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In the presented thesis, the most advanced photon reconstruction technique of ground-based γ-ray astronomy is adapted to the H.E.S.S. 28 m telescope. The method is based on a semi-analytical model of electromagnetic particle showers in the atmosphere. The properties of cosmic γ-rays are reconstructed by comparing the camera image of the telescope with the Cherenkov emission that is expected from the shower model. To suppress the dominant background from charged cosmic rays, events are selected based on several criteria. The performance of the analysis is evaluated with simulated events. The method is then applied to two sources that are known to emit γ-rays. The first of these is the Crab Nebula, the standard candle of ground-based γ-ray astronomy. The results of this source confirm the expected performance of the reconstruction method, where the much lower energy threshold compared to H.E.S.S. I is of particular importance. A second analysis is performed on the region around the Galactic Centre. The analysis results emphasise the capabilities of the new telescope to measure γ-rays in an energy range that is interesting for both theoretical and experimental astrophysics. The presented analysis features the lowest energy threshold that has ever been reached in ground-based γ-ray astronomy, opening a new window to the precise measurement of the physical properties of time-variable sources at energies of several tens of GeV.
Die vorliegende Arbeit behandelt Untersuchungen zum Einfluss ionischer Flüssigkeiten sowohl auf den Rekombinationsprozess photolytisch generierter Lophylradikale als auch auf die photoinduzierte Polymerisation. Im Fokus standen hierbei pyrrolidiniumbasierte ionische Flüssigkeiten sowie polymerisierbare imidazoliumbasierte ionische Flüssigkeiten. Mittels UV-Vis-Spektroskopie wurde in den ionischen Flüssigkeiten im Vergleich zu ausgewählten organischen Lösungsmitteln die Rekombinationskinetik der aus o-Cl-HABI photolytisch generierten Lophylradikale bei unterschiedlichen Temperaturen verfolgt und die Geschwindigkeitskonstanten der Radikalrekombination bestimmt. Die Charakterisierung des Rekombinationsprozesses erfolgt dabei insbesondere unter Verwendung der mittels Eyring-Gleichung ermittelten Aktivierungsparameter. Hierbei konnte gezeigt werden, dass die Rekombination der Lophylradikale in den ionischen Flüssigkeiten im Gegensatz zu den organischen Lösungsmitteln zu einem großen Anteil innerhalb des Lösungsmittelkäfigs erfolgt. Weiterhin wurden für den Einsatz von o-Cl-HABI als Radikalbildner in den photoinduzierten Polymerisationen mehrere mögliche Co-Initiatoren über photokalorimetrische Messungen untersucht. Hierbei wurde auch ein neuer Aspekt zur Kettenübertragung vom Lophylradikal auf den heterocyclischen Co-Initiator vorgestellt. Darüber hinaus wurden photoinduzierte Polymerisationen unter Einsatz eines Initiatorsystems, bestehend aus o-Cl-HABI als Radikalbildner und einem heterocyclischen Co-Initiator, in den ionischen Flüssigkeiten untersucht. Diese Untersuchungen beinhalten zum einen photokalorimetrische Messungen der photoinduzierten Polymerisation von polymerisierbaren imidazoliumbasierten ionischen Flüssigkeiten. Zum anderen wurden Untersuchungen zur photoinduzierten Polymerisation von Methylmethacrylat in pyrrolidiniumbasierten ionischen Flüssigkeiten durchgeführt. Dabei wurden Einflussparameter wie Zeit, Temperatur, Viskosität, Lösungsmittelkäfigeffekt und die Alkylkettenlänge am Kation der ionischen Flüssigkeiten auf die Ausbeuten und Molmassen sowie Molmassenverteilungen der Polymere hin untersucht.
The objective and motivation behind this research is to provide applications with easy-to-use interfaces to communities of deaf and functionally illiterate users, which enables them to work without any human assistance. Although recent years have witnessed technological advancements, the availability of technology does not ensure accessibility to information and communication technologies (ICT). Extensive use of text from menus to document contents means that deaf or functionally illiterate can not access services implemented on most computer software. Consequently, most existing computer applications pose an accessibility barrier to those who are unable to read fluently. Online technologies intended for such groups should be developed in continuous partnership with primary users and include a thorough investigation into their limitations, requirements and usability barriers. In this research, I investigated existing tools in voice, web and other multimedia technologies to identify learning gaps and explored ways to enhance the information literacy for deaf and functionally illiterate users. I worked on the development of user-centered interfaces to increase the capabilities of deaf and low literacy users by enhancing lexical resources and by evaluating several multimedia interfaces for them. The interface of the platform-independent Italian Sign Language (LIS) Dictionary has been developed to enhance the lexical resources for deaf users. The Sign Language Dictionary accepts Italian lemmas as input and provides their representation in the Italian Sign Language as output. The Sign Language dictionary has 3082 signs as set of Avatar animations in which each sign is linked to a corresponding Italian lemma. I integrated the LIS lexical resources with MultiWordNet (MWN) database to form the first LIS MultiWordNet(LMWN). LMWN contains information about lexical relations between words, semantic relations between lexical concepts (synsets), correspondences between Italian and sign language lexical concepts and semantic fields (domains). The approach enhances the deaf users’ understanding of written Italian language and shows that a relatively small set of lexicon can cover a significant portion of MWN. Integration of LIS signs with MWN made it useful tool for computational linguistics and natural language processing. The rule-based translation process from written Italian text to LIS has been transformed into service-oriented system. The translation process is composed of various modules including parser, semantic interpreter, generator, and spatial allocation planner. This translation procedure has been implemented in the Java Application Building Center (jABC), which is a framework for extreme model driven design (XMDD). The XMDD approach focuses on bringing software development closer to conceptual design, so that the functionality of a software solution could be understood by someone who is unfamiliar with programming concepts. The transformation addresses the heterogeneity challenge and enhances the re-usability of the system. For enhancing the e-participation of functionally illiterate users, two detailed studies were conducted in the Republic of Rwanda. In the first study, the traditional (textual) interface was compared with the virtual character-based interactive interface. The study helped to identify usability barriers and users evaluated these interfaces according to three fundamental areas of usability, i.e. effectiveness, efficiency and satisfaction. In another study, we developed four different interfaces to analyze the usability and effects of online assistance (consistent help) for functionally illiterate users and compared different help modes including textual, vocal and virtual character on the performance of semi-literate users. In our newly designed interfaces the instructions were automatically translated in Swahili language. All the interfaces were evaluated on the basis of task accomplishment, time consumption, System Usability Scale (SUS) rating and number of times the help was acquired. The results show that the performance of semi-literate users improved significantly when using the online assistance. The dissertation thus introduces a new development approach in which virtual characters are used as additional support for barely literate or naturally challenged users. Such components enhanced the application utility by offering a variety of services like translating contents in local language, providing additional vocal information, and performing automatic translation from text to sign language. Obviously, there is no such thing as one design solution that fits for all in the underlying domain. Context sensitivity, literacy and mental abilities are key factors on which I concentrated and the results emphasize that computer interfaces must be based on a thoughtful definition of target groups, purposes and objectives.
Permafrost, defined as ground that is frozen for at least two consecutive years, is a distinct feature of the terrestrial unglaciated Arctic. It covers approximately one quarter of the land area of the Northern Hemisphere (23,000,000 km²). Arctic landscapes, especially those underlain by permafrost, are threatened by climate warming and may degrade in different ways, including active layer deepening, thermal erosion, and development of rapid thaw features. In Siberian and Alaskan late Pleistocene ice-rich Yedoma permafrost, rapid and deep thaw processes (called thermokarst) can mobilize deep organic carbon (below 3 m depth) by surface subsidence due to loss of ground ice. Increased permafrost thaw could cause a feedback loop of global significance if its stored frozen organic carbon is reintroduced into the active carbon cycle as greenhouse gases, which accelerate warming and inducing more permafrost thaw and carbon release. To assess this concern, the major objective of the thesis was to enhance the understanding of the origin of Yedoma as well as to assess the associated organic carbon pool size and carbon quality (concerning degradability). The key research questions were:
- How did Yedoma deposits accumulate?
- How much organic carbon is stored in the Yedoma region?
- What is the susceptibility of the Yedoma region's carbon for future decomposition?
