbeit. Um die Flexibilität der Konjugationsmethode zu erhöhen konnte auch eine postsynthetische Kupplung an das festphasengebundene RNA-Oligomer etabliert werden. Dies wurde durch den Einbau des geeignet geschützten 2´-Aminopropyl-Nucleosidbausteins in ein RNA-Oligomer erreicht: Durch einfache Zugabe von Bocanhydrid in den Reduktionsansatzes gelang eine simultane Boc-Schützung des 2´-O-Aminopropylderivats in quantitativer Ausbeute. Diese Prozedur konnte auch auf ein 7N-Purinnucleosidanalogon übertragen werden, welches im Hinblick auf die thermodynamische Stabilisierung eines RNA-Duplexes einem 4,6-Difluorbenzimidazolbaustein gegenüber überlegen zu sein scheint. Die Boc-geschützen Derivate wurden als Phosphoramidite in die automatisierte Festphasensynthese von Oligonucleotiden eingesetzt. Der große synthetische Vorteil dieser Methode besteht einerseits in ihrer einfachen Durchführbarkeit, andererseits in ihrer effizienteren und ökonomischeren Vorbereitung: Es muss nur jeweils ein Phosphoramiditbaustein (mit Boc-geschützter 2´-O-Aminopropylfunktion) synthetisiert und in ein Oligonucleotid eingebaut werden. Sowohl mit dem 4,6-Difluorbenzimidazolnucleosid, als auch mit seinem 7N-Purin-Pendant konnten erfolgreiche Festphasenkupplungen durchgeführt werden. Im Hinblick auf die thermodynamischen Eigenschaften konnten vor allem für das 7N-Purinnucleosid interessante Resultate erzielt werden: Das via Festphasenkupplung erhaltene RNA-12mer, welches eine Argininmodifikation am 2´-O-Aminopropyl-7N-Purinnucleosid trägt, zeigt eine im Vergleich zum unmodifizierten A-U-Basenpaar ähnliche Stabilität bei leicht erhöhtem Tm-Wert. Um den Ursprung dieses Effekts genauer zu ergründen wären weitere thermo-dynamische Untersuchungen anhand des 7N-Purinbausteines z.B. mit anderen Modifikations-motiven oder auch an unterschiedlichen Positionen im Oligomer sinnvoll.
Im Rahmen dieser Arbeit ist es gelungen, die über die 1,´-Position phenylenverbrückten Bis(silolyl)verbindungen 120, 123, 125, 156, 158, 160, 135, 137 und 139, sowie die entsprechenden Phenylsilole 126, 163 und 141 (siehe Schema 4.1) zu synthetisieren und NMR-spektroskopisch, massenspektroskopisch und zum Teil auch durch Kristallstrukturen zu charakterisieren. Weiterhin ist es gelungen eine über die 3,3´-Position verknüpfte phenylenverbrückte Bis(silolyl)verbindung 175, sowie auch die Vorstufe zu einer 2,2´-verknüpften Bis(silolyl)verbindung 177 zu synthetisieren und zweifelsfrei zu charakterisieren.
Im Rahmen dieser Doktorarbeit wurden modifizierte Nukleoside synthetisiert, um ihren Einfluss auf die Stabilität von RNA-Duplexen zu untersuchen. Bei den fluorierten Benzimidazol-Nukleosidanaloga handelt es sich um universelle Basen, die bei der Basenpaarung nicht zwischen den vier natürlichen Nukleosiden unterscheiden können. Die dabei auftretende Destabilisierung der RNA-Duplexe sollte durch die Änderung physikalisch-chemischer Eigenschaften vermindert werden. Durch die Synthese der fluorierten Indol-Nukleosidanaloga mit denselben Fluoratompositionen sollte nachgewiesen werden, welche Rolle ein ausfallendes Stickstoffatom im Fünfring-System spielt. Weitere Untersuchungen wurden so entwickelt, dass die zwei spC-F in 4,6DFBI wie auch in 4,6DFI mit Stickstoffatomen getauscht wurden. So wurde noch eine neue Serie Nukleosidanaloga synthetisiert (Abbildung 9.2). Schließlich wurde noch 1-Desoxy-D-ribofuranose AS als absischer Baustein synthetisiert. Die Synthese der Indol- und 9-Deazapurin-Nukleosidanaloga wurde über eine Glycsilierungsreaktion mit geeignet geschützter Deoxyribose durchgeführt. Dies wurde über vier Stufen, ohne Aufreinigung, aus Deoxyribose synthetisiert. Die entsprechenden Deoxy-nukleoside wurden danach in fünf Schritten zu Ribo-nukleosiden transformiert. Nach der Entschützung von Toluoyl-Gruppen wurden die 5´- und 3´-OH Gruppen sukzessiv geschützt. Nach simultaner 5´-OH Entschützung und 3´-OMs Eliminierung, wurden die gewünschten Ribonukleoside durch katalytische Dihydroxilierung erhalten. Die Darstellung der Verbindung 7NP erfolgte über die Silyl-Hilbert-Johnson-Reaktion. Der abasische Baustein AS wurde ausgehend von 2,3,5-Tri-O-benzyl-ribofuranose durch Dehydroxylierung und anschließende Entschützung erreicht. Von allen Nukleosiden gelang es Kristalle aus Wasser oder Methanol zu erhalten und röntgenkristallographisch zu untersuchen. Die Kristallpackungen zeigten eine sehr interessante Anordnung der Moleküle. Alle Fluorindol-Nukleoside mit Ausnahme von 7-N-Purin-Nukleosid 7NP zeigten nicht die für aromatische Systeme normale Fischgräten-Struktur, sondern eine Anordnung, in der die Moleküle gegenüberliegen. Die Kristallpackung besteht abwechselnd aus hydrophilen und lipophilen Schichten. Die hydrophilen Schichten bestehen aus den Zuckeruntereinheiten und die lipophilen aus den Fluoraromaten. Die Zucker sind durch Wasserstoffbrücken miteinander verbunden. Für die Orientierung der Moleküle zueinander sind aber die Fluoratome verantwortlich. In der Kristallpackung von 7-Fluorindol-Nukleosid 7FI kann ein Fluor-Wasserstoff-Abstand von nur 230 pm detektiert werden. Dies ist deutlich kürzer als die Summe der van-der-Waals Radien von Fluor und Wasserstoff von 2,55 Å. Der Abstand wird zwischen dem Fluor des einen Nukleosids und einem Wasserstoff eines gegenüberliegenden Nukleosids gemessen. Der Abstand von 2,30 Å ist einer der kürzesten jemals in Kristallen gemessenen F-H Abstände des Typs Csp²-F...H-Csp². Bedingt durch diesen kurzen Abstand kann von einer F...H Wasserstoffbrücke gesprochen werden. Auf der anderen Seite in der Kristallstruktur von 4-Fluorindol-Nukleosid 4FI konnte ein F-H Abstand von 2,69 Å nachgewiesen werden, welcher deutlich länger als die Summe der van-der-Waals Radien von Fluor und Wasserstoff ist. Die Nukleoside wurden auf ihre Lipophilie hin untersucht. Zu diesem Zweck wurden Octanol-Wasser Verteilungskoeffizienten der Nukleoside gemessen. Die fluorierten Nukleoside zeigten im Gegensatz zu den nichtfluorierten Nukleosiden eine deutlich größere Lipophilie. Nach Umsetzung der Nukleoside zu den Phosphoramiditen konnten diese kupplungsfähigen Monomere in den RNA-Festphasensynthesen eingesetzt und in RNA 12mere eingebaut werden. Um den Einfluss der aromatischen Fluorosubstitutionen auf die thermodynamische Stabilität von RNA-Duplexen zu untersuchen, wurden UV/VIS- und CD- spektroskopische Messungen an monomodifizierten RNA 12meren durchgeführt. Aus den erhaltenen Schmelzkurven wurden die Schmelzpunkte bestimmt (Abbildung 9.3) und die thermodynamischen Daten ausgerechnet. Die Anwendung hydrophober, Fluorsubstituierter Nukleobasen führte im Fall der fluorierten Indol-Nukleoside zu Destabilisierung im Vergleich mit natürlichen Basenpaaren. Aus den folgenden Resultaten lässt sich zusammenfassen: 1. Position der Fluoratom in fluorierten Indole spielt eine wesentliche Rolle für die Stabilität des RNA-Duplex 2. 6FI bildet die stabilste Basenpaaren mit natürlichen Basen. 3. Basenpaarung von 4FI trägt eine deutlich höhere Destabilisierung. Für diese Modifikation wurden auch die längsten Abstandwerte zwischen C-F…H in der Kristallpackung gemessen. (Die Vermutung liegt nahe, dass diese Base sich außerhalb des Duplex befindet). 4. Alle Fluorindol-Basenanaloga zeigen die Tendenz zur Paarung mit Adenosin. 5. Bei 4,6DFI handelt sich um universelle Base. Um noch weniger destabilisierende universelle Basen zu finden, wurde das Forschungsfeld mit Methoden aus dem Bereich der strukturellen Bioinformatik, Molekül-dynamiksimulationen und freie Energie-Rechnungen ausgeweitet. Resultierende Simulationen führten zu zwei neuen Basen: 7NP als Analogon zu 4,6DFBI und 9DP als Analogon zu 4,6DFI (siehe Kapitel 8). Theoretische Rechnungen ließen sich bestätigen durch experimentelle Ergebnisse Die so entstandene Serie von Purin-Basenanaloga hat uns gezeigt, dass der Austausch von Fluoratomen durch Stickstoffatome stabilisierende Effekte bringt. Die chemischen Änderungen beeinflussen die physikalischen Eigenschaften, welche dadurch Stabilisierung oder Destabilisierung des RNA-Duuplex dirigieren. In Abbildung 9.5 befinden sich ausgerechnete Dipolmomente. Somit können wir für diese Serie folgendes resümieren: * 4,6FI als universelles Base Analogon zu 4,6DFBI zeigt geringere destabilisierende Effekte auf den 12mer RNA-Duplex. * Umtausch von Fluoratomen in den beiden Basen (4,6DFI und 4,6DFBI) resultiert in deutlich besserer Basenpaarung. * Auserrechnete thermodynamische Parametern (von gemessenen Tm-Werten) wurde ersichtlicht, dass höhere Tm-Werte durch geringere Destabilisierung aus Solvatation resultieren, nicht aus erhöhten Stacking Effekten des RNA-Duplex.
