Refine
Year of publication
- 2009 (116) (remove)
Document Type
- Doctoral Thesis (116) (remove)
Language
- English (116) (remove)
Has Fulltext
- yes (116)
Is part of the Bibliography
- no (116) (remove)
Keywords
- Wirkstoff-Rezeptor-Bindung (4)
- Licht-Sammel-Komplex (3)
- Ligand <Biochemie> (3)
- Membranproteine (3)
- Theoretische Physik (3)
- Algebraische Geometrie (2)
- Biochemie (2)
- Crystallography (2)
- FT-IR-Spektroskopie (2)
- Gestaltwahrnehmung (2)
Institute
- Biochemie und Chemie (33)
- Physik (24)
- Biowissenschaften (19)
- Geowissenschaften (6)
- Medizin (6)
- Pharmazie (5)
- Mathematik (4)
- Psychologie (4)
- Informatik (3)
- Frankfurt Institute for Advanced Studies (FIAS) (2)
The current thesis is devoted to a systematic study of fluctuations and correlations in heavy-ion collisions, which might be considered as probes for the phase transition and the critical point in the phase diagram, within the Hadron-String- Dynamics (HSD) microscopic transport approach. This is a powerful tool to study nucleus-nucleus collisions and allows to completely simulate experimental collisions on an event-by-event basis. Thus, the transport model has been used to study fluctuations and correlations including the influence of experimental acceptance as well as centrality, system size and collision energy. The comparison to experimental data can separate the effects induced by a phase transition since there is no phase transition in the HSD version used here. Firstly the centrality dependence of multiplicity fluctuations has been studied. Different centrality selections have been performed in the analysis in correspondence to the experimental situation. For the fixed target experiment NA49 events with fixed numbers of the projectile participants have been studied while in the collider experiment PHENIX centrality classes of events have been defined by the multiplicity in certain phase space region. A decrease of participant number fluctuations (and thus volume fluctuations) in more central collisions for both experiments has been obtained. Another area of this work addresses to transport model calculations of multiplicity fluctuations in nucleus-nucleus collisions as a function of colliding energy and system size. This study is in full correspondence to the experimental program of the NA61 Collaboration at the SPS. Central C+C, S+S, In+In, and Pb+Pb nuclear collisions at Elab = 10, 20, 30, 40, 80, 158 AGeV have been investigated. The expected enhanced fluctuations - attributed to the critical point and phase transition - can be observed experimentally on top of a monotonic and smooth ‘hadronic background’. These findings should be helpful for the optimal choice of collision systems and collision energies for the experimental search of the QCD critical point. Other observables are fluctuations of ratios of hadrons (e.g. pions, kaons, protons, etc.) which are not so much affected by volume fluctuations. In particular HSD results for the kaon-to-pion ratio fluctuations, which has been regarded as promising observable for a long time, are presented from low SPS energies up to high energies at RHIC. In addition to the HSD calculations statistical model is also used in terms of microcanonical, canonical and grand canonical ensembles. Further a study of the system size event-by-event fluctuations causing rapidity forward-backward correlations in relativistic heavy-ion collisions is presented. The HSD simulations reveal strong forward-backward correlations and reproduce the main qualitative features of the STAR data in A+A collisions at RHIC energies. It has been shown that strong forward-backward correlations arise due to an averaging over many different events that belong to one centrality bin. An optimization of the experimental selection of centrality classes is presented, which is relevant for the program of the NA61 collaboration at CERN, the low-energy program at RHIC, as well as future experiments at FAIR.
Ein wesentliches Ziel der Physik mit schweren Ionen ist die Untersuchung der Zustände von Kernmaterie bei hohen Dichten bzw. Temperaturen. Solche Zustände lassen sich durch Kollisionen von hochenergetischen schweren Ionen in Teilchenbeschleunigern wie dem Super Proton Synchrotron SPS am Europäischen Kernforschungszentrum CERN in Genf erzeugen und untersuchen. Die vorliegende Arbeit beschäftigt sich mit der Analyse des Einflusses des in einer solchen Kollision erzeugten Mediums auf hochenergetische Teilchen, welche dieses Medium durchqueren. Hierzu werden Korrelationen zwischen Teilchen mit hohem Transversalimpuls pt als Funktion der Zentralität der Kollisionen und der Ladung der beteiligten Teilchen untersucht. Ziel ist es, hierdurch eine experimentelle Grundlage für die theoretische Beschreibung der Eigenschaften des Mediums in solchen Kollisionen bereitzustellen. ...
Kaon and pion production in centrality selected minimum bias Pb+Pb collisions at 40 and 158A GeV
(2009)
Results on charged kaon and negatively charged pion production and spectra for centrality selected Pb+Pb mininimum bias events at 40 and 158A GeV have been presented in this thesis. All analysis are based on data taken by the NA49 experiment at the accelerator Super Proton Synchrotron (SPS) at the European Organization for Nuclear Research (CERN) in Geneva, Switzerland. The kaon results are based on an analysis of the mean energy loss <dE/dx> of the charged particles traversing the detector gas of the time projection chambers (TPCs). The pion results are from an analysis of all negatively charged particles h- corrected for contributions from particle decays and secondary interactions. For the dE/dx analysis of charged kaons, main TPC tracks with a total momentum between 4 and 50 GeV have been analyzed in logarithmic momentum log(p) and transverse momentum pt bins. The resulting dE/dx spectra have been fitted by the sum of 5 Gaussians, one for each main particle type (electrons, pions, kaons, protons, deuterons). The amplitude of the Gaussian used for the kaon part of the spectra has been corrected for efficiency and acceptance and the binning has been transformed to rapidity y and transverse momentum pt bins. The multiplicity dN/dy of the single rapidity bins has been derived by summing the measured range of the transverse momentum spectra and an extrapolation to full coverage with a single exponential function fitted to the measured range. The results have been combined with the mid-rapidity measurements from the time-of-flight detectors and a double Gaussian fit to the dN/dy spectra has been used for extrapolation to rapidity outside of the acceptance of the dE/dx analysis. For the h- analysis of negatively charged pions, all negatively charged tracks have been analyzed. The background from secondary reactions, particle decays, and gamma-conversions has been corrected with the VENUS event generator. The results were also corrected for efficiency and acceptance and the pt spectra were analyzed and extrapolated where necessary to derive the mean yield per rapidity bin dN/dy. The mean multiplicity <pi-> has been derived by summing up the measured dN/dy and extrapolating the rapidity spectrum with a double Gaussian fit to 4pi coverage. The results have been discussed in detail and compared to various model calculations. Microscopical models like URQMD and HSD do not describe the full complexity of Pb+Pb collisions. Especially the production of the positively charged kaons, which carry the major part of strange quarks, cannot be consistently reproduced by the model calculations. Centrality selected minimum bias Pb+Pb collisions can be described as a mixture of a high-density region of multiply colliding nucleons (core) and practically independent nucleon-nucleon collisions (corona). This leads to a smooth evolution from peripheral to central collisions. A more detailed approach derives the ensemble volume from a percolation of elementary clusters. In the percolation model all clusters are formed from coalescing strings that are assumed to decay statistically with the volume dependence of canonical strangeness suppression. The percolation model describes the measured data for top SPS and RHIC energies. At 40A GeV, the system size dependence of the relative strangeness production starts to evolve from the saturation seen at higher energies from peripheral events onwards towards a linear dependence at SIS and AGS. This change of the dependence on system size occurs in the energy region of the observed maximum of the K+ to pi ratio for central Pb+Pb collisions. Future measurements with heavy ion beam energies around this maximum at RHIC and FAIR as well as the upgraded NA49 successor experiment NA61 will further improve our understanding of quark matter and its reflection in modern heavy ion physics and theories.
