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In this dissertation the formal abstraction and verification of analog circuit is examined. An approach is introduced that automatically abstracts a transistor level circuit with full Spice accuracy into a hybrid automaton (HA) in various output languages. The generated behavioral model exhibits a significant simulation speed-up compared to the original netlist, while maintaining an acceptable accuracy, and can be therefore used in various verification and validation routines. On top of that, the generated models can be formally verified against their Spice netlists, making the obtained models correct by construction.
The generated abstract models can be extended to enclose modeling as well as technology dependent parameter variations with little over approximations. As these models enclose the various behaviors of the sampled netlists, the obtained models are of significant importance as they can replace several simulations with just a single reachability analysis or symbolic simulation. Moreover, these models can be as well be used in different verification routines as demonstrated in this dissertation.
As the obtained models are described by HAs with linear behaviors in the locations, the abstract models can be as well compositionally linked, allowing thereby the abstraction of complex analog circuits.
Depending on the specified modeling settings, including for example the number of locations of the HA and the description of the system behavior, the accuracy, speedup, and various additional properties of the HA can be influenced. This is examined in detail in this dissertation. The underlying abstraction process is first covered in detail. Several extensions are then handled including the modeling of the HAs with parameter variations. The obtained models are then verified using various verification methodologies. The accuracy and speed-up of the abstraction methodology is finally evaluated on several transistor level circuits ranging from simple operational amplifiers up to a complex circuits.
The development of a drug product, beginning with the synthesis of the drug substance through approval for marketing, may take up to 15 years and a total amount of investment of up to half a billion Euro. After the discovery of a potential drug substance, many different investigations have to be performed: e.g. characterization of the physical-chemical properties, the pharmacological and toxicological profile and, especially relevant for this work, the development of the first dosage forms. After achieving these steps, first investigations in human studies can be carried out. After a positive assessment of the benefit to risk ratio, further investigations, such as food effects on the pharmacokinetics, multiple dosing studies and further studies on patients can be implemented. After successfully completing this second part the new drug product can be approved. With broader clinical experience it often becomes apparent that changes in relevant aspects of the formulation of the registered drug product e.g. excipients, concentration of the drug substance or excipient versus drug substance ratio, are necessary to optimise the therapy. This often leads to additional clinical investigations and a new registration, a procedure which is time and cost intensive. A possible way to reduce the financial and time investments, is to establish an appropriate in vivo- in vitro correlation (IVIVC). If it is possible to predict the in vivo performance of a drug product adequately with in vitro methods (dissolutions tests), it will no longer be necessary to perform additional clinical investigations. In this work, IVIVCs were investigated for three different drug substances and several different types of formulations.... ...Results of this work clearly show that successful IVIVCs can be achieved for the fasted state using biorelevant dissolution media. A prerequisite of achieving a good IVIVC is the availability of in vivo data of a reference product (i.v., oral solution or IR) tested within the same group of volunteers as the product of interest. Only with this procedure, one can obtain adequate IVIVCs for drug substances with high inter-individual variability of the plasma concentrations and with high first-pass metabolism. This work also shows that predictions of the in vivo behavior of a modified release dosage form after administration with a high fat meal are more difficult to obtain. This is mainly related to an absence of a medium, which could mimic the situation of the fed stomach adequately. Ensure plus®, which was chosen in this work, failed to simulate the fed stomach adequately in several cases; it suppressed the release of rosiglitazone from lipid formulations and led to rapid disruption of the HPMC-matrix of the 5-ISMN Geomatrix formulations. Future work should be directed towards optimization of the test media in the BioDis apparatus. This work clearly shows the inability of Ensure plus® to predict the in vivo performance of a drug under fed state conditions and indicates that alternative media must be developed. It is known that the pH of the stomach rises up to six after the intake of a meal. During the following hours the pH decreases until reaching the baseline value of approximately 1.8. One possibility of simulating the fed state stomach more precisely will be to divide the overall residence time into 4 different parts: 1. half a hour at pH 6 2. half a hour at pH 4 3. one hour at pH 3 4. two hours at pH 1.8 Another option is not only to modify the pH of the medium, but also to change its composition. During the decomposition of the food contents, the composition of the gastric juice changes, the ionic strength, the buffer capacity and the osmolarity rises, while the pH value decreases. A third possibility will be the addition of enzymes, mainly pepsin, lipases and amylases. Again, the quantity of the enzymes differs during the residence time of the food in the stomach. Highest quantities are expected in the first two hours after food intake and decreases in the remaining two hours. Another issue of this work was an assessment of the two dissolution apparatus, Paddle and BioDis. In general, the choice of the dissolution apparatus should be done primarily with respect to the solubility behavior of the drug substance. For high soluble drugs the USP apparatus II, Paddle, is sufficient (e.g. diltiazem or 5-ISMN). In cases of a poorly soluble drug (rosiglitazone), where the release strongly depends on the medium used, the USP apparatus III (BioDis) is favored, due to the advantage of simulating the GI-tract with a gradient of different dissolution media, each simulating one part of the GI-tract. In summary, the results of this work indicate that it is acurrently possible to predict fasted state behavior of a variety of controlled release products using in vitro tests. Prognoses was also made in terms of predicting food effects on the behavior of controlled release products, although it is clear that the media compositions will have to be revised to establish releiable predictive methods for the fed state.