To address these three research questions, an interdisciplinary approach, including detailed field studies and sampling in Siberia and Alaska as well as methods of sedimentology, organic biogeochemistry, remote sensing, statistical analyses, and computational modeling were applied. To provide a panarctic context, this thesis additionally includes results both from a newly compiled northern circumpolar carbon database and from a model assessment of carbon fluxes in a warming Arctic.
The Yedoma samples show a homogeneous grain-size composition. All samples were poorly sorted with a multi-modal grain-size distribution, indicating various (re-) transport processes. This contradicts the popular pure loess deposition hypothesis for the origin of Yedoma permafrost. The absence of large-scale grinding processes via glaciers and ice sheets in northeast Siberian lowlands, processes which are necessary to create loess as material source, suggests the polygenetic origin of Yedoma deposits.
Based on the largest available data set of the key parameters, including organic carbon content, bulk density, ground ice content, and deposit volume (thickness and coverage) from Siberian and Alaskan study sites, this thesis further shows that deep frozen organic carbon in the Yedoma region consists of two distinct major reservoirs, Yedoma deposits and thermokarst deposits (formed in thaw-lake basins). Yedoma deposits contain ~80 Gt and thermokarst deposits ~130 Gt organic carbon, or a total of ~210 Gt. Depending on the approach used for calculating uncertainty, the range for the total Yedoma region carbon store is ±75 % and ±20 % for conservative single and multiple bootstrapping calculations, respectively. Despite the fact that these findings reduce the Yedoma region carbon pool by nearly a factor of two compared to previous estimates, this frozen organic carbon is still capable of inducing a permafrost carbon feedback to climate warming. The complete northern circumpolar permafrost region contains between 1100 and 1500 Gt organic carbon, of which ~60 % is perennially frozen and decoupled from the short-term carbon cycle.
When thawed and reintroduced into the active carbon cycle, the organic matter qualities become relevant. Furthermore, results from investigations into Yedoma and thermokarst organic matter quality studies showed that Yedoma and thermokarst organic matter exhibit no depth-dependent quality trend. This is evidence that after freezing, the ancient organic matter is preserved in a state of constant quality. The applied alkane and fatty-acid-based biomarker proxies including the carbon-preference and the higher-land-plant-fatty-acid indices show a broad range of organic matter quality and thus no significantly different qualities of the organic matter stored in thermokarst deposits compared to Yedoma deposits. This lack of quality differences shows that the organic matter biodegradability depends on different decomposition trajectories and the previous decomposition/incorporation history. Finally, the fate of the organic matter has been assessed by implementing deep carbon pools and thermokarst processes in a permafrost carbon model. Under various warming scenarios for the northern circumpolar permafrost region, model results show a carbon release from permafrost regions of up to ~140 Gt and ~310 Gt by the years 2100 and 2300, respectively. The additional warming caused by the carbon release from newly-thawed permafrost contributes 0.03 to 0.14°C by the year 2100. The model simulations predict that a further increase by the 23rd century will add 0.4°C to global mean surface air temperatures.
In conclusion, Yedoma deposit formation during the late Pleistocene was dominated by water-related (alluvial/fluvial/lacustrine) as well as aeolian processes under periglacial conditions. The circumarctic permafrost region, including the Yedoma region, contains a substantial amount of currently frozen organic carbon. The carbon of the Yedoma region is well-preserved and therefore available for decomposition after thaw. A missing quality-depth trend shows that permafrost preserves the quality of ancient organic matter. When the organic matter is mobilized by deep degradation processes, the northern permafrost region may add up to 0.4°C to the global warming by the year 2300.
It is generally agreed upon that stars typically form in open clusters and stellar associations, but little is known about the structure of the open cluster system. Do open clusters and stellar associations form isolated or do they prefer to form in groups and complexes? Open cluster groups and complexes could verify star forming regions to be larger than expected, which would explain the chemical homogeneity over large areas in the Galactic disk. They would also define an additional level in the hierarchy of star formation and could be used as tracers for the scales of fragmentation in giant molecular clouds? Furthermore, open cluster groups and complexes could affect Galactic dynamics and should be considered in investigations and simulations on the dynamical processes, such as radial migration, disc heating, differential rotation, kinematic resonances, and spiral structure.
In the past decade there were a few studies on open cluster pairs (de La Fuente Marcos & de La Fuente Marcos 2009a,b,c) and on open cluster groups and complexes (Piskunov et al. 2006). The former only considered spatial proximity for the identification of the pairs, while the latter also required tangential velocities to be similar for the members. In this work I used the full set of 6D phase-space information to draw a more detailed picture on these structures. For this purpose I utilised the most homogeneous cluster catalogue available, namely the Catalogue of Open Cluster Data (COCD; Kharchenko et al. 2005a,b), which contains parameters for 650 open clusters and compact associations, as well as for their uniformly selected members. Additional radial velocity (RV) and metallicity ([M/H]) information on the members were obtained from the RAdial Velocity Experiment (RAVE; Steinmetz et al. 2006; Kordopatis et al. 2013) for 110 and 81 clusters, respectively. The RAVE sample was cleaned considering quality parameters and flags provided by RAVE (Matijevič et al. 2012; Kordopatis et al. 2013). To ensure that only real members were included for the mean values, also the cluster membership, as provided by Kharchenko et al. (2005a,b), was considered for the stars cross-matched in RAVE.
6D phase-space information could be derived for 432 out of the 650 COCD objects and I used an adaption of the Friends-of-Friends algorithm, as used in cosmology, to identify potential groupings. The vast majority of the 19 identified groupings were pairs, but I also found four groups of 4-5 members and one complex with 15 members. For the verification of the identified structures, I compared the results to a randomly selected subsample of the catalogue for the Milky Way global survey of Star Clusters (MWSC; Kharchenko et al. 2013), which became available recently, and was used as reference sample. Furthermore, I implemented Monte-Carlo simulations with randomised samples created from two distinguished input distributions for the spatial and velocity parameters. On the one hand, assuming a uniform distribution in the Galactic disc and, on the other hand, assuming the COCD data distributions to be representative for the whole open cluster population.
The results suggested that the majority of identified pairs are rather by chance alignments, but the groups and the complex seemed to be genuine. A comparison of my results to the pairs, groups and complexes proposed in the literature yielded a partial overlap, which was most likely because of selection effects and different parameters considered. This is another verification for the existence of such structures.
The characteristics of the found groupings favour that members of an open cluster grouping originate from a common giant molecular cloud and formed in a single, but possibly sequential, star formation event. Moreover, the fact that the young open cluster population showed smaller spatial separations between nearest neighbours than the old cluster population indicated that the lifetime of open cluster groupings is most likely comparable to that of the Galactic open cluster population itself. Still even among the old open clusters I could identify groupings, which suggested that the detected structure could be in some cases more long lived as one might think.
In this thesis I could only present a pilot study on structures in the Galactic open cluster population, since the data sample used was highly incomplete. For further investigations a far more complete sample would be required. One step in this direction would be to use data from large current surveys, like SDSS, RAVE, Gaia-ESO and VVV, as well as including results from studies on individual clusters. Later the sample can be completed by data from upcoming missions, like Gaia and 4MOST. Future studies using this more complete open cluster sample will reveal the effect of open cluster groupings on star formation theory and their significance for the kinematics, dynamics and evolution of the Milky Way, and thereby of spiral galaxies.