This thesis contributes to the field of soft matter research and studies the importance of hydrodynamic interactions during free-solution electrophoresis of linear polyelectrolytes by means of coarse-grained molecular dynamics simulations including full electro-hydrodynamic interactions. The center of attention is the specific role of hydrodynamic interactions on the electrophoretic behaviour of charged macromolecules. Points of interest are the dependence of hydrodynamic interactions on the chain length, the chain flexibility and the surrounding counterions, and their combined influence on important observables such as the static chain conformations and the dynamic transport coefficients, i.e., the diffusion and the electrophoretic mobility. These problems are addressed by extensive computer simulations that are quantitatively matched with experimental results. Existing theoretical predictions are carefully examined and are augmented by the observations in this thesis.
Central America is one of the world’s most herpetological diverse areas in relation to its size. Nicaragua is the largest country in this region and separates Nuclear from Lower Central America. It is one of the least herpetological explored countries in Central America and few studies dealing with the herpetofauna of a potion or the entire country have been published. I here update the checklist of the Nicaraguan herpetofauna, present taxonomic revisions of some difficult species complexes, compare the similarities of the composition of the herpetofaunal communities in the major forest formations present in the country within a zoogeographical context, and identify those species with a greater vulnerability risk in Nicaragua. Taxonomy The herpetofauna of Nicaragua currently consists of 244 species representing 134 genera and 42 families with 78 amphibian species representing 35 genera and 15 families, and 166 reptile species representing 99 genera and 27 families, which includes six marine species. Sixteen species (12 amphibians and four reptiles) are endemic to the country. Of the 12 endemic amphibian species, three are here described. In addition, five genera (Anotheca, Cerrophidion, Duellmanohyla, Isthmohyla, and Rhinobothryum) and two species (Rhadinea godmani and Urotheca decipiens) are known to occur both north and south of Nicaragua although there are no voucher specimens of these taxa to confirm their presence in country. I complete a bibliographic research updating the nomenclature changes and provide a brief herpetological history of Nicaragua, a recompilation of all species described upon Nicaraguan material and their current synonymy, the first time each species was recorded from the country, and a list of all recognized subspecies occurring in Nicaragua. I discuss the taxonomic uncertainties among the Nicaraguan populations of amphibians and reptiles and take further detailed taxonomic revisions on selected Nicaraguan species groups from the genera Anolis, Bolitoglossa, and Craugastor along their known distributional range. I describe five new species of herpetofauna (three of which are based on Nicaraguan material), redescribe five species of Anolis (three of which occur in Nicaragua), and provide voucher specimens of five other species for the first time in Nicaragua. In detail: • I studied the pholidosis, morphometrics as well as hemipenis and dewlap morphology in Anolis wermuthi, an anole endemic to the highlands of northern Nicaragua. I examine patterns of geographic variation using discriminant function analysis and discuss the characters that vary both individually and among populations. The results indicate that A. wermuthi is a single species with several disjunct, slightly divergent populations. I provide a standardized description, illustrations of the everted hemipenis of an adult topotype, the male and female dewlap, and a distribution map. I also provide brief descriptions of the localities where this species occurs and some ecological notes. • I studied the pholidosis, morphometrics as well as hemipenis morphology in the Central American anole species Anolis humilis, A. quaggulus, and A. uniformis. The three taxa are distinct in hemipenis morphology. However, very little differentiation in pholidotic and morphometric characters is documented. I document interspecific variation in several characters but with overlap of the documented ranges. A discriminant function analysis based on five pholidotic characters yielded a scatter diagram that showed large overlap between the clusters of the three taxa. I provide head scalation illustrations, an identification key, a distribution map, and standardized descriptions of the commonly distributed in Nicaragua A. quaggulus as well as of the other two species. • I describe two new species of anoles (genus Anolis) from Panama formerly referred to as Anolis limifrons. The two new species, Anolis apletophallus and Anolis cryptolimifrons, differ from A. limifrons by having a large bilobed hemipenis (small and unilobed in A. limifrons). The new species differ from each other in male dewlap size and coloration. I provide illustrations of the head scalation, everted hemipenis, and dewlap, an identification key, a distribution map, and standardized descriptions of the commonly distributed in Nicaragua A. limifrons and the two new species described herein. • I describe two new species of salamanders of Bolitoglossa from southern Nicaragua. Bolitoglossa indio is known from Río Indio in the lowlands of the Río San Juan area and Bolitoglossa insularis from the premontane slopes of Volcán Maderas on Ometepe Island. The two new species are of unknown affinities but both differ from their congeners in coloration. Bolitoglossa indio is most similar to B. mexicana and B. odonnelli from which differ by having both broad dorsolateral pale brown stripes not clearly delimited in outline. Bolitoglossa insularis is most similar to B. mombachoensis and B. striatula from which differ by the absence of dark or light defined stripes on dorsum and venter. • I describe a new species of frog of the genus Craugastor from Río San Juan, Nicaragua. The new species, Craugastor chingopetaca, is assigned to the fitzingeri group and differs from most Central American species of that group by the absence of a midgular pale stripe. Within the fitzingeri group it is most similar to C. crassidigitus and C. talamancae from which it differs in several morphological characteristics such as more extensive webbing, retuse disk covers on some digits, and relative toe length. • I provide voucher specimens of Cochranella spinosa, Kinosternon angustipons, Mesaspis moreletii, Cnemidophorus lemniscatus and Adelphicos quadrivirgatum for the first time in Nicaragua. I include descriptions, illustrations, and brief ecological notes for the five new country records. Zoogeography Based on the concept of ecological formations proposed by HOLDRIDGE (1967), nine forest formations are found in Nicaragua. Of the total number of terrestrial species of herpetofauna found in Nicaragua, 131 species (55.0%) occur in Lowland Wet Forest, 21 of which (8.8%) are restricted to this forest formation, 168 species (70.6%) occur in Lowland Moist Forest, 15 of which (6.3%) are restricted to this forest formation, 84 species (35.3%) occur in Lowland Dry Forest, four of which (1.7%) are restricted to this forest formation, 47 species (19.7%) occur in Lowland Arid Forest, with no species restricted to this forest formation, 59 species (24.8%) occur in Premontane Wet Forest, three of which (1.3%) are restricted to this forest formation, 116 species (48.7%) occur in Premontane Moist Forest, 10 of which (4.2%) are restricted to this forest formation, 51 (21.4%) species occur in Premontane Dry Forest, with no species restricted to this forest formation, 13 species (5.5%) occur in Lower Montane Wet Forest, two of which (0.8%) are restricted to this forest formation, and 50 species (21.0%) occur Lower Montane Moist Forest, seven of which (2.9%) are restricted to this forest formation. The Coefficient of Biogeographic Resemblance algorithm show a distinct composition of the herpetofauna from the isolated highlands of northeastern Nicaragua, which is characterized by a high proportion of endemic species. Two other clusters are evident when analyzing the herpetofaunal similarities among Nicaragua, the Pacific versant and the central mountains and the Atlantic lowlands. In addition, the Pacific lowlands are characterized by a relatively homogeneous composition of the herpetofauna. In contrast, many species have their northern limit of distribution in the Atlantic lowlands with the ranges of most of these species ending in southern Nicaragua. The central mountains constitute the southern limit of distribution of several highland species. In general, there is a greater contribution of reptile than amphibian species to the total herpetofauna present in each forest formation. This unbalance is slightly higher in the dry than in the moist parts of the country. The similarities in the composition of the reptiles between the different forests formations seem to be relatively distinct on an elevation factor, whereas in amphibians similarities might be better explained in correlation with humidity. The total amount of amphibian and reptile species in Nicaragua has a Middle American Element dominance and varies between amphibians and reptiles, with and a greater South American Element influence in anurans and a greater Old Northern Element influence in reptiles. In general, there is a greater percentage of species with a South American Element in extreme southeastern Nicaragua with a decreasing tendency towards northern Nicaragua. Taking in account the geography and geologic history of Nicaragua as well as the known Central American dispersal routes, I identify species of probable occurrence in Nicaragua as well as those places with a greater potential to hold undescribed endemic species. Conservation In Nicaragua, no amphibian or reptile populations are entirely free from anthropogenic impact. I determine the endangerment level of all Nicaraguan amphibian and reptile species using the IUCN categorizations and the Environmental Vulnerability Scores. Seventy-six species (31.9%) of Nicaraguan amphibians and terrestrial reptiles have high vulnerability, 118 (49.6%) medium vulnerability, and 44 (18.5%) low vulnerability. Eighteen species (7.4% of the total herpetofauna) are unknown from protected areas, including 13 high vulnerability species (three are endemic), four medium vulnerability species, and one low vulnerability species. To preserve the future of Nicaragua’s amphibians and reptiles, every species should reside in at least one protected area, the protected areas must be guarded, and monitoring programs are needed to detect changes in amphibian and reptile populations, prioritizing highly vulnerable species.