To reconstruct ocean circulation changes during specific periods of Earth history, benthic and planktic foraminifera were used as proxies in the different parts of this thesis. Both studied time periods, the Late Cretaceous and the early Pleistocene, are characterized by long-term climate cooling and major changes in ocean circulation. The first part of this thesis concentrated in the Late Cretaceous. During the Late Cretaceous long-term cooling phase, benthic foraminiferal δ18O values show a positive shift lasting about 1.5 Myr (71.5–70 Ma). This shift can be observed on a global scale and has become known as the Campanian-Maastrichtian Boundary Event (CMBE). It is proposed that this δ18O excursion is influenced either by changing intermediate- to deep-water circulation or by temporal build-up of Antarctic ice sheets. Benthic foraminiferal assemblage counts from a southern high-latitudinal site near Antarctica (ODP Site 690) are analyzed to test if the influence of the CMBE on the benthic species composition. One of the two discussed hypotheses for the causation of the δ18O transition is a change in intermediate- to deep-water circulation from low-latitude to high-latitude water masses. This change would result in cooler temperatures, higher oxygen concentration, and possibly lower organic-matter flux at the seafloor, causing a major benthic foraminiferal assemblage change. Another possible explanation of the δ18O transition of the CMBE is significant ice formation on Antarctica. However no major benthic foraminiferal assemblage change would be expected in this case. The benthic foraminiferal assemblage of Site 690 shows a separation of the studied succession into two parts with significantly different species composition. The older part (73.0–70.5 Ma) is dominated by species, which are typical for lower bottom water oxygen concentration and more common in low-latitude assemblages. Species dominating the younger part (70.0–68.0 Ma) are indicators for well-oxygenated bottom waters and more common in high-latitude assemblages. This change in the benthic foraminiferal assemblages is interpreted to represent a shift of low-latitude toward high-latitude dominated intermediateto deep-water sources. A change in oceanic circulation was therefore at least a major component of the CMBE. The Pacific Ocean contributed significantly to the climatic development during the Late Cretaceous cooling period. The contribution of ocean circulation changes in the Pacific Ocean to the Late Cretaceous climatic development in general and the CMBE and Mid-Maastrichtian Event (MME) in particular, however, is poorly understood. Previously measured high resolution planktic and benthic stable isotope data and a neodymium (Nd) isotope record from the Pacific ODP Site 1210 (Shatsky Rise, tropical Pacific Ocean) for the Campanian to Maastrichtian (69.5 to 72.5 Ma) are used to reconstruct changes in surface- and bottom water temperatures as well as changes in the source region of deep- to intermediate waters [see Appendix 4; Jung et al. 2013]. The results of the benthic foraminiferal δ18O and Nd isotope records in combination with Nd isotope records from other studies indicate changes in the intensity of intermediate- to deep ocean circulation in the tropical Pacific across the Campanian-Maastrichtian interval [see Appendix 4; Jung et al. 2013]. During the early Maastrichtian (72.5 to 69.5 Ma), a three-million-year-long period of cooler conditions and a simultaneous change towards less radiogenic Nd isotope signatures is interpreted to represent a period of increased admixture and northward flow of deep waters from the Southern Ocean (Southern Component Water, SCW). This change was probably caused by an intensified formation of deep waters in the Southern Ocean. This was reduced again during the MME (69.5 to 68.5 Ma). This early Maastrichtian cold interval is similar to the CMBEδ13C fall and succeeding δ13C rise towards the MME and is therefore also interpreted to represent tectonically forced, long-term changes in the global carbon cycle and thus a tectonic forcing of the early Maastrichtian climate cooling. Overall, the Campanian-Maastrichtian Nd and stable isotope records of Shatsky Rise indicate changes in ocean circulation that are paralleled by global warming and cooling periods. The fluctuating strength of SCW contribution in the tropical Pacific points towards an increased respectively weakened ocean circulation, which is probably related to the strength of deep-water formation in the Southern Ocean [see Appendix 4; Jung et al. 2013]. For this study, the analysis of benthic foraminiferal assemblages of Site 1210 is carried out for the same time interval (69.5 to 72.5 Ma) as Nd and stable isotopes to evaluate the influence of intermediate- to deep ocean circulation changes on the benthic foraminiferal community. The possible reaction of benthic foraminiferal assemblages is compared to the results of stable isotope and neodymium isotopes. The observed changes in species abundances only partly reflect the circulation changes reconstructed with Nd and stable oxygen istopes. For example, Stensioina spp., Aragonia spp. and Lenticulina spp., cold-water preferring species, start to be increasingly abundant at the beginning of enhanced influence of SCW. However, their abundance pattern does not follow the varying strength of the cold SCW influence at Shatsky Rise. Other species prefer lesser oxygen concentrations and warmer bottom water, e.g. Paralabamina spp. and Globorotalites spp. Paralabamina spp. has its highest relativ abundance at the beginning of the studied succession, where the influence of SCW is small. However, this taxa occurs throughout the record, even though the influence of SCW increases. Globorotalites spp. is even most abundance after the CMBE, where bottom waters are till cold and influenced by SCW. This leads to the conclusion that the varying strength of SCW in the tropical Pacific at Shatsky Rise through the studied interval is not facilitating a significant faunal turnover as has been observed at the South Atlantic Site 690 (Chapter 3). These results of the benthic foraminiferal assemblage analysis suggest a rather minor influence of the SCW on the major environmental factors that are generally influencing benthic foraminiferal communities (e.g., oxygen concentration, organic matter flux to the sea floor, bottom-water temperature). The second major part of this thesis focused on the late Pliocene-earliest Pleistocene. The