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On the Fragility Index
(2011)
The Fragility Index captures the amount of risk in a stochastic system of arbitrary dimension. Its main mathematical tool is the asymptotic distribution of exceedance counts within the system which can be derived by use of multivariate extreme value theory. Thereby the basic assumption is that data comes from a distribution which lies in the domain of attraction of a multivariate extreme value distribution. The Fragility Index itself and its extension can serve as a quantitative measure for tail dependence in arbitrary dimensions. It is linked to the well known extremal index for stochastic processes as well the extremal coefficient of an extreme value distribution.
Understanding the mechanisms of fragmentation within silicate melts is of great interest not only for material science, but also for volcanology, particularly regarding molten fuel coolant-interactions (MFCIs). Therefore edge-on hammer impact experiments (HIEs) have been carried out in order to analyze the fracture dynamics in well defined targets by applying a Cranz-Schardin highspeed camera technique. This thesis presents the corresponding results and provides a thorough insight into the dynamics of fragmentation, particularly focussing on the processes of energy dissipation. In HIEs two main classes of cracks can be identified, characterized by completely different fracture mechanisms: Shock wave induced “damage cracks” and “normal cracks”, which are exclusively caused by shear-stresses. This dual fracture situation is taken into account by introducing a new concept, according to which the crack class-specific fracture energies are linearly correlated with the corresponding fracture areas. The respective proportionality constants - denoted “fracture surface energy densities” (FSEDs) - have been quantified for all studied targets under various constraints. By analyzing the corresponding high speed image sequences and introducing useful dynamic parameters it has been possible to specify and describe in detail the evolution of fractures and, moreover, to quantify the energy dissipation rates during the fragmentation. Additionally, comprehensive multivariate statistical analyses have been carried out which have revealed general dependencies of all relevant fracture parameters as well as characteristics of the resulting particles. As a result, an important principle of fracture dynamics has been found, referred to as the “local anisotropy effect”: According to this principle, the fracture dynamics in a material is significantly affected by the location of directed stresses. High local stress gradients cause a more stable crack propagation and consequently a reduction of the energy dissipation rates. As a final step, this thesis focusses on the volcanological conclusions which can be drawn on the basis of the presented HIE results. Therefore fragments stemming from HIEs have been compared with natural and experimental volcanic ash particles of basaltic Grimsvötn and rhyolitic Tepexitl melts. The results of these comparative particle analyses substantiate HIEs to be a very suitable method for reproducing the MFCI loading conditions in silicate melts and prove the FSED concept to be a model which is well transferable to volcanic fragmentation processes.
The material system of interest in this thesis are II-VI-semiconductors. The first part of this thesis focuses on the formation of self-assembled CdSe-based quantum dots (QD) on ZnSe. The lattice constants of ZnSe and CdSe differ as much as about 7\% and therefore a CdSe layer grown on top of ZnSe experiences a huge strain. The aspired strain relief constitutes in the self-assembly of QDs (i.e. a roughened layer structure). Additionally, this QD layer is intermixed with Zn as this is also a possibility to decrease the strain in the layer. For CdSe on ZnSe, in Molecular Beam Epitaxy (MBE), various QD growth procedures were analysed with respect to the resulting Cd-content of the non-stoichiometric ternary (Zn,Cd)Se. The evaluation was performed by Raman Spectroscopy as the phonon frequency depends on the Cd-content. The second part of the thesis emphasis on the interface properties of n-ZnSe on n-GaAs. Different growth start procedures of the ZnSe epilayer may lead to different interface configurations with characteristic band-offsets and carrier depletion layer widths. The analysis is mainly focused on the individual depletion layer widths in the GaAs and ZnSe. This non-destructive analysis is performed by evaluating the Raman signal which comprises of phonon scattering from the depleted regions and coupled plasmon-phonon scattering from regions with free carriers.