Zusammenfassung Die Alzheimersche Krankheit (AD) ist mit 60% die am häufigsten auftretende Art der Demenz. Weltweit sind ca. 24 Mio. Menschen von der neurodegenerativen Krankheit betroffen, welche sich durch den Verlust der kognitiven Fähigkeiten auszeichnet. Es gibt zwei Ausprägungen der Demenz, zum einen die sporadische Verlaufsform, die bei Menschen in einem Alter ab 65 Jahren auftritt und zum anderen die familiäre Alzheimersche Krankheit (FAD), die schon weitaus jüngere Menschen betrifft und auf genetische Mutationen zurück zu führen ist. Beide Formen der Demenz zeigen den gleichen neuropathologische Phänotyp, der zur Ausbildung von extrazellulären Plaques und intrazellulären Neurofibrillen führt. Durch die Entstehung der Plaques und der Neurofibrillen werden die Verbindungen zwischen den einzelnen Neuronen verringert und die Neuronen sterben ab. Für das Auftreten der FAD sind Mutationen in den Genen des Amyloid Vorläufer Proteins (APP, Substrat) sowie der Aspartatprotease Einheit des γ-Sekretase Komplexes, Presenilin 1 (PS1) oder Presenilin 2 (PS2), verantwortlich. Die γ-Sekretase ist ein membranständiger Komplex bestehend aus den vier Untereinheiten PS1 oder PS2, Nicastrin (Nct), Aph-1 und Pen-2. Um ausreichende Informationen über den γ-Sekretase Komplex bezüglich seiner Interaktionsflächen, seines Katalysemechanismus und seiner Substraterkennung zu erhalten, wäre es hilfreich seine 3 Dimensionale Struktur aufzuklären, wozu große Mengen der sauberen und homogenen Proteine benötigt werden. Die Herstellung von ausreichenden Proteinmengen stellt derzeit aber einen Engpass für die strukturelle und funktionelle Charakterisierung des γ-Sekretase Komplexes in-vitro dar. Alzheimer’s disease (AD) is the most common cause of dementia, which affects 24 million people worldwide. It is a neurodegenerative disorder, which occurs either in its most common form in people over 65 years or in the rare early-onset familial AD (FAD). Responsible for the autosomal dominant FAD are mutations in the genes encoding for the β-amyloid precursor protein (APP) and the two homologues integral membrane proteins Presenilin 1 (PS1) and Presenilin 2 (PS2). The two PSs are major but alternative components of the intramembrane aspartyl protease γ-secretase. Further components are the membrane proteins Nicastrin (Nct), Aph-1 and Pen-2. Production of sufficient amounts of protein samples is still the major bottleneck for the detailed functional and structural in-vitro characterization of the γ-secretase complex. Due to toxicity, stability and targeting problems, the overproduction of MPs in conventional in-vivo systems often has only limited success. Therefore, efficient expression protocols using the cell-free (CF) system were established in this work. After optimization, I was able to produce up to milligram amounts of the single proteins PS1 and PS2, the cleavage products PS1-NTF and PS1-CTF, and Pen-2. The in-vitro produced γ-secretase subunits were further characterized, concerning their purity, secondary fold, thermal stability and homogeneity. Highest purities with over 90% after affinity chromatography could be achieved for PS1-CTF and Pen-2. Reconstitution of PS1, PS1-NTF, PS1-CTF and Pen-2 into E. coli liposomes results in a homogeneously distribution, which gives evidence for a structural folding. This was confirmed by CD spectroscopy of PS1-CTF and Pen-2. The thermal stability of Pen-2 shows a transition at 68°C, whereas PS1-CTF is stable up to 95°C. Both proteins show in addition homogeneous elution profiles investigated by analytical SEC and exhibit a monomeric (Pen-2) or dimeric (PS1-CTF) character analyzed by blue native PAGE. Different methods were performed to get evidence about the assembly of the complex, like pull-down experiments, immunoprecipitation, co-expression of radioactive labeled subunits and titration assays by liquid-state NMR. First hints for an interaction of the CF synthesized proteins could be observed by co-expression. Supplemental, Pen-2 and CTF could be purified in sufficient amounts and to apparent homogeneity that allow structural approaches by X-ray crystallography and liquid-state NMR spectroscopy. First conditions for protein crystals were achieved for Pen-2 and structural investigations of PS1-CTF by liquid-state NMR could be performed after optimization of the expression-, purification- and detergent conditions.
Despite the well-known importance of ribonucleic acids (RNA) in cell biology, it is astounding to realize the pace at which new fundamental functions of RNAs have been discovered. One of the fundamental reasons for the multitude of functions of RNA is the property of RNA to adopt different conformations or folds. The primary sequence of RNA, a linear polymer built from four different repetition units, can fold into alternate secondary structure motifs which in turn form alternate long-range interactions in complex tertiary structures. Ligands such as metal ions or small molecular weight metabolites and also proteins or peptides can bind to RNA and induce the changes in tertiary conformation. For example, in the cell, RNA participates in gene regulation in the form of riboswitches. Riboswitches are found in untranslated regions of messenger RNA (mRNA) and adopt alternate conformations depending on the presence or absence of specific metabolites. If a metabolite is present above a specific concentration, it induces a conformational change in the respective riboswitch by binding and thereby alters gene expression. Another example is the RNA thermometer which participates in the cell translational mechanism by a similar strategy. Translation initiation requires the binding of RNA thermometers to the ribosome. The ribosome binding region is located in the 5’ untranslated region of mRNA. At low temperatures this region is prevented from binding to the ribosome by forming basepairs. At higher temperatures, these basepairs dissociate allowing ribosome binding and subsequent translation. Therefore, the characterization and delineation of the kinetics and pathway of RNA folding is important to understand the function of RNA and is an important contribution to fundamentally understand RNA’s role in the cell. RNA conformational transitions occur over a wide range of timescales. Depending on the timescale, various biophysical techniques are used to study RNA conformational transitions. In these biophysical studies, achieving good structural and temporal resolution constitute frequently encountered challenges or limitations. For example, single molecule FRET spectroscopy provides high temporal resolution in the milliseconds at high sensitivity but lacks atomic resolution. Recent advances in the field of Nuclear Magnetic Resonance (NMR) spectroscopy have enabled the elucidation of tertiary folding events to be characterized with atomic resolution. This thesis involves the use of NMR spectroscopy to characterize the folding of RNA molecules. Kinetics experiments require rapid initiation of the kinetics followed by monitoring of the reaction. In this thesis, two different folding initiation techniques have been applied and coupled to the subsequent detection of RNA folding using NMR spectroscopy, namely, photocaging and rapid mixing. The method of photocaging is well established (Kuhn and Schwalbe, 2000) and builds on the following principle: A photolabile moiety is attached to a molecule that prevents a specific interaction. Upon irradiation of the molecule with the photolabile group using laser light at a specific wave length, at which the molecule of interest is not absorbing, the protecting group is released. In our group, together with the group of S. Pitsch, ETH Lausanne, we could "cage" RNA at its equilibrium state by a photolabile molecule (similar work has been carried out in the group of A. Heckel). Rapid and traceless release of the photolabile precursor compound by a laser pulse releases the RNA to fold into its native state; the build-up of the native state of the RNA is monitored by NMR signals that are uniquely characteristic for the native state of the RNA. By optically coupling a laser source to an NMR magnet, the above procedure can take place in situ and the kinetics recorded by NMR. Several different molecules can be caged: The photocage can be attached to RNA. Then, a modified photolabile nucleotide can be placed at strategic positions of a target RNA whose folding properties is to be studied. The photocage can also be attached to a ligand: if folding is dependent on ligand binding then the ligand can be modified to carry a photosensitive unit whose degradation allows binding to RNA. In this thesis, an alternative method for photocaging is introduced. Here, metal ions essential for folding of the RNA are photocaged using the photolabile chelating agent Dimethyl-nitrophen (DMN). Photolysis of DMNr releases the metal ion, thereby RNA folding is initiated. In the rapid-mixing technique, one of (several) components required for proper folding of the RNA is rapidly injected into an NMR sample in situ by the use of a pneumatic injection device. ...