late Pliocene is characterized by a long-term global cooling trend resulting in a major increase of Arctic ice sheets from around 3 Ma onwards, culminating in the Plio-Pleistocene intensification of the Northern Hemisphere glaciation. At around 2.7 Ma, large amplitude glacial-interglacial excursions (~1‰ δ18O in benthic foraminiferal calcite) in benthic oxygen isotopes can be observed. Marine isotope stage (MIS) 100 at around 2.55 Ma is the first glacial, when widespread ice rafted debris has been found in sediments in the North Atlantic Ocean. To gain a deeper understanding of the climatic evolution of the latest Pliocene-early Pleistocene, it is necessary to improve the reconstructions of North Atlantic paleohydrography, as the North Atlantic provides a key region for global climate. The consequences of the intensification of Northern Hemisphere on the early Pleistocene North Atlantic thermocline stratification and intermediate waters are still poorly understood. However, surface hydrography, the history of the thermocline and development of North Atlantic intermediate waters are well-studied for the Last Glacial Maximum (LGM). These well-known mechanisms responsible for the LGM in comparison with the present-day interglacial North Atlantic are used as an analogue for te early Pleistocene glacialinterglacials cycles. In this study, suborbitally resolved stable oxygen and carbon isotope and Mg/Ca records are measured from a deep-dwelling planktic foraminifera (Globorotaliacrassaformis) from Integrated Ocean Drilling Program Site U1313 (North Atlantic, 41°N) covering marine oxygen isotope stages MIS 103 to 95 (early Pleistocene, 2.6 to 2.4 Ma). The results are interpreted to represent a change in intermediate-water masses on glacialinterglacial timescales. During glacials geochemical records in G. crassaformis (~500–1000 m) bear the imprint of Glacial North Atlantic Intermediate Water (GNAIW), while during interglacials this species reflects the signature of the influence of Mediterranean Outflow Water (MOW) in combination with the subtropical gyre. The comparison of this data with the published records from G. ruber from the same samples facilitates the reconstruction of glacial-interglacial stratification changes of the upper water column at Site U1313. The results show that larger gradients of temperature, salinity and δ13C prevailed during glacials, suggesting a stronger stratification of the upper water column. This can be seen to indicate glacial-interglacial changes in ntermediate water masses in the North Atlantic similar to those reconstructed for the latest Pleistocene. As an additional proxy, the clumped isotope paleothermometer is applied for the Late Cretaceous study as well as for the early Pleistocene. This proxy is commonly assumed to be independent of other factors than temperature. Clumped isotopes are measured for the Late Cretaceous Site 690 on the planktic foraminiferal species Archaeoglobigerina australis and compared to already existing stable oxygen isotopes of this species. This is assumed to enable the reconstruction of paleotemperature independent of ice volume and therefore contribute to the long-lasting discussion whether there was a temporal ice build-up on Antarctic during the Campanian-Maastrichtian cooling period. For the early Pleistocene, the planktic foraminiferal species G. crassaformis is used from Site U1313 from MIS 99 (interglacial) and MIS 98 (glacial). This provides the opportunity to separate ice volume, salinity and temperature effects on the measured δ18O record of G. crassaformis. The results of the clumped isotope measurements reveal comparatively large standard errors. For the Late Cretaceous the standard error of the clumped isotope measurements proved too large to allow any conclusions on the temperature component on the δ18O record of A. australis. For the early Pleistocene, the temperature difference is also too small to be reconstructed with the standard error of the clumped isotope measurements in this study. Measuring many replicates of one sample would minimize the standard error considerably. However, the amount necessary to measure replicates cannot be gained for either time period, as almost all foraminifera were picked from the respective samples. It is concluded that the respective questions may be solved with a different method of clumped isotope analysis requiring less sample material. This method is, for example, available at the ETH Zurich.
Se il legislatore volesse incriminare nuove condotte o aggravare il trattamento sanzionatorio previsto per tipologie di condotte già penalmente rilevanti, lo potrebbe fare solo con efficacia per il futuro.
Il divieto costituzionale di retroattività impedisce, da un lato, che un comportamento penalmente irrilevante possa essere soggetto a sanzione penale dopo la sua commissione e, dall’altro lato, che una condotta già penalmente rilevante possa essere oggetto di un incremento del trattamento sanzionatorio rispetto a quello previsto al momento del fatto.
Qualora un comportamento penalmente irrilevante al momento della sua commissione diventi, al contrario, penalmente rilevante a seguito del verificarsi di un cambio di interpretazione giurisprudenziale oppure finisca per essere sanzionato (in astratto) con pene più sfavorevoli, quali garanzie sono riconosciute al cittadino?
La Corte costituzionale nel 1988 aveva dichiarato la parziale illegittimità costituzionale della disciplina dell’ignorantia legis, consacrando il principio secondo cui l’ignoranza inevitabile della legge penale scusa il soggetto. Principio che però non ha impedito in tutti questi anni alla giurisprudenza (di legittimità, anche nella sua massima istanza) di riconoscere ai mutamenti giurisprudenziali sfavorevoli efficacia retroattiva, quindi rispetto a fatti già verificatisi.
Più recentemente si è diffusa, su impulso della Corte di Strasburgo, l’idea secondo cui i mutamenti giurisprudenziali peggiorativi non possono retroagire solo laddove imprevedibili.
Secondo l’opinione tuttora maggioritaria, il divieto di retroattività non potrebbe o non dovrebbe svolgere alcun ruolo di garanzia in questi casi in quanto il riconoscimento del medesimo divieto anche rispetto ai mutamenti giurisprudenziali in malam partem determinerebbe l’equiparazione del “diritto giurisprudenziale” alla legge sul piano delle fonti del diritto penale, equiparazione evidentemente insostenibile sulla base del nostro modello costituzionale di separazione dei poteri. È davvero così?