In dieser Arbeit werden nichtlineare Kopplungsmechanismen von akustischen Oszillatoren untersucht, die zu Synchronisation führen können. Aufbauend auf die Fragestellungen vorangegangener Arbeiten werden mit Hilfe theoretischer und experimenteller Studien sowie mit Hilfe numerischer Simulationen die Elemente der Tonentstehung in der Orgelpfeife und die Mechanismen der gegenseitigen Wechselwirkung von Orgelpfeifen identifiziert. Daraus wird erstmalig ein vollständig auf den aeroakustischen und fluiddynamischen Grundprinzipien basierendes nichtlinear gekoppeltes Modell selbst-erregter Oszillatoren für die Beschreibung des Verhaltens zweier wechselwirkender Orgelpfeifen entwickelt. Die durchgeführten Modellrechnungen werden mit den experimentellen Befunden verglichen. Es zeigt sich, dass die Tonentstehung und die Kopplungsmechanismen von Orgelpfeifen durch das entwickelte Oszillatormodell in weiten Teilen richtig beschrieben werden. Insbesondere kann damit die Ursache für den nichtlinearen Zusammenhang von Kopplungsstärke und Synchronisation des gekoppelten Zwei-Pfeifen Systems, welcher sich in einem nichtlinearen Verlauf der Arnoldzunge darstellt, geklärt werden. Mit den gewonnenen Erkenntnissen wird der Einfluss des Raumes auf die Tonentstehung bei Orgelpfeifen betrachtet. Dafür werden numerische Simulationen der Wechselwirkung einer Orgelpfeife mit verschiedenen Raumgeometrien, wie z. B. ebene, konvexe, konkave, und gezahnte Geometrien, exemplarisch untersucht. Auch der Einfluss von Schwellkästen auf die Tonentstehung und die Klangbildung der Orgelpfeife wird studiert. In weiteren, neuartigen Synchronisationsexperimenten mit identisch gestimmten Orgelpfeifen, sowie mit Mixturen wird die Synchronisation für verschiedene, horizontale und vertikale Pfeifenabstände in der Ebene der Schallabstrahlung, untersucht. Die dabei erstmalig beobachteten räumlich isotropen Unstetigkeiten im Schwingungsverhalten der gekoppelten Pfeifensysteme, deuten auf abstandsabhängige Wechsel zwischen gegen- und gleichphasigen Sychronisationsregimen hin. Abschließend wird die Möglichkeit dokumentiert, das Phänomen der Synchronisation zweier Orgelpfeifen durch numerische Simulationen, also der Behandlung der kompressiblen Navier-Stokes Gleichungen mit entsprechenden Rand- und Anfangsbedingungen, realitätsnah abzubilden. Auch dies stellt ein Novum dar.
Der Bittergeschmack dient Säugern vermutlich zur Wahrnehmung und Vermeidung toxischer Substanzen. Bitterstoffe können jedoch auch gesund sein oder werden oft bereitwillig mit der Nahrung aufgenommen. Ob sie geschmacklich unterschieden werden können, ist allerdings umstritten. Detektiert werden Bitterstoffe von oralen Bittergeschmacksrezeptoren, den TAS2R (human) bzw. Tas2r (murin). In der Literatur gibt es aber immer mehr Hinweise darauf, dass überdies Tas2r nicht nur in extragustatorischen Organen exprimiert werden, sondern dort auch wichtige Aufgaben erfüllen könnten, was wiederum die Aufklärung ihrer noch nicht vollständig entschlüsselten Funktionsweisen erfordert. So ist noch unbekannt, ob alle bisher als funktionell identifizierten Tas2r wirklich gustatorische Funktionen erfüllen.
Im Rahmen der Charakterisierung neu generierter, im Locus des Bittergeschmacksrezeptors Tas2r131 genetisch modifizierter Mauslinien, wurde in vorliegender Arbeit die gustatorische sowie extragustatorische Expression von Tas2r131 untersucht. Dass Tas2r131 nicht nur in Pilzpapillen, Wall- und Blätterpapillen (VP+FoP), Gaumen, Ductus nasopalatinus, Vomeronasalorgan und Kehldeckel, sondern auch in Thymus, Testes und Nebenhodenkopf, in Gehirnarealen sowie im Ganglion geniculatum nachgewiesen wurde, bildete die Grundlage für weiterführende Studien. Die vorliegende Arbeit zeigt außerdem, dass Tas2r108, Tas2r126, Tas2r135, Tas2r137 und Tas2r143 in Blut exprimiert werden, was auf eine heterogene Funktion der Tas2r hindeutet. Dass zusätzlich erstmals die Expression aller 35 als funktionell beschriebenen Tas2r im gustatorischen VP+FoP-Epithel von C57BL/6-Mäusen nachgewiesen wurde, verweist auf deren Relevanz als funktionelle Geschmacksrezeptoren.
Weiter zeigten Untersuchungen zur Aufklärung eines möglichen Bitter-Unterscheidungsvermögens in Geschmackspapillen von Mäusen mit fluoreszenzmarkierten oder ablatierten Tas2r131-Zellen, dass Tas2r131 exprimierende Zellen eine Tas2r-Zellsubpopulation bilden. Darüber hinaus existieren innerhalb der Bitterzellen geordnete Tas2r-Expressionsmuster, die sich nach der chromosomalen Lage ihrer Gene richten. Isolierte Bitterzellen reagieren heterogen auf bekannte Bitterstoffe. Und Mäuse mit ablatierter Tas2r131-Zellpopulation besitzen noch andere Tas2r-Zellen und schmecken damit einige Bitterstoffe kaum noch, andere aber noch sehr gut. Diese Befunde belegen die Existenz verschiedener gustatorischer Tas2r-Zellpopulationen, welche die Voraussetzung bilden, Bitterstoffe heterogen zu detektieren. Ob dies die Grundlage für ein divergierendes Verhalten gegenüber unverträglichen und harmlosen oder gar nützlichen Bitterstoffen darstellt, kann mit Hilfe der dargelegten Tas2r-Expressionsmuster künftig in Verhaltensexperimenten geprüft werden.
Die Bittergeschmackswahrnehmung in Säugetieren stellt sich als ein hochkomplexer Mechanismus dar, dessen Vielschichtigkeit durch die hier neu aufgezeigten heterogenen Tas2r-Expressions- und Funktionsmuster erneut verdeutlicht wird.
Mathematical modeling of biological systems is a powerful tool to systematically investigate the functions of biological processes and their relationship with the environment. To obtain accurate and biologically interpretable predictions, a modeling framework has to be devised whose assumptions best approximate the examined scenario and which copes with the trade-off of complexity of the underlying mathematical description: with attention to detail or high coverage. Correspondingly, the system can be examined in detail on a smaller scale or in a simplified manner on a larger scale. In this thesis, the role of photosynthesis and its related biochemical processes in the context of plant metabolism was dissected by employing modeling approaches ranging from kinetic to stoichiometric models. The Calvin-Benson cycle, as primary pathway of carbon fixation in C3 plants, is the initial step for producing starch and sucrose, necessary for plant growth. Based on an integrative analysis for model ranking applied on the largest compendium of (kinetic) models for the Calvin-Benson cycle, those suitable for development of metabolic engineering strategies were identified. Driven by the question why starch rather than sucrose is the predominant transitory carbon storage in higher plants, the metabolic costs for their synthesis were examined. The incorporation of the maintenance costs for the involved enzymes provided a model-based support for the preference of starch as transitory carbon storage, by only exploiting the stoichiometry of synthesis pathways. Many photosynthetic organisms have to cope with processes which compete with carbon fixation, such as photorespiration whose impact on plant metabolism is still controversial. A systematic model-oriented review provided a detailed assessment for the role of this pathway in inhibiting the rate of carbon fixation, bridging carbon and nitrogen metabolism, shaping the C1 metabolism, and influencing redox signal transduction. The demand of understanding photosynthesis in its metabolic context calls for the examination of the related processes of the primary carbon metabolism. To this end, the Arabidopsis core model was assembled via a bottom-up approach. This large-scale model can be used to simulate photoautotrophic biomass production, as an indicator for plant growth, under so-called optimal, carbon-limiting and nitrogen-limiting growth conditions. Finally, the introduced model was employed to investigate the effects of the environment, in particular, nitrogen, carbon and energy sources, on the metabolic behavior. This resulted in a purely stoichiometry-based explanation for the experimental evidence for preferred simultaneous acquisition of nitrogen in both forms, as nitrate and ammonium, for optimal growth in various plant species. The findings presented in this thesis provide new insights into plant system's behavior, further support existing opinions for which mounting experimental evidences arise, and posit novel hypotheses for further directed large-scale experiments.
Monoclonal antibodies (mAbs) are engineered immunoglobulins G (IgG) used for more than 20 years as targeted therapy in oncology, infectious diseases and (auto-)immune disorders. Their protein nature greatly influences their pharmacokinetics (PK), presenting typical linear and non-linear behaviors.