The study of the electromagnetic structure of hadrons plays an important role in understanding the nature of matter. In particular the emission of lepton pairs out of the hot and dense collision zone in heavy-ion reactions is a promising probe to investigate in-medium properties of hadrons and in general the properties of matter under such extreme conditions. The first experimental observation of an enhanced di-electron yield in the invariant-mass region 0:3 - 0:7 GeV/c2 in p+Be collisions at 4:9 GeV/u beam energy [2] was announced by the DLS collaboration [1]. Recent results of the HADES collaboration show a moderate enhancement above n Dalitz decay contributions for 12C+12C at 1 and 2 GeV/u [3, 4] confirming the DLS results. There are several theoretical explanations of this observation, most of them focusing on possible in-medium modifications of the properties of vector mesons. At low beam energies the question whether the observed excess is related to any in-medium effects remains open because of uncertainties in the description of elementary di-electron sources. In this work the di-electron production in p+p and d+p reactions at a kinetic beam energy of 1:25 GeV/u measured by the HADES spectrometer is discussed. At Ekin = 1:25 GeV/u, i.e. below the n meson production threshold in proton-proton reactions, the delta Dalitz decay is expected to be the most abundant source above the pi 0 Dalitz decay region. The observed large difference in di-electron production in p+p and d+p collisions suggests that di-electron production in the d+p system is dominated by the n+p interaction. In order to separate delta Dalitz decays and np bremsstrahlung the di-electron yield observed in p+p and n+p reactions, both measured at the same beam energy, has been compared. The main interest here is the investigation of iso-spin effects in baryonic resonance excitations and the off-shell production of vector mesons [5]. We indeed observe a large difference in di-electron production in p+p and n+p reactions. Results of these studies will be compared to recent calculations. We will also present our experimentally defined cocktail for heavy-ion data. At much higher beam energies experimental results of the CERES [6] and NA60 [7] collaborations also show an enhancement in the invariant mass region 0:3 - 0:7 GeV/c2, in principle similar to the situation in DLS. A strong excess of lepton pairs observed by recent high energy heavy-ion dilepton experiments hint to a strong influence of baryons, however no data exist at highly compressed baryonic matter, achievable in heavy-ion collisions from 8 - 45 GeV/u beam energy. These conditions would allow to study the expected restoration of chiral symmetry by measuring in-medium modifications of hadronic properties, an experimental program which is foreseen by the future CBM experiment at FAIR. The experimental challenge is to suppress the large physical background on the one hand and to provide a clean identification of electrons on the other hand. In this work, strategies to reduce the combinatorial background in electron pair measurements with the CBM detector are discussed. The main goal is to study the feasibility of effectively reducing combinatorial background with the currently foreseen experimental setup, which does not provide electron identification in front of the magnetic field.
The documentation of life on Earth, that is, the inventorization of nature and the naming and classification of organisms found therein, is a major task for biologists today and a fundamental precondition for nature conservation efforts. This study aimed at contributing to the inventory of amphibians and reptiles in selected, previously understudied ecoregions of Bolivia. I strove to document diversity patterns and seek possible ecological and historical reasons for these patterns. Special attention was paid to the Chiquitano Region situated in the eastern lowlands of Bolivia in a climatic transition zone between the humid evergreen Amazon Forests and the deciduous thorn-scrub vegetation of the Gran Chaco. In congruence with its location in the transition zone, the Chiquitano Region displays a mosaic of habitats: The vegetation is dominated by the endemic Chiquitano Dry Forest, which is probably the largest extant patch of Seasonal Dry Tropical Forest, with enclaves of savanna, the western outliers of the Cerrado biome of central Brazil. Taxonomic revisions: The taxonomic data in this study are used as a tool to measure biodiversity, to assess biogeographic relationships, and to evaluate conservation needs. Since all is predicated on the taxonomic decisions made, an adequate taxonomy is essential, and taxonomy can be regarded as the foundation of this study. The methodology encompassed a variety of herpetological field techniques, such as different survey methods, preparation and documentation of voucher specimens, recording of frog calls, and herpetological laboratory techniques, such as morphology, molecular procedures with mtDNA, phylogenetic analyses, and bioacoustic analysis and descriptions of frog calls. A total of 1251 specimens belonging to 200 species were obtained during this study, including 87 amphibian and 123 reptile species. This constitutes about 36% of the herpetofauna currently known for Bolivia, about 34% of the amphibians currently known for Bolivia and about 40% of the reptiles, respectively. In the course of this study, a new species of frog was described from the study site Caparu in the eastern lowlands of Bolivia; this species, Hydrolaetare caparu Jansen, Gonzales & G. Köhler 2007, differs from the other two congeners in external morphology (e.g., lateral fringes and relative length of fingers, size of palmar tubercle, webbing of toes, and colouration) and advertisement call. Two new colubrid snake species were also described from the study site San Sebastián. Thus far, both are known only from the Chiquitano Region, Provincia Ñuflo de Chávez. Phalotris sansebastiani Jansen & G. Köhler 2008 differs from all the other species in the genus in having a triangular projection of the red snout colouration reaching onto the parietals. Xenopholis werdingorum Jansen, Gonzales & G. Köhler 2009 can be identified as a member of the genus Xenopholis by its vertebral morphology. It differs from the other two species of Xenopholis in having a unique uniform dorsal colour pattern, and from X. scalaris in having two prefrontals and a narrow septum within the neural spine and perpendicular to its long axis as evident in the x-ray images. A review of a small collection of pitvipers from different lowland localities and from the Inter-Andean dry valleys of the region of Pampagrande revealed one new species of Bothrops and one of Bothrocophias (both to be formally described elsewhere). The two pitviper species differ morphologically and genetically from their congeners. The results of a brief review of a small collection of frogs of the genus Scinax (Anura: Hylidae) from different localities in the lowlands, together with analyses of their bioacoustics, suggest an unknown cryptic diversity in Bolivian species of Scinax cf. fuscomarginatus and allies. However, further studies are necessary to clarify the taxonomic status of these populations. In addition, this study provides new data on the morphology (e.g., pholidosis) of snakes, many of them previously known only from few museum specimens. Keys to the Bolivian lizard species of Cercosaura and the Bolivian snake species of Chironius, Clelia, Liophis, Lystrophis, Phalotris, and Xenodon are presented here for the first time. New information on distribution includes many range extensions of amphibian and reptile species, such as five new country records (one frog species, four snake species) and six new departmental records (two frog species, four snake species). Observations on ecology and natural history: Several observations on ecology and natural history were made during field work. Visual signaling, an aspect of territorial behavior that was already known for several species of the genus Phyllomedusa, could be described for the first time for Phyllomedusa boliviana (Jansen & J. Köhler 2007). Furthermore, during audio surveys of an anuran community at the study site San Sebastián from 2005 to 2007, a decline of certain amphibian populations was observed in the rainy season 2006/2007 (Jansen et al., in press). This is possibly related to an extreme drought in the dry season of 2006 where 158 consecutive days without rainfall were recorded. In addition, a new method for measuring intensity of anuran choruses by means of a continuous sound pressure metre was developed (Jansen 2009). The method was suitable to detect calling phenology (during one night), as well as differences in calling activity (between two nights). Biodiversity and biogeographical relationships: Species lists were compiled at the six study sites Pampagrande, Los Volcanes, San Sebastián, Caparú, El Espinal und El Corbalan. The total amphibian and reptile species numbers observed ranged from 37 to 101 with the highest species numbers in San Sebastián (101) and Caparú (89) and the lowest in Los Volcanes (37) and El Espinal (41). A preliminary species list of the herpetofauna of the Chiquitano Region was presented, including 60 amphibian and 84 reptile species. The majority of the amphibians of the Chiquitano Region are classified predominantly as inhabitants of open formations (41 species, 68.3%). Interestingly, even the majority of species recorded from the Chiquitano Dry Forest (32 species) are usually associated with open formations (22 species, 66.7%), followed by the number of species associated with open and forest formations (8 species, 24.4%). Only two of the observed species (6.0%) are predominant forest dwellers. The amphibian assemblage of the Chiquitano Region is most similar in composition to that of the Cerrado biome: 46 species (76.7%) occur in the Cerrado as well, and three species are regarded as Cerrado endemics (5.0%). The Chiquitano Region shares considerably fewer amphibian species with the other biomes (Amazon: 22 species, 36.7%; Gran Chaco: 13 species, 21.7%; Caatinga: 16 species, 26.7%). The reptile assemblage also has significant affinities to the Cerrado, which can be seen in the high proportion of reptile species distributed in that biome (68 