Poly(pyrazol-1-yl)borate, die sogenannten Skorpionate, repräsentieren eine der etabliertesten Ligandenklassen in der Koordinationschemie und finden aufgrund ihrer Vielseitigkeit zahlreiche Anwendungen. In den letzten Jahren hat sich ein besonderes Interesse an Bis- und Tris(pyrazol-1-yl)boratliganden entwickelt, die mehrere Skorpionateinheiten im selben Molekül vereinen und dadurch kooperative Effekte zwischen den Metallionen fördern. Diese Liganden können sowohl Einsatz in der homogenen Katalyse als auch in den Materialwissenschaften finden. Die bisher in unserer Arbeitsgruppe entwickelten ditopen Bis(pyrazol-1-yl)borate des Typs L (Abb. 3.1) weisen allerdings eine recht hohe Hydrolyseempfindlichkeit auf, deren Ursache wahrscheinlich im elektronenschiebenden Charakter und der Raumerfüllung der Alkylsubstituenten begründet liegt. Im Rahmen der vorliegenden Arbeit wurden daher zunächst die ditopen Skorpionatliganden M2[3] und M2[6] mit Phenyl- und Pentafluorphenylsubstituenten dargestellt, die in darauf folgenden Hydrolysestudien eine im Vergleich zu L erheblich höhere Beständigkeit gegenüber Feuchtigkeit zeigten. Die Umsetzungen der Liganden Li2[Lpara] (Dissertation Dr. Susanne Bieller; Frankfurt 2005) und Li2[6] mit MnII-chlorid verdeutlichten, dass sich das C6F5-substituierte Heteroskorpionat auch in Bezug auf sein koordinationschemisches Verhalten vom tertButyl-substituierten Liganden unterscheidet. Während Li2[Lpara] mit MnCl2 zu einem chlorid-überbrückten, makrozyklischen, dinuklearen Mangankomplex reagiert, wird mit Li2[6] das in Abb. 3.2 dargestellte Koordinationspolymer {(MnCl2)2(Li(THF)3)2[6]}∞ erhalten. Die Ladung der anionischen Polymerkette wird durch Lithium-Gegenionen ausgeglichen. Um die Bildung von diskreten Komplexen einerseits bzw. von Koordinationspolymeren andererseits gezielt steuern zu können, wurden die mit sterisch anspruchsvollen Pyrazolylsubstituenten versehenen Liganden M2[4], M2[5] und M2[7] (Abb. 3.1) dargestellt. Im Zuge der Kristallisation von Li2[4] zeigte sich, dass diese Verbindung eine hohe Affinität für Chloridionen besitzt. Auch in Anwesenheit eines Überschusses Kronenether führen Spuren des Halogenids zur Ausbildung des in Abb 3.3 gezeigten dinuklearen, chloridverbrückten Lithiumkomplexes Li2Cl[4]. Die ausgeprägte Komplexbildungstendenz lässt Li2Cl[4] im Hinblick auf die Entwicklung von Anionenrezeptoren interessant erscheinen. Komplexe, in denen zwei Metallionen durch zwei Heteroskorpionatliganden in eine makrozyklische Struktur eingebunden werden (Tmeta/para in Abb. 3.4), konnten im Rahmen dieser Arbeit nicht isoliert werden. Ein Hinweis, warum dieses Strukturmotiv ungünstig sein könnte, wurde durch die Charakterisierung des auf einem partiell hydrolysierten Derivat von Li2[Lpara] beruhenden CoII-Makrozyklus Co2[23]2 erhalten. Die Analyse der Strukturparameter dieser Verbindung deutet an, dass die Bildung eines Makrozyklus im Fallder unhydrolysierten Heteroskorpionate aufgrund sterischer Wechselwirkungen zwischen den Pyrazolylringen und der Phenylenbrücke benachteiligt sein sollte. Obwohl zwischen Aryl- und Alkyl-basierte n Heteroskorpionaten erhebliche Unterschiede hinsichtlich ihrer Neigung zur hydrolytischen Zersetzung erkennbar sind, zeigen beide Ligandentypen ähnliche Labilitäten gegenüber der stark Lewis-aziden Verbindung Brommanganpentacarbonyl. Die Reaktionen von Li2[Lpara], Li2[3] und Li2[6] mit Mn(CO)5Br führten zur Spaltung von B-N-Bindungen, die in allen drei Fällen durch Kristallisation des in Abb. 3.5 gezeigten, pyrazolid-verbrückten MnI-Carbonylkomplexes 21 dokumentiert werden konnte. Im Gegensatz zu den Heteroskorpionatliganden zeigen oligotope phenylenverknüpfte Homoskorpionate keine Tendenz, sich unter dem Einfluss von Mn(CO)5Br zu zersetzen. Reaktionen der di- und tritopen Tris(pyrazol-1-yl)borate Li2[15], Li2[16] und Li3[18] lieferten die in Abb. 3.6 dargestellten Mangantricarbonylkomplexe (Mn(CO)3)2[15], (Mn(CO)3)2[16] und (Mn(CO)3)3[18] in guten Ausbeuten. Neben der Darstellung dieser, für materialwissenschaftliche Fragestellungen (Koordinationspolymere, Metallorganische Netzwerke) interessanten Liganden, wurde im Rahmen der vorliegenden Arbeit auch der Frage nachgegangen, ob die Verknüpfung zweier Heteroskorpionateinheiten Auswirkungen auf die katalytische Aktivität entsprechender Rhodium-Cyclooctadien-Komplexe in der Polymerisation von Phenylacetylen hat. Sterisch anspruchsvolle Pyrazolylsubstituenten tragende monotope Rhodium-Cyclooctadien- Skorpionatkomplexe konnten in dieser Reaktion bereits erfolgreich als Katalysatoren eingesetzt werden und lieferten regioselektiv cis-transoid-verknüpftes Poly(phenylacetylen). Zunächst wurden die in Abb. 3.7 dargestellten Rhodiumkomplexe (Rh(cod))2[3] und (Rh(cod))2[6] von Bis(pyrazol-1-yl)boraten, die keine sterisch anspruchsvollen Pyrazolylsubstituenten tragen, synthetisiert. Ähnlich wie der analoge einkernige Komplex Rh(cod)[H2Bpz2 ] zeigten (Rh(cod))2[3] und (Rh(cod))2[6] keinerlei katalytische Aktivität. Daher sollten im Anschluss die mit Phenylpyrazolylgruppen ausgestatteten Derivate (Rh(cod))2[5] und (Rh(cod))2[7] synthetisiert und im katalytischen Prozess eingesetzt werden. Im Verlauf dieser Experimente stellte sich heraus, dass die Reaktionen der Alkalimetallskorpionate Li2[5] und K2[7] mit (Rh(Cl)(cod))2 nicht zu den Zielverbindungen, sondern zur Zersetzung der Ligandgerüste führen. In beiden Fällen konnte das Abbauprodukt 22 isoliert werden (Abb. 3.8). Weitere Untersuchungen ergaben, dass 22 in der Lage ist, Phenylacetylen in guten Ausbeuten und regioselektiv (cis-transoid-verknüpftes Poly(phenylacetylen)) zu polymerisieren. 22 stellt somit ein gut zugängliches und leicht zu modifizierendes Katalysatorsystem dar, dessen Optimierung Thema zukünftiger Untersuchungen sein wird.
Bei Investigator Initiated Trials (IITs) werden alternative risikoadaptierte Monitoring-Strategien in Abhängigkeit vom individuellen Studiendesign und dem Risikoprofil diskutiert, um bei oft restriktiven Ressourcen eine den gesetzlichen Vorgaben genügende Qualität der Studiendurchführung und der Daten zu gewährleisten. Aufgrund einer Literaturanalyse sollten in der vorliegenden Arbeit Untersuchungen ausgewertet werden, in denen quantitative Aussagen zu Datenqualität und Prüfplan-Compliance in klinischen Prüfungen gemacht wurden. Bei der Interpretation der Ergebnisse sollten die implementierten Qualitätssicherungsmaßnahmen berücksichtigt werden. Aufgrund einer systematischen Recherche in MEDLINE konnten 21 Publikationen identifiziert werden, bei denen die Daten- und Prozessqualität in klinischen Prüfungen untersucht, die Qualität durch Überprüfungen mit Source Data Verification vor Ort oder Überprüfung übermittelter Quelldaten in der Studienzentrale ermittelt wurde und quantitative Informationen zu den Bereichen Datenqualität, Protokoll-Compliance oder Defizite bei Einwilligungserklärungen vorlagen. Die Mehrzahl der Untersuchungen ist drei Organisationen zuzuordnen: European Organization für Research and Treatment of Cancer (EORTC) (n=7), National Cancer Institute (NCI) (n=7) und Untersuchungen der Trans-Tasman Radiation Oncology Group (TROG) (n=4). Darüber hinaus wurden drei Untersuchungen weiterer Studiengruppen identifiziert. Die Untersuchungen wurden im Zeitraum von 1981 bis 2003 publiziert. Überwiegend wurden in der Literatur onkologische Studien betrachtet (n=19), wobei die Radiotherapie im Vordergrund stand (n=8). Für die EORTC-Studien wurde in der Regel eine gute Datenqualität berichtet (80-90% korrekte Daten). Punktuelle Probleme wurden im Hinblick auf die Protokoll-Compliance und das Berichten von Nebenwirkungen/schwerwiegenden unerwünschten Ereignissen festgestellt. Eine gute Qualität wurde ebenfalls bzgl. des korrekten Einschlusses von Patienten beobachtet. Durch das NCI wurde ein standardisiertes Audit-System eingeführt und innerhalb von kooperativen Studiengruppen implementiert. Im Rahmen dieser Audits wurden verschiedene Kriterien überprüft und eine überwiegend gute Datenqualität und Protokoll-Compliance festgestellt. Mängel wurden in ca. 5% der Fälle im Hinblick auf die Einwilligungserklärung, die korrekte Anwendung der Einschlusskriterien, Protokollverletzungen, bei der Ermittlung des Zielkriteriums, der Erfassung der Toxizität, der adäquaten Datenlieferung und bei der Datenverifikation beobachtet. In einzelnen Untersuchungen ergaben sich Probleme mit der Behandlungscompliance (10-20%), bei Protokollabweichungen im Hinblick auf die Arzneimitteldosis (10%) und bei der Drug Accountability (15%). Von der TROG wurde ein Qualitätssicherungsprozess implementiert, der auf zentralem Monitoring von kopierten Quelldaten basiert. Durch den Qualitätssicherungsansatz der TROG konnten schwerwiegende Probleme mit der Protokoll-Compliance unter 10% gesenkt werden, ebenso konnte eine gute Datenqualität mit einer Fehlerrate unter 5% erreicht werden. Die korrekte Handhabung von Ein- und Ausschlusskriterien stellte in Einzelfällen ein Problem dar. Zusammenfassend kann festgestellt werden, dass die in dem Review erfassten Studiengruppen von einer guten Datenqualität und einer guten bis moderaten Protokoll-Compliance berichten. Diese basiert nach Aussage der Autoren im wesentlichen auf etablierten Qualitätssicherungs-Prozeduren, wobei das durchgeführte Audit ebenfalls einen potentiellen Einflussfaktor darstellt. Geringe Probleme wurden in der Regel im Hinblick auf die Einwilligungserklärung, die korrekte Handhabung der Ein- und Ausschlusskriterien und die Datenqualität beobachtet. In einzelnen Studien gab es jedoch Probleme mit der Protokoll-Compliance. Insgesamt hängen Anzahl und Art der Mängel von dem Studientyp, dem Qualitätsmanagement und der Organisation der Studiengruppe ab. Wissenschaftsbetrug wurde nur in sehr wenigen Fällen durch die Audits festgestellt. Die vorgelegten Informationen beziehen sich nahezu ausschließlich auf etablierte Studiengruppen; bezüglich Datenqualität und Protokoll-Compliance außerhalb der Studiengruppen liegen kaum Informationen in der Literatur vor. Bei der Bewertung der Ergebnisse sollte berücksichtigt werden, dass es sich zum Teil um Eigenauswertungen der Studiengruppen und nicht um unabhängige externe Prüfungen (z.B. externe Audits) handelt. Inwieweit die Ergebnisse einer konsequenten Überprüfung nach derzeitigen Good Clinical Practice (GCP) – Regeln standhalten würden, kann aus der Analyse nicht beantwortet werden. Aus der vorliegenden Literaturanalyse ergeben sich Konsequenzen für die Planung einer prospektiven kontrollierten Studie zum Vergleich unterschiedlicher Monitoring-Strategien. Wesentlicher Einflussfaktor für die Datenqualität und Protokollcompliance in einer klinischen Studie ist das Qualitätsmanagement. Dieses Qualitätsmanagement umfasst neben Monitoring zahlreiche andere Maßnahmen. Um zu einer Bewertung von Monitoringstrategien kommen zu können, müssen daher alle Qualitätssicherungsmaßnahmen im Rahmen einer Studie berücksichtigt werden. Für den Vergleich unterschiedlicher Monitoringstrategien sind geeignete Zielparameter zu definieren (z.B. schwerwiegende Defizite bzgl. Ein- und Ausschlusskriterien, Sicherheit). Die vorliegende Analyse ergibt, dass bei gutem Qualitätsmanagement ohne umfassendes vor Ort Monitoring schwerwiegende Fehler nur mit relativ niedriger Häufigkeit festgestellt wurden. Unterschiede zwischen Monitoringstrategien könnten, gegeben ein funktionierendes Qualitätsmanagementssystem, sich als quantitativ gering erweisen. Testet man auf Äquivalenz von Monitoringstrategien, sind nur niedrige Differenzen zu akzeptieren, was wiederum eine Auswirkung auf die Fallzahlplanung hat. Weiterhin muss berücksichtigt werden, dass zur Feststellung der Auswirkung unterschiedlicher Monitoringstrategien auf die Sicherheit der Patienten und die Validität der Daten im Rahmen einer kontrollierten Untersuchung ein unabhängiges Audit notwendig ist. Dabei ist zu berücksichtigen, dass ein Audit bereits einen möglichen Einflussfaktor für die Datenqualität und Protokoll-Compliance darstellen kann, und damit eine Bewertung des Nutzens einer Monitoringstrategie erschwert werden könnte. Schlüsselwörter: systematisches Review, Datenqualität, Protokoll-Compliance, klinische Studie
Le présent ouvrage représente la version électronique d’un numéro spécial des Cahiers du Centre d’Études et de Recherche en Lettres Sciences Humaines et Sociales, publié en 2001 par la Direction des Presses Universitaires de l’Université de Ouagadougou, pour l’Unité de Formation et de Recherche (UFR/LAC & UFR/SH)
Tale of an African Woman
(2008)
The village of Yakiri has been cursed by ancestral wrath because of the treatment of Yaa, the first girl who wrestled her male goatherd peers to earn the right to be initiated into the society of manhood. Her struggle is taken up generations later by Yaya, the granddaughter of Tafan and Wirba. Orphaned like her forebear, Yaya becomes a star student in the village's primary school and promises to go far. But, ask the villagers, is it right to invest in an education for an African girl who may become the property of another village? An educated woman will abandon the farm where she is needed, wear high heels and try to order men around! In the midst of it all, one Irish missionary, living in Africa and for the most time with Africans, literally wiggles his way into hearts and minds. With his intervention, Yaya leaves the village to school in the city, but her troubles as a woman have not really begun. Yarns of cultural borrowing, indigestion and transcendence reveal the simple and complex ways in which community matters are confronted and decided. This happens in shrines where seers are consulted and cowry shells thrown, in palm wine houses, but also around the school and presbytery. The untold stories and perspectives of girls and women burst through in illuminating and uplifting ways. Quarrels, squabbles, near collisions and mutual conversions give way to innovative traditions.