Il lavoro affronta, in prospettiva anche europea e comparata, il tema delle garanzie costituzionali riconosciute al singolo cittadino a fronte del verificarsi di un mutamento giurisprudenziale (soprattutto in seno alle Sezioni unite) produttivo di conseguenze sfavorevoli.
One possible approach to study systematically the influence of the deformation regime on the geometry of geological structures like folds and boudins is analogue modelling. For a complete understanding of the resulting structures, consideration of the third dimension is required. This PhD study deals with scaled analogue modelling under constriction and plane-strain conditions to improve our knowledge of folding and boudinage of lower crustal rocks in space and time. Plasticine is an appropriate analogue material for rocks in the lower crust. Therefore, this material was used for the experiments. The macroscopic behaviour of most types of plasticine is quite similar to rocks undergoing strain-rate softening and strain hardening regardless of the different microscopic aspects of deformation. Therefore, if one is aware that the stress exponent and viscosity increase with increasing strain, the original plasticine types used with stress exponents ranging from 5.8 to 8.0 are adequate for modelling geologic structures. The same holds for plasticine/oil mixtures. Thus, plasticine and plasticine/oil mixtures can be used to model the viscous flow of different rock types in the lower crust. If climb-accommodated dislocation creep and associated steady-state flow is assumed for the natural rocks, the plasticine/oil mixtures should be used, which flow under steady-state conditions. Three different experimental studies of plane-strain coaxial deformation of stiff layers, with viscosity η2 and stress exponent n2, embedded in a weak matrix, with viscosity η1 and stress exponent n1, have been carried out. The undeformed samples (matrix plus layer) were cubes with an edge length of 12 cm. All experimental runs have been carried out at T = 25 ± 1°C and varying strain rates ė, ranging from 7.9 x 10 high -6 s high -1 to 1.7 x 10 high -2 s high -1, until a finite longitudinal strain of 30% – 40% was achieved. The first experimental study improved the understanding about the evolution of folds and boudins when the layer is oriented perpendicular to the Y-axis of the finite strain ellipsoid. The rock analogues used were Beck’s green plasticine (matrix) and Beck’s black plasticine (competent layer), both of which are strain-rate softening modelling materials with stress exponent n = ca. 8. The effective viscosity η of the matrix plasticine was changed by adding different amounts of oil to the original plasticine. At a strain rate ė of 10 high -3 s high -1 and a finite strain e of 10%, the effective viscosity of the matrix ranges from 1.2 x 10 high 6 to 7.2 x 10 high 6 Pa s. The effective viscosity of the competent layer has been determined as 4.2 x 10 high 7 Pa s. If the viscosity ratio is large (> ca. 20) and the initial thickness of the competent layer is small, both folds and boudins develop simultaneously. Although the growth rate of the folds seems to be higher than the growth rate of the boudins, the wavelength of both structures is approximately the same as is suggested by analytical solutions. A further unexpected, but characteristic, aspect of the deformed competent layer is a significant increase in thickness, which can be used to distinguish plane-strain folds and boudins from constrictional folds and boudins. In the second experimental study, the impact of varying strain rates on growing folds and boudins under plane strain have been investigated. The strain rates used range from 7.9 x 10 high -6 s high -1 to 1.7 x 10 high -2 s high -1. The stiff layer and matrix consist of non-linear viscous Kolb grey and Beck’s green plasticine, respectively, both of which are strain-rate softening modelling materials with power law exponents (n) and apparent viscosities (η) ranging from 6.5 to 7.9 and 8.5 x 10 high 6 to 7.2 x 10 high 6 Pa s, respectively. The effective viscosity (η) of the matrix plasticine was partly modified by adding oil to the original plasticine. At the strain rates used in the experiments the viscosity ratio between layer and matrix ranges between 3 and 10. Different runs have been carried out where the layer was oriented perpendicular to the principal strain axes (X>Y>Z). The results suggest a considerable influence of the strain rate on the geometry of the deformed stiff layer including its thickness. This holds for every type of layer orientation (S ┴ X, S ┴ Y, S ┴ Z). If the stiff layer is oriented perpendicular to the short axis Z of the finite strain ellipsoid, the number of the resulting boudins and the thickness of the stiff layer increase, whereas the length of boudins decreases with increasing strain rate. If the stiff layer is oriented perpendicular to the long axis, X, of the finite strain ellipsoid, enlargement of the strain rate results in increasing wavelength of folds, whereas the number of folds and the degree of thickening of the stiff layer decreased. If the stiff layer is oriented perpendicular to the intermediate Y-axis of the finite strain ellipsoid enlargement of the strain rate results in a decreasing number of boudins and folds associated with increasing wavelengths of both structures. The wavelength of folds is approximately half of the boudins wavelength. This is true for the case where folds and boudins develop simultaneously (S ┴ Y) and for cases where both structures develop independently (folds at S ┴ X and boudins at S ┴ Z). In the third experimental study, scaled analogue experiments have been carried out to demonstrate the growth of plane-strain folds and boudins through space and time. Previous 3D-studies are based only on finite deformation structures. Their results can therefore not be used to prove if both structures grew simultaneously or in sequence. Plane strain acted on a single stiff layer that was embedded in a weak matrix, with the layer oriented perpendicular to the intermediate Y-axis of the finite strain ellipsoid. Two different experimental runs have been carried out using computer tomography (CT) to analyse the results. The first run was carried out without interruption. During the second run, the deformation was stopped in each case at longitudinal