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- 242175 (1)
Inhaltsübersicht zum Schwerpunktthema: - Wozu Metalle nützlich sein können - Ein Beitrag zur "grünen Chemie" - Der gezielte Aufbau "chiraler Achsen" - Selektiver Aufbau von Naturstoffen mit Hilfe von Metallkomplexen - Dynamik des Energietransportes innerhalb von Molekülen - Von Erdöl über Kohlenwasserstoffe zu interessanten Zielmolekülen u.a.
This study explores and examines the geomorphology of a large endorheic basin, approximately twice the size of Luxemburg, situated in the Etosha National Park, Namibia. The main focus is directed on how and when this depression, known as Etosha Pan, came into being. Geomorphological investigation was complemented and guided primarily by the application and interpretation of satellite-derived information. Etosha Pan has attracted scientific investigations for nearly a century. Unfortunately, their efforts resulted into two diverging and mutually exclusive views with respect to its development. The first and oldest view dates back to the 1920s. It hypothesized Etosha Pan as a desiccated palaeolake which was abandoned following the river capture of its major fluvial system, the Kunene River. The river capture was assumed to have taken place in the Pliocene/Early Pleistocene. In spite of the absence of fluvial input that the Kunene contributed, the original lake was thought to have persisted until some 35 ka ago, long after the Kunene severed its ties with the basin. The current size of the basin and its playa status was interpreted to have resulted from deteriorating climatic conditions. The opposing view emerged in the 1980s and gained prominence in the 1990s. This view assumed that there were an innumerable number of small pans on the then surface of what later to become Etosha Pan. Since the turn of the Pliocene to Early Pleistocene, these individual pans started to experience a combined effect of fluvial erosion during the rainy season and wind deflation during the dry period. The climatic regime during that entire period was postulated to be semi-arid as today. This climatic status was used to rule out any existence of a perennial lake within the boundary of Etosha since the Quaternary. Ultimately, these denudational processes, taking place in a seasonal rhythm, caused the individual pans to deepen and widen laterally into each other and formed a super-pan that we call Etosha today. Thus the Kunene River had no role to play in the development of the Etosha Pan according to this model. However, proponents of this model acknowledged that the Kunene once fed into the Owambo Basin and assigned the end of the Tertiary to the terminal phase of that inflow. Findings of this study included field evidence endorsing the postulation that the Kunene River had once flowed into the Owambo Basin. Its infilled valley, bounding with the contemporary valley of the Kunene near Calueque, was identified and points towards the Etosha Pan. It is deliberated that a large lake, called Lake Kunene, existed in the basin during the time. Following the deflection of the Kunene River to the coast under the influence of river incision and neo-tectonic during the Late Pliocene, new dynamics were introduced over the Owambo Basin surface. After the basin was deprived of its major water and sediment budget that the Kunene River contributed, it was left with only smaller rivers, most notably the Cuvelai System, as the only remaining supplier. This resulted in the Cuvelai System concentrating and limiting its collective load deposition to a lobe of Lake Kunene basin floor. The accident of that lobe is unclear, but it is likely that it constituted the deepest part of the basin at the time or it was influenced by neo-tectonic that helped divert the Kunene River or both. Against the backdrop of fluvial action that was initiating the new lake, most parts of the rest of the basin, then denied of lacustrine activity, were intermittently riddled with a veneer of sediment, especially during phases of intensified aeolian activity. In the mean time, the area that was regularly receiving fluvial input started to shape up as a distinct lake with the depositions of sediments around the water-body, primarily via littoral action, serving as embankment. Gradually, a shoreline is formed and assisted in fixing and delineating the spatial extent of the new and much smaller lake, called Lake Etosha. That Lake Etosha is the predecessor of the modern day Etosha Pan. Indicators for a perennial lake found in this study at Etosha include fossil fragments of Clariidae species comparable to modern species measuring some 90 cm, and those of sitatunga dated to approximately 5 ka. None of these creatures exist today at Etosha because of their ecological requirements, which among others, include permanent water. The sitatunga, in addition, is known as the only truly amphibious antelope in the world. Since its inception, the new lake underwent a number of geomorphological modifications. A prominent character amongst these modifications is the orientation of the lake, which has its long-axis oriented in the ENE-WSW direction. It resulted from wave action affected by the prevailing dominant northeasterly wind, which is believed to have been in force since the Middle Pleistocene. Lake Etosha has also witnessed phases of waning and waxing under the influence of the prevailing climatic regime. Over the last 150 ka, the available data intercepted about seven phases of high lake levels. These data are generally in agreement with regional palaeoclimatic data, particularly when compared with those obtained from neighbouring Makgadikgadi Pans in Botswana. The last recorded episode of the wet phase at Etosha was some 2,400 years before the present.