Target2-Securities (T2S) is a project of the Eurosystem (central banking system of the Euro area) aiming to create a common platform to settle securities transactions in central bank money. This platform is another step of the European Union towards harmonization of capital markets and enhancement of competitive conditions in the Euro area. T2S is planned to go live in 2013 and to operate on a full costrecovery and non-profit base.
Background Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. Methods In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Results Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Conclusion Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy.
Die akute myeloische Leukämie (AML) ist charakterisiert durch einen Differenzierungsblock sowie aberrante Selbsterneuerung („self-renewal“) hämatopoetischer Vorläuferzellen im Knochenmark (Grignani, 1993). Bei Patienten mit akuter Promyelozyten-Leukämie (APL), einem Subtyp der AML, bezeichnet als M3 gemäß FAB(„French-American-British“)-Klassifikation, ist dieser Phänotyp induziert durch die spezifischen Leukämie-assoziierten chromosomalen Translokationen t(15;17) sowie t(11/17). Beide involvieren einen identischen Anteil des Retinsäure-Rezeptors Alpha (RAR-Alpha) und jeweils entweder Gene der Promyelozyten-Leukämie (PML) oder promyelozytäre Zinkfinger (PLZF). Durch homologe Oligomerisierung, vermittelt durch die PCC(“coiled-coil”)-Domäne beim PML (Grignani, 1999) und die BTB/POZDomäne beim PLZF (Benedetti, 1997), formieren die Fusionsproteine PML/RAR und PLZF/RAR-Alpha in vivo HMW(“high molecular weight“)-Komplexe (Melnick, 1999). Im Vergleich zum RAR-Alpha von Wildtyp-Zellen zeigen diese erhöhte Affinität zu “Histone-Deacetylase-Recruiting-Nuclear- Corepressor”-Komplexen, was über aberrante Rekrutierung der Histon- Deazetylase zu konstitutiver Hypoazetylierung der Histone und schließlich zur Blockade der Transkription von Genen, die für eine Ausdifferenzierung von hämatopoetischen Vorläuferzellen bedeutsam sind, führt. Gegenstand der vorliegenden Dissertation ist das molekulare Targeting der Oligomerisierungsdomänen von PML/RAR-Alpha und PLZF/RAR-Alpha in vitro. Hierfür werden retrovirale Vektoren mit artifiziellen Fusionsgenen kloniert. Diese bestehen aus jeweils PCC-ABL oder POZ-ABL, welche sich aus der ABLKinase des Philadelphia-Chromosoms BCR/ABL und den spezifischen Oligomerisierungsdomänen von PML/RAR-Alpha und PLZF/RAR-Alpha zusammensetzen sowie den Peptiden PCC und POZ mit analogen Strukturen zu diesen Domänen. Fusionen der ABL-Kinase mit den Oligomerisierungsdomänen von PML und PLZF führen wie bei BCR (Beissert, 2003) zur konstitutiven ABLAktivität und vermitteln IL-3-unabhängiges Wachstum von Ba/F3-Zellen (murine Pro-B-Zelllinie). Die jeweils koexprimierten Peptide lagern sich an die analogen Proteinstrukturen von PCC-ABL und POZ-ABL an und stören deren homologe Oligomerisierung, was die IL-3-Unabhängigkeit gänzlich aufhebt. Dies wird über Wachstumskurven, Durchflusszytometrie (FACS) und Westernblot gezeigt. Folgend werden Vektoren zur Koexpression der kompletten APLcharakterisierenden Fusionsgene PML/RAR-Alpha und PLZF/RAR-Alpha zusammen mit identischen Peptiden kloniert, um mit diesen Sca1+/lin--selektionierte, murine, hämatopoetische Stammzellen zu infizieren. Deren Differenzierungsgrad wird über Zählung der Kolonien-formenden Einheiten (“Colony Forming Units” - CFUs), über deren Kolonie-Morphologie, deren Zytologie sowie Stammzell- und Differenzierungsoberflächenmarker bestimmt. Die Kontrollen mit alleiniger Expression der Fusionsproteine sowie zusammen mit vertauschten Peptiden zeigen die bekannte Morphologie von Promyelozyten, während die Koexpression der interferierenden Peptide zu deutlich akzelerierter Ausdifferenzierung führt. Eine erhöhte Replating-Effizienz durch die aberrante Fähigkeit zur Selbsterneuerung, eine typische Eigenschaften leukämischer Blasten, wird unter Einfluss interferierender Peptide nicht beobachtet. Hierfür wird ursächlich eine Störung der HMW-Komplex-Bildung beschrieben. Die Fusionsproteine PML/RAR-Alpha und PLZF/RAR-Alpha werden durch dieses Targeting über Westernblot nicht mehr nachgewiesen und somit als proteasomal degradiert angenommen. Das Vorliegen der Fusionsgene von PML/RAR-Alpha und PLZF/RAR-Alpha in den bei diesen Experimenten verwendeten Zellen kann auf RNA-Ebene über RT-PCR gezeigt werden. Zusammenfassend beschreibt die Koexpression von spezifischen Peptiden, die mit Oligomerisierungsdomänen von Fusionsproteinen, wie hier PML/RAR-Alpha und PLZF/RAR-Alpha, interferieren, einen neuen, vielversprechenden Ansatz bei der Therapie von Leukämien.
The influence of visual tasks on short and long-term memory for visual features was investigated using a change-detection paradigm. Subjects completed 2 tasks: (a) describing objects in natural images, reporting a specific property of each object when a crosshair appeared above it, and (b) viewing a modified version of each scene, and detecting which of the previously described objects had changed. When tested over short delays (seconds), no task effects were found. Over longer delays (minutes) we found the describing task influenced what types of changes were detected in a variety of explicit and incidental memory experiments. Furthermore, we found surprisingly high performance in the incidental memory experiment, suggesting that simple tasks are sufficient to instill long-lasting visual memories. Keywords: visual working memory, natural scenes, natural tasks, change detection
This dissertation analyzes tax policy, corporations, and capital market effects. First, the Savings Directive, which has left a loophole by providing grandfathering for some securities, is examined. It can be shown that investors are not willing to pay a premium for bonds that are exempt from the withholding rate, so it may be concluded that the supply of existing loopholes is large enough to allow tax evaders to continue evasion at no additional cost. Second, tax neutrality towards alternative financing instruments for corporate investment is a ubiquitous demand in the political debate. However, the magnitude of possible efficiency costs of a departure from tax neutrality is hardly discussed. Against this background, this dissertation discusses the theory of capital structure and provides back-ofthe-envelope calculations of the possible efficiency cost of a tax distortion of the debt-equity decision. Third, the ex-dividend-day effect in relation to the Gennan tax reform of 2000/2001 is discussed. The abolishment of the imputation system allows reinvestigating the size of the exdividend- day effect. I find no structural break in the size of the German ex-dividend-day effect and no evidence of an ex-dividend-day price drop that exceeds the dividend paid. Fourth, an account of the quantitative development of tax legislation in post-war Germany is presented. It can be shown that the legislative output did not increase over the decades and is not affected by a split majority in the upper and lower houses. Finally, it turns out that an increasing fraction of this legislation is passed in December.
The Tetragonoderus (Peronoscelis) quadriguttatus assemblage is a postulated monophyletic part of the intersectus complex. This assemblage is characterized against a background that includes review of a classification of the genus and comparison, in the form of a key, to other unrelated Western Hemisphere genera that share elongate tibial spurs with Tetragonoderus Dejean. The principal, easily observed feature that unites the three members (T. laevigatus Chaudoir, 1876; T. deuvei, new species (type locality: Cuijaba, Mato Grosso, Brazil), and T. quadriguttatus Dejean) of the quadriguttatus assemblage is the four-spotted elytra (two spots per elytron). These species are treated in detail, including key, synonymy (as required), comparisons, description (external and male genitalic features), habitat (if known), locality data, and geographical range map. Also, T. subfasciatus Putzeys, 1846, the elytral color pattern of whose members may be confused with the spotted pattern of the quadriguttatus assemblage, is treated similarly. The following new synonymies were established: T. quadriguttatus Dejean 1829 = T. columbicus Steinheil 1875 = T. lacordairei Chaudoir 1876 = T. tetragrammus Chaudoir 1876; and T. laevigatus Chaudoir 1876 = T. chaudoiri Liebke 1928 (replacement name for the junior homonym, T. unicolor Chaudoir, 1876). Lectotypes are designated for T. unicolor Chaudoir, T. lacordairei Chaudoir, and T. subfasciatus Putzeys. A neotype is designated for T. quadriguttatus Dejean. New distribution records in the West Indies for T. quadriguttatus are recorded for the islands of Grand Cayman, Jamaica and Hispaniola. These records may be the result of recent natural overseas dispersal from northern South America, or they may be the result of human-mediated accidental introduction, or a combination of both. The southern Floridian (Nearctic) records for T. laevigatus probably represent a recent accidental introduction through commerce, followed by dispersal through flights of adults.