This thesis concerned the quantification of cell adhesion molecules (CAM) in and on thin hydrogel films as surface modification of biomaterials. The established and well characterized, per se inert NCO-sP(EO-stat-PO) hydrogel system which allows the easy and reproducible bioactivation with peptides was used as basis for this thesis. Two methods can be used to functionalize the coatings. Ligands can either be mixed into the prepolymer solution in prior to layer formation (mix-in method), or freshly prepared coatings can be incubated with ligand solution (incubation method). Divided into three major parts, the first part of the thesis dealt with the concentration of ligands in the bulk hydrogel, whereas the second part of the thesis focused on the surface sensitive quantification of CAMs at the biointerface. The results were correlated with cell adhesion kinetics. The third part of this thesis investigated the biochemical and the structural mimicry of the extracellular matrix (ECM). ECM proteins were presented via sugar-lectin mediated binding and cell behavior on these surfaces was analyzed. Cell behavior on three-dimensional fibers with identical surface chemistry as the coatings in the previous sections of the thesis was analyzed and correlated with the amount of peptide used for bioactivation. Overall, the main question of this work was ‘How much?’ regarding maximal as well as optimal ligand concentrations for controlled cell-hydrogel interactions. The focus in the first practical part of this thesis was to analyze the amount of ligands in NCO-sP(EO-stat-PO) hydrogels using classical quantification methods. Coatings in 96-well plates as well as on glass were functionalized with GRGDS and 125I-YRGDS for radioisotopic detection (Chapter 3). Using the incubation method for functionalization, a maximal ligand binding using peptide concentrations of 600 µg/mL could be determined. When functionalization was introduced via the mix-in method, a clear tendency for higher ligand concentrations with increasing ligand to prepolymer ratio was observed, but no maximal ligand binding could be detected with a ligand to prepolymer ratio of 2/1 being the highest ratio investigated. This ratio of 2/1 was not exceeded to ensure that complete crosslinking of the hydrogel was not affected. In Chapter 4, a fluorinated amino acid and an iodinated peptide were immobilized to the hydrogels using the mix-in method and were detected by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS). In these measurements, maximal ligand binding was detected for a ligand to prepolymer ratio of 1/1. Higher ligand to prepolymer ratios did not result in any significant increase in ligand concentrations in the surface near regions of the crosslinked hydrogels. To address the question of how many ligands were actually accessible for cell interaction at the interface, surface sensitive quantification methods were applied in the second part of this thesis. For the quantification with surface plasmon resonance (SPR) and surface acoustic wave technology (SAW) (Chapter 5), the hydrogel coating procedure needed to be transferred onto cystamine functionalized gold surfaces. Characterization with ellipsometry and atomic force microscopy (AFM) revealed inhomogeneous cystamine binding to the activated surfaces, which resulted in inhomogeneous coatings. Nevertheless, it could be shown that SPR as well as SAW were suitable methods for the surface sensitive quantification of the ligand concentration on NCO-sP(EO-stat-PO) hydrogels. Non-functionalized coatings resisted non-specific serum as well as streptavidin (SA) adsorption. Coatings functionalized with biocytin and GRGDSK-biotin introduced specific SA binding that was dependent on the biotin concentration at the surface. Additionally, enzyme linked immunosorbent assay (ELISA) and enzyme linked lectin assay (ELLA) (Chapter 6) were applied to coatings in 96-well plates and on glass. Coatings were functionalized with the model molecule biocytin, the biotinylated peptide GRGDSK-biotin, the ECM protein fibronectin (FN), as well as the carbohydrates N-acetylglucosamine (GlcNAc) and N-acetyllactosamine (LacNAc). All ligands could be successfully detected with antibodies or SA via ELISA or ELLA. Maximal GRGDSK-biotin binding to the hydrogel coatings on glass was achieved at a peptide to prepolymer ratio of 1/5, which was used as reference value in Chapter 8. Last but not least, cell adhesion (Chapter 7) was quantified depending on the GRGDS concentration on hydrogel coatings on glass. Maximal adhesion of primary human dermal fibroblast (HDF) was observed at GRGDS to prepolymer ratios of 1/5, when adherent cells were counted on life cell images. Quantification of adherent cells using the CASY® cell counter revealed maximal HDF adhesion at molar ligand to prepolymer ratios of 1/2. However, cell vitality detected by intracellular enzyme activities was not dependent on the GRGDS concentration. Cells which managed to adhere were vital