strain increments of 10%. Every experiment was carried out at a temperature T of 25°C and a strain rate, ė, of ca. 4 x 10 high -3 s high -1 until a finite longitudinal strain of 40% was achieved with a viscosity contrast m of 18.6 between the non-linear viscous layer (Kolb brown plasticine) and the matrix (Beck’s green plasticine with 150 ml oil kg high -1). The apparent viscosity, η, and the stress exponent, n, for the layer at a strain rate ė = ca. 10 high -3 s high -1 and a finite strain e = 10% are 2.23 x 10 high 7 Pa s and n = 5.8 and for the matrix 1.2 x 10 high 6 Pa s and 10.5. These new data that result from incremental analogue modelling corroborate previous suggestions that folds and boudins are coeval structures in cases of plane-strain coaxial deformation with the stiff layer oriented perpendicular to the intermediate Y-axis of the finite strain ellipsoid. They will be of interest for all workers who are dealing with plane-strain boudins and folds, where the fold axes are parallel to the major axis (X) of the finite strain ellipsoid. As has been demonstrated by the first experimental study, coeval folding and boudinage under plane strain, with S ┴ Y, are associated with a significant increase in the thickness of the competent layer. The latter phenomenon does not occur in other cases of simultaneous folding and boudinage, such as bulk pure constriction. To study the impact of layer thickness on the geometry of folds and boudins under pure constriction, we carried out additional experiments using different types of plasticine for a stiff layer and a weaker matrix to model folding and boudinaging under pure constriction, with the initially planar layer oriented parallel to the Xaxis of the finite strain ellipsoid. The stiff layer and matrix consist of non-linear viscous Kolb brown and Beck’s green plasticine, respectively, both of which are strain-rate softening modelling materials. Six runs have been carried out using thicknesses of the stiff layer of 1, 2, 4, 6, 8 and 10 ± 0.2 mm. All experimental runs were carried out at a temperature T of 30 ± 2°C and a strain rate, ė, of ca. 1.1 x 10 high -4 s high -1 until a finite longitudinal strain of 40% was achieved with a viscosity contrast m of 3.1 between the stiff layer (Kolb brown plasticine) and the matrix (Beck’s green plasticine). The apparent viscosity, η, and the stress exponent, n, for the layer at a strain rate ė = ca. 10 high -3 s high -1 and a finite strain e = 10% are 2.23 x 10 high 7 Pa s and n = 5.8 and for the matrix 7.2 x 10 high 6 Pa s and 7.9. Our results suggest a considerable influence of the initial thickness of the stiff layer on the geometry of the deformed stiff layer. There is no evidence for folding in XY=XZ-sections if the initial thickness of the competent layer is larger than ca. 8 mm. If the initial thickness of the competent layer is set at ca. 10 ± 0.2 mm, both folds and boudins develop simultaneously. However, the growth rate of the boudins seems to be higher than the growth rate of the folds. A further expected, but characteristic, aspect of the deformed competent layer is no change in thickness of the competent layer, which can be used to distinguish plane-strain folds and boudins from constrictional folds and boudins. The model results are important for the analysis and interpretation of deformation structures in rheologically stratified rocks undergoing dislocation creep under bulk constriction. Tectonic settings where constrictional folds and boudins may develop simultaneously are stems of salt diapirs, subduction zones or thermal plumes. To make (paleo) viscosimetric statements possible, the rheological data of the different plasticine types were related to the geometrical data. When comparing the normalized dominant wavelength Wd obtained from the deformed layer of the models with the theoretical dominant wavelength (Ld) calculated using the Smith equation (1977, 1979), the latter probably also holds when folding and boudinage develop simultaneously (S ┴ Y) and when boudins develop independently (S ┴ Z), but can obviously not be applied at very low viscosity ratios as is indicated by the low-strain-rate experiments.
In einer Gabor-Linse wird durch ein axiales magnetisches Feld und ein longitudinales Potential ein so genanntes nichtneutrales Plasma (NNP) stabil eingeschlossen. Das elektrische Feld der Ladungsträgerwolke wirkt fokussierend auf Ionenstrahlen, die das Linsenvolumen passieren. Dieses Konzept, das D. Gabor 1946 vorstellte, wurde hinsichtlich seiner Eignung zur Ionenstrahlfokussierung seit den 1970-er Jahren untersucht, denn Gabor-Linsen ermöglichen eine elektrostatische Fokussierung erster Ordnung bei gleichzeitiger Raumladungskompensation im gesamten Transportkanal und haben damit einen großen Vorteil gegenüber den konventionellen Linsensystemen. Hauptsächlich zwei Gründe sprachen jedoch nach den meisten Experimenten gegen einen Einsatz dieses Linsentyps in Beschleunigern: Die erreichte Einschlusseffizienz und die Abbildungseigenschaften der eingeschlossenen Raumladungswolke blieben weit hinter den Erwartungen zurück. Erst ein geändertes Konzept zur Befüllung der Linse mit Elektronen und ein parallel zu den Experimenten entwickeltes numerisches Verfahren zur Bestimmung der Plasmaparameter ermöglichte die Entwicklung eines Linsensystems, das die Vorteile gegenüber konventionellen Ionenoptiken sichtbar werden ließ In der vorliegenden Arbeit wird neben der theoretischen Beschreibung des Plasmaeinschlusses der Aufbau und die Funktionsweise einer Gabor-Linse dargestellt. Experimentelle Befunde zur Strahlinjektion in einen RFQ unter Verwendung einer LEBT-Sektion, bestehend aus zwei Gabor-Linsen werden präsentiert. Nach der Beschleunigung des Ionenstrahles durch einen RFQ auf eine Energie von etwa 440 keV sollten Transportexperimente zeigen, ob eine neu entwickelte Hochfeld Gabor-Linse (HGL) zur Fokussierung dieses Strahles eingesetzt werden kann. Die Strahlenergie ist dabei mit der vergleichbar, die im HIF-Projekt (Heavy Ion Fusion) für die Injektion des Bi1+-Strahles in die erste Beschleunigerstruktur geplant ist. Insbesondere war bei den Experimenten mit dem durch den RFQ beschleunigten Strahl die Einschlusseffizienz bezüglich der Elektronendichte in der HGL von Interesse und auch das Verhalten des NNP bei der Fokussierung eines gepulsten Ionenstrahles.