Both, gas and particle scavenging contribute to the transport of organic compounds by ice crystals in the troposphere. To simulate these processes an experimental setup was developed to form airborne ice crystals under atmospheric conditions. Experiments were performed in a wall independent reactor (WIR) installed in a walk-in cold chamber maintained constantly at -20°C. Aerosol particles were added to the carrier gas of ambient air by an aerosol generator to allow heterogeneous ice formation. Temperature variations and hydrodynamic conditions of the WIR were investigated to determine the conditions for ice crystal formation and crystal growth by vapour deposition. In detail, the dependence of temperature variations from flow rate and temperature of the physical wall as well as temperature variations with an increasing reactor depth were studied. The conditions to provide a stable aerosol concentration in the carrier gas flow were also studied. The temperature distribution inside the reactor was strongly dependent on flow rate and physical wall temperature. At an inlet temperature of -20°C, a flow rate of 30 L•min exp -1 and a physical wall temperature of +5°C turned out to provide ideal conditions for ice formation. At these conditions a sharp and stable laminar down draft "jet stream" of cold air in the centre of the reactor was produced. Temperatures measured at the chamber outlet were kept well below the freezing point in the whole reactor depth of 1.0 m. Thus, melting did not affect ice formation and crystal growth. The maximum residence time for airborne ice crystals was calculated to at 40 s. Ice crystal growth rates increased also with increasing reactor depth. The maximum ice crystal growth rate was calculated at 2.82 mg• exp -1. Further, the removal efficiency of the cleaning device for aerosol particles was 99.8% after 10 min. A reliable particle supply was attained after a preliminary lead time of 15 min. Thus, the minimum lead time was determined at 25 min. Several test runs revealed that the WIR is suitable to perform experiments with airborne ice crystals.
Im EU-Vogelschutzgebiet Düsterdieker Niederung (Kreis Steinfurt, Nordrhein-Westfalen) wurden in den Jahren 2005 und 2006 telemetrische Untersuchungen an Küken von Wiesenlimikolen durchgeführt. In den beiden Jahren wurden 34 Kiebitzküken von 14 Familien und 58 Küken des Großen Brachvogels aus 20 Familien mit 0,8 schweren Sendern der Firma Biotrack (Dorset, UK) versehen, die auf den Rücken aufgeklebt wurden. Große Brachvögel wurden im Alter von 1-2 Tagen, Kiebitze auch noch in älteren Stadien besendert. Die Sender wurden in einem Abstand von höchstens drei Tagen geortet und das Schicksal der Küken bis zu einem Alter von etwa 30 Tagen verfolgt. Die Besenderung der Küken hatte keinen negativen Einfluss auf die Überlebenschancen der Küken, Die Überlebenschancen unbesenderter Küken waren nicht höher als von besenderten Küken. Dies wurde auch durch Verhaltensbeobachtungen bestätigt. 35 % der besenderten Küken des Kiebitzes und 28 % der Großen Brachvögel wurden flügge. Prädationsverluste machten beim Kiebitz mindestens 38 % und beim Großen Brachvogel mindestens 24 % aus. Beim Großen Brachvogel waren die festgestellten Prädatoren zu höheren Anteilen Raubsäuger, beim Kiebitz etwas häufiger Vögel. Als Prädatoren wurden sicher nachgewiesen: Mäusebussard (5), Turmfalke (1), Steinkauz (1), unbekannte Vögel (4), Fuchs (1), Marderartige (11), unbekannte Raubsäuger (3), weitere unbekannte (1). 20 % der Sender beim Kiebitz und 46 % beim Großen Brachvogel konnten nicht wieder gefunden werden, wobei die Küken mit Sicherheit nicht flügge wurden. Die Ursachen werden diskutiert. Ein hoher Anteil der nicht aufgefundenen Sender ist vermutlich ebenfalls Prädationsverlusten zuzurechnen. Nur ein Küken (Kiebitz) ging durch landwirtschaftliche Arbeiten verloren, je ein Küken beider Arten ertrank in einem Graben. Beim Großen Brachvogel lagen etwa 70 % der Kükenverluste in den ersten 14 Lebenstagen. Die Ergebnisse werden auch vor dem Hintergrund der Schutzmaßnahmen im EU-Vogelschutzgebiet diskutiert. Die geringen Verluste durch landwirtschaftliche Arbeiten können als Erfolg der Schutzbemühungen betrachtet werden. Die Kükenprädation wird im Untersuchungsgebiet als kein besonders auffälliges Problem bewertet. Zur Vermeidung von Kükenverlusten wurden an einigen Gräben bereits Verbesserungen vorgenommen.
The correspondence between the terminology used for querying and the one used in content objects to be retrieved, is a crucial prerequisite for effective retrieval technology. However, as terminology is evolving over time, a growing gap opens up between older documents in (long-term) archives and the active language used for querying such archives. Thus, technologies for detecting and systematically handling terminology evolution are required to ensure "semantic" accessibility of (Web) archive content on the long run. As a starting point for dealing with terminology evolution this paper formalizes the problem and discusses issues, first ideas and relevant technologies.
Als Terrence Malicks Kinodebüt BADLANDS im Oktober 1973 Premiere auf dem New Yorker Filmfest feierte, saß auch Vincent Canby, Kritiker der New York Times, im Kinosaal. Canby schrieb eine überaus positive Rezension über dieses Drama um ein junges Paar auf der Flucht (1973/1). Wenige Tage später war BADLANDS für ihn „The Movie that Made the Festival Memorable“ – so die Überschrift seines abschließenden Festivalberichts (1973/2). Doch über die in dem Film verwendete Musik verlor er kein Wort. Pauline Kael, Kritikerin des New Yorker, erwähnte die Musik in ihrer Rezension des Films zum US-Kinostart wenige Monate später nur am Rande (vgl. Kael 1974). Und auch in einem Interview, das Michel Ciment, Herausgeber des französischen Filmmagazins Positif, im März 1975 in Los Angeles mit Malick führte, wird nur kurz auf die musikalische Ebene eingegangen (1975, 32). Dabei ist der Soundtrack eine ganz zentrale Dimension dieses Films. Umso dringlicher erscheint es, BADLANDS mit Blick auf die Musik genauer zu untersuchen.
Wir haben das Feld der sozialen Situationen sondiert und die spektatorische Situation als eine spezifische Zeichensituation und Verkehrsform erörtert. Darüber hinaus sind problemgeschichtliche Aspekte der Figur des Zuschauers zur Sprache gekommen; gleichsam als Bestandteil konzeptioneller Vorarbeiten zur konkreten kultursemiotischen Untersuchung historischer Modelle von Spectatorship in ihrer funktionellen Typenvielfalt.
Editionen separieren Texte von den Kontexten, in denen sie bei ihrem Entstehungsprozess mit der Hand und technischen Schreibwerkzeugen unterschiedlichster Art geschrieben, als Erstdruck publiziert und von den Zeitgenossen ursprünglich rezipiert worden sind. Zugleich generieren sie, je nach ihren editorischen Prämissen, für die späteren Leser durch die von ihnen vollzogene Selektion, die Anordnung nach Textsorten oder die Anwendung anderer Strukturierungsregeln sowie durch die dabei vorgenommene Hierarchisierung, Kommentierung oder auch Nicht-Kommentierung ihrerseits neue Kontexte und konstruieren so ein bestimmtes, die Rezeption lenkendes Profil von Autor und Werk. Das ist, wie bei anderen prominenten Autoren, auch in der Wirkungsgeschichte Walter Benjamins der Fall. Ich möchte diesem Spannungsverhältnis von Dekontextualisierung und Rekontextualisierung im Folgenden am Beispiel der sogenannten 'kleineren' literaturkritischen Arbeiten - schon das Epitheton ist ein Beispiel für den erwähnten Selektions- und Hierarchisierungsprozess - nachgehen, also anhand der 'Kritiken und Rezensionen', die Benjamin seit der zweiten Hälfte der 1920er Jahre in der 'Frankfurter Zeitung', der 'Literarischen Welt' und an anderer Stelle veröffentlicht hat und deren Korpus im Wesentlichen in dem 1972 publizierten dritten Band der 'Gesammelten Schriften' publiziert worden ist. Ich werde mich dabei, in Blick auf den für diesen Beitrag zur Verfügung stehenden Raum, auf die Skizze zentraler Grundprobleme, auf pointierte Thesen und exemplarische Beispiele beschränken – in der Hoffnung, gerade durch solche Verknappung und Pointierung Impulse für eine weiterführende Diskussion der angesprochenen Probleme zu liefern. Einleitend werde ich zunächst einige grundsätzliche Fragen der Benjamin-Edition skizzieren. Im Anschluss daran werde ich die aktuelle Editionslage von Benjamins Arbeiten zur Literaturkritik im Hinblick auf die Leitfrage meines Beitrags, also auf das Spannungsverhältnis von Text(en) und Kontext(en), kritisch analysieren. Schließlich soll anhand einiger ausgewählter Rezensionen exemplarisch gezeigt werden, welche Bedeutung die in der bisherigen Editionspraxis meist ausgeblendeten Kontexte (z.B. Publikations-, Medien-, Wissenschaftskontexte, biografisch-soziale Kontexte, historische und politische Kontexte etc.) für ein Verständnis des Literaturkritikers Benjamin gewinnen können, sofern man ihnen editorisch die gebührende Beachtung schenkt. Dabei werden Umrisse eines neuen und anderen Benjamin-Bildes sichtbar, das sich von dem bisher verbreiteten nicht nur in Nuancen unterscheidet.
This article parts from an interdisciplinary point of view. Its main interest lies in the rich and complex interaction between the literary text and the image. These relations are understood as a “reciprocal illumination between the arts”, according to a publication of Oskar Walzel (Berlin, 1917). It will first investigate two historical landmarks in relation to literature and the image: first, the social differentiation around 1800 and its imposition of a purely textual literature and second, the avant-garde with its intense interaction between the various forms of artistic communication. The paper will then approach two contemporary examples of novels which combine visual and textual material.
' The United Nations-organised plebiscite on 11 February 1961 was one of the most significant events in the history of the southern and northern parts of the British-administered trust territory in Cameroon. John Percival was sent by the then Colonial Office as part of the team to oversee the process. This book captures the story of the plebiscite in all its dimensions and intricacies and celebrates the author's admiration for things African through a series of reminiscences of what life was like in the 1960s, both for the Africans themselves and for John Percival as a very young man. The complex story is also a series of reflections about the effect of the modern world on Africa. It is a thorough, insightful, rich and enlightening first-hand source on a political landmark that has never been told before in this way. In a vivid style with a great sense of humour, Percival's witty, cogent, eyewitness and active-participant account deconstructs the rumours and misrepresentations about the February 1961 Plebiscite which was a prelude to reunification and to the present day politics of 'belonging' in Cameroon. ''One of the major merits of this book is to provide us with a deeper insight into the role of those actors who have never been the subject of plebiscite studies, namely the Plebiscite Supervisory Officers.'' - Piet Konings, African Studies Centre, Leiden, The Netherlands John Percival-Anthropologist, Writer, Television Broadcaster of many innovative BBC series on the environment, history and anthropology. As a young graduate he was recruited and sent to serve in the Southern Cameroons as a Plesbiscite Supervisory Officer in 1961. He died in 2005 after a recent return visit to Cameroon with Nigel Wenban-Smith who writes an epilogue. This posthumous memoir has been edited by his wife, Lalage Neal.'
We perform a detailed study of the adjoint static potential in the pseudoparticle approach, which is a model for SU(2) Yang-Mills theory. We find agreement with the Casimir scaling hypothesis and there is clear evidence for string breaking. At the same time the potential in the fundamental representation is linear for large separations. Our results are in qualitative agreement with results from lattice computations.