species; 81.0%). Affinities to the other biomes are as follows: Amazon (48 species, 57.1%), Chaco (37 species, 40.1%), and Caatinga (30 species, 35.7%). When arranged in mutually exclusive biome categories, reptiles and amphibians showed similar patterns so that the majority of both amphibians and reptiles of the Chiquitano Region can be regarded as widespread. The high proportion of reptile species probably endemic to this region (5 species, 6.0%) is remarkable (i.e. Tropidurus xanthochilus, Apostolepis phillipsi, Phalotris sansebastiani, Xenopholis werdingorum, and Micrurus diana). In an analysis of the biodiversity patterns and biogeographical relationships of the herpetofauna of the study sites, these sites were compared with literature data from 37 localities and included in a presence/absence matrix with a total of 657 amphibian and reptile species in the surrounding South American biomes Amazon, Cerrado and Gran Chaco. The biogeographic relationships between these sites were evaluated using the Coefficient of Biogeographic Resemblance (CBR), cluster analysis, and multidimensional scaling (MDS) of sites. The analyses were first conducted on amphibians and reptiles combined, and than group-specific each for amphibians, reptiles, lizards, and snakes, separately. A “bias-reduced analysis” was developed for a better understanding of the affinities of the amphibians. In this analysis, e.g., the distinct habitat types of the Chiquitano Region, the Chiquitano Dry Forest and the Cerrado were taken into account. Analyses of the biodiversity patterns revealed that the sites in the Amazon comprise highest species numbers, as expected, followed successively by the sites in the Cerrado biome and sites in-between the two biomes. Within the eastern lowlands of Bolivia, the Chiquitano Region is the most rich in species. Comparing it with the other South American sites, the Chiquitano Region has a surprisingly high alpha diversity, especially in amphibians. The microgeographic variation in species composition (beta diversity) in the Chiquitano Region is also remarkably high and obviously related to the mosaic character of the vegetation and habitats. However, the bias-reduced analysis revealed that the amphibian fauna of the open areas and savannas at Hacienda San Sebastián (with 36 species in the Cerrado and pastureland) was one of the most species-rich savanna sites known for amphibians in South America. Considering that the Hacienda San Sebastián site is only ca. 3300 ha (= 1.29 amphibian species per km2), this outcome is particularly suprising. The results of the analyses of the biogeographical relationships suggest that the herpetofauna of Bolivia’s lowlands, including the Beni, the Pantanal and the Chiquitano Region, is as distinct from the herpetofauna of the Gran Chaco, Amazon, and Cerrado as these biomes are from each other. The Chiquitano herpetofauna in particular represents a unique and well-defined herpetofaunal assemblage when compared to all surrounding localities and biomes. This is supported by high CBR-values, findings from the cluster analysis, as well as a clear separation of the Chiquitano sites in the MDS. Biogeographic relations exist in all the surrounding biomes, but are strongest to Cerrado, followed by the Amazon. This study strongly suggests that the Chiquitano herpetofauna is composite and has multiple affinities. This is congruent with a well-defined Chiquitano flora, avifauna and mammalian fauna, suggesting a similar history. The bias-reduced analysis revealed a more detailed picture of the biogeographic relations of the Chiquitano Region, especially the Chiquitano Dry Forest. I argue here that the Chiquitano Dry Forest herpetofauna is a “young”, and “former savanna herpetofauna”. Whereas the Chiquitano Dry Forest is rather poor in amphibian and reptile species, and endemics are lacking from this forest type, the isolated Cerrado enclaves are especially diverse in species and probably contain locally endemic species, such as Phalotris sansebastiani and Xenopholis werdingorum. The colonization of the young Chiquitano Dry Forest may have taken place from savannas by mainly open area species, and only briefly through the Amazon. The results emphasise the importance of bias-reduction in studies of biogeography, e.g., by using group-specific analyses or by taking into account criterias as area size and heterogeneity of compared sites. The different biogeographic patterns of reptiles and amphibians of the Andean valleys indicate a different history of these two groups. In regard to reptiles, dispersals and withdrawals into the valleys in warm humid and dry cool periods in the Pleistocene seem likely, supported by a relation between the valleys and the dry lowland (e.g., Chaco). However, it is more plausible that, during these climatic fluctuations, amphibians migrated to adjacent, more humid regions, such as Yungas. The study verified the known patterns of sister-species pairs in the Inter-Andean Dry Forest and the lowlands. Additionally, pairs of populations with slight differences in morphology were found in the valleys and in the lowlands (Cercosaura parkeri and Xenodon rhapdocephalus). Further studies must test the taxonomic status of these populations. The discovery of new species of Bothrops and Bothrocophias from the Andean valleys has several implications, and possible reasons for the high endemism in the dry valleys are discussed. Conservation and outlook: The high local alpha and beta diversity of the Chiquitano herpetofauna shows that this is a region of complex faunal interaction, which reflects the present heterogeneity of the region, but which is possibly also related to a complex geological and environmental history. The Chiquitano Region can be assessed as a region of distinct regional herpetofaunal diversity charaterised by small scale diversity patterns. It therefore merits recognition as a unique ecoregion, and conservation effort should be increased. Further research is necessary to solve the taxonomic problems addressed in this study. Moreover, future work should be directed towards the development and institution of longterm monitoring programs to evaluate the effects of climate change and changes in land-use on biodiversity, especially that of the Chiquitano Region.
The physiology of our most complex organ, the brain, is still not comprehensively understood. The brain basically serves the processing, storing and binding of external and internal information, and thereby generates amazing phenomena like the understanding of oneself as an individual entitiy. How exactly information is encoded and represented, how individual neurons or networks of neurons actually interact, is a gigantic puzzle, whose pieces were collected since many decades. Subject of scientific discussions are the basic spatiotemporal structures of neuronal representations. Suggestions and observations reach hereby from simple rate coding of individual neurons to synchronous activity of larger ensembles. To approach answers to these questions, our working group has used a combination of different recording techniques that allowed for the comparison of neuronal interactions on different spatial scales. We focused on prefrontal neuronal interactions during visual short-term memory. Herefore two rhesus monkeys had been trained to perform a visual short-term memory task. We measured and recorded their neuronal activity by means of a microelectrode matrix that could be inserted into the cortex via a closable chamber, which had been previously implanted above prefrontal cortex. The acquired signal was separated into two components: a high-frequency component, that represents the spiking output activity of few neurons in the vicinity of each electrode tip (multi-unit activity), and a low-frequency component, that results from dendritic input activity of larger neuronal assemblies (local field potential). From one of the experimental animals we also recorded mass signals of even larger neuronal populations by means of small silverball electrodes, that had been implated into the skull above prefrontal cortex (skull EEG) in the context of a pilot project. In the first subproject, we analyzed the selectivity of output signals with respect to the memorized stimulus and task performance. We compared selectivities of local recording sites (multi-unit activity) with the selectivities of patterns created by the combined activity of all recording sites, thus representing the activity of large and distributed ensembles. Local neuronal activity correlated with the course of the visual short-term memory task, but was not highly discriminative with respect to different visual stimuli. We could show that the population activity was significantly more specific. Concerning task performance, we obtained the same result, albeit less pronounced. Further analyses revealed that the patterns of distributed ensemble activity were only partly based on realtime coordination of neuronal activity, and in addition, did not remain stable across the time course of the short-term memory task. In the second subproject, we focused on the oscillatory behavior of the local field potential. After a time-frequency analysis, we studied different frequency bands concerning stimulus selectivity and task performance of the monkey. We hereby found significant modulations of oscillations in the beta- and gamma-frequency range, that correlated with different periods of the task. Especially for oscillations in beta- and low-gamma-range, we observed phase-locking of oscillations between different recording sites, which could play an important role as internal clock to coordinate spatially separate activity. Local high-gamma oscillations themselves seemed to be important for the maintenance of information. These results could be partly confirmed by mass signals of EEG. In sum, our results support the hypothesis that information is represented in the brain by means of concerted activity of spatially distributed neuronal ensembles. This activity again appears to be coordinated by oscillatory activity in beta- and low-gamma-frequency ranges. A deeper understanding of central nervous information processing could contribute to better treatment of diseases like Parkinson’s, Alzheimer’s as well as epilepsy, and neuropsychiatric disorders like schizophrenia.