Ausgangspunkt dieser Dissertation waren 23 aus den Jahren 1883 und 1893 überlieferte handschriftliche Krankenblätter der chirurgischen Abteilung des Juliusspitals zu Würzburg. Ziel war es, anhand dieser Krankenblätter eine retrospektive Sicht in den Operationssaal des Juliusspitals zu ermöglichen und insbesondere die chirurgische Hernienbehandlung im ausgehenden 19. Jahrhundert zu rekonstruieren. Das Augenmerk galt dem chirurgischen Tagesgeschäft: Es sollte aufgezeigt werden, wie sich dieses innerhalb von 10 Jahren verändert hat und wie diese Veränderung im Kontext interpretiert werden können. Es wurden quantitative und qualitative Aspekte untersucht (quantitative Aspekte: 1. Geschlechterrelation, 2. Relation Überlebende/Verstorbene, 3. Relation operative/konservative Behandlung; qualitative Aspekte: 1. formaler Vergleich, 2. stilistische Vergleich, 3. Arzt-Patienten-Verhältnis, 4. Anti-/Asepsis 5. Arzneimittel 6. Heilungsbegriff 7. Vergleich Operationstechniken). Eine besondere Bedeutung kommt dem glücklichen Zufall zu, dass zeitgenössische Publikationen existieren, welche zum Teil die im Original überlieferten Krankengeschichten enthalten. Somit konnte eine Querverbindung zwischen gelehrter Theorie und Praxis gezogen werden und untersucht werden, ob Erstere auch im Alltag umgesetzt wurde. Trotz der nur lückenhaften Überlieferung und der Tatsache, dass die Krankenblätter ursprünglich nicht zu dem Zweck geschrieben wurden, zu welchem sie im Rahmen dieser Dissertation verwendet wurden, war durch sie eine retrospektive Sicht in den Operationssaal des Juliusspitals des ausgehenden 19. Jahrhunderts möglich, welche ohne ihre Überlieferung vom heutigen Standpunkt aus nicht mehr zu rekonstruieren wäre.
Die Palliativmedizin gilt oft als ein vergleichsweise junges Themengebiet, welches in den zurückliegenden Jahrzehnten kontinuierlich an Bedeutung gewinnen konnte. Palliativmedizin ist jedoch keine reine Erfindung des 20. Jahrhunderts. So galt die Versorgung Schwerkranker oder Sterbender bereits viel früher als ärztliche Pflicht. Grundgedanke der Arbeit war es, palliativmedizinische Facetten im ärztlichen Handeln zu Beginn des 19. Jahrhunderts nachzuweisen. Hierzu erfolgte eine beispielhafte Betrachtung der chirurgische Hernien-Therapie des St. Johanns Spitals in Salzburg. Als Grundlage dienten handschriftlich verfasste Krankengeschichten des St. Johanns Spitals aus der ersten Hälfte des 19. Jahrhunderts. Neben der Detektion und einer vergleichenden Darstellung palliativmedizinischer Handlungsweisen gelang mit Hilfe der in ihrer Ausführlichkeit bemerkenswerten Primärquelle eine Darstellung der damaligen chirurgischen Hernientherapie am Salzburger St. Johanns Spital. Ergänzend erfolgt ein Vergleich mit zeitgenössischen Veröffentlichungen zur Thematik der Hernienchirurgie, welche sich zum damaligen Zeitpunkt am Vorabend zur Asepsis bereits in einem Prozess des Umbruchs befand.
Inhaltsübersicht zum Schwerpunktthema: - Suchtforschung als Basis der Gesundheitspolitik - Einstiegsdroge Nikotin kickt Gehirn in Sekunden - Betrunkene Fliegen bringen die Suchtforschung voran - Stichwort: Lidschlagreflex - Umweltreize entfachen die Gier nach Zigaretten - Das Suchtgedächtnis messbar machen - ADHS: Psychisches Leiden führt häufig zu Alkoholismus - Die Klinische Forschergruppe ADHS - Jagd nach den Genen für Alkoholabhängigkeit - Hoch chlorierte endogene Alkaloide im Menschen - Alkohol am Arbeitsplatz: Vorgesetzte sind gefordert u.a.
This thesis deals with the isolation and structural elucidation of bioactive naphthylisoquinoline alkaloids and related analogs. The mode of action of the antiplasmodial activity exhibited by the naphthylisoquinoline alkaloids was explored and compared to that of the antimalarial drug chloroquine. Furthermore, the phase 1 and 2 metabolism of dioncophyllines A and C and dioncopeltine A were investigated. In detail the following results have been obtained: • From the leaves of the recently discovered East African liana A. tanzaniensis six naphthylisoquinoline alkaloids were isolated. • The leaves of a botanical yet undescribed Ancistrocladus species, collected by Prof. Dr. V. Mudogo in the Democratic Republic of Congo in the habitat Yeteto near the town Ikela, were analyzed for naphthylisoquinoline alkaloids for the first time. The isolation work led to the first identification of an N,C-coupled naphthyldihydroisoquinoline alkaloid; ancistrocladinium B. Phytochemical investigation of the roots of the Congolese Ancistrocladus species (habitat Yeteto), , afforded five new derivatives of known naphthylisoquinoline alkaloids, namely 5'-O-demethylhamatine, 5'-O-demethylhamatinine, 6-O-demethylancistroealaine A, 6,5'-O,O-didemethylancistroealaine A, and 5-epi-6-O-methylancistrobertsonine A, along with six known naphthylisoquinoline alkaloids. • The antiplasmodial activity guided purification of 60Co irradiated samples containing commercially available naphthylisoquinoline related substances, afforded the isolation of the irradiation products 3,4-dihydro-1-isoquinolinone, 3,4-dihydro-1-isoquinolineamine, and 1,2,3,4-tetrahydro-1,2-diazirino-isoquinoline. The compounds were found to be more active than the starting material, although only exhibiting weak antiplasmodial activity against P. falciparum. • The effect on the absorption spectrum of FPIX due to complex formation with the naphthylisoquinoline alkaloids dioncophyllines A and C, dioncopeltine A korupensamine A, and ancistrocladine was examined by a titration study. Job's plot analyses by UV-spectroscopy determined the stoichiometry for the complex formation of FPIX and naphthylisoquinoline alkaloids to be 2:1. Furthermore, the dissociation constants for the complexation with FPIX were determined for each of the naphthylisoquinoline alkaloids investigated. Dioncophylline C and dioncopeltine A were found to possess dissociation constants, which are comparable to the one reported for the antimalarial drug chloroquine. The ability of ESI to transfer noncovalent solution-phase assemblies intact into the gas phase, was conducted on solution mixtures of naphthylisoquinoline alkaloid and FPIX, as well as on mixtures of chloroquine and FPIX. The mass spectrometry analyses revealed several peaks, which corresponded to the complex formation of FPIX to the respective ligands investigated. The most interesting results obtained were the detection of peaks corresponding to the complex formation between a chelated dimer of FPIX and dioncophylline Cand of peaks corresponding to a double protonated tetramer of FPIX – consisting of two chelated -oxo dimers of FPIX – in complex formation with two molecules of chloroquine. • Two phase 1 metabolism products of dioncophylline A were identified. Coelution in combination with HPLC-MS/MS, NMR, and CD investigations assigned the major metabolic product as 5'-O-demethyldioncophylline A. The minor metabolic product was only present in small amounts, which disabled an unambiguous structural characterization of the compound. However, as deduced from the mass spectrometry analyses and exclusion of a possible metabolic oxidation product by coelution with authentic reference material, the metabolite should possess a 4-hydroxylated isoquinoline portion and is assumed to be represented by structure. Dioncophylline C and dioncopeltine A were found to be stable to phase 1 metabolism reactions caused by rat liver microsomes.