Naturalness is one of the most important criteria in nature conservation. This paper examines the fundamental concepts underlying the definition and assessment of naturalness. Its role in nature conservation and forest management under conditions of global change is also discussed. The degree of naturalness may be defined in ordinal classes. The “static” concept of the potential natural vegetation (pnV), developed in the 1950ies, is mostly used as the reference state. In other cases, its reversed concept, the hemeroby (degree of articifiality) is assessed, based on the intensity and frequency of human impacts. Since the 1970ies, more attention has been given to natural dynamics than in earlier approaches, e.g. in forest succession models. At the end of the 1980ies, the previous importance was increasingly stressed of natural browsing by large herbivores and the role of predators. These large herbivors are extinct today in most cultural European landscapes. It is assumed, that they open up the canopy, and create park-like forest structures which contain a diversity of habitats for other types of organism (birds, insects). Changed and permanently changing environments and altering patterns of competition between species continue to modify natural processes today. Some of the more conspicuous effects are the extinction of native species and immigration of species to new regions. Long-lived ecosystems like forests are however not able to adapt quickly to such changes and may be unable to find a new balance with the environment. Today, such changes occur very rapidly, and are reducing the original naturalness of ecosystems. Because of this, the criterion “naturalness” must be downweighted. Conversely, more importance should be attached to other criteria: particularly originality (= original naturalness) and restorability. Forestry is contributing to this accelerated change of biocoenoses by increasing disturbances and introducing exotic tree species. Naturalisation of some exotic tree species modifies the natural processes and creates a “new allochthonous naturalness”. Because of this, forest planning should try to preserve or restore stands with attributes of the “original forest”. Exotic species should not be planted, or only in a very restricted way.
The Barn
(2008)
As a veteran playwright and actor, Kwo Victor Elame Musinga is more than just a pioneer in popular theatre. His simple but profound messages demonstrate a depth of understanding and insight into human nature and the nature of society. The texts he crafts are universal and timeless in their content and appeal, even as the themes and situations that inspire them are localized in specific places, experiences and histories. The Barn is a collection of three topical plays. Njema captures the predicament of love in a context where innocence and trust are preyed upon by deceit, dishonesty, promiscuity, waywardness, callous indifference to human life, the reckless abandon of parental authority and wisdom by youth in a hurry to celebrate sexuality, irresponsible manhood with or without the connivance of girls/women, and HIV/AIDS and its terror. Invitation to God addresses elitism and fair-weather friendship even among believers. In Moka, the theme of friendship is explored through the simple act of dishonesty and greed, especially to those with whom one should be nothing but virtuous, open, generous and kind. In these plays Kwo Victor Elame Musinga explores the virtues of being human, while addressing the dark side of humanity.
The bee fauna of the Greater Puerto Rico area was studied. A review of the previous relevant studies is presented. An annotated catalog and information about the origin and distributional patterns are also provided. Thirty-nine species of bees occur in Puerto Rico and adjacent islands. This fauna is composed of four elements: exclusive Puerto Rican endemics (26.5%); Antillean endemics occurring on multiple islands (76.5%); continental species that have also colonized the Antilles (23.5%); and species introduced through human activity (12.8%). The bee fauna was both low in its diversity and showed the highest level of disharmony in relation to other faunas of the Greater Antilles. A lectotype is here designated for Agapostemon krugii Wolcott, 1936.
Cellular metabolism can be envisaged by fluorescence lifetime imaging of fluorophores sensitive to specific intracellular factors such as [H+], [Ca2+], [O2], membrane potential, temperature, polarity of the probe environment, and alterations in the conformation and interactions of macromolecules. Lifetime measurements of the probes allow the quantitative determination of the intracellular factors. Fluorescence microscopy taking advantage of time-correlated single photon counting is a novel method that outperforms all other techniques with its single photon sensitivity and picoseconds time resolution. In this work, a time- and space-correlated single photon counting system was established to investigate the behavior of 2-(4-(dimethylamino)styryl)-1-methylpyridinium iodide (DASPMI) in living cells. DASPMI is known to selectively stain mitochondria in living cells. The uptake and fluorescence intensity of DASPMI in mitochondria is a dynamic measure of membrane potential. Hence, an endeavour was made to elucidate the mechanism of DASPMI fluorescence by obtaining spectrally-resolved fluorescence decays in different solvents. A bi-exponential decay model was sufficient to globally describe the wavelength dependent fluorescence in ethanol and chloroform. While in glycerol, a three-exponential decay model was necessary for global analysis. In the polar low-viscous solvent water, a mono-exponential decay model fitted the decay data. The sensitivity of DASPMI fluorescence to solvent viscosity was analysed using various proportions of glycerol/ethanol mixtures. The lifetimes were found to increase with increasing solvent viscosity. The negative amplitudes of the short lifetime component found in chloroform and glycerol at the longer wavelengths validated the formation of new excited state species from the initially excited state. Time-resolved emission spectra in chloroform and glycerol showed a biphasic increase of spectral width and emission maxima. The spectral width had an initial fast increase within 150 ps and a near constant thereafter. A two-state model based on solvation of the initially excited state and further formation of TICT state has been proposed to explain the excited state kinetics and has been substantiated by the de-composition of time-resolved spectra. The knowledge of DASPMI photophysics in a variety of solvents now provides the means of deducing complex physiological parameters of mitochondria from its behavior in living cells. Spatially-resolved fluorescence decays from single mitochondria or only very few organelles of XTH2 cells signified distinctive three-exponential decay kinetics of viscous environment. Based on DASPMI photophysics in a variety of solvents, these lifetimes have been attributed to the fluorescence from locally excited state (LE), intramolecular charge transfer state (ICT) and twisted intramolecular charge transfer (TICT) state. A considerable variation in lifetime among mitochondria of different morphology and within single cell was evident corresponding to the high physiological variations within single cells. Considerable shortening of the short lifetime component (τ1) under high membrane potential condition, such as in the presence of ATP and/or substrate, was similar to quenching and dramatic decrease of lifetime in polar solvents. Under these conditions τ2 and τ3 increased with decreasing contribution. Upon treatment with ionophore nigericin, hyperpolarization of mitochondria resulted in remarkable shortening of τ1 from 159 ps to 38 ps. Inhibiting respiration by cyanide resulted in notable increase of mean lifetime and decrease of mitochondrial fluorescence. Increase of DASPMI fluorescence on conditions elevating mitochondrial membrane potential has been attributed to uptake according Nernst distributions, to de-localisation of π electrons, quenching processes of the methyl pyridinium moiety and restricted torsional dynamics at the mitochondrial inner membrane. Accordingly, determination of anisotropy in DASPMI stained mitochondria in living XTH2 cells, revealed dependence of anisotropy on membrane potential. Such changes in anisotropy attributed to restriction of the torsional dynamics about the flexible single bonds neighboring the olefinic double bond revealed the previously known sub-mitochondrial zones with higher membrane potential along its length. Membrane-potential-dependent changes in anisotropy have further been demonstrated in senescent chick embryo fibroblasts. In conclusion, spectroscopic observations of excited-state kinetics of DASPMI in solvents and its behavior in living cells had revealed for the first time its localisation, mechanism of voltage sensitive fluorescence and its membrane-potential-dependent anisotropy in living cells. The simultaneous dependence of DASPMI photophysics on mitochondrial inner membrane viscosity and transmembrane potential has been highlighted.
A list of all liverworts and mosses reported from the Maltese Islands with references has been compiled from the literature, which includes 23 species of liverworts and hornworts as well as 96 taxa of mosses. The list is completed by the results of a bryological fieldtrip in March 2008. During this trip, 14 species of liverworts and 40 species of mosses were collected, of which Cephaloziella baumgartneri, Didymodon luridus, Fissidens gracilifolius, Fossombronia echinata, Funaria pulchella, Riccia cavernosa and Weissia fallax are new to Malta. This raises the number of species known from the Maltese Islands to 23 horn- and liverworts and 100 mosses.
This book richly documents the battles fought by the Anglophone community in Cameroon to safeguard the General Certificate of Education (GCE), a symbol of their cherished colonial heritage from Britain, from attempts by agents of the Ministry of National Education to subvert it. These battles opposed a mobilised and determined Anglophone civil society against numerous machinations by successive Francophone-dominated governments to destroy their much prided educational system in the name of 'national integration'. When Southern Cameroonians re-united with La R?publique du Cameroun in 1961, they claimed that they were bringing into the union 'a fine education system' from which their Francophone compatriots could borrow. Instead, they found themselves battling for decades to save their way of life. Central to their concerns and survival as a community is an urgent need for cultural recognition and representation, of which an educational system free of corruption and trivialisation through politicisation is a key component.
The Chanukah omission
(2008)
In a charter issued on 5 May 1513, the mayor and city council of the city of Freiburg/Breisgau reported that several citizens wanted to be allowed to establish a bruderschaft der sengerye, a confraternity of singing. “God, the almighty, would be praised thereby, the souls would be consoled, and all men listening to the concerts would be kept from blasphemy, gaming and other secular vices” (“gott der allmechtig [würde] dardurch gelopt, die selen getröst und die menschen zu zyten, so sy dem gesang zuhorten, von gotslesterung, ouch vom spyl vnd anderer weltlicher uppigkeyt gezogen”). Considering not least the “positive effects on the pour souls” (“guettaeten, so den armen selen dardurch nachgeschechen mocht”), the request was allowed. But the petitioners had to establish their bruderschaft in exactly the form that is described in detail in the regulations (ordnung) added to the request and cited “word for word” (“von wort zu wort”) in 17 articles in the foundation charter of the confraternity.
Hong Kong’s Linked Exchange Rate System (LERS) has been in operation for twenty-five years during which time many other fixed exchange rate systems have succumbed to shocks and/or speculative attacks. This fact alone suggests that the LERS is a robust system which enjoys a large measure of credibility in financial markets. This paper intends to investigate whether this is indeed the case, and whether it has been the case throughout its 25-year history. In particular we will use the tools of modern finance to extract information from financial asset prices about market expectations that are related to the credibility of the LERS. The main focus is on how market participants ‘judged’ the various changes made to the LERS, such as the ‘seven technical measures’ introduced in September 1998 and the ‘three refinements’ made in May 2005. These changes have been characterizes as making the system less discretionary over time, and we hypothesize that they have also made it more credible as revealed in the prices of exchange rate related asset prices. We also investigate the relationship between interest rates and exchange rates in the current system in light of modern models of target-zone exchange rate systems. We will examine whether the intramarginal intervention in November 2007 changed the dynamic properties of the exchange rate as suggested by such models.
Ribosome biogenesis in eukaryotes requires the participation of a large number of ribosome assembly factors. The highly conserved eukaryotic nucleolar protein Nep1 has an essential but unknown function in 18S rRNA processing and ribosome biogenesis. In Saccharomyces cerevisiae the malfunction of a temperature-sensitive Nep1 protein (nep1-1ts) was suppressed by the addition of S-adenosylmethionine (SAM). This suggests the participation of Nep1 in a methyltransferase reaction during ribosome biogenesis. In addition, yeast Nep1 binds to a 6-nt RNA-binding motif also found in 18S rRNA and facilitates the incorporation of ribosomal protein Rps19 during the formation of pre-ribosomes. Here, we present the X-ray structure of the Nep1 homolog from the archaebacterium Methanocaldococcus jannaschii in its free form (2.2 Å resolution) and bound to the S-adenosylmethionine analog S-adenosylhomocysteine (SAH, 2.15 Å resolution) and the antibiotic and general methyltransferase inhibitor sinefungin (2.25 Å resolution). The structure reveals a fold which is very similar to the conserved core fold of the SPOUT-class methyltransferases but contains a novel extension of this common core fold. SAH and sinefungin bind to Nep1 at a preformed binding site that is topologically equivalent to the cofactor-binding site in other SPOUT-class methyltransferases. Therefore, our structures together with previous genetic data suggest that Nep1 is a genuine rRNA methyltransferase.