Epidermal growth factor (EGF) receptor belongs to the broad family of enzymatic receptors called receptor tyrosine kinases (RTKs). Generally, the binding of a ligand to these receptors leads to activation of their intracellular kinase activity that sets in motion a cascade of signaling events. In order to ensure appropriate responses to physiological stimuli, the cell is endowed with the ability to regulate signal transduction via numerous mechanisms such as dephosphorylation of the RTK and its substrates as well as downregulation of the RTK. Activation of EGFR is a potent mitogenic (proliferative) and motogenic (cell motility) signal that plays crucial roles during embryonic development and maintenance of adult tissue. EGFR signaling is primarily regulated by ligand-induced receptor internalization with subsequent degradation in lysosomes. While the complex of proteins that are recruited to EGFR after its activation is well understood, proteins that interact with the receptor in the absence of ligand binding are still not systematically studied. With the goal of identifying novel binding partners of non-activated EGFR, a membrane based yeast-two hybrid screen (MYTH) was conducted. MYTH is based on the principle of in vivo reconstitution of the N-terminus (Nub) and C-terminus (Cub) halves of ubiquitin once brought into close proximity. A chimeric protein consisting of EGFR fused to Cub and a transcription factor was used as a bait to screen Nub-tagged cDNA library. Analysis of resultant yeast transformants revealed a total of 87 proteins to interact with EGFR. Of these only 11 were previously shown to bind to EGFR. A majority of the other proteins were shown to interact with the receptor by yeast retransformation. Fifteen were confirmed to bind to EGFR by coimmunoprecipitation assays in mammalian cells. One of the novel EGFR interactors identified in the screen was histone deacetylase 6 (HDAC6). This deacetylase is localized in the cytoplasm and known to deacetylate alpha-tubulin, HSP90 and cortactin. The juxtamembrane region of EGFR binds to the Cterminus of HDAC6. Functionally, overexpression of wild type HDAC6 stabilized ligand-induced degradation of the receptor. On the other hand, deacetylase deficient or EGFR binding compromised mutants of HDAC6 were able to stabilize EGFR only partially. Downmodulation of HDAC6 expression by RNAi markedly accelerated degradation of the receptor. Taken together, HDAC6 is a negative regulator of EGFR downregulation that is dependent on its deacetylase activity and ability to bind to the receptor. Imaging studies revealed that HDAC6 does not affect internalization of EGFR from the plasma membrane but rather influences the post-endocytic trafficking of the receptor-ligand complex to lysosomes. Pulse-chase experiments using fluorophoretagged EGF showed that EGFR is transported faster towards the peri-nuclear region and delivered to late endosomes rapidly in HDAC6 depleted cells. HDAC6 is demonstrated to act, at least partly, by regulating the acetylation of alpha-tubulin. Upon EGFR activation, acetylation of alpha-tubulin on lysine 40 is progressively increased as shown by mass spectrometry and immunoblotting. Forced expression of a dominant negative mutant of alpha-tubulin, but not wild type alpha-tubulin, led to reduced speed and processive movement of early endosomes in GFP-Rab5 expressing cells. In a surprising twist, EGFR is able to phosphorylate HDAC6 on Tyr570. Phosphorylation of Tyr570 and Ser568 leads to inactivation of the deacetylase function of HDAC6 as shown by in vivo and in vitro assays. In summary, HDAC6 diminishes EGFR downregulation by slowing the transport of intracellular vesicles. The inhibitory effect is removed once HDAC6 is phosphorylated on key residues. In line with these findings, two recent reports have shown that hyper-acetylation of alpha-tubulin induced by inhibition of HDAC6 increases the transport of brain derived neurotrophic factor and JNK interacting protein-1 in different cell systems. Acetylated microtubules are more efficient in recruiting motor proteins like kinesin-1 and dynein. These findings indicate that HDAC6 plays an important regulatory role in intracellular trafficking pathways. However, several outstanding issues still remain unresolved. How does acetylation of microtubules influence vesicular trafficking? In this regard, the temporal and spatial dynamics of alpha-tubulin acetylation following EGFR activation should be studied. Furthermore, whether HDAC6 affects the trafficking of other endocytic cargos and additional organelles is an interesting question to address.
In this thesis we have studied the physics of different ultracold Bose-Fermi mixtures in optical lattices, as well as spin 1=2 fermions in a harmonic trap. To study these systems we generalized dynamical mean-field theory for a mixture of fermions and bosons, as well as for an inhomogeneous environment. Generalized dynamical mean-field theory (GDMFT) is a method that describes a mixture of fermions and bosons. This method consists of Gutzwiller mean-field for the bosons, and dynamical mean-field theory for the fermions, which are coupled on-site by the Bose-Fermi density-density interaction and possibly a Feshbach term which converts a pair of up and down fermions into a molecule, i.e. a boson. We derived the self-consistency equations and showed that this method is well-controlled in the limit of high lattice coordination number z. We develop real-space dynamical mean-field theory for studying systems in an inhomogeneous environment, e.g. in a harmonic trap. The crucial difference compared to standard DMFT is that we are taking into account that different sites are not equivalent to each other and thus take into account the inhomogeneity of the system. Different sites are coupled by the real-space Dyson equation. ...
Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
(2009)
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown etiology, characterized by a loss of tolerance against hepatocytes leading to the progressive destruction of hepatic parenchyma and cirrhosis. Clinical signs for AIH are interface hepatitis and portal plasma cell infiltration, hypergammaglobulinemia, and autoantibodies. Based on serological markers AIH is defined in subtypes. The hallmark of AIH type 2 are type 1 liver/kidney microsomal autoantibodies (LKM-1), whereas AIH type 1 is characterized by the presence of anti-nuclear (ANA) and/or anti-smooth muscular (SMA) autoantibodies. The major autoantigen recognized specifically by LKM-1 autoantibodies was identified as the 2D6 isoform of the cytochrome P450 enzyme family (CYP2D6). Not much is known about the etiology and pathogenic mechanisms of AIH so far and most animal models available result in only transient hepatic liver damage after a rather complex initiation method. It was the aim of my project to generate a novel animal model for AIH that reflects the chronic and progressive destruction of the liver characteristic for the human disease while using a defined and feasible initiating event to further analyze the pathogenic mechanisms leading to the autoimmune-mediated destruction of the liver. Therefore, mice transgenically expressing the human CYP2D6 in the liver and wild-type mice were infected with a liver-tropic adenovirus expressing the human CYP2D6 (Ad-2D6). Selftolerance to CYP2D6 was broken in Ad-2D6-infected mice, resulting in persistent autoimmune liver damage, apparent by cellular infiltration, hepatic fibrosis and necrosis. Similar to type 2 AIH patients, Ad-2D6-infected mice generated LKM-1-like antibodies recognizing the same immunodominant epitope of CYP2D6. Taken together, we could introduce a new animal model that reflects the persistent autoimmune-mediated liver damage as well as the serological marker characteristic for AIH type 2 and we could demonstrate that chronic autoimmune diseases targeting the liver can be triggered by molecular mimicry occurring in the context of a hepatotropic viral infection.