Alveolar echinococcosis (AE) is a severe and life-threatening disease caused by the metacestode larva of the fox-tapeworm Echinococcus multilocularis. Parasite entry into the host evokes an early and potentially parasiticidal Th1 immune response that is gradually replaced by a permissive Th2 response. An immunoregulatory environment has also been reported in the host as the disease progresses. As a result of immunomodulation, E. multilocularis larvae persist in the host for decades without being expelled, and thus almost act like a perfect transplant. Very little is currently known on the molecular basis of the host immunomodulation by E. multilocularis. In this work, in vitro cultivation systems were used to assess the influence of metabolites released by the parasite larvae (E/S products) on host immune effector cells. E/S products of cultivated larvae that respresent the early (primary cells) and chronic (metacestode vesicles) phase of AE induced apoptosis and tolerogenic properties (poor responsiveness to LPS stimulation) in host dendritic cells (DC) whereas those of control larvae (protoscoleces) failed to do so. These findings show that the early infective stage of E. multilocularis induces tolerogenicity in host DC, which is most probably important for generating an immunosuppressive environment at an infection phase in which the parasite is highly vulnerable to host attacks. Interestingly, metacestode E/S products promoted the conversion of naïve CD4+ T-cells into Foxp3+ regulatory T-cells in vitro, whereas primary cell and protoscolex E/S products failed to do it. Since Foxp3+ regulatory T-cells are generally known to mediate immunosuppression, the present finding indicates that Foxp3+ regulatory T-cells, expanded by E/S products of the metacestode larva, could play a role in the parasite-driven immunomodulation of the host observed during AE. Furthermore, a substantial increase in number and frequency of suppressive Foxp3+ regulatory T-cells could be observed within peritoneal exudates of mice following intraperitoneal injection of E. multilocularis metacestodes, indicating that Foxp3+ regulatory T-cells could also play an important role in E. multilocularis-driven immunomodulation in vivo. Interestingly, a parasite activin ortholog, EmACT, secreted by metacestodes, was shown to expand host regulatory T-cells in a TGF-β-dependent manner, similarly to mammalian activin A. This observation indicated that E. multilocularis utilizes evolutionarily conserved TGF-β superfamily ligands, like EmACT, to expand host regulatory T-cells. Taken together, the present findings suggest EmACT, a parasite activin secreted by the metacestode and capable of expanding host regulatory T-cells, as an important player in the host immunomodulation by E. multilocularis larvae. Another parasite factor EmTIP, homologous to mammalian T-cell immunomodulatory protein (TIP) was characterized in this work. EmTIP could be detected in the secretions of the parasite primary cells and localized to the intercellular space within the parasite larvae. EmTIP blockade inhibited the proliferation of E. multilocularis primary cells and the formation of metacestode vesicles indicating a major role for parasite development. Furthermore, EmTIP evoked a strong release of IFN-γ by CD4+ T-cells hence suggesting that the secretion of this factor as a result of its role in parasite development could “secondarily” induce a potentially protective Th1 response. In conclusion, this work identified two molecules, EmACT and EmTIP, with high immunomodulatory potential that are released by E. multilocularis larvae. The data presented do provide insights into the mechanisms of parasite-driven host immunomodulation during AE that are highly relevant for the development of anti-parasitic immune therapies.