While it is common to use empirical modeling to analyze clinical PK data of mAbs, there is neither clear consensus nor guidance to, on one hand, select the structure of classical compartment models and on the other hand, interpret mechanistically PK parameters. The mechanistic knowledge present in physiologically-based PK (PBPK) models is likely to support rational classical model selection and thus, a methodology to link empirical and PBPK models is desirable. However, published PBPK models for mAbs are quite diverse in respect to the physiology of distribution spaces and the parameterization of the non-specific elimination involving the neonatal Fc receptor (FcRn) and endogenous IgG (IgGendo). The remarkable discrepancy between the simplicity of biodistribution data and the complexity of published PBPK models translates in parameter identifiability issues.
In this thesis, we address this problem with a simplified PBPK model—derived from a hierarchy of more detailed PBPK models and based on simplifications of tissue distribution model. With the novel tissue model, we are breaking new grounds in mechanistic modeling of mAbs disposition: We demonstrate that binding to FcRn is indeed linear and that it is not possible to infer which tissues are involved in the unspecific elimination of wild-type mAbs. We also provide a new approach to predict tissue partition coefficients based on mechanistic insights: We directly link tissue partition coefficients (Ktis) to data-driven and species-independent published antibody biodistribution coefficients (ABCtis) and thus, we ensure the extrapolation from pre-clinical species to human with the simplified PBPK model. We further extend the simplified PBPK model to account for a target, relevant to characterize the non-linear clearance due to mAb-target interaction.
With model reduction techniques, we reduce the dimensionality of the simplified PBPK model to design 2-compartment models, thus guiding classical model development with physiological and mechanistic interpretation of the PK parameters. We finally derive a new scaling approach for anatomical and physiological parameters in PBPK models that translates the inter-individual variability into the design of mechanistic covariate models with direct link to classical compartment models, specially useful for PK population analysis during clinical development.
Mars is one of the best candidates among planetary bodies for supporting life. The presence of water in the form of ice and atmospheric vapour together with the availability of biogenic elements and energy are indicators of the possibility of hosting life as we know it. The occurrence of permanently frozen ground – permafrost, is a common phenomenon on Mars and it shows multiple morphological analogies with terrestrial permafrost. Despite the extreme inhospitable conditions, highly diverse microbial communities inhabit terrestrial permafrost in large numbers. Among these are methanogenic archaea, which are anaerobic chemotrophic microorganisms that meet many of the metabolic and physiological requirements for survival on the martian subsurface. Moreover, methanogens from Siberian permafrost are extremely resistant against different types of physiological stresses as well as simulated martian thermo-physical and subsurface conditions, making them promising model organisms for potential life on Mars. The main aims of this investigation are to assess the survival of methanogenic archaea under Mars conditions, focusing on methanogens from Siberian permafrost, and to characterize their biosignatures by means of Raman spectroscopy, a powerful technology for microbial identification that will be used in the ExoMars mission. For this purpose, methanogens from Siberian permafrost and non-permafrost habitats were subjected to simulated martian desiccation by exposure to an ultra-low subfreezing temperature (-80ºC) and to Mars regolith (S-MRS and P-MRS) and atmospheric analogues. They were also exposed to different concentrations of perchlorate, a strong oxidant found in martian soils. Moreover, the biosignatures of methanogens were characterized at the single-cell level using confocal Raman microspectroscopy (CRM). The results showed survival and methane production in all methanogenic strains under simulated martian desiccation. After exposure to subfreezing temperatures, Siberian permafrost strains had a faster metabolic recovery, whereas the membranes of non-permafrost methanogens remained intact to a greater extent. The strain Methanosarcina soligelidi SMA-21 from Siberian permafrost showed significantly higher methane production rates than all other strains after the exposure to martian soil and atmospheric analogues, and all strains survived the presence of perchlorate at the concentration on Mars. Furthermore, CRM analyses revealed remarkable differences in the overall chemical composition of permafrost and non-permafrost strains of methanogens, regardless of their phylogenetic relationship. The convergence of the chemical composition in non-sister permafrost strains may be the consequence of adaptations to the environment, and could explain their greater resistance compared to the non-permafrost strains. As part of this study, Raman spectroscopy was evaluated as an analytical technique for remote detection of methanogens embedded in a mineral matrix. This thesis contributes to the understanding of the survival limits of methanogenic archaea under simulated martian conditions to further assess the hypothetical existence of life similar to methanogens on the martian subsurface. In addition, the overall chemical composition of methanogens was characterized for the first time by means of confocal Raman microspectroscopy, with potential implications for astrobiological research.
What is a radical? Somebody who goes against mainstream opinions? An agitator who suggests transforming society at the risk of endangering its harmony? In the political context of the British Isles at the end of the eighteenth century, the word radical had a negative connotation. It referred to the Levellers and the English Civil War, it brought back a period of history which was felt as a traumatic experience. Its stigmas were still vivid in the mind of the political leaders of these times. The reign of Cromwell was certainly the main reason for the general aversion of any form of virulent contestation of the power, especially when it contained political claims.
In the English political context, radicalism can be understood as the different campaigns for parliamentary reforms establishing universal suffrage. However, it became evident that not all those who were supporting such a reform originated from the same social class or shared the same ideals. As a matter of fact, the reformist associations and their leaders often disagreed with each other. Edward Royle and Hames Walvin claimed that radicalism could not be analyzed historically as a concept, because it was not a homogeneous movement, nor it had common leaders and a clear ideology. For them, radicalism was merely a loose concept, « a state of mind rather than a plan of action. »
At the beginning of the nineteenth-century, the newspaper The Northern Star used the word radical in a positive way to designate a person or a group of people whose ideas were conform to those of the newspaper. However, an opponent of parliamentary reform will use the same word in a negative way, in this case the word radical will convey a notion of menace. From the very beginning, the term radical covered a large spectrum of ideas and conceptions. In fact, the plurality of what the word conveys is the main characteristic of what a radical is. As a consequence, because the radicals tended to differentiate themselves with their plurality and their differences rather than with common features, it seems impossible to define what radicalism (whose suffix in –ism implies that it designate a doctrine, an ideology) is. Nevertheless, today it is accepted by all historians. From the mid-twentieth century, we could say that it was taken from granted to consider radicalism as a movement that fitted with the democratic precepts (universal suffrage, freedom of speech) of our modern world.
Let us first look at radicalism as a convenient way to designate the different popular movements appealing to universal suffrage during the time period 1792-1848. We could easily observe through the successions of men and associations, a long lasting radical state of mind: Cartwright, Horne Tooke, Thomas Hardy, Francis Burdett, William Cobbett, Henry Hunt, William Lovett, Bronterre O’Brien, Feargus O’Connor, The London Society for Constitutional information (SCI), The London Corresponding Society (LCS), The Hampden Clubs, The Chartists, etc. These organizations and people acknowledged having many things in common and being inspired by one another in carrying out their activities. These influences can be seen in the language and the political ideology that British historians name as "Constitutionalist", but also, in the political organization of extra-parliamentary societies. Most of the radicals were eager to redress injustices and, in practice, they were inspired by a plan of actions drawn on from the pamphlets of the True Whigs of the eighteenth-century. We contest the argument that the radicals lacked coherence and imagination or that they did not know how to put into practice their ambitions. In fact, their innovative forms of protest left a mark on history and found many successors in the twentieth century. Radicals’ prevarications were the result of prohibitive legislation that regulated the life of associations and the refusal of the authorities to cooperate with them.
As mentioned above, the term radical was greatly used and the contemporaries of the period starting from the French Revolution to Chartism never had to quarrel about the notions the word radical covered. However, this does not imply that all radicals were the same or that they belong to the same entity. Equally to Horne Tooke, the Reverend and ultra-Tory Stephens was considered as a radical, it went also with the shoemaker Thomas Hardy and the extravagant aristocrat Francis Burdett. Whether one belonged to the Aristocracy, the middle-class, the lower class or the Church, nothing could prevent him from being a radical. Surely, anybody could be a radical in its own way. Radicalism was wide enough to embrace everybody, from revolutionary reformers to paternalistic Tories.
We were interested to clarify the meaning of the term radical because its inclusive nature was overlooked by historians. That’s why the term radical figures in the original title of our dissertation Les voix/voies radicales (radical voices/ways to radicalism). In the French title, both words voix/voies are homonymous; the first one voix (voice) correspond to people, the second one voies (ways) refers to ideas. By this, we wanted to show that the word radical belongs to the sphere of ideas and common experience but also to the nature of human beings.