Die hier vorgelegte empirische Untersuchung der Fokuspartikeln im Georgischen zeichnet sich u.a. durch die sprach¬immanente Tatsache aus, dass die Fokusstrukturen im Georgischen mit expliziten Partikeln markiert werden können. Die in dieser Arbeit untersuchten Fokuspartikelgruppen ( ġa, c und c+ḳi) sind entsprechend den semantischen Implikationen der Restriktion, Addition und der Skalierung gegliedert worden.
Trotz gewisser Unterschiede im Einzelnen ergab sich folgendes gemeinsames Modell für die Stellungseinschränkungen in Relation zum Prädikatsverb:
• Durch Fokuspartikeln fokussierte Wörter stehen im Georgischen in der Regel unmittelbar vor dem Prädikatsverb.
• Die Skopi der Fokuspartikeln (wenn die fokusmarkierten Worte grammatische Köpfe der NPs sind) stehen im Georgischen in der Regel vor dem Prädikatsverb.
• Die nächstmögliche optimale Interpretationsposition für fokusmarkierte Wörter ist in der Regel die unmittelbare Verbnachstellung.
• Die nächstmögliche optimale Interpretationsposition der
Fokusgruppe ist in der Regel die unmittelbare Verbnachstellung.
Aufgrund der herausgearbeiteten Stellungseinschränkungen entwerfe ich das pragmatische Modell der informationsgliedernden Verbfinalität als Basisabfolge im georgischen Satz.
Die Kommunikation von Zellen mit ihrer Umgebung wird durch Rezeptorproteine arrangiert, die sich in der Plasmamembran befinden. Membranrezeptoren werden durch die Bindung von extrazellulären Liganden, Pathogenen oder Zell-Zell-Interaktionen aktiviert, wodurch die Bildung eines aktiven Zustands gefördert wird, der eine intrazelluläre Reaktion einleitet. Eine Beschreibung auf molekularer Ebene, wie sich Membranrezeptoren in Proteinanordnungen organisieren und wie diese Proteinanordnungen eine spezifische funktionelle Aufgabe ausführen, ist der Ausgangspunkt für das Verständnis der molekularen Mechanismen, die Gesundheit und Krankheit zugrunde liegen.
Die Fluoreszenzmikroskopie gibt Aufschluss über die Lage von Proteinen in Zellen, und mit der Einführung der höchstauflösenden Mikroskopie wurde der Nachweis einzelner Proteingruppierungen möglich. Eine Einschränkung der meisten Methoden der höchstauflösenden Mikroskopie ist, dass einzelne Komponenten einer Proteingruppierung optisch nicht aufgelöst werden können, was an der geringen Größe und dichten Packung der Bestandteile im Vergleich zur erreichbaren räumlichen Auflösung liegt. Eine Lösung, die für Einzelmolekül-Lokalisierungsmethoden gezeigt wurde, besteht darin, zusätzliche experimentelle Informationen in die Analyse zu implementieren, also „die Aufl sungsgrenze der höchstauflösenden Mikroskopie zu umgehen". Bei der Einzelmolekül-Bildgebung kann diese zusätzliche Information zum Beispiel die Kinetik von mehrfachen und wiederkehrenden
Emissionsereignissen sein, die bei einzelnen Fluorophoren beobachtet werden, was als "Blinken" bezeichnet wird. Das Ziel dieser Arbeit war die Entwicklung einer höchstauflösenden Fluoreszenzmikroskopiemethode zur Detektion von Proteinmonomeren und -dimeren in der Plasmamembran von Zellen durch die Verwendung der kinetischen Information.
Im ersten Teil dieser Arbeit wurden photoschaltbare fluoreszierende Proteine als Reporter verwendet, deren photoschaltbare Kinetik mit kinetischen Gleichungen analysiert wurden.
Synthetische, genetische und zelluläre Referenzproteine wurden konstruiert und dienten als Kalibrierungsreferenzen für monomere und dimere Proteine.
Im zweiten Teil dieser Arbeit wurde das kinetische Modell, das zur Annäherung des Häufigkeitshistogramms von Blinkereignissen einzelner Fluorophore verwendet wird, auf Oligomere höherer Ordnung erweitert. Ein Vergleich mit einem zuvor entwickelten Modell zeigte, dass das erweiterte Modell genauere Ergebnisse für Oligomere höherer Ordnung und Mischungen verschiedener Oligomere liefert. Zusätzlich wird die Anwesenheit von unerkannten Oligomeren berücksichtigt. Die erweiterte Theorie bietet somit die Grundlage, um größere Oligomere und Mischungen unterschiedlicher Stöchiometrie mit besserer Genauigkeit zu untersuchen.