Im Rahmen dieser Disseration wurden im Einzelnen folgende Ergebnisse erzielt: A. Isolierung und Strukturaufklärung von Naphthylisochinolin-Alkaloiden aus verschiedenen Ancistrocladus-Spezies: • Die bisher noch nicht phytochemisch untersuchten Rindenextrakte der vietnamesischen Unterart Ancistrocladus tectorius ssp. cochinchinensis wurden im Hinblick auf ihre Sekundärmetabolite analysiert. Dabei identifizierte man vier bereits bekannte und drei neuartige Naphthylisochinoline-Alkaloide. Die Strukturen dieser drei Metabolite wurden nach Isolierung unter Verwendung diverser 2D-NMR-Techniken aufgeklärt. Die entdeckten Substanzen – Ancistrocladinium A (30) und seine beiden O-Demethylderivate 31 und 32 – waren die drei ersten Vertreter des neuartigen N,8'-Naphthyldihydroisochinolin-Kupplungstyps. Diese Naturstoffe verfügen über vielversprechende pharmakologische Wirkungen – vor allem gegen den Erreger der Leishmaniose. • Die botanisch noch nicht vollständig charakterisierte Lianenart ''A. ikela'', die aus der Demokratischen Republik Kongo stammt, wurde im Laufe der Arbeit morphologisch und phytochemisch untersucht und beschrieben. Neben den beiden N,C-verknüpften Naphthylisochinolinen Ancistrocladinium A (30) und Ancistrocladinium B [(M/P)-39] wurde bei der phytochemischen Analyse ein neuartiges C,C-gekuppeltes Alkaloid – 8-O-Methylancistrogriffin C (40) – isoliert. Des weiteren wurde ein Gradient entwickelt, der die vollständige Trennung der beiden Atrop-Diastereomere von 39 und dadurch HPLC-NMR- und HPLC-CD-Analysen der einzelen Epimere ermöglichte, so dass die Rotationsbarriere der bei Raumtemperatur langsam drehenden Biarylachse bestimmt werden konnte. • Aus Blättern der bereits gut untersuchten indischen Ancistrocladus-Art A. heyneanus wurde mit 6-O-Methyl-8,4'-O-didemethylancistrocladin (42) ein weiteres neues Naphthylisochinolin-Alkaloid isoliert. • Eine phytochemische Untersuchung der Familie der Ancistrocladaceae auf das Vorkommen von N,C-verküpften Naphtylisochinolinen ergab, dass diese strukturell außergewöhnlichen Alkaloide in diesen Lianen weit verbreitet sind. B: Die Rolle des Phloems bei der Pathogen-vermittelten Ausbreitung von Signalen: • Im Rahmen des Teilprojektes B8 des SFBs 567 wurden Untersuchungen zur Rolle des Phloems bei der Weiterleitung von Langstreckensignalen nach Infektion von Arabidopsis-thaliana-Pflanzen mit virulenten oder avirulenten Stämmen von Pseudomonas syringae pv. tomato durchgeführt. Zunächst wurde dazu eine im nL-Maßstab anwendbare Analysenmethode für die Hauptmetabolite von A. thaliana – die Glucosinolate – entwickelt. Mit Hilfe dieser empfindlichen Methode wurden in Pflanzenextrakten von A. thaliana viele bekannte und einige neue Glucosinolate (8-Methylsulfonyl-n-octyl-, 2-Hydroxy-4-methylsulfinyl-n-butyl-, 2-Hydroxy-4-methylsulfonyl-n-butyl- und 4-Hydroxy- benzoyloxymethylglucosinolat) identifiziert. Des weiteren wurden MS/MS-Analysen der Glucosinolate durchgeführt, bei denen neben mehreren typischen Fragmenten für die Thiozucker-Einheit auch einige charakteristische Fragmente für die unterschiedlichen Seitenketten (z.B. Methylsulfinyl-n-alkyl- oder Methylthio-n-alkyl-Struktur) detektiert wurden. Leider ergaben vor allem die aromatischen und heteroaromatischen Seitenketten-Typen kein typisches Fragmentierungs-muster. • Bei der Analyse der Phloemexsudate konnte in Phloemsäften von unbehandelten Pflanzen neben Methoxyglucobrassicin (73) ein für Pflanzen neuartiges Phosphat 87 (1-Glycero-1-myo-inositolphosphat) identifiziert werden. In den Phloemsäften der unterschiedlich behandelten Pflanzen (infiltriert mit MgCl2, einem virulentem oder einem avirulentem Pseudomonas-Stamm) kamen sämtliche Hauptmetabolite der Blätter vor. Lediglich ein leichter, nicht signifikanter Konzentrationsanstieg von Methoxyglucobrassicin (73) wurde im Phloemsaft von mit avirulenten Pathogenen infizierten Pflanzen festgestellt. Dieser Anstieg muss aber kritisch betrachtet werden, da er auch ein Artefakt des starken mechanischen Reizes des Infiltrationsprozesses sein könnte. Andere kleine Konzentrationsänderungen könnten außerdem durch das starke ''Grundrauschen'' der Infiltration überlagert werden. C: Strukturaufklärung polyketidischer Sekundärmetabolite aus Mikroorganismen: • Zwei niedermolekulare Naturstoffe aus dem extremophilen Streptomyceten-Stamm KC 1030, die in der Arbeitsgruppe von Prof. H.-P. Fiedler (Universität Tübingen) isoliert worden waren, wurden strukturell aufgeklärt. Bei dem einen handelt es sich um das bereits bekannte Frigocyclinon (89), bei dem anderen um ein neues Angucyclinon 88 mit Fridamycin-E-Grundkörper. Darüber hinaus wurden aus einem weiteren Streptomyces-Stamm (AK 671) zwei neue (97, 98) und drei (96, 99, 100) bekannte biosynthetisch interessante Sekundärmetabolite isoliert.
Inhaltsübersicht zum Schwerpunktthema: - Neurobiologie, Ökologie und Evolution des Verhaltens - "Unsere Forschungen werden international sehr stark beachtet" - Kleine Gehirne - großer Fortschritt - Fruchtfliegen verhelfen Laufrobotern zu sicherem Tritt - Mehr als eine Nummer aus dem Flohzirkus - DNA-Fingerabdruck weist Sklaverei bei Ameisen nach u. a.