Methodoloy
The thesis stresses less on the question of class and its formation than on the circumstances that brought people to change their destiny and those of their fellows or to modernize the whole society. We challenged the work of E.P. Thompson, who in his famous book, The Making of the English Working Class, defined the radical movements in accordance with an idea of class.
How a simple shoe-maker, Thomas Hardy, could become the center of attention during a trial where he was accused of being the mastermind of a modern revolution? What brought William Cobbett, an ultra-Tory, self-taught intellectual, to gradually espouse the cause of universal suffrage at a period where it was unpopular to do so? Why a whole population gathered to hear Henry Hunt, a gentleman farmer whose background did not destine him for becoming the champion of the people? It seemed that the easiest way to answer to these questions and to understand the nature of the popular movements consisted in studying the life of their leaders. We aimed at reconstructing the universe which surrounded the principal actors of the reform movements as if we were a privileged witness of theses times.
This idea to associate the biographies of historical characters for a period of more than fifty years arouse when we realized that key events of the reform movements were echoing each other, such the trial of Thomas Hardy in 1794 and the massacre of Peterloo of 1819. The more we learned about the major events of radicalism and the life of their leaders, the more we were intrigued. Finally, one could ask himself if being a radical was not after all a question of character rather than one of class. The different popular movements in favour of a parliamentary reform were in fact far more inclusive and diversified from what historians traditionally let us to believe. For instance, once he manage to gather a sufficient number of members of the popular classes, Thomas Hardy projected to give the control of his association to an intellectual elite led by Horne Tooke.
Moreover, supporters of the radical reforms followed leaders whose background was completely different as theirs. For example, O’Connor claimed royal descent from the ancient kings of Ireland. William Cobbett, owner of a popular newspaper was proud of his origins as a farmer. William Lovett, close to the liberals and a few members of parliament came from a very poor family of fishermen. We have thus put together the life of these five men, Thomas hardy, William Cobbett, Henry Hunt, William Lovett and Feargus O’Connor in order to compose a sort of a saga of the radicals. This association gives us a better idea of the characteristics of the different movements in which they participated, but also, throw light on the circumstances of their formation and their failures, on the particular atmosphere which prevailed at these times, on the men who influenced these epochs, and finally on the marks they had left. These men were at the heart of a whole network and in contact with other actors of peripheral movements. They gathered around themselves close and loyal fellows with whom they shared many struggles but also quarreled and had strong words.
The original part of our approach is reflected in the choice to not consider studying the fluctuations of the radical movements in a linear fashion where the story follows a strict chronology. We decided to split up the main issue of the thesis through different topics. To do so, we simply have described the life of the people who inspired these movements. Each historical figure covers a chapter, and the general story follows a chronological progression. Sometimes we had to go back through time or discuss the same events in different chapters when the main protagonists lived in the same period of time.
Radical movements were influenced by people of different backgrounds. What united them above all was their wish to obtain a normalization of the political world, to redress injustices and obtain parliamentary reform. We paid particular attention to the moments where the life of these men corresponded to an intense activity of the radical movement or to a transition of its ideas and organization. We were not so much interested in their feelings about secondary topics nor did we about their affective relations. Furthermore, we had little interest in their opinions on things which were not connected to our topic unless it helped us to have a better understanding of their personality. We have purposely reduced the description of our protagonists to their radical sphere. Of course we talked about their background and their intellectual development; people are prone to experience reversals of opinions, the case of Cobbett is the most striking one.
The life of these personalities coincided with particular moments of the radical movement, such as the first popular political associations, the first open-air mass meetings, the first popular newspapers, etc. We wanted to emphasize the personalities of those who addressed speeches and who were present in the radical associations. One could argue that the inconvenience of focusing on a particular person presents a high risk of overlooking events and people who were not part of his world. However, it was essential to differ from an analysis or a chronicle which had prevailed in the studies of the radical movements, as we aimed at offering a point of view that completed the precedents works written on that topic. In order to do so, we have deliberately put the humane character of the radical movement at the center of our work and used the techniques of biography as a narrative thread.
Conclusion
The life of each historical figure that we have portrayed corresponded to a particular epoch of the radical movement. Comparing the speeches of the radical leaders over a long period of time, we noticed that the radical ideology evolved. The principles of the Rights of Men faded away and gave place to more concrete reasoning, such as the right to benefit from one’s own labour. This transition is characterized by the Chartist period of Feargus O’Connor. This does not mean that collective memory and radical tradition ceased to play an important part. The popular classes were always appealed to Constitutional rhetoric and popular myths. Indeed, thanks to them they identified themselves and justified their claims to universal suffrage.
We focused on the life of a few influent leaders of radicalism in order to understand its evolution and its nature. The description of their lives constituted our narrative thread and it enabled us to maintain consistency in our thesis. If the chapters are independent the one from the other, events and speeches are in correspondences. Sometimes we could believe that we were witnessing a repetition of facts and events as if history was repeating itself endlessly. However, like technical progress, the spirit of time, Zeitgeist, experiences changes and mutations. These features are fundamental elements to comprehend historical phenomena; the latter cannot be simplified to philosophical, sociological, or historical concept. History is a science which has this particularity that the physical reality of phenomena has a human dimension. As a consequence, it is essential not to lose touch with the human aspect of history when one pursues studies and intellectual activities on a historical phenomenon.
We decided to take a route opposite to the one taken by many historians. We have first identified influential people from different epochs before entering into concepts analysis. Thanks to this compilation of radical leaders, a new and fresh look to the understanding of radicalism was possible. Of course, we were not the first one to have studied them, but we ordered them following a chronology, like Plutarch enjoyed juxtaposing Greeks and Romans historical figures. Thanks to this technique we wanted to highlight the features of the radical leaders’ speeches, personalities and epochs, but also their differences. At last, we tried to draw the outlines and the heart of different radical movements in order to follow the ways that led to radicalism. We do not pretend to have offered an original and exclusive definition of radicalism, we mainly wanted to understand the nature of what defines somebody as a radical and explain the reasons why thousands of people decided to believe in this man. Moreover, we wanted to distance ourselves from the ideological debate of the Cold War which permeated also the interpretation of past events. Too often, the history of radicalism was either narrated with a form of revolutionary nostalgia or in order to praise the merits of liberalism.
If the great mass meetings ends in the mid-nineteenth-century with the fall of Chartism, this practice spread out in the whole world in the twentieth-century. Incidentally, the Arab Spring of the beginning of the twenty-first-century demonstrated that a popular platform was the best way for the people to claim their rights and destabilize a political system which they found too authoritative. Through protest the people express an essential quality of revolt, which is an expression of emancipation from fear. From then on, a despotic regime loses this psychological terror which helped it to maintain itself into power. The balance of power between the government and its people would also take a new turn. The radicals won this psychological victory more than 150 years ago and yet universal suffrage was obtained only a century later. From the acceptance of the principles of liberties to their cultural practice, a long route has to be taken to change people’s mind. It is a wearisome struggle for the most vulnerable people. In the light of western history, fundamental liberties must be constantly defended. Paradoxically, revolt is an essential and constitutive element of the maintenance of democracy.