The Day God Blinked
(2008)
The Day God Blinked x-rays the politico-economic and socio-moral life of a rich and resourceful country called Ewawa from 1982 to 2007. The country had been ruled by a dynamic and insightful miser known as the Old Man. But because he had been in power for too long, his citizens longed for change. It happened when nobody expected it. The old man died suddenly in his sleep and was replaced by his handpicked successor. Unfortunately, the successor whom everybody had expected would do better plunged the country into terrible economic and moral crises. Lucia, the protagonist, narrates her predicament. To her, Ewawa is rotten in all totality. There is nowhere to turn for salvation. The custodians of the economic, social, moral and spiritual values of the land are not up to the task. The country is without hope. Is all doomed?
Previous evidence suggests that less liquid stocks entail higher average returns. Using NYSE data, we present evidence that both the sensitivity of returns to liquidity and liquidity premia have significantly declined over the past four decades to levels that we cannot statistically distinguish from zero. Furthermore, the profitability of trading strategies based on buying illiquid stocks and selling illiquid stocks has declined over the past four decades, rendering such strategies virtually unprofitable. Our results are robust to several conventional liquidity measures related to volume. When using liquidity measure that is not related to volume, we find just weak evidence of a liquidity premium even in the early periods of our sample. The gradual introduction and proliferation of index funds and exchange traded funds is a possible explanation for these results.
Vertov defined the basic qualities of his Cine-Eye by means of a simple negation: it sees what remains inaccessible to the human eye. This means that in his films we see media-based and media-produced images that have nothing to do with the imitation of human perception. According to Vertov, such filmic, telescopic, or microscopic perception develops, educates, and expands the viewer’s analytical abilities. Thus, we have on the one hand a media-induced perception and on the other a new assemblage or montage of the fragments of this mediated perception. This new montage is based on a specific interaction and follows poetic rather than prosaic rules. It is freed from such constraints as time, space, causality, or speed. In other words it is based on properly media-specific qualities and, following the terminology of the Russian Futurists who influenced Vertov in his youth, it constitutes zaum or transrationality.
The case for privatization, whether defined in a broad or narrow sense, has been forcefully made by its advocates against the backdrop of the much advertised poor performances of state-owned enterprises (SOEs) and theoretical arguments relating to the efficiency of private firms over public enterprises. Consequently, privatization and commercialization have been key components of the structural adjustment programmes foisted by the Bretton Woods institutions on Third World countries. Yet, the empirical findings on privatization, especially outside Africa where they exist, do not portray the strategy to be a panacea that works in all circumstances in all branches of economic activity. In spite of this, since the late 1980s, privatization has been stepped up in almost all African countries. And after about two decades of vigorous implementation of privatization programmes in Africa, there is a compelling need for a comprehensive and systematic analysis of various privatization issues, particularly the economic and social impact. This book thus establishes a clear case for a comprehensive and systematic analysis of the impact of privatization in Africa. Specifically, the book provides a state-of-the art review of privatization issues and research questions as a prelude to an in-depth study of the economic and social impact of privatization. In the light of the rich insights brought to bear on the issues, this book should stimulate the interest of researchers, donors and policy makers to undertake or support the follow-up in-depth research envisaged.
Based on a unique dataset of legislative changes in industrial countries, we identify events that strengthen the competition control of mergers and acquisitions, analyze their impact on banks and non-financial firms and explain the different reactions observed with specific regulatory characteristics of the banking sector. Covering nineteen countries for the period 1987 to 2004, we find that more competition-oriented merger control increases the stock prices of banks and decreases the stock prices of non-financial firms. Bank targets become more profitable and larger, while those of non-financial firms remain mostly unaffected. A major determinant of the positive bank returns is the degree of opaqueness that characterizes the institutional setup for supervisory bank merger reviews. The legal design of the supervisory control of bank mergers may therefore have important implications for real activity.
Generally, information provision and certifcation have been identified as the major economic functions of rating agencies. This paper analyzes whether the “watchlist” (rating review) instrument has extended the agencies' role towards a monitoring position, as proposed by Boot, Milbourn, and Schmeits (2006). Using a data set of Moody's rating history between 1982 and 2004, we find that the overall information content of rating action has indeed increased since the introduction of the watchlist procedure. Our findings suggest that rating reviews help to establish implicit monitoring contracts between agencies and borrowers and as such enable a finer partition of rating information, thereby contributing to a higher information quality.
Generally, information provision and certification have been identified as the major economic functions of rating agencies. This paper analyzes whether the “watchlist" (rating review) instrument has extended the agencies' role towards a monitoring position, as proposed by Boot, Milbourn, and Schmeits (2006). Using a data set of Moody's rating history between 1982 and 2004, we find that the overall information content of rating action has indeed increased since the introduction of the watchlist procedure. Our findings suggest that rating reviews help to establish implicit monitoring contracts between agencies and borrowers and as such enable a finer partition of rating information, thereby contributing to a higher information quality.
Poster presentation A central problem in neuroscience is to bridge local synaptic plasticity and the global behavior of a system. It has been shown that Hebbian learning of connections in a feedforward network performs PCA on its inputs [1]. In recurrent Hopfield network with binary units, the Hebbian-learnt patterns form the attractors of the network [2]. Starting from a random recurrent network, Hebbian learning reduces system complexity from chaotic to fixed point [3]. In this paper, we investigate the effect of Hebbian plasticity on the attractors of a continuous dynamical system. In a Hopfield network with binary units, it can be shown that Hebbian learning of an attractor stabilizes it with deepened energy landscape and larger basin of attraction. We are interested in how these properties carry over to continuous dynamical systems. Consider system of the form Math(1) where xi is a real variable, and fi a nondecreasing nonlinear function with range [-1,1]. T is the synaptic matrix, which is assumed to have been learned from orthogonal binary ({1,-1}) patterns ξμ, by the Hebbian rule: Math. Similar to the continuous Hopfield network [4], ξμ are no longer attractors, unless the gains gi are big. Assume that the system settles down to an attractor X*, and undergoes Hebbian plasticity: T´ = T + εX*X*T, where ε > 0 is the learning rate. We study how the attractor dynamics change following this plasticity. We show that, in system (1) under certain general conditions, Hebbian plasticity makes the attractor move towards its corner of the hypercube. Linear stability analysis around the attractor shows that the maximum eigenvalue becomes more negative with learning, indicating a deeper landscape. This in a way improves the system´s ability to retrieve the corresponding stored binary pattern, although the attractor itself is no longer stabilized the way it does in binary Hopfield networks.
In this paper, we examine the impact of mergers among German savings banks on the extent to which these savings banks engage in small business lending. The ongoing consolidation in the banking industry has sparked concerns about the continuous availability of credit to small businesses which has been further fueled by empirical studies that partly confirm a reduction in small business lending in the aftermath of mergers. However, using a proprietary data set of German savings banks we find strong evidence that in Germany merging savings banks do not significantly change the extent to which they lend to small businesses compared to prior to the merger or compared to the contemporaneous lending by non-merging banks. We investigate the merger related effects on small business lending in Germany from a bank-level perspective. Furthermore, we estimate small business lending and its continuous adjustment process simultaneously using recent General Method of Moments (GMM) techniques for panel data as proposed by Arellano and Bond (1991).
We study the effect of randomness in the adversarial queueing model. All proofs of instability for deterministic queueing strategies exploit a finespun strategy of insertions by an adversary. If the local queueing decisions in the network are subject to randomness, it is far from obvious, that an adversary can still trick the network into instability. We show that uniform queueing is unstable even against an oblivious adversary. Consequently, randomizing the queueing decisions made to operate a network is not in itself a suitable fix for poor network performances due to packet pileups.
Motivated by the recent discussion of the declining importance of deposits as banks´ major source of funding we investigate which factors determine funding costs at local banks. Using a panel data set of more than 800 German local savings and cooperative banks for the period from 1998 to 2004 we show that funding costs are not only driven by the relative share of comparatively cheap deposits of bank´s liabilities but among other factors especially by the size of the bank. In our empirical analysis we find strong and robust evidence that, ceteris paribus, smaller banks exhibit lower funding costs than larger banks suggesting that small banks are able to attract deposits more cheaply than their larger counterparts. We argue that this is the case because smaller banks interact more personally with customers, operate in customers´ geographic proximity and have longer and stronger relationships than larger banks and, hence, are able to charge higher prices for their services. Our finding of a strong influence of bank size on funding costs is also in an in- ternational context of great interest as mergers among small local banks - the key driver of bank growth - are a recent phenomenon not only in European banking that is expected to continue in the future. At the same time, net interest income remains by far the most important source of revenue for most local banks, accounting for approximately 70% of total operating revenues in the case of German local banks. The influence of size on funding costs is of strong economic relevance: our results suggest that an increase in size by 50%, for example, from EUR 500 million in total assets to EUR 750 million (exemplary for M&A transactions among local banks) increases funding costs, ceteris paribus, by approximately 18 basis points which relates to approx. 7% of banks´ average net interest margin.
The emperor's new colonies
(2008)
The Colonial Picture Archive in Frankfurt offers a unique pictorial record of German colonial history. For many years the collection was virtually forgotten. However, following painstaking description and digitalisation, the photo documents are now available on the Internet to researchers in Germany and abroad.
The enigmatic R. David Lida
(2008)
On 27 and 28 September 2007, a commission formed on the initiative of the authors held its first meeting in Aarhus, Denmark to deliberate on its goal of drafting a "European Model Company Law Act" (EMCLA). This project, outlined in the following pages, aims neither to force a mandatory harmonization of national company law nor to create a further, European corporate form. The goal is rather to draft model rules for a corporation that national legislatures would be free to adopt in whole or in part. Thus, the project is thought as an alternative and supplement to the existing EU instruments for the convergence of company law. The present EU instruments, their prerequisites and limits will be discussed in more detail in Part II, below. Part III will examine the US experience with such "model acts" in the area of company law. Part IV will then conclude by discussing several topics concerning the content of an EMCLA, introducing the members of the EMCLA Working Group, and explaining the Group's preliminary working plan.
The term cephalic sensory organ (CSO) is used for specialised structures in the head region of adult Opisthobranchia. These sensory organs show a high diversity in form and function, and the gross morphology of these organs differs considerably among taxa. They can be identified as cephalic shields, oral veils, Hancocks organs, lip organs, rhinophores or oral tentacles. Because of this extremely high diversity, the homology and the evolution of these organs have not been clarified yet. My intention was to use neuroanatomical data sets in order to find putative homologous CSOs. In this study, I will show data about immunohistochemical neurotransmitter content and cellular innervation patterns and their applicability as morphological characters for the homologisation of structures. I support earlier investigations that neurotransmitter content is often related to function. In contrast, axonal tracing patterns can be used to homologise nerves. Overall the aim of this study was to reconstruct the evolution of the CSOs of the Opisthobranchia, by projecting our neuroanatomical data sets onto a molecular phylogeny.
We report progress in our exploration of the finite-temperature phase structure of two-flavour lattice
QCD with twisted-mass Wilson fermions and a tree-level Symanzik-improved gauge action
for a temporal lattice size Nt = 8. Extending our investigations to a wider region of parameter
space we gain a global view of the rich phase structure. We identify the finite temperature transition/
crossover for a non-vanishing twisted-mass parameter in the neighbourhood of the zerotemperature
critical line at sufficiently high b . Our findings are consistent with Creutz’s conjecture
of a conical shape of the finite temperature transition surface. Comparing with NLO lattice
cPT we achieve an improved understanding of this shape.