Ziel der Arbeit war es die Quellenlage Hildegard von Bingens ‚Physica‘ zu beleuchten. Dazu werden die Kapitel der exotischen Gewürze (Kap. I,13-21 und I,26-27), der Duftpflanzen (Kap. I,22-25), und der heimischen Gewürze (Kap. I,63-70) mit den entsprechenden Kapiteln aus ‚Macer floridus‘ (Odo Magdunensis), ‚Circa instans‘ (Matthaeus Platearius), ‚Liber graduum‘ (Constantinus Africanus), ‚Naturalis historia‘ (Plinius der Ältere) und ‚Materia medica‘ (Pedanius Dioskurides) verglichen. Es konnten verschiedenartige Bezüge zur Tradition hergestellt werden, jedoch ist hervorzuheben, dass Hildegard dennoch in den Anwendungen eine ausgeprägte Originalität aufweist.
The work presented in this thesis was mainly targeted at exploring the capabilities of evaporation based LC detectors as well as further alternatives for the control of impurities in substances not exhibiting a suitable chromophore for UV-detection. In the course of the work carried out, several new methods for the identification, impurities control and composition testing of APIs were elaborated. An evaporation based detector that entered into the field of pharmaceutical analysis in the recent years was the Evaporative Light Scattering Detector (ELSD). However, non-reproducible spikes were reported when injecting concentrated test solutions as they are usually required for the control of impurities. The reasons, for the appearance of these spikes as well as possibilities for their avoidance were explored in a systematic study. Moreover, the dependence of the detector sensitivity on different eluent composition, eluent flow-rate and ELSD settings was investigated. In the course of the revision of the Ph.Eur. monographs for aspartic acid and alanine, a C18 reversed phase ion-pair LC method using 1 mmol/L of perfluoroheptanoic acid as an ion-pair reagent and a charged aerosol detector (CAD) was developed and fully validated for the purity control of Asp. The method was capable of separating the organic acids and major amino acids known to occur as process related impurities. With a slight modification, the method was also applicable for the purity control of Ala. Based on the developed LC-CAD method for the impurity control of alanine, a comparative study of the performance characteristics of different evaporation based LC detectors, i.e. ELSD, CAD and the recently developed Nano Quantity Analyte Detector (NQAD) was carried out. Additionally, an MS detector and qNMR were included in this study. It was found that the control of impurities in Alanine at an ICH conform level could be ensured using LC coupled to CAD, MSD and NQAD detection as well as by the use of qNMR. In terms of performance, prize and ease of use CAD and NQAD were found to be the most suitable alternatives. In terms of repeatability and sensitivity, the CAD appeared slightly superior to the NQAD. The quality of streptomycin sulfate is not sufficiently controlled by the current Ph.Eur. monograph in that an appropriate test for the control of the related substances is missing. A study was carried out to develop a C18 reversed phase ion-pair LC method using pentafluoropropionic acid as an ion-pair reagent and a CAD for the identification and control of the related substances. The developed method allowed the separation of 21 impurities from streptomycin. Moreover, coupling of the method to MS allowed the identification of the separated impurities. The method was shown to be sufficiently sensitive to control the related substances with a disregard limit of 0.1% as it is normally applied in the Ph.Eur. for products derived from fermentation. Currently, the aescin content of horse-chestnut standardized dry extract is determined using a complex and laborious photometric determination. A more selective LC-UV assay determination for beta-aescin has been proposed for the Ph.Eur. draft monograph of horse-chestnut standardized dry extract. Possibilities were explored to further improve the LC-method using detection by CAD. It was demonstrated that by the use of a modified LC-CAD method several problems related to the differences in the UV-response of the various components contained in the active aescin fraction could be eliminated. Moreover the proposed reference standard strategy was reviewed. Eventually, it was demonstrated on the example of two different clusters of pharmacologically active peptides how low energy collision induced dissociation mass spectrometry (low energy CID-MS) can successfully be used for identification testing in pharmacopoeial monographs. In this respect, the combination of a direct confirmation of the molecular mass via the m/z-ratio of the molecule ions with structural sequence information obtained by low energy CID-MS experiments was found to deliver a higher degree of certainty of the identity of a given substance than the set of tests currently described in the monographs. A significant gain in efficiency and throughput and important reduction of the amount of sample consumed during testing were identified as being additional advantages of this approach. Taken together, it could be demonstrated on various examples how recent technological advancements in the field of analytical chemistry can contribute to improve the quality control of APIs.