The subsurface upper Palaeozoic sedimentary successions of the Loppa High half-graben and the Finnmark platform in the Norwegian Barents Sea (southwest Barents Sea) were investigated using 2D/3D seismic datasets combined with well and core data. These sedimentary successions represent a case of mixed siliciclastic-carbonates depositional systems, which formed during the earliest phase of the Atlantic rifting between Greenland and Norway. During the Carboniferous and Permian the southwest part of the Barents Sea was located along the northern margin of Pangaea, which experienced a northward drift at a speed of ~2–3 mm per year. This gradual shift in the paleolatitudinal position is reflected by changes in regional climatic conditions: from warm-humid in the early Carboniferous, changing to warm-arid in the middle to late Carboniferous and finally to colder conditions in the late Permian. Such changes in paleolatitude and climate have resulted in major changes in the style of sedimentation including variations in the type of carbonate factories. The upper Palaeozoic sedimentary succession is composed of four major depositional units comprising chronologically the Billefjorden Group dominated by siliciclastic deposition in extensional tectonic-controlled wedges, the Gipsdalen Group dominated by warm-water carbonates, stacked buildups and evaporites, the Bjarmeland Group characterized by cool-water carbonates as well as by the presence of buildup networks, and the Tempelfjorden Group characterized by fine-grained sedimentation dominated by biological silica production. In the Loppa High, the integration of a core study with multi-attribute seismic facies classification allowed highlighting the main sedimentary unconformities and mapping the spatial extent of a buried paleokarst terrain. This geological feature is interpreted to have formed during a protracted episode of subaerial exposure occurring between the late Palaeozoic and middle Triassic. Based on seismic sequence stratigraphy analysis the palaeogeography in time and space of the Loppa High basin was furthermore reconstructed and a new and more detailed tectono-sedimentary model for this area was proposed. In the Finnmark platform area, a detailed core analysis of two main exploration wells combined with key 2D seismic sections located along the main depositional profile, allowed the evaluation of depositional scenarios for the two main lithostratigraphic units: the Ørn Formation (Gipsdalen Group) and the Isbjørn Formation (Bjarmeland Group). During the mid-Sakmarian, two major changes were observed between the two formations including (1) the variation in the type of the carbonate factories, which is interpreted to be depth-controlled and (2) the change in platform morphology, which evolved from a distally steepened ramp to a homoclinal ramp. The results of this study may help supporting future reservoirs characterization of the upper Palaeozoic units in the Barents Sea, particularly in the Loppa High half-graben and the Finmmark platform area.
Large-scale floodplain sediment dynamics in the Mekong Delta : present state and future prospects
(2014)
The Mekong Delta (MD) sustains the livelihood and food security of millions of people in Vietnam and Cambodia. It is known as the “rice bowl” of South East Asia and has one of the world’s most productive fisheries. Sediment dynamics play a major role for the high productivity of agriculture and fishery in the delta. However, the MD is threatened by climate change, sea level rise and unsustainable development activities in the Mekong Basin. But despite its importance and the expected threats, the understanding of the present and future sediment dynamics in the MD is very limited. This is a consequence of its large extent, the intricate system of rivers, channels and floodplains and the scarcity of observations. Thus this thesis aimed at (1) the quantification of suspended sediment dynamics and associated sediment-nutrient deposition in floodplains of the MD, and (2) assessed the impacts of likely future boundary changes on the sediment dynamics in the MD. The applied methodology combines field experiments and numerical simulation to quantify and predict the sediment dynamics in the entire delta in a spatially explicit manner. The experimental part consists of a comprehensive procedure to monitor quantity and spatial variability of sediment and associated nutrient deposition for large and complex river floodplains, including an uncertainty analysis. The measurement campaign applied 450 sediment mat traps in 19 floodplains over the MD for a complete flood season. The data also supports quantification of nutrient deposition in floodplains based on laboratory analysis of nutrient fractions of trapped sedimentation.The main findings are that the distribution of grain size and nutrient fractions of suspended sediment are homogeneous over the Vietnamese floodplains. But the sediment deposition within and between ring dike floodplains shows very high spatial variability due to a high level of human inference. The experimental findings provide the essential data for setting up and calibration of a large-scale sediment transport model for the MD. For the simulation studies a large scale hydrodynamic model was developed in order to quantify large-scale floodplain sediment dynamics. The complex river-channel-floodplain system of the MD is described by a quasi-2D model linking a hydrodynamic and a cohesive sediment transport model. The floodplains are described as quasi-2D presentations linked to rivers and channels modeled in 1D by using control structures. The model setup, based on the experimental findings, ignored erosion and re-suspension processes due to a very high degree of human interference during the flood season. A two-stage calibration with six objective functions was developed in order to calibrate both the hydrodynamic and sediment transport modules. The objective functions include hydraulic and sediment transport parameters in main rivers, channels and floodplains. The model results show, for the first time, the tempo-spatial distribution of sediment and associated nutrient deposition rates in the whole MD. The patterns of sediment transport and deposition are quantified for different sub-systems. The main factors influencing spatial sediment dynamics are the network of rivers, channels and dike-rings, sluice gate operations, magnitude of the floods and tidal influences. The superposition of these factors leads to high spatial variability of the sediment transport and deposition, in particular in the Vietnamese floodplains. Depending on the flood magnitude, annual sediment loads reaching the coast vary from 48% to 60% of the sediment load at Kratie, the upper boundary of the MD. Deposited sediment varies from 19% to 23% of the annual load at Kratie in Cambodian floodplains, and from 1% to 6% in the compartmented and diked floodplains in Vietnam. Annual deposited nutrients (N, P, K), which are associated to the sediment deposition, provide on average more than 50% of mineral fertilizers typically applied for rice crops in non-flooded ring dike compartments in Vietnam. This large-scale quantification provides a basis for estimating the benefits of the annual Mekong floods for agriculture and fishery, for assessing the impacts of future changes on the delta system, and further studies on coastal deposition/erosion. For the estimation of future prospects a sensitivity-based approach is applied to assess the response of floodplain hydraulics and sediment dynamics to the changes in the delta boundaries including hydropower development, climate change in the Mekong River Basin and effective sea level rise. The developed sediment model is used to simulate the mean sediment transport and sediment deposition in the whole delta system for the baseline (2000-2010) and future (2050-2060) periods. For each driver we derive a plausible range of future changes and discretize it into five levels, resulting in altogether 216 possible factor combinations. Our results thus cover all plausible future pathways of sediment dynamics in the delta based on current knowledge. The uncertainty of the range of the resulting impacts can be decreased in case more information on these drivers becomes available. Our results indicate that the hydropower development dominates the changes in sediment dynamics of the Mekong Delta, while sea level rise has the smallest effect. The floodplains of Vietnamese Mekong Delta are much more sensitive to the changes compared to the other subsystems of the delta. In terms of median changes of the three combined drivers, the inundation extent is predicted to increase slightly, but the overall floodplain sedimentation would be reduced by approximately 40%, while the sediment load to the Sea would diminish to half of the current rates. These findings provide new and valuable information on the possible impacts of future development on the delta, and indicate the most vulnerable areas. Thus, the presented results are a significant contribution to the ongoing international discussion on the hydropower development in the Mekong basin and its impact on the Mekong delta.
Organische Halbleiter besitzen neue, bemerkenswerte Materialeigenschaften, die sie für die grundlegende Forschung wie auch aktuelle technologische Entwicklung (bsw. org. Leuchtdioden, org. Solarzellen) interessant werden lassen. Aufgrund der starken konformative Freiheit der konjugierten Polymerketten führt die Vielzahl der möglichen Anordnungen und die schwache intermolekulare Wechselwirkung für gewöhnlich zu geringer struktureller Ordnung im Festkörper. Die Morphologie hat gleichzeitig direkten Einfluss auf die elektronische Struktur der organischen Halbleiter, welches sich meistens in einer deutlichen Reduktion der Ladungsträgerbeweglichkeit gegenüber den anorganischen Verwandten zeigt. So stellt die Beweglichkeit der Ladungen im Halbleiter einen der limitierenden Faktoren für die Leistungsfähigkeit bzw. den Wirkungsgrad von funktionellen organischen Bauteilen dar. Im Jahr 2009 wurde ein neues auf Naphthalindiimid und Bithiophen basierendes Dornor/Akzeptor Copolymer vorgestellt [P(NDI2OD‑T2)], welches sich durch seine außergewöhnlich hohe Ladungsträgermobilität auszeichnet. In dieser Arbeit wird die Ladungsträgermobilität in P(NDI2OD‑T2) bestimmt, und der Transport durch eine geringe energetischer Unordnung charakterisiert. Obwohl dieses Material zunächst als amorph beschrieben wurde zeigt eine detaillierte Analyse der optischen Eigenschaften von P(NDI2OD‑T2), dass bereits in Lösung geordnete Vorstufen supramolekularer Strukturen (Aggregate) existieren. Quantenchemische Berechnungen belegen die beobachteten spektralen Änderungen. Mithilfe der NMR-Spektroskopie kann die Bildung der Aggregate unabhängig von optischer Spektroskopie bestätigt werden. Die Analytische Ultrazentrifugation an P(NDI2OD‑T2) Lösungen legt nahe, dass sich die Aggregation innerhalb der einzelnen Ketten unter Reduktion des hydrodynamischen Radius vollzieht. Die Ausbildung supramolekularen Strukturen nimmt auch eine signifikante Rolle bei der Filmbildung ein und verhindert gleichzeitig die Herstellung amorpher P(NDI2OD‑T2) Filme. Durch chemische Modifikation der P(NDI2OD‑T2)-Kette und verschiedener Prozessierungs-Methoden wurde eine Änderung des Kristallinitätsgrades und gleichzeitig der Orientierung der kristallinen Domänen erreicht und mittels Röntgenbeugung quantifiziert. In hochauflösenden Elektronenmikroskopie-Messungen werden die Netzebenen und deren Einbettung in die semikristallinen Strukturen direkt abgebildet. Aus der Kombination der verschiedenen Methoden erschließt sich ein Gesamtbild der Nah- und Fernordnung in P(NDI2OD‑T2). Über die Messung der Elektronenmobilität dieser Schichten wird die Anisotropie des Ladungstransports in den kristallographischen Raumrichtungen von P(NDI2OD‑T2) charakterisiert und die Bedeutung der intramolekularen Wechselwirkung für effizienten Ladungstransport herausgearbeitet. Gleichzeitig wird deutlich, wie die Verwendung von größeren und planaren funktionellen Gruppen zu höheren Ladungsträgermobilitäten führt, welche im Vergleich zu klassischen semikristallinen Polymeren weniger sensitiv auf die strukturelle Unordnung im Film sind.