The Fire Within
(2008)
In Africa, there is unrest, and possibly tragedy, when new trends clash with traditional values. With a curmudgeonly stepmother who harasses her even as she spoils her own biological daughter, Mungeu', the protagonist, blazes a path for herself in the face of many odds. But things go terribly wrong when she falls pregnant. The dilemma of whether or not to keep the pregnancy, given society's expectations, flings this young woman into direct confrontation with a life that is beyond her years. She is bent on succeeding: she will keep her baby, and with her training at a girls' craft center, start a business and bring up her illegitimate child. But Mungeu' can only make plans as she realises before long that the authority to dispose of them does not rest with her alone; there are other powerful forces out there.
The function of APOBEC3G in the innate immune response against the HIV infection of primary cells
(2008)
In the past few years the regulation of HIV-1 replication by cellular cofactors has been a major topic of ongoing research. These factors potentially represent new targets for antiviral therapy as resistance will be minimized. However this requires a better understanding of the interaction of HIV-1 with these cellular factors and the immune system. The virus infects the cells of the immune system, beginning with macrophages and dendritic cells as primary target cells during transmission. The cellular cofactor, APOBEC3G was found to be an antiviral factor in macrophages, dendritic cells and primary T cells. APOBEC3G is a cytidindeaminase which causes G->A hypermutations in the HIV-Genome. Another protein which has a strong inhibitory effect on the HIV infection is Interferon alpha (IFN-alpha), however the exact reason for this has not yet been elucidated. The bacterial protein, Lipopolysaccharide (LPS) also induces a strong antiviral state in macrophages. In micro-array analysis it was shown that APOBEC3G was upregulated after the stimulation with both IFN-alpha and LPS in macrophages. The goal of this work was to investigate the role of APOBEC3G in the innate immune response to APOBEC3G. For this, the expression of APOBEC3G was examined in HIV-1 target cells after stimulation with IFN-alpha or LPS and the effect of the protein on the viral infection was examined. In the first experiments it could be shown through real time quantitative PCR that APOBEC3G was overexpressed after the stimulation with IFN-alpha or LPS. This result could be shown in monocytes derived macrophages from different blood donors. It was also shown that the overexpression of APOBEC3G correlated directly with the concentration of IFN-alpha. Through mutational analysis it could be then shown that the overexpressed APOBEC3G protein was also functional in the cells. In order to show that this was the result of APOBEC3G, the protein was the regulated through lentiviral vectors. After transduction of cell lines with lentiviral vectors containing APOBEC3G, the infection was inhibited by up to 70%. The infection was restored after the addition of shRNAs against APOBEC3G. For the further experiments, CD34+ stem cells were used. The cells were transduced the day after thawing with lentiviral vectors containing an eGFP marker gene and either APOBEC3G or shRNAs against APOBEC3G. The CD34+ cells were then cultivated and differentiated to macrophages. The cells transduced with Lentiviral vectors containing APOBEC3G had a very high expression of APOBEC3G in the cells, however the cells transduced with shRNA against APOBEC3G did not show a reduction in the protein expression. The infectivity of the transduced CD34+ and CD34 derived macrophages was then examined. It was expected that the cells transduced with APOBEC3G would show a reduced HIV-1 infection, and the cells transduced with shRNA against APOBEC3G would show an increase in infection. After the transduction and differentiation the CD34+ cells from the 3 donors were stimulated and infected with wild type HIV-1 and Vif defective HIV-1 virus. Vif is a viral protein that can bind to APOBEC3G leading it to the proteasome for degradation. The cells from the first donor transduced with APOBEC3G, were very difficult to infect. In general the shRNA against APOBEC3G had little effect on the course of infection; presumably, the shRNA against APOBEC3G was not active in most of these cells. Only the cells from the first donor showed an increase in HIV infection after the transduction with the shRNAs against APOBEC3G, this was most notably the case in the cells stimulated with IFN-alpha, which usually show very little infection. This work showed that APOBEC3G plays an important role in the innate immune response to HIV-1. The effect of APOBEC3G is both cell type as well as donor dependent. Recently, an interesting study also showed that there is a correlation between the expression of APOBEC3G in HIV infected individuals and their progression to AIDS. A better understanding of the role that APOBEC3G plays in the innate immune response would help in the search of new therapeutic possibilities. This could be done by inhibiting the Vif-APOBEC3G interaction in order to increase the amount of active APOBEC3G in the cells or increasing the APOBEC3G concentration in the cells in some manner.
The future of securitization
(2008)
Securitization is a financial innovation that experiences a boom-bust cycle, as many other innovations before. This paper analyzes possible reasons for the breakdown of primary and secondary securitization markets, and argues that misaligned incentives along the value chain are the primary cause of the problems. The illiquidity of asset and interbank markets, in this view, is a market failure derived from ill-designed mechanisms of coordinating financial intermediaries and investors. Thus, illiquidity is closely related to the design of the financial chains. Our policy conclusions emphasize crisis prevention rather than crisis management, and the objective is to restore a “comprehensive incentive alignment”. The toe-hold for strengthening regulation is surprisingly small. First, we emphasize the importance of equity piece retention for the long-term quality of the underlying asset pool. As a consequence, equity piece allocation needs to be publicly known, alleviating market pricing. Second, on a micro level, accountability of managers can be improved by compensation packages aiming at long term incentives, and penalizing policies with destabilizing effects on financial markets. Third, on a macro level, increased transparency relating to effective risk transfer, risk-related management compensation, and credible measurement of rating performance stabilizes the valuation of financial assets and, hence, improves the solvency of financial intermediaries. Fourth, financial intermediaries, whose risk is opaque, may be subjected to higher capital requirements.
In the eastern United States, the genus Cotinis Burmeister previously contained only C. nitida (L.), the common economic pest known as the "Green June Beetle". A new species from the Florida Keys, Cotinis aliena, is here described and illustrated. A checklist is provided for the genus, which includes 27 valid New World species, and 44 synonyms.
The Glenn Miller story
(2008)
Der Film verfolgt das Leben des Jazzmusikers und späteren Bandleaders Glenn Miller. Zunächst wird er als armer Künstler dargestellt, der häufiger im Pfandleihhaus als auf der Bühne ist. Motiviert durch seinen Freund reist er nach New York, wo er ein Engagement am Broadway erhält. Auf dem Weg trifft er sich mit seiner unglücklich in einen anderen Mann verlobten Ex-Freundin, die er später nach New York holt und zügig und sehr zu ihrer Überraschung heiratet.
A new global crop water model was developed to compute blue (irrigation) water requirements and crop evapotranspiration from green (precipitation) water at a spatial resolution of 5 arc minutes by 5 arc minutes for 26 different crop classes. The model is based on soil water balances performed for each crop and each grid cell. For the first time a new global data set was applied consisting of monthly growing areas of irrigated crops and related cropping calendars. Crop water use was computed for irrigated land and the period 1998 – 2002. In this documentation report the data sets used as model input and methods used in the model calculations are described, followed by a presentation of the first results for blue and green water use at the global scale, for countries and specific crops. Additionally the simulated seasonal distribution of water use on irrigated land is presented. The computed model results are compared to census based statistical information on irrigation water use and to results of another crop water model developed at FAO.
Rising atmospheric CO2 is regarded as the main driver of global warming (Crowley, 2000). While temperature changes directly affect plants and animals (Root et al., 2003; Parmesan, 2006), the effects of CO2 on herbivores are mediated through changes in nutrient quality. Elevated concentrations of atmospheric CO2 are likely to increase photosynthetic activity and thus provide more C-based compounds which may alter plant chemical profiles and plant–herbivore–natural enemy interactions. There are several scenarios how insects will react when confronted with a different food quality. A nutrient poor diet, induced by nitrogen dilution, may result in compensatory feeding with either no adverse effects on insect performance or with negative effects on insect growth due to low digestibility of plant structural compounds (e.g. lignin) or toxic effects of secondary metabolites (e.g. tannins). Here we present data from on-tree feeding trials with larvae of the generalist herbivore Lymantria dispar and one of its natural enemies, the hymenopteran endoparasitoid Glyptapanteles liparidis, studied in 2005. The experiments were conducted at the Swiss free-air CO2 enrichment (FACE) site near Basel, in an approximately 80-100-yr-old, mixed-species forest. The data link changes in foliar chemistry of three tree species (Quercus petraea, Fagus sylvatica, Carpinus betulus) exposed to 540 ppm CO2 with herbivore and parasitoid performance.
We determine the hard-loop resummed propagator in an anisotropic QCD plasma in general covariant gauges and define a potential between heavy quarks from the Fourier transform of its static limit. We find that there is stronger attraction on distance scales on the order of the inverse Debye mass for quark pairs aligned along the direction of anisotropy than for transverse alignment.
Histone deacetylase (HDAC) inhibitors represent a promising class of antineoplastic agents which affect tumour growth, differentiation and invasion. The effects of the HDAC inhibitor valproic acid (VPA) were tested in vitro and in vivo on pre-clinical renal cell carcinoma (RCC) models. Caki-1, KTC-26 or A498 cells were treated with various concentrations of VPA during in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and to evaluate cell cycle manipulation. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. The anti-tumoural potential of VPA combined with low-dosed interferon-α (IFN-α) was also investigated. VPA significantly and dose-dependently up-regulated histones H3 and H4 acetylation and caused growth arrest in RCC cells. VPA altered cell cycle regulating proteins, in particular CDK2, cyclin B, cyclin D3, p21 and Rb. In vivo, VPA significantly inhibited the growth of Caki-1 in subcutaneous xenografts, accompanied by a strong accumulation of p21 and bax in tissue specimens of VPA-treated animals. VPA–IFN-α combination markedly enhanced the effects of VPA monotherapy on RCC proliferation in vitro, but did not further enhance the anti-tumoural potential of VPA in vivo. VPA was found to have profound effects on RCC cell growth, lending support to the initiation of clinical testing of VPA for treating advanced RCC.
The House of Falling Women
(2008)
House of Falling Women is the story of a young woman with quixotic ideas about improving the lot of women who finds out that the crusader's cloak is an uncomfortable one. Martha Elive, armed with a university education and a substantial legacy from a Dutchwoman she meets while studying abroad on a scholarship, decides to create an institute for the empowerment of women, only to find that the contradictions to be resolved are more firmly anchored in her psyche than elsewhere. In addition to her unexorcised ghosts and the legacies of a chequered love life, she has to contend with recalcitrant public opinion and moral inertia, the opposition of old-guard reactionaries, and the incomprehension of her small-town parents. House of Falling Women is a poignant, often hilarious story of the search by a group of women for a new place in society in a world where women are dissatisfied with the old values and bewildered by the new.
The impact of European integration on the German system of pharmaceutical product authorization
(2008)
The European Union has evolved since 1965 into an influential political player in the regulation of pharmaceutical safety standards. The objective of establishing a single European market for pharmaceuticals makes it necessary for member-states to adopt uniform safety standards and marketing authorization procedures. This article investigates the impact of the European integration process on the German marketing authorization system for pharmaceuticals. The analysis shows that the main focal points and objectives of European regulation of pharmaceutical safety have shifted since 1965. The initial phase saw the introduction of uniform European safety standards as a result of which Germany was obliged to undertake “catch-up” modernization. From the mid-1970s, these standards were extended and specified in greater detail. Since the mid-1990s, a process of reorientation has been under way. The formation of the European Agency for the Evaluation of Medicinal Products (EMEA) and the growing importance of the European authorization procedure, combined with intensified global competition on pharmaceutical markets, are exerting indirect pressure for EU member-states to adjust their medicines policies. Consequently, over the past few years Germany has been engaged in a competition-oriented reorganization of its pharmaceutical product authorization system the outcome of which will be to give higher priority to economic interests.