Die Arbeit beinhaltet einen Theorie- und einen Praxisteil. Es handelt sich um die theoretische Konzeption und praktische Ausarbeitung eines Lesebuchs für den Unterricht mit jugendlichen SchülerInnen mit einer geistigen Behinderung oder mit Leseschwierigkeiten. Hauptanliegen ist die Zusammenstellung und Aufbereitung von Lesematerial, das sowohl die Leseinteressen der Jugendlichen anspricht als auch ihren Lesefähigkeiten entspricht. Im Theorieteil wird auf der Basis allgemeiner literaturdidaktischer Überlegungen insbesondere zu Aufgaben und Zielen von Lese- und Literaturunterricht, zu handlungs- und produktionsorientiertem Unterricht, zu Lesekompetenz und zu Leseförderung eine Konzeption mit leitenden Prinzipien für das Lesebuch ausgearbeitet. Dabei finden Bedingungen im und Erkenntnisse zum Lese- und Literaturunterricht bei SchülerInnen mit einer geistigen Behinderung Beachtung, darunter der "erweiterte Lesebegriff" nach Hublow und Aspekte zur leichten Lesbarkeit und Textverständlichkeit. Folgende wichtige Aspekte bilden die Eckpfeiler der Lesebuchkonzeption: Das Buch enthält leicht lesbare Texte von bis zu drei Seiten Umfang zu Themen aus der Lebenswelt der Jugendlichen. Für SchülerInnen, die nicht oder nur bruchstückhaft Schrift lesen, gibt es Material zum Lesen von Fotos, Zeichnungen, Symbolen, Signal- oder Ganzwörtern. Um integrativen Unterricht bei heterogener Schülerschaft realisieren zu können, gibt es Texte mit gleichem Inhalt oder Thema in verschiedenen Darstellungsformen. Auch der Einsatz vielfältiger Medientexte z.B. von Comics, Cartoons oder Liedern soll dies ermöglichen. Daneben gibt es Material zur Förderung von Lesefähigkeiten und -fertigkeiten auf unterschiedlichen Niveaus. Wichtige Prinzipien sind darüber hinaus die Ausgewogenheit von pragmatischen, lebenspraktisch relevanten Texten und belletristischen Texten sowie das Angebot einer Vielfalt an Textsorten (z.B. Erzählungen, Gedichte, Tabellen, Rezepte, Sprichwörter). Der praktische Teil der Arbeit beinhaltet das Lesebuch "Lesestoff", das acht Kapitel enthält, dazu ein Schülerarbeitsheft mit Aufgaben zu Texten aus dem Lesebuch, insbesondere zum vertieften Textverständnis und zum handlungs- und produktionsorientierten Umgang mit den Texten. Die Aufgaben sind mit Lösungen versehen und daher zur selbstständigen Bearbeitung in offenen Unterrichtsformen geeignet. Ein Lehrerband enthält die Lesebuchkonzeption, Unterrichtsideen, Hinweise und Zusatzinformationen zu den Texten.
During the last decades the number of biologics increased dramatically and several biopharmaceutical drugs such as peptides, therapeutic proteins, hormones, enzymes, vaccines, monoclonal antibodies and antibody-drug conjugates conquered the market. Moreover, administration and local delivery of growth factors has gained substantial importance in the field of tissue engineering. Despite progress that has been made over the last decades formulation and delivery of therapeutic proteins is still a challenge. Thus, we worked on formulation and delivery strategies of therapeutic proteins to improve their biological performance.
Phase I of this work deals with protein stability with the main focus on a liquid protein formulation of the dimeric fusion protein PR-15, a lesion specific platelet adhesion inhibitor. In order to develop an adequate formulation ensuring the stability and bioactivity of PR-15 during storage at 4 °C, a pH screening, a forced degradation and a Design of Experiments (DoE) was performed. First the stability and bioactivity of PR-15 in 50 mM histidine buffer in relation to pH was evaluated in a short-term storage stability study at 25 °C and 40 °C for 4 and 8 weeks using different analytical methods. Additionally, potential degradation pathways of PR-15 were investigated under stressed conditions such as heat treatment, acidic or basic pH, freeze-thaw cycles, light exposure, induced oxidation and induced deamidation during the forced degradation study. Moreover, we were able to identify the main degradation product of PR-15 by performing LC/ESI-MS analysis. Further optimization of the injectable PR 15 formulation concerning pH, the choice of buffer and the addition of excipients was studied in the following DoE and finally an optimal PR-15 formulation was found.
The growth factors BMP-2, IGF-I and TGF-β3 were selected for the differentiation of stem cells for tissue engineering of cartilage and bone in order to prepare multifunctionalized osteochondral implants for the regeneration of cartilage defects.
Silk fibroin (SF) was chosen as biomaterial because of its biocompatibility, mechanical properties and its opportunity for biofunctionalization. Ideal geometry of SF scaffolds with optimal porosity was found in order to generate both tissues on one scaffold.
The growth factors BMP-2 and IGF-I were modified to allow spatially restricted covalent immobilization on the generated porous SF scaffolds. In order to perform site-directed covalent coupling by the usage of click chemistry on two opposite sides of the scaffold, we genetically engineered BMP-2 (not shown in this work; performed by Barbara Tabisz) and IGF-I for the introduction of alkyne or azide bearing artificial amino acids. TGF β3 was immobilized to beads through common EDC/NHS chemistry requiring no modification and distributed in the pores of the entire scaffold.
For this reason protein modification, protein engineering, protein immobilization and bioconjugation are investigated in phase II. Beside the synthesis the focus was on the characterization of such modified proteins and its conjugates. The field of protein engineering offers a wide range of possibilities to modify existing proteins or to design new proteins with prolonged serum half-life, increased conformational stability or improved release rates according to their clinical use.
Site-directed click chemistry and non-site-directed EDC/NHS chemistry were used for bioconjugation and protein immobilization with the aim to underline the preferences of site-directed coupling.
We chose three strategies for the incorporation of alkyne or azide functionality for the performance of click reaction into the protein of interest: diazonium coupling reaction, PEGylation and genetic engineering. Azido groups were successfully introduced into SF by implementation of diazonium coupling and alkyne, amino or acid functionality was incorporated into FGF-2 as model protein by means of thiol PEGylation. The proper folding of FGF-2 after PEGylation was assessed by fluorescence spectroscopy, WST-1 proliferation assay ensured moderate bioactivity and the purity of PEGylated FGF-2 samples was monitored with RP-HPLC. Moreover, the modification of native FGF-2 with 10 kDa PEG chains resulted in enhanced thermal stability.
Additionally, we genetically engineered one IGF-I mutant by incorporating the unnatural amino acid propargyl-L-lysine (plk) at position 65 into the IGF-I amino acid sequence and were able to express hardly verifiable amounts of plk-IGF-I. Consequently, plk-IGF-I expression has to be further optimized in future studies in order to generate plk-IGF-I with higher yields.