Im dritten Teil dieser Arbeit wurde eine Methode zur stöchiometrischen endogenen Markierung von Proteinen verwendet, um zwei Rezeptortyrosinkinasen, MET und EGFR, mit einem photoschaltbaren fluoreszierenden Protein zu markieren. Das Vorkommen von monomerem und dimerem MET-Rezeptor wurde auf der Plasmamembran von HEK293T- Zellen mittels quantitativer höchstauflösender Mikroskopie bestimmt. Der Diffusionskoeffizient und der Diffusionsmodus des MET-Rezeptors in lebenden HEK293T-Zellen wurden mit
Einzelpartikelverfolgung gemessen. Dieser Teil der Arbeit zeigte, dass die Kombination von CRISPR/Cas12a-gestützter endogener Markierung und Einzelmolekül-Lokalisierungsmikroskopie ein leistungsfähiges Werkzeug zur Untersuchung der molekularen Organisation und Dynamik von Membranproteinen ist.
Im vierten Teil dieser Arbeit wurde die Einzelmoleküldatenanalyse durch ein Softwaretool beschleunigt, das eine automatisierte und unvoreingenommene Detektion von Einzelmolekül-Emissionsereignissen ermöglicht. Der Anteil von Monomeren und Dimeren von fluoreszierenden Reportern wurde durch die Implementierung eines neuronalen Netzwerks bestimmt (die Software wurde von Alon Saguy geschrieben; Gruppe von Prof. Yoav Shechtman, Technion, Israel). Der oligomere Zustand der monomeren und dimeren Referenzproteine CD86 und CTLA-4 wurde erfolgreich bestimmt. Die automatisierte Detektion einzelner Proteingruppierungen ermöglichte die Analyse von MET-mEos4b in einzelnen Zellen, wodurch die Heterogenität zwischen den Zellen bestimmt und das Expressionsniveau des Rezeptors mit der Dimerisierung korreliert werden konnte.
Zusammenfassend wurden in dieser Arbeit Ergebnisse zu elementaren Aspekten hin zu einer molekularen Quantifizierung von Proteinzahlen mittels Einzelmolekül-
Lokalisationsmikroskopie generiert, die fluoreszierende Reporter, stöchiometrische Markierung von zellulären Proteinen und Bildanalyse umfassen. Das Potential dieser
Entwicklungen wurde anhand der Beobachtung der Liganden-induzierten Verschiebung von monomeren zu dimeren MET-Rezeptoren in einzelnen HEK293T-Zellen gezeigt.
Benzodiazepine stehen in den Medikamentenmissbrauchslisten an erster Stelle und sind deswegen auch von Interesse in der Kriminalistik. Grundlage der vorliegenden Arbeit war die Analyse sämtlicher Benzodiazepin-Fälle, die in den Jahren 1998 bis 2003 im Institut für Forensische Toxikologie, Zentrum der Rechtsmedizin der Johann Wolfgang Goethe Universität in Frankfurt am Main untersucht wurden. Zur Auswertung kamen insgesamt 2695 Fälle, wobei das Hauptaugenmerk auf die 410 Personen gelegt wurde, bei denen Flunitrazepam nachgewiesen werden konnte. Anhand der gesammelten Daten war es möglich, Flunitrazepam unter verschiedenen Gesichtspunkten zu betrachten: 1. Welche Bedeutung hat Flunitrazepam in der Gruppe der Benzodiazepine und kann man im Laufe der Jahre Änderungen im Konsummuster feststellen? 2. Wie ist die Geschlechtsverteilung? 3. Gibt es im Untersuchungszeitraum monokausale Flunitrazepam – Todesfälle? 4. Lassen sich anhand des Vergleichs zwischen Flunitrazepam und Diazepam Unterschiede im Beigebrauch feststellen? 5. Lassen sich anhand des Vergleichs zwischen Flunitrazepam und Benzodiazepinen-Gesamt Unterschiede in der Deliktart feststellen? 6. Gibt es einen Zusammenhang zwischen Konzentration und Deliktart? 7. Welche Bedeutung hat Flunitrazepam in der Drogenszene? Die Auswertung der Daten erbrachte folgende Resultate: 1. Der Pharmakonzern Hofmann La-Roche führte an seinem Produkt Rohypnol® einige Veränderungen durch, um den zunehmenden Missbrauch zu verhindern. 1994 wurde die Darreichungsform von 2 mg auf 1 mg reduziert und 1998 wurde der Farbstoff Indigocarmin hinzugefügt. Von Interesse bei der Analyse der Daten war, ob sich diese Änderungen auf den Konsum von Flunitrazepam auswirkten. Aus diesem Grund wurde zusätzlich noch eine Auswertung über die Benzodiazepinverteilung der Jahre 1993 bis 1997, in denen insgesamt 1630 Benzodiazepin-Fälle registriert wurden, durchgeführt. Bei der Analyse der Benzodiazepinverteilung konnte in den Jahren 1993 bis 1997 und 1998 bis 2003 ein ständiger Zuwachs der Gesamtbenzodiazepin-Fälle festgestellt werden. Dieser Zuwachs ist auf den Anstieg der Untersuchungszahlen im Institut zurückzuführen. Jedoch ließen sich bei den Flunitrazepam-Fällen, gerade in den Jahren 1994 und 1998, Abweichungen im Konsumverlauf feststellen, welche auf die Veränderungen des Pharmakonzerns zurückzuführen sein könnten. Bei den Fragebögen, die mit 15 Schwerstabhängigen aus der Frankfurter Drogenszene durchgeführt wurden, kam es zu folgenden Ergebnissen: nach 1994 wurde der Konsum erhöht, nach 1998 gab es bei den meisten entweder gar keine Veränderung oder die Tabletten wurden anfangs vermehrt oral konsumiert. 