In this work, we extend the Hegselmann and Krause (HK) model, presented in [16] to an arbitrary metric space. We also present some theoretical analysis and some numerical results of the condensing of particles in finite and continuous metric spaces. For simulations in a finite metric space, we introduce the notion "random metric" using the split metrics studies by Dress and al. [2, 11, 12].
SIVsmmPBj-derived lentiviral vectors are capable of efficient primary human monocyte transduction, a capacity which is linked to the viral accessory protein Vpx. To enable novel gene therapy approaches targeting monocytes, in this thesis it was aimed to generate enhanced lentiviral vectors that meet the required standards for clinical applications with respect to gene transfer efficiency and safety. The vectors were tested for their suitability in a relevant therapeutic gene transfer approach. At first, it was investigated whether vectors derived from another Vpx-carrying lentivirus reveal the same capacity for monocyte transduction as SIVsmmPBj-derived vectors. A transduction experiment using HIV-2-derived vectors in comparison to PBj-derived vectors revealed a comparable transduction capacity, thus disproving the assumed uniqueness of the PBj vectors. The further generation and analysis of expression constructs for the vpx genes of HIV-2 and SIVmac demonstrated a similar functionality in monocyte transduction as the Vpx of PBj. As VpxPBj, both Vpx proteins facilitated monocyte transduction of a vpx-deficient PBj-derived vector system. For the generation of enhanced SIVsmmPBj and HIV-2 vector systems, only the transfer vectors were optimized, since the packaging vectors available already meet current standards. At first, several modifications were introduced into an available preliminary PBj-derived transfer vector by conventional cloning. The modifications included insertions of cPPT/CTS and WPRE as well as the deletions of the remaining pol sequence, the second exons of tat end rev, and the U3-region within the 3’LTR to generate a SIN vector. Thus, beside safety enhancement, the vector titers were also increased from 9.1x105 TU/ml achieved after concentration with the initial transfer vector up to 1.1x107 TU/ml with the final transfer vector. The PBj vector retained its capability of monocyte transduction when supplemented with Vpx. This conventional method of vector enhancement is time-consuming and may result in only sub-optimal vectors, since it depends on the presence of restriction sites which may not allow deletion of all needless sequences. Moreover, mutations may accumulate during the high number of cloning and amplification steps. Therefore, a new and easier method for lentiviral transfer vector generation was conceived. Three essential segments of the viral genome (5‘ LTR, RRE, ΔU3-3’ LTR) are amplified on the template of the lentiviral wild-type genome and fused by Fusion-PCR. Further necessary elements namely the cPPT/CTS-element, MCS, and PPT are included into the resulting vector by extension of the nucleotide primers used for the PCRs. The amplified and fused vector-scaffold can easily be integrated into a plasmid backbone, followed by insertion of the expression cassette of choice. By applying this approach, two novel lentiviral transfer vectors, based on the non-human SIVsmmPBj and the human HIV-2, were derived. Vector titers achieved for PBj and HIV-2 vectors supplemented with Vpx reached up to 4.0x108 TU/ml and 5.4x108 TU/ml, respectively. The capacity for monocyte transduction was maintained. Thus, safe and efficient, state of the art HIV-2- and PBj-derived vector systems are now available for future gene therapy strategies. Finally, the new vectors were used to set up an approach for gene correction of gp91phox-deficient monocytes for the treatment of X-linked chronic granulomatous disease (xCGD). The administration of autologous, gene-corrected monocytes to counteract systemic and acute infections could lead to a decreased infection load, dissolve granulomas and therefore improve the survival rate of hematopoietic stem cell transplantation (HSCT) which is the current treatment of choice for this disease. First, methods for analysis of gp91phox function were established. Next, they were employed to demonstrate the capacity of monocytes, obtained from healthy humans or mice, for phagocytosis, oxidative burst, and Staphylococcus aureus killing. The in vivo half-life of murine monocytes in the bloodstream and their distribution to specific tissues was determined. Lastly, HIV-1 vectors were used to transfer the gp91phox gene into monocytes from gp91phox-deficient mice. This resulted in the successful restoration of the oxidative burst ability in the cells. In summary, the general suitability of the new vectors for treatment of CGD by monocyte transduction was demonstrated. The results of the mouse experiments provide the foundation for future challenge experiments to evaluate the capability of gene-corrected monocytes to kill off microbes in vivo.
Das libor Markt Modell (LMM) ist seit seiner Entwicklung in den Veröffentlichungen von Brace, Gatarek, Musiela (1997), einerseits, und unabhängig von diesen von Miltersen, Sandmann, Sondermann (1997), andererseits, zu dem anerkanntesten Instrument zur Modellierung der Zinsstruktur und der damit verbundenen Preisfindung für relevante Finanzderivate geworden. libor steht dabei für London Inter-Bank Offered Rate, ein täglich in London fixierter Referenz-Zins für kurzfristige Anlagen. Drei- oder sechsmonatige Laufzeiten sind in Verbindung mit dem LMM üblich. Die Forschung zur Verbesserung dieses Modells hat in den letzten Jahren an Zuwachs gewonnen. Beim Versuch den Fehler der Anpassung an die täglich beobachteten Preise von Zinsoptionen wie Caps und Swaptions zu verringern, erhält man in der Folge auch genauere Bewertungen für andere, exotischere, Derivate. Die zugrunde liegende und zentrale Idee des LMM besteht darin, die Forward (Termin) Zinsen direkt als primären (Vektor) Prozess mehrerer libor Sätze zu betrachten und diese simultan zu modellieren, anstatt sie nur herzuleiten aus einem übergeordneten, unendlich dimensionalen Forward Zinsprozess, wie im zeitlich früher entwickelten Heath-Jarrow-Morton Modell. Das überzeugendste Argument für diese Diskretisierung ist, dass die libor Sätze direkt im Markt beobachtbar sind und ihre Volatilitäten auf eine natürliche Weise in Beziehung gebracht werden können zu bereits liquide gehandelten Produkten, eben jenen Caps und Swaptions. Dennoch beinhaltet das Modell eine gravierende Insuffizienz, indem es keine Krümmung der Volatilitätsoberfläche, im Hinblick auf Optionen mit verschiedenen Basiszinsen, abbildet. Wie im einfachen eindimensionalen Black-Scholes Modell prägen sich auch hier die Ungenauigkeiten der Verteilung in fehlenden heavy tails deutlich aus. Smile und Skew Effekte sind erkennbar. Im klassischen liborMarkt Modell wird in Richtung der Basiszinsdimension nur eine affine Struktur erzeugt, welche bestenfalls als Approximation für die erwünschte Oberfläche dienen kann. Die beobachteten Verzerrungen führen naturgemäss zu einer ungenauen Abbildung der Realität und fehlerhaften Reproduktion der Preise in Regionen, die ein wenig entfernt vom Bereich am Geld liegen. Derartig ungewollte Dissonanzen in Gewinn und Verlustzahlen führten z.B. in 1998 zu gravierenden Verlusten im Zinsderivateportfolio der heutigen Royal Bank of Scotland. ...
The bulk viscosity of several quark matter phases is calculated. It is found that the effect of color superconductivity is not trivial, it may suppress, or enhance the bulk viscosity depending on the critical temperature and the temperature at which the bulk viscosity is calculated. Also, is it found that the effect of neutrino-emitting Urca processes cannot be neglected in the consideration of the bulk viscosity of strange quark matter. The results for the bulk viscosity of strange quark matter are used to calculate the r-mode instability window of quark stars with several possible phases. It is shown that each possible phase has a different structure for the r-mode instability window.