Das Europäische Parlament ist zweifelsohne die mächtigste parlamentarische Versammlung auf supranationaler Ebene. Das provoziert die Frage, wie Entscheidungen in diesem Parlament gefällt werden und wie sie begründet werden können. Darin liegt das Hauptanliegen dieser Arbeit, die zur Beantwortung dieser Frage auf soziologische Ansätze der Erklärung sozialen Handelns zurückgreift und damit einen neuen Zugang zur Beobachtung parlamentarischen Handelns schafft. Dabei arbeitet sie heraus, wie wichtig es ist, bei der Analyse politischer Entscheidungsprozesse zu beachten, wie politische Probleme von Akteuren interpretiert und gegenüber Verhandlungspartnern dargestellt werden. An den Fallbeispielen der Entscheidungsprozesse zur Dienstleistungsrichtlinie, zur Chemikalien-Verordnung REACH und dem TDIP (CIA)-Ausschuss in der Legislaturperiode 2004–2009, wird der soziale Mechanismus dargestellt, der hinter Einigungen im Europäischen Parlament steckt. Kultur als Interpretation der Welt wird so zum Schlüssel des Verständnisses politischer Entscheidungen auf supranationaler Ebene.
Anorexia nervosa und unipolare Affektive Störungen stellen häufige und schwerwiegende kinder- und jugendpsychiatrische Störungsbilder dar, deren Pathogenese bislang nicht vollständig entschlüsselt ist. Verschiedene Studien zeigen bei erwachsenen Patienten gravierende Auffälligkeiten in den kognitiven Funktionen. Dahingegen scheinen bei adoleszenten Patienten lediglich leichtere Einschränkungen in den kognitiven Funktionen vorzuliegen. Die Prävalenz der Anorexia nervosa und unipolaren Affektiven Störung ist mit Beginn der Adoleszenz deutlich erhöht. Es ist anzunehmen, dass kognitive Dysfunktionen, die sich bereits in diesem Alter abzeichnen, den weiteren Krankheitsverlauf bis in das Erwachsenenalter, die Behandlungsergebnisse und die Prognose maßgeblich beeinträchtigen könnten. Zudem ist von einem höheren Chronifizierungsrisiko auszugehen. In der vorliegenden Arbeit wurden daher kognitive Funktionen bei adoleszenten Patientinnen mit Anorexia nervosa sowie Patienten mit unipolaren Affektiven Störungen untersucht. Die Überprüfung der kognitiven Funktionen bei Patientinnen mit Anorexia nervosa erfolgte vor und nach Gewichtszunahme. Weiterhin wurden zugrundeliegende biologische Mechanismen überprüft. Zudem wurde die Spezifität kognitiver Dysfunktionen für beide Störungsbilder untersucht und bei Patienten mit unipolaren Affektiven Störungen geschlechtsbezogene Unterschiede exploriert. Insgesamt gingen 47 Patientinnen mit Anorexia nervosa (mittleres Alter 16,3 + 1,6 Jahre), 39 Patienten mit unipolaren Affektiven Störungen (mittleres Alter 15,5 + 1,3 Jahre) sowie 78 Kontrollprobanden (mittleres Alter 16,5 + 1,3 Jahre) in die Untersuchung ein. Sämtliche Studienteilnehmer durchliefen eine neuropsychologische Testbatterie, bestehend aus Verfahren zur Überprüfung der kognitiven Flexibilität sowie visuellen und psychomotorischen Verarbeitungsgeschwindigkeit. Neben einem Intelligenzscreening wurden zudem das Ausmaß der depressiven Symptomatik sowie die allgemeine psychische Belastung erfasst. Die Ergebnisse legen nahe, dass bei adoleszenten Patientinnen mit Anorexia nervosa, sowohl im akut untergewichtigen Zustand als auch nach Gewichtszunahme, lediglich milde Beeinträchtigungen in den kognitiven Funktionen vorliegen. Im akut untergewichtigen Zustand offenbarten sich deutliche Zusammenhänge zwischen dem appetitregulierenden Peptid Agouti-related Protein und kognitiver Flexibilität, nicht jedoch zwischen Agouti-related Protein und visueller oder psychomotorischer Verarbeitungsgeschwindigkeit. Bei dem Vergleich von Anorexia nervosa und unipolaren Affektiven Störungen prädizierte die Zugehörigkeit zu der Patientengruppe Anorexia nervosa ein Risiko für das Vorliegen kognitiver Dysfunktionen. Es zeigte sich zudem, dass adoleszente Patienten mit unipolaren Affektiven Störungen lediglich in der psychomotorischen Verarbeitungsgeschwindigkeit tendenziell schwächere Leistungen offenbarten als gesunde Kontrollprobanden. Es ergab sich jedoch ein genereller geschlechtsbezogener Vorteil für weibliche Probanden in der visuellen und psychomotorischen Verarbeitungsgeschwindigkeit. Die vorliegenden Befunde unterstreichen die Notwendigkeit der Überprüfung kognitiver Funktionen bei adoleszenten Patienten mit Anorexia nervosa sowie unipolaren Affektiven Störungen in der klinischen Routinediagnostik. Die Patienten könnten von spezifischen Therapieprogrammen profitieren, die Beeinträchtigungen in den kognitiven Funktionen mildern bzw. präventiv behandeln.
The purpose of this thesis is to develop an automated inversion scheme to derive point and finite source parameters for weak earthquakes, here intended with the unusual meaning of earthquakes with magnitudes at the limit or below the bottom magnitude threshold of standard source inversion routines. The adopted inversion approaches entirely rely on existing inversion software, the methodological work mostly targeting the development and tuning of optimized inversion flows. The resulting inversion scheme is tested for very different datasets, and thus allows the discussion on the source inversion problem at different scales. In the first application, dealing with mining induced seismicity, the source parameters determination is addressed at a local scale, with source-sensor distance of less than 3 km. In this context, weak seismicity corresponds to event below magnitude MW 2.0, which are rarely target of automated source inversion routines. The second application considers a regional dataset, namely the aftershock sequence of the 2010 Maule earthquake (Chile), using broadband stations at regional distances, below 300 km. In this case, the magnitude range of the target aftershocks range down to MW 4.0. This dataset is here considered as a weak seismicity case, since the analysis of such moderate seismicity is generally investigated only by moment tensor inversion routines, with no attempt to resolve source duration or finite source parameters. In this work, automated multi-step inversion schemes are applied to both datasets with the aim of resolving point source parameters, both using double couple (DC) and full moment tensor (MT) models, source duration and finite source parameters. A major result of the analysis of weaker events is the increased size of resulting moment tensor catalogues, which interpretation may become not trivial. For this reason, a novel focal mechanism clustering approach is used to automatically classify focal mechanisms, allowing the investigation of the most relevant and repetitive rupture features. The inversion of the mining induced seismicity dataset reveals the repetitive occurrence of similar rupture processes, where the source geometry is controlled by the shape of the mined panel. Moreover, moment tensor solutions indicate a significant contribution of tensile processes. Also the second application highlights some characteristic geometrical features of the fault planes, which show a general consistency with the orientation of the slab. The additional inversion for source duration allowed to verify the empirical correlation for moment normalized earthquakes in subduction zones among a decreasing rupture duration with increasing source depth, which was so far only observed for larger events.