Bioconjugation of PEGylated FGF-2 with functionalized silk was performed in solution and was successful for click as well as EDC/NHS chemistry. However, substantial amounts of unreacted PEG-FGF-2 were adsorbed to SF and could not be removed from the reaction mixture making it impossible to expose the advantages of click chemistry in relation to EDC/NHS chemistry. The immobilization of PEG-FGF-2 to microspheres was a trial to increase product yield and to remove unreacted PEG-FGF-2 from reaction mixture. Bound PEG-FGF-2 was visualized by fluorescence imaging or flow cytometry and bioactivity was assessed by analysis of the proliferation of NIH 3T3 cells. However, immobilization on beads raised the same issue as in solution: adsorption caused by electrostatic interactions of positively charged FGF-2 and negatively charged SF or beads. Finally, we were not able to prove superiority of site-directed click chemistry over non-site-directed EDC/NHS.
The skills and knowledge in protein immobilization as well as protein characterization acquired during phase II helped us in phase III to engineer cartilage tissue in biofunctionalized SF scaffolds.
The approach of covalent immobilization of the required growth factors is relevant because of their short in vivo half-lives and aimed at controlling their bioavailability. So TGF-β3 was covalently coupled by means of EDC/NHS chemistry to biocompatible and biostable PMMA beads. Herein, we directly compared bioactivity of covalently coupled and adsorbed TGF-β3. During the so-called luciferase assay bioactivity of covalent coupled as well as adsorbed TGF-β3 on PMMA beads was ensured. In order to investigate the real influence of EDC/NHS chemistry on TGF-β3’s bioactivity, the amount of immobilized TGF-β3 on PMMA beads was determined. Therefore, an ELISA method was established. The assessment of total amount of TGF-β3 immobilized on the PMMA beads allowed as to calculate coupling efficiency. A significantly higher coupling efficiency was determined for the coupling of TGF-β3 via EDC/NHS chemistry compared to the reaction without coupling reagents indicating a small amount of adsorbed TGF-β3. These results provide opportunity to determine the consequence of coupling by means of EDC/NHS chemistry for TGF β3 bioactivity. At first sight, no statistically significant difference between covalent immobilized and adsorbed TGF-β3 was observed regarding relative luciferase activities. But during comparison of total and active amount of TGF-β3 on PMMA beads detected by ELISA or luciferase assay, respectively, a decrease of TGF-β3’s bioactivity became apparent. Nevertheless, immobilized TGF β3 was further investigated in combination with SF scaffolds in order to drive BMSCs to the chondrogenic lineage. According to the results obtained through histological and immunohistochemical studies, biochemical assays as well as qRT-PCR of gene expression from BMSCs after 21 days in culture immobilized TGF-β3 was able to engineer cartilage tissue. These findings support the thesis that local presentation of TGF β3 is superior towards exogenous TGF β3 for the development of hyaline cartilage. Furthermore, we conclude that covalent immobilized TGF β3 is not only superior towards exogenously supplemented TGF-β3 but also superior towards adsorbed TGF-β3 for articular hyaline cartilage tissue engineering. Diffusion processes were inhibited through covalent immobilization of TGF-β3 to PMMA beads and thereby a stable and consistent TGF-β3 concentration was maintained in the target area.
With the knowledge acquired during phase II and III as well as during the studies of Barbara Tabisz concerning the expression and purification of plk-BMP-2 we made considerable progress towards the formation of multifunctionalized osteochondral implants for the regeneration of cartilage defects. However, further studies are required for the translation of these insights into the development of multifunctionalized osteochondral SF scaffolds.
Die Archäobotanik
(2016)
Feudvar bei Mošorin ist eine mehrschichtige Burgsiedlung der Bronzezeit und frühen Eisenzeit im Mündungsgebiet der Theiß in die Donau (Serbien). Mit 2173 archäobotanischen Proben hat die Siedlung einen der umfangreichsten archäobotanischen Datenpools der prähistorischen Metallzeiten Südosteuropas geliefert. In zwei separaten Studien von Helmut Kroll und Kelly Reed werden Pflanzenbau und Pflanzennutzung in Feudvar untersucht. Die Studien werden ergänzt durch eine Zusammenfassung der archäologischen Forschungen zu Feudvar in den vergangenen drei Jahrzehnten sowie einen Überblick zum Stand der frühmetallzeitlichen Archäobotanikforschung in Serbien.
Herein described is the discovery of three novel types of dimeric naphthylisoquinoline alkaloids, named mbandakamines, cyclombandakamines, and spirombandakamines. They were found in the leaves of a botanically as yet unidentified, potentially new Ancistrocladus species, collected in the rainforest of the Democratic Republic of the Congo (DRC). Mbandakamines showed an exceptional 6′,1′′-coupling, in the peri-position neighboring one of the outer axes, leading to an extremely high steric hindrance at the central axis, and to U-turn-like molecular shape, which – different from all other dimeric NIQs, whose basic structures are all quite linear – brings three of the four bicyclic ring systems in close proximity to each other. This created an unprecedented follow-up chemistry, involving ring closure reactions, leading to two further, structurally even more intriguing subclasses, the cyclo- and the spirombandakamines, displaying eight stereogenic elements (the highest total number ever found in naphthylisoquinoline alkaloids). The metabolites exhibited pronounced antiplasmodial and antitrypanosomal activities. Likewise reported in this doctoral thesis are the isolation and structural elucidation of naphthylisoquinoline alkaloids from two further potentially new Ancistrocladus species from DRC. Some of these metabolites have shown pronounced antiausterity activities against human pancreatic cancer PANC-1 cells.