2. Aufgrund der Kriminalitätsrate mit überwiegend männlicher Beteiligung lag der Frauenanteil der erfassten Personen bei nur etwa 1/5 (Benzodiazepine-Gesamt: 21,8%, Flunitrazepam: 15,9%). 3. Während des Untersuchungszeitraums konnten keine „reinen“ Flunitrazepam –Todesfälle festgestellt werden. 4. Im Vergleich der Cobefunde waren die Substanzen THC, Morphin, Codein und Methadon in der Diazepam-Gruppe häufiger anzutreffen als in der Flunitrazepam-Gruppe. Lediglich Kokain wurde in der Flunitrazepam-Gruppe vermehrt konsumiert. 5. Als führende Deliktart konnten in der Flunitrazepam-Gruppe die Eigentumsdelikte ermittelt werden. In der Benzodiazepin-Gruppe kam es am häufigsten zu Verkehrsdelikten. 6. Die höchsten Flunitrazepam - Konzentrationen im Blut wurden ebenfalls bei den Eigentumsdelikten gefunden. 7. Aufgrund seiner stärkeren euphorisierenden und hypnotischen Wirksamkeit steht Flunitrazepam in der Frankfurter Drogenszene an erster Stelle unter den Benzodiazepinen. Das Erleben eines Rauschzustandes als Euphorie, als ein unendliches und allumfassendes Glücksgefühl, ist ein - vorrangig bei uns Menschen - bestehendes Phänomen. Den Drang dieses Gefühl zu erleben und beizubehalten gab es seit jeher und wird es auch immer geben werden. Übermäßiges Verlangen und das Nachgeben dieses Impulses führen zu Abhängigkeit und Sucht. Die aus diesem Zustand resultierenden sozialen Auswirkungen äußern sich in Dissozialität und Kriminalität. „Ein süchtig gewordener hat nur eine fixe Idee: das Gift! Seine Sucht treibt ihn zur Unehrlichkeit und zu Verbrechen“ (Georg Siegmund, 1962). Sucht und Abhängigkeit sind Tatsachen die sich nicht verleugnen lassen. Um den Missbrauch eines Medikamentes verhindern zu können, genügt es nicht, nur seine Form zu verändern, es bedarf vielmehr einer umfangreicheren Aufklärung und einer generell bewussteren Umgangsweise mit potentiell suchterzeugenden Substanzen.
Quasi-zweidimensionale organischen Ladungstransfersalze weisen gewisse Analogien zu den Hochtemperatur-Kupratsupraleitern (HTSL) auf. Zu nennen ist einerseits der ähnliche schichtartige Aufbau, wobei sich leitfähige und isolierende Ebenen abwechseln. Zum anderen liegt der antiferromagnetische Grundzustand in direkter Nachbarschaft zur Supraleitung und bei höheren Temperaturen wird ebenfalls die Entstehung einer Pseudo-Energielücke diskutiert. Im Gegensatz zu den HTSL können die elektronischen Eigenschaften der organischen Ladungstransfersalze jedoch leicht durch äußere Parameter wie hydrostatischen bzw. chemischen Druck - die Verwendung verschiedener Anionen X läßt sich in einem verallgemeinerten Phasendiagramm ebenfalls auf die Achse W/U abbilden, siehe Abschn. 4.2 - oder moderate Temperaturen beeinflußt werden. In den quasi-zweidimensionalen K-(BEDT-TTF)2X-Salzen ist bspw. ein moderater Druck p ~ 250 bar ausreichend, um das antiferromagnetisch-isolierende System (X=Cu[N(CN)2]Cl) auf die metallische Seite des Phasendiagramms zu verschieben, wobei dann im Grundzustand Supraleitung auftritt (Tc ~ 12,8 K). Eine Dotierung wie bei den HTSL und die damit einhergehende unerwünschte Unordnung ist nicht notwendig um einen Isolator-Metall-übergang zu induzieren. Demnach sind die experimentellen Anforderungen im Vergleich zu anderen stark korrelierten Elektronensystemen auf relativ einfache Weise zu realisieren. Auch das macht die organischen Ladungstransfersalze zu idealen Modellsystemen, um fundamentale Konzepte der theoretischen Festkörperphysik zu studieren, wovon einige bislang lediglich von akademischem Interesse waren. Erstmalig wird in dieser Arbeit die Fluktuationsspektroskopie als experimentelle Methode angewendet, um die Dynamik des TT-Elektronensystems in den quasi-zweidimensionalen organischen Ladungstransfersalzen K-(BEDT-TTF)2X bei niedrigen Frequenzen zu studieren. Ziel ist es, Informationen über die Temperatur-, Druck- und Magnetfeld-Abhängigkeit der spektralen Leistungsdichte des Widerstandsrauschens und damit über die Dynamik der Ladungsfluktuationen zu gewinnen. Insbesondere in der Nähe korrelationsgetriebener Ordnungsphänomene spielt die Dynamik der Ladungsträger eine entscheidende Rolle. Auch die Kopplung des elektronischen Systems an bestimmte strukturelle Anregungen hat Einfluß auf das Widerstandsrauschen. Zu Beginn wird eine kurze Einführung in die Signalanalyse gegeben und daran anschließend werden verschiedene Arten des Rauschens in Festkörpern dargestellt (Kap. 1). Einige der für diese Arbeit relevanten Ordnungsphänomene werden in Kap. 2 in knapper Form eingeführt, wobei auf die dynamischen Eigenschaften in der Nähe eines Glasübergangs etwas ausführlicher eingegangen wird. Nach der Vorstellung der eingesetzten Meßmethoden, des Versuchsaufbaus und der Probenkontaktierung (Kap. 3) werden die experimentellen Ergebnisse an den K-(BEDT-TTF)2X-Salzen in Kap. 4 ausführlich diskutiert.