In this thesis the first fully integrated Boltzmann+hydrodynamics approach to relativistic heavy ion reactions has been developed. After a short introduction that motivates the study of heavy ion reactions as the tool to get insights about the QCD phase diagram, the most important theoretical approaches to describe the system are reviewed. To model the dynamical evolution of the collective system assuming local thermal equilibrium ideal hydrodynamics seems to be a good tool. Nowadays, the development of either viscous hydrodynamic codes or hybrid approaches is favoured. For the microscopic description of the hadronic as well as the partonic stage of the evolution transport approaches have beeen successfully applied, since they generate the full phse-space dynamics of all the particles. The hadron-string transport approach that this work is based on is the Ultra-relativistic Quantum Molecular Dynamics (UrQMD) approach. It constitutes an effective solution of the relativistic Boltzmann equation and is restricted to binary collisions of the propagated hadrons. Therefore, the Boltzmann equation and the basic assumptions of this model are introduced. Furthermore, predictions for the charged particle multiplicities at LHC energies are made. The next step is the development of a new framework to calculate the baryon number density in a transport approach. Time evolutions of the net baryon number and the quark density have been calculated at AGS, SPS and RHIC energies and the new approach leads to reasonable results over the whole energy range. Studies of phase diagram trajectories using hydrodynamics are performed as a first move into the direction of the development of the hybrid approach. The hybrid approach that has been developed as the main part of this thesis is based on the UrQMD transport approach with an intermediate hydrodynamical evolution for the hot and dense stage of the collision. The initial energy and baryon number density distributions are not smooth and not symmetric in any direction and the initial velocity profiles are non-trivial since they are generated by the non-equilibrium transport approach. The fulll (3+1) dimensional ideal relativistic one fluid dynamics evolution is solved using the SHASTA algorithm. For the present work, three different equations of state have been used, namely a hadron gas equation of state without a QGP phase transition, a chiral EoS and a bag model EoS including a strong first order phase transition. For the freeze-out transition from hydrodynamics to the cascade calculation two different set-ups are employed. Either an in the computational frame isochronous freeze-out or an gradual freeze-out that mimics an iso-eigentime criterion. The particle vectors are generated by Monte Carlo methods according to the Cooper-Frye formula and UrQMD takes care of the final decoupling procedure of the particles. The parameter dependences of the model are investigated and the time evolution of different quantities is explored. The final pion and proton multiplicities are lower in the hybrid model calculation due to the isentropic hydrodynamic expansion while the yields for strange particles are enhanced due to the local equilibrium in the hydrodynamic evolution. The elliptic flow values at SPS energies are shown to be in line with an ideal hydrodynamic evolution if a proper initial state is used and the final freeze-out proceeds gradually. The hybrid model calculation is able to reproduce the experimentally measured integrated as well as transverse momentum dependent $v_2$ values for charged particles. The multiplicity and mean transverse mass excitation function is calculated for pions, protons and kaons in the energy range from $E_{\rm lab}=2-160A~$GeV. It is observed that the different freeze-out procedures have almost as much influence on the mean transverse mass excitation function as the equation of state. The experimentally observed step-like behaviour of the mean transverse mass excitation function is only reproduced, if a first order phase transition with a large latent heat is applied or the EoS is effectively softened due to non-equilibrium effects in the hadronic transport calculation. The HBT correlation of the negatively charged pion source created in central Pb+Pb collisions at SPS energies are investigated with the hybrid model. It has been found that the latent heat influences the emission of particles visibly and hence the HBT radii of the pion source. The final hadronic interactions after the hydrodynamic freeze-out are very important for the HBT correlation since a large amount of collisions and decays still takes place during this period.
Induced charge computation
(2009)
One of the main aspects of statistical mechanics is that the properties of a thermodynamics state point do not depend on the choice of the statistical ensemble. It breaks down for small systems e.g. single molecules. Hence, the choice of the statistical ensemble is crucial for the interpretation of single molecule experiments, where the outcome of measurements depends on which variables or control parameters, are held fixed and which ones are allowed to fluctuate. Following this principle, this thesis investigates the thermodynamics of a single polymer pulling experiments within two different statistical ensembles. The scaling of the conjugate chain ensembles, the fixed end-to-end vector (Helmholtz) and the fixed applied force (Gibbs), are studied in depth. This thesis further investigates the ensemble equivalence for different force regimes and polymer-chain contour lengths. Using coarse-grained molecular dynamic simulations, i.e. Langevin dynamics, the simulations were found to complement the theoretical predictions for the scaling of ensemble difference of Gaussian chains in different force-regimes, giving special attention to the zero force regime. After constructing Helmholtz and Gibbs conjugate ensembles for a Gaussian chain, two different data sets of thermodynamic states on the force-extension plane, i.e. force-extension curves, were generated. The ensemble difference is computed for different polymer-chain lengths by using force-extension curves. The scaling of the ensemble difference versus relative polymer-chain length under different force regimes has been derived from the simulation data and compared to theoretical predictions. The results demonstrate that the Gaussian chain in the zero force limit generates nonequivalent ensembles, regardless of its equilibrium bond length and polymer-chain contour length. Moreover, if polymers are charged in confinement, coarse-graining is problematic, owing to dielectric interfaces. Hence, the effect of dielectric interfaces must be taken into account when describing physical systems such as ionic channels or biopolymers inside nanopores. It is shown that the effect of dielectrics is crucial for the dynamics of a biopolymer or an ion inside a nanopore. In the simulations, the feasibility of an efficient and accurate computation of electrostatic interactions in the presence of an arbitrarily shaped dielectric domain is challenging. Several solutions for this problem have been previously proposed in the literature such as a density functional approach, or transforming problem at hand into an algebraic problem ( Induced Charge Computation (ICC) ) and boundary element methods. Even though the essential concept is the same, which is to replace the dielectric interface with a polarization charge density, these approaches have been analyzed and the ICC algorithm has been implemented. A new superior boundary element method has been devised utilizing the force computation via the Particle-Particle Particle-Mesh (P3M) method for periodic geometries (ICCP3M). This method has been compared to the ICC algorithm, the algebraic solutions, and to density functional approaches. Extensive numerical tests against analytically tractable geometries have confirmed the correctness and applicability of developed and implemented algorithms, demonstrating that the ICCP3M is the fastest and the most versatile algorithm. Further optimization issues are also discussed in obtaining accurate induced charge densities. The potential of mean force (PMF) of DNA modelled on a coarsed-grain level inside a nanopore is investigated with and without the inclusion of dielectric effects. Despite the simplicity of the model, the dramatic effect of dielectric inclusions is clearly seen in the observed force profile.
In this work the preparation of organic donor-acceptor thin films was studied. A chamber for organic molecular beam deposition was designed and integrated into an existing deposition system for metallic thin films. Furthermore, the deposition system was extended by a load-lock with integrated bake-out function, a chamber for the deposition of metallic contacts via stencil mask technique and a sputtering chamber. For the sublimation of the organic compounds several effusion cells were designed. The evaporation characteristic and the temperature profile within the cells was studied. Additionally, a simulation program was developed, which calculates the evaporation characteristics of different cell types. The following processes were integrated: evaporation of particles, migration on the cell walls and collisions in the gas phase. It is also possible to consider a temperature gradient within the cell. All processes can be studied separately and their relative strength can be varied. To verify the simulation results several evaporation experiments with different cell types were employed. The thickness profile of the prepared thin films was measured position-dependently. The results are in good agreement with the simulation. Furthermore, the simulation program was extended to the field of electron beam induced deposition (EBID). The second part of this work deals with the preparation and characterization of organic thin films. The focus hereby lies on the charge transfer salt (BEDT-TTF)(TCNQ), which has three known structure variants. Thin films were prepared by different methods of co-evaporation and were studied with optical microscopy, X-ray diffraction and energy dispersive X-ray spectroscopy (EDX).The formation of the monoclinic phase of (BEDT-TTF)(TCNQ) could be shown. As a last part tunnel structures were prepared as first thin film devices and measured in a He4 cryostat.