This paper analyzes liquidity in an order driven market. We only investigate the best limits in the limit order book, but also take into account the book behind these inside prices. When subsequent prices are close to the best ones and depth at them is substantial, larger orders can be executed without an extensive price impact and without deterring liquidity. We develop and estimate several econometric models, based on depth and prices in the book, as well as on the slopes of the limit order book. The dynamics of different dimensions of liquidity are analyzed: prices, depth at and beyond the best prices, as well as resiliency, i.e. how fast the different liquidity measures recover after a liquidity shock. Our results show a somewhat less favorable image of liquidity than often found in the literature. After a liquidity shock (in the spread or depth or in the book beyond the best limits), several dimension of liquidity deteriorate at the same time. Not only does the inside spread increase, and depth at the best prices decrease, also the difference between subsequent bid and ask prices may become larger and depth provided at them decreases. The impacts are both econometrically and economically significant. Also, our findings point to an interaction between different measures of liquidity, between liquidity at the best prices and beyond in the book, and between ask and bid side of the market.
We report evidence that the presence of hidden liquidity is associated with greater liquidity in the order books, greater trading volume, and smaller price impact. Limit and market order submission behavior changes when hidden liquidity is present consistent with at least some traders being able to detect hidden liquidity. We estimate a model of liquidity provision that allows us to measure variations in the marginal and total payoffs from liquidity provision in states with and without hidden liquidity. Our estimates of the expected surplus to providers of visible and hidden liquidity are positive and typically of the order of one-half to one basis points per trade. The positive liquidity provider surpluses combined with the increased trading volume when hidden liquidity is present are both consistent with liquidity externalities.
The Match method for the quantification of polar chemical ozone loss is investigated mainly with respect to the impact of the transport of air masses across the vortex edge. For the winter 2002/03, we show that significant transport across the vortex edge occurred and was simulated by the Chemical Lagrangian Model of the Stratosphere. In-situ observations of inert tracers and ozone from HAGAR on the Geophysica aircraft and balloon-borne sondes, and remote observations from MIPAS on the ENVISAT satellite were reproduced well by CLaMS. The model even reproduced a small vortex remnant that remained a distinct feature until June 2003 and was also observed in-situ by a balloon-borne whole air sampler. We use this CLaMS simulation to quantify the impact of transport across the vortex edge on ozone loss estimates from the Match method. We show that a time integration of the determined vortex average ozone loss rates, as performed in Match, results in a larger ozone loss than the polar vortex average ozone loss in CLaMS. The determination of the Match ozone loss rates is also influenced by the transport of air across the vortex edge. We use the model to investigate how the sampling of the ozone sondes on which Match is based represents the vortex average ozone loss rate. Both the time integration of ozone loss and the determination of ozone loss rates for Match are evaluated using the winter 2002/2003 CLaMS simulation. These impacts can explain the majority of the differences between CLaMS and Match column ozone loss. While the investigated effects somewhat reduce the apparent discrepancy in January ozone loss rates reported earlier, a distinct discrepancy between simulations and Match remains. However, its contribution to the accumulated ozone loss over the winter is not large.
Winterweizen bedeckte 1999-2004 64 % der Ackerfläche Schleswig-Holsteins, Winterraps 31 %. Die wichtigsten Schädlinge an Winterweizen waren die drei Getreideblattlausarten (Hom., Aphididae)(Sitobion avenae und Metopolophium dirhodum, selten Rhopalosiphum padi) und die beiden Oulema-Arten (Getreidehähnchen)(O. melanopus und O. lichenis) (Col., Chrysomelidae). An Winterraps traten im Untersuchungszeitraum auf: Meligethes aeneus (F.) (Rapsglanzkäfer) (Col., Nitidulidae) und Ceutorrhynchus assimilis (Payk.) (Kohlschotenrüßler) (Col., Curculionidae). In beiden Kulturen wurden sechs Feldversuche durchgeführt, mit frühen und späten Insektizid-Applikationen (an je zwei Standorten, mit vierfacher Wiederholung). Bei Weizen waren die Parzellen 50 m² groß, bei Raps 90 m². Bei Winterweizen zeigten beide Schaderreger-Gruppen negative Einflüsse auf den Ertrag, wenn sie nicht bei Bekämpfungsschwellen bekämpft wurden. Sowohl der Getreidehähnchen - als auch der Blattlausbefall waren signifikant negativ mit dem Ertrag korreliert. Die ökonomische Auswertung ergab, dass im Untersuchungszeitraum – bei Beachtung der Bekämpfungsschwellen - die frühe Bekämpfung der Getreidehähnchen-Larven wirtschaftlicher war als die spätere der Getreideblattläuse. Bei Winterraps erwies sich die Bekämpfung des Kohlschotenrüsslers als ertraglich und ökonomisch vorteilhaft, selbst ohne Auftreten von Dasineura brassicae (Winn.), der Kohlschotenmücke. Die Bekämpfung des Rapsglanzkäfers hingegen war nur in einem von sechs Versuchen ertragsmäßig und ökonomisch erfolgreich. Die Probleme bei diesem Schädling sind 1. die zu niedrige Bekämpfungsschwelle und 2. die Resistenz gegenüber synthetischen Pyrethroiden. Wurden in Schleswig-Holstein 1999 75.000 ha Ackerfläche mit Insektiziden behandelt (22.7 % AF), stieg die Fläche bis 2004 auf 220.000 (66.5 % AF). Die Anteile der einzelnen Wirkstoffe haben sich verändert.
The execution, clearing, and settlement of financial transactions are all subject to substantial scale and scope economies which make each of these complementary functions a natural monopoly. Integration of trade, execution, and settlement in an exchange improves efficiency by economizing on transactions costs. When scope economies in clearing are more extensive than those in execution, integration is more costly, and efficient organization involves a trade-off of scope economies and transactions costs. A properly organized clearing cooperative can eliminate double marginalization problems and exploit scope economies, but can result in opportunism and underinvestment. Moreover, a clearing cooperative may exercise market power. Vertical integration and tying can foreclose entry, but foreclosure can be efficient because market power rents attract excessive entry. Integration of trading and post-trade services is the modal form of organization in financial markets, which is consistent with the hypothesis that transactional efficiencies explain organizational arrangements in these markets.
This monograph describes the overall language situation in Luxembourg, a highly multilingual country in Western Europe, from a language policy and planning perspective. The first part discusses the social and historical contexts, including major societal changes and uncertainties about the future, which are bound up with Europeanisation and the accelerated processes of globalisation. It also deconstructs the notions of Luxembourgish as a 'minority language' and French as the 'language of prestige', and describes a two-pronged language ideology that allows for either monolingual identification with Luxembourgish or trilingual identification with the languages recognised by the language law of 1984 (Luxembourgish / German / French). The second part discusses the trilingual school-system, a system in which large numbers of romanophone students are forced to go through a German-language literacy programme. The third part provides an overview of language spread in the areas of the media and literary writing. The fourth part examines language purism and tensions concerning the standardisation of Luxembourgish, as well as the debates about language requirements for citizenship. The discussion shows how language policy scholarship needs to be approached from a multidimensional perspective, that is, by taking into account dynamics on the global, regional and local levels in addition to those at the state level.
After the pioneering German “Aktiengesetz” of 1965 and the Brazilian “Lei das Sociedades Anónimas” of 1976, Portugal has become the third country in the world to enact a specific regulation on groups of companies. The Code of Commercial Companies (“Código das Sociedades Comerciais”, abbreviately hereinafter CSC), enacted in 1986, contains a unitary set of rules regulating the relationships between companies, in general, and the groups of companies, in particular (arts. 481° to 508°-E CSC). With this set of rules, the Portuguese legislator has dealt with one of the major topics of modern Company Law. While this branch of law is traditionally conceived as the law of the individual company, modern economic reality is characterized by the massive emergence of large-scale enterprise networks, where parts of a whole business are allocated and insulated in several legally independent companies submitted to an unified economic direction. As Tom HADDEN put it: “Company lawyers still write and talk as if the single independent company, with its shareholders, directors and employees, was the norm. In reality, the individual company ceased to be the most significant form of organization in the 1920s and 1930s. The commercial world is now dominated both nationally and internationally by complex groups of companies”. This trend, which is now observable in any of the largest economies in the world, holds also true for small markets such as Portugal. Although Portuguese economy is still dominated by small and medium-sized enterprises, the organizational structure of the group has always been extremely common. During the 70s, it was estimated that the seven largest groups of companies owned about 50% of the equity capital of all domestic enterprises and were alone responsible for 3/4 of the internal national product. Such a trend has continued and even highlighted in the next decades, surviving to different political and economic scenarios: during the 80s, due to the process of state nationalization of these groups, an enormous public group with more than one thousand controlled companies has been created (“IPE - Instituto de Participações do Estado”); and during the 90s until today, thanks to the reprivatisation movement and the opening of our national market, we assisted to the re-emergence of some large private groups, composed of several hundred subsidiaries each, some of which are listed in foreign stock exchange markets (e.g., in the banking sector, “BCP – Banco Comercial Português”, in the industrial area, “SONAE”, and in the media and communication area, “Portugal-Telecom”).
In left critiques of globalization, it is often argued that liberal-egalitarian principles are inadequate for thinking about and struggling for global justice; that they are, in fact, part of the problem. For the case of identity politics as a left alternative, the paper points at two fallacies in this notion, regarding two ‘liberal’ elements: individualism and universalism. The paper examines groupidentity claims in far right conceptions of global injustice, and shows that cultural diversity of groups does not necessitate or even favour equality and democratic participation. It then examines the left group-based claims in the global justice discourse, showing that the aspirations for equality and freedom assume the liberal notions that have been often rejected as inadequate. The paper concludes that this ambivalent position undermines the democratic and egalitarian aspirations of left critiques of the global order. The analysis is based on manifestos and publications of political parties and movements in Western Europe (France, Germany and Austria).
The market reaction to legal shocks and their antidotes : lessons from the sovereign debt market
(2008)
This Article examines the market reaction to a series of legal events concerning the judicial interpretation of the pari passu clause in sovereign debt instruments. More generally, the Article provides insights into the reactions of investors (predominantly financial institutions), issuers (sovereigns), and those who draft bond covenants (lawyers), to unanticipated changes in the judicial interpretation of certain covenant terms.
Production of reactive oxygen species (ROS) by the mitochondrial respiratory chain is considered to be one of the major causes of degenerative processes associated with oxidative stress. Mitochondrial ROS has also been shown to be involved in cellular signaling. It is generally assumed that ubisemiquinone formed at the ubiquinol oxidation center of the cytochrome bc(1) complex is one of two sources of electrons for superoxide formation in mitochondria. Here we show that superoxide formation at the ubiquinol oxidation center of the membrane-bound or purified cytochrome bc(1) complex is stimulated by the presence of oxidized ubiquinone indicating that in a reverse reaction the electron is transferred onto oxygen from reduced cytochrome b(L) via ubiquinone rather than during the forward ubiquinone cycle reaction. In fact, from mechanistic studies it seems unlikely that during normal catalysis the ubisemiquinone intermediate reaches significant occupancies at the ubiquinol oxidation site. We conclude that cytochrome bc(1) complex-linked ROS production is primarily promoted by a partially oxidized rather than by a fully reduced ubiquinone pool. The resulting mechanism of ROS production offers a straightforward explanation of how the redox state of the ubiquinone pool could play a central role in mitochondrial redox signaling.