Linked Open Data (LOD) comprises very many and often large public data sets and knowledge bases. Those datasets are mostly presented in the RDF triple structure of subject, predicate, and object, where each triple represents a statement or fact. Unfortunately, the heterogeneity of available open data requires significant integration steps before it can be used in applications. Meta information, such as ontological definitions and exact range definitions of predicates, are desirable and ideally provided by an ontology. However in the context of LOD, ontologies are often incomplete or simply not available. Thus, it is useful to automatically generate meta information, such as ontological dependencies, range definitions, and topical classifications. Association rule mining, which was originally applied for sales analysis on transactional databases, is a promising and novel technique to explore such data. We designed an adaptation of this technique for min-ing Rdf data and introduce the concept of “mining configurations”, which allows us to mine RDF data sets in various ways. Different configurations enable us to identify schema and value dependencies that in combination result in interesting use cases. To this end, we present rule-based approaches for auto-completion, data enrichment, ontology improvement, and query relaxation. Auto-completion remedies the problem of inconsistent ontology usage, providing an editing user with a sorted list of commonly used predicates. A combination of different configurations step extends this approach to create completely new facts for a knowledge base. We present two approaches for fact generation, a user-based approach where a user selects the entity to be amended with new facts and a data-driven approach where an algorithm discovers entities that have to be amended with missing facts. As knowledge bases constantly grow and evolve, another approach to improve the usage of RDF data is to improve existing ontologies. Here, we present an association rule based approach to reconcile ontology and data. Interlacing different mining configurations, we infer an algorithm to discover synonymously used predicates. Those predicates can be used to expand query results and to support users during query formulation. We provide a wide range of experiments on real world datasets for each use case. The experiments and evaluations show the added value of association rule mining for the integration and usability of RDF data and confirm the appropriateness of our mining configuration methodology.
Cyanobacteria produce about 40 percent of the world’s primary biomass, but also a variety of often toxic peptides such as microcystin. Mass developments, so called blooms, can pose a real threat to the drinking water supply in many parts of the world. This study aimed at characterizing the biological function of microcystin production in one of the most common bloom-forming cyanobacterium Microcystis aeruginosa.
In a first attempt, the effect of elevated light intensity on microcystin production and its binding to cellular proteins was studied. Therefore, conventional microcystin quantification techniques were combined with protein-biochemical methods. RubisCO, the key enzyme for primary carbon fixation was a major microcystin interaction partner. High light exposition strongly stimulated microcystin-protein interactions. Up to 60 percent of the total cellular microcystin was detected bound to proteins, i.e. inaccessible for standard quantification procedures. Underestimation of total microcystin contents when neglecting the protein fraction was also demonstrated in field samples. Finally, an immuno-fluorescence based method was developed to identify microcystin producing cyanobacteria in mixed populations.
The high light induced microcystin interaction with proteins suggested an impact of the secondary metabolite on the primary metabolism of Microcystis by e.g. modulating the activity of enzymes. For addressing that question, a comprehensive GC/MS-based approach was conducted to compare the accumulation of metabolites in the wild-type of Microcystis aeruginosa PCC 7806 and the microcystin deficient ΔmcyB mutant. From all 501 detected non-redundant metabolites 85 (17 percent) accumulated significantly different in either of both genotypes upon high light exposition. Accumulation of compatible solutes in the ΔmcyB mutant suggests a role of microcystin in fine-tuning the metabolic flow to prevent stress related to excess light, high oxygen concentration and carbon limitation.
Co-analysis of the widely used model cyanobacterium Synechocystis PCC 6803 revealed profound metabolic differences between species of cyanobacteria. Whereas Microcystis channeled more resources towards carbohydrate synthesis, Synechocystis invested more in amino acids. These findings were supported by electron microscopy of high light treated cells and the quantification of storage compounds. While Microcystis accumulated mainly glycogen to about 8.5 percent of its fresh weight within three hours, Synechocystis produced higher amounts of cyanophycin. The results showed that the characterization of species-specific metabolic features should gain more attention with regard to the biotechnological use of cyanobacteria.
Tierische und menschliche Fäkalien aus Landwirtschaft und Haushalten enthalten zahlreiche obligat und opportunistisch pathogene Mikroorganismen, deren Konzentration u. a. je nach Gesundheitszustand der betrachteten Gruppe schwankt. Neben den Krankheitserregern enthalten Fäkalien aber auch essentielle Pflanzennährstoffe (276) und dienen seit Jahrtausenden (63) als Dünger für Feldfrüchte. Mit der unbedarften Verwendung von pathogenbelastetem Fäkaldünger steigt jedoch auch das Risiko einer Infektion von Mensch und Tier. Diese Gefahr erhöht sich mit der globalen Vernetzung der Landwirtschaft, z. B. durch den Import von kontaminierten Futter- bzw. Lebensmitteln (29).
Die vorliegende Arbeit stellt die milchsaure Fermentation von Rindergülle und Klärschlamm als alternative Hygienisierungsmethode gegenüber der Pasteurisation in Biogasanlagen bzw. gebräuchlichen Kompostierung vor.
Dabei wird ein Abfall der Gram-negativen Bakterienflora sowie der Enterokokken, Schimmel- und Hefepilze unter die Nachweisgrenze von 3 log10KbE/g beobachtet, gleichzeitig steigt die Konzentration der Lactobacillaceae um das Tausendfache. Darüber hinaus wird gezeigt, dass pathogene Bakterien wie Staphylococcus aureus, Salmonella spp., Listeria monocytogenes, EHEC O:157 und vegetative Clostridum perfringens-Zellen innerhalb von 3 Tagen inaktiviert werden. Die Inaktivierung von ECBO-Viren und Spulwurmeiern erfolgt innerhalb von 7 bzw. 56 Tagen. Zur Aufklärung der Ursache der beobachteten Hygienisierung wurde das fermentierte Material auf flüchtige Fettsäuren sowie pH-Wertänderungen untersucht. Es konnte festgestellt werden, dass die gemessenen Werte nicht die alleinige Ursache für das Absterben der Erreger sind, vielmehr wird eine zusätzliche bakterizide Wirkung durch eine mutmaßliche Bildung von Bakteriozinen in Betracht gezogen. Die parasitizide Wirkung wird auf die physikalischen Bedingungen der Fermentation zurückgeführt.
Die methodischen Grundlagen basieren auf Analysen mittels zahlreicher klassisch-kultureller Verfahren, wie z. B. der Lebendkeimzahlbestimmung. Darüber hinaus findet die MALDI-TOF-Massenspektrometrie und die klassische PCR in Kombination mit der Gradienten-Gelelektrophorese Anwendung, um kultivierbare Bakterienfloren zu beschreiben bzw. nicht kultivierbare Bakterienfloren stichprobenartig zu erfassen.
Neben den Aspekten der Hygienisierung wird zudem die Eignung der Methode für die landwirtschaftliche Nutzung berücksichtigt. Dies findet sich insbesondere in der Komposition des zu fermentierenden Materials wieder, welches für die verstärkte Humusakkumulation im Ackerboden optimiert wurde. Darüber hinaus wird die Masseverlustbilanz während der milchsauren Fermentation mit denen der Kompostierung sowie der Verarbeitung in der Biogasanlage verglichen und als positiv bewertet, da sie mit insgesamt 2,45 % sehr deutlich unter den bisherigen Alternativen liegt (73, 138, 458). Weniger Verluste an organischem Material während der Hygienisierung führen zu einer größeren verwendbaren Düngermenge, die auf Grund ihres organischen Ursprungs zu einer Verstärkung des Humusanteiles im Ackerboden beitragen kann (56, 132).