In der Dissertation wird vornehmlich die Perspektive des Römischen Staates eingenommen, aus der heraus er zu Maßnahmen gegen die Institution der Kirche, deren Amtsträger und Anhänger aus dem Laienstand schritt. Es wird zu zeigen versucht, welche (religions-)politischen Überlegungen und Hintergründe die antichristliche Agenda der einzelnen Verfolgerkaiser hervorriefen und v.a. inwiefern die einmal gemachten Erfahrungen das Vorgehen der späteren Verfolger beeinflussten, so dass eine sich steigernde, auf einem "Vorwissen" um die Beschaffenheit des "Gegners" aufbauende Logik der Verfolgungsmaßnahmen erkennbar wird.
Der Schwerpunkt der Arbeit liegt auf den Christenverfolgungen von Kaiser Decius bis Maximinus Daia, wobei ein umfangreicheres Kapitel über die Gepflogenheiten der römischen Religion und des Kaiserkultes vorausgeschickt wird.
Thermoplastic polymers have a history of decades of safe and effective use in the clinic as implantable medical devices. In recent years additive manufacturing (AM) saw increased clinical interest for the fabrication of customizable and implantable medical devices and training models using the patients’ own radiological data. However, approval from the various regulatory bodies remains a significant hurdle. A possible solution is to fabricate the AM scaffolds using materials and techniques with a clinical safety record, e.g. melt processing of polymers. Melt Electrowriting (MEW) is a novel, high resolution AM technique which uses thermoplastic polymers. MEW produces scaffolds with microscale fibers and precise fiber placement, allowing the control of the scaffold microarchitecture. Additionally, MEW can process medical-grade thermoplastic polymers, without the use of solvents paving the way for the production of medical devices for clinical applications. This pathway is investigated in this thesis, where the layout is designed to resemble the journey of a medical device produced via MEW from conception to early in vivo experiments. To do so, first, a brief history of the development of medical implants and the regenerative capability of the human body is given in Chapter 1. In Chapter 2, a review of the use of thermoplastic polymers in medicine, with a focus on poly(ε-caprolactone) (PCL), is illustrated, as this is the polymer used in the rest of the thesis. This review is followed by a comparison of the state of the art, regarding in vivo and clinical experiments, of three polymer melt AM technologies: melt-extrusion, selective laser sintering and MEW. The first two techniques already saw successful translation to the bedside, producing patient-specific, regulatory-approved AM implants. To follow in the footsteps of these two technologies, the MEW device parameters need to be optimized. The MEW process parameters and their interplay are further discussed in Chapter 3 focusing on the importance of a steady mass flow rate of the polymer during printing. MEW reaches a balance between polymer flow, the stabilizing electric field and moving collector to produce reproducible, high-resolution scaffolds. An imbalance creates phenomena like fiber pulsing or arcing which result in defective scaffolds and potential printer damage. Chapter 4 shows the use of X-ray microtomography (µCT) as a non-destructive method to characterize the pore-related features: total porosity and the pore size distribution. MEW scaffolds are three-dimensional (3D) constructs but have long been treated in the literature as two-dimensional (2D) ones and characterized mainly by microscopy, including stereo- and scanning electron microscopy, where pore size was simply reported as the distance between the fibers in a single layer. These methods, together with the trend of producing scaffolds with symmetrical pores in the 0/90° and 0/60/120° laydown patterns, disregarded the lateral connections between pores and the potential of MEW to be used for more complex 3D structures, mimicking the extracellular matrix. Here we characterized scaffolds in the aforementioned symmetrical laydown patterns, along with the more complex 0/45/90/135° and 0/30/60/90/120/150° ones. A 2D pore size estimation was done first using stereomicroscopy, followed by and compared to µCT scanning. The scaffolds with symmetrical laydown patterns resulted in the predominance of one pore size, while those with more complex patterns had a broader distribution, which could be better shown by µCT scans. Moreover, in the symmetrical scaffolds, the size of 3D pores was not able to reach the value of the fiber spacing due to a flattening effect of the scaffold, where the thickness of the scaffold was less than the fiber spacing, further restricting the pore size distribution in such scaffolds. This method could be used for quality assurance of fabricated scaffolds prior to use in in vitro or in vivo experiments and would be important for a clinical translation. Chapter 5 illustrates a proof of principle subcutaneous implantation in vivo experiment. MEW scaffolds were already featured in small animal in vivo experiments, but to date, no analysis of the foreign body reaction (FBR) to such implants was performed. FBR is an immune reaction to implanted foreign materials, including medical devices, aimed at protecting the host from potential adverse effects and can interfere with the function of some medical implants. Medical-grade PCL was used to melt electrowrite scaffolds with 50 and 60 µm fiber spacing for the 0/90° and 0/60/120° laydown patterns, respectively. These implants were implanted subcutaneously in immunocompetent, outbred mice, with appropriate controls, and explanted after 2, 4, 7 and 14 days. A thorough characterization of the scaffolds before implantation was done, followed by a full histopathological analysis of the FBR to the implants after excision. The scaffolds, irrespective of their pore geometry, induced an extensive FBR in the form of accumulation of foreign body giant cells around the fiber walls, in a manner that almost occluded available pore spaces with little to no neovascularization. This reaction was not induced by the material itself, as the same reaction failed to develop in the PCL solid film controls. A discussion of the results was given with special regard to the literature available on flat surgical meshes, as well as other hydrogel-based porous scaffolds with similar pore sizes. Finally, a general summary of the thesis in Chapter 6 recapitulates the most important points with a focus on future directions for MEW.