regardless of the amount of ligands present. Additionally, adhesion of fibroblasts from the murine cell line NIH L929 was analyzed by counting on life cell images. These cells, being much smaller than the HDF cells, needed higher GRGDS to prepolymer ratios (2/1) for proper cell adhesion. All quantification methods applied to analyze hydrogels which were functionalized by the mix-in method in Chapter 3, 4, 6 and 7, were compared in Chapter 8. Radiodetection gave information about the ligand concentrations throughout the whole hydrogel and no maximal amount of ligands could be detected when increasing the peptide to prepolymer ratio. In contrast, XPS and TOF-SIMS which only penetrated the surface near regions of the coating, a maximal ligand binding to the hydrogel was detected for 1/1 ratios. SPR and SAW were not included in this comparison, as the coatings on gold need to be optimized first. The two surface sensitive quantification methods (ELISA and HDF adhesion) could give information about the quantity of peptide which was sterically available for SA or cell binding. With these methods, maximal SA and cell binding was detected at ratios of 1/5. These results underline the importance of carefully compare the different methods. Beside ligand quantification on hydrogels, the third part of this thesis was concerned with the biochemical and structural mimicry of the ECM by advanced ECM engineering to design biomimetic biomaterials that are better accepted by cells and tissue. The subject of Chapter 9 was the biomimetic and flexible presentation of the ECM protein FN. FN was attached via sugar-lectin mediated binding to NCO-sP(EO-stat-PO) hydrogels. The build-up of the covalently immobilized sugar poly-N-acetyllactosamine (polyLacNAc), the subsequent non-covalent binding of the fungal galectin His6CGL2, and FN could be elegantly proven by fluorescent staining on coatings which were functionalized with the sugar by micro contact printing (MCP). Further experiments were carried out on build-ups, where polyLacNAc was immobilized on the hydrogel by incubation. Optimal parameters for the layer build-up were determined by ELLA/ELISA. Only the complete build-up induced proper adhesion of HDFs. Compared to tissue culture polystyrene (TCPS), cells adhered and spread faster on the biomimetic surfaces. The flexible presentation of FN allowed HDFs to rearrange homogenously immobilized FN into fibrillar structures, which seemed not to be possible when FN was adsorbed on glass or covalently bound directly to the hydrogel coatings. This new approach of a flexible and biomimetic presentation of an ECM protein allows new ways to design biomaterials with best possible cell-material interactions. The work described in Chapter 10 focused on the structural mimicry of the fibrous ECM structures by electrospinning of synthetic, bioactive, and degradable fibers. Poly(D,L-lactide-co-glycolide) (PLGA) and NCO-sP(EO-stat-PO) were electrospun out of one solution in an easy one-step preparation resulting in fibers with an ultrathin inert hydrogel layer at the surface. By adding GRGDS to the solution prior to electrospinning, specifically interacting fibers could be obtained. In comparison to PLGA, the adsorption of bovine serum albumin (BSA) could be reduced by 99.2%. As a control, the non-active peptide GRGES was immobilized to the fiber. These fibers did not allow cell adhesion, showing that the integrity of the hydrogel coated fibers was not affected by the immobilization of peptides. HDF adhesion was obtained by functionalization with GRGDS, leading to the adhesion, spreading, and proliferation of HDFs. Also mesenchymal stem cells (MSC) could adhere to GRGDS functionalized fibers. Additionally, for ligand quantification, the ELISA technique was successfully transferred to fiber substrates. To highlight the potential of the approaches for the biochemical and structural mimicry of the ECM, the sugar polyLacNAc was immobilized on the PLGA/sP(EO-stat-PO) fibers followed by the subsequent layer build-up with His6CGL2 and FN. These fibers triggered HDF adhesion.
Type 1 diabetes is an autoimmune disease that leads to the destruction of insulin-producing pancreatic beta cells and consequently to hyperglycemia. In the last 60 years, the prevalence of type 1 diabetes has been increasing constantly and is predicted to continue rising. About 80% of the disease risk is attributable to the genetic variation. Thanks to genome wide association studies the number of known disease-associated polymorphisms climbed from five to 53 in the last 10 years. As these studies reveal possible candidate genes but not underlying mechanisms we strove to take the next step and explore the association of two genes suggested by these studies with type 1 diabetes. As a method of choice we decided to use lentiviral RNAi in non obese diabetic (NOD) mice, a widely-used model for type 1 diabetes, introducing a shRNA directed against the target message into the genome of this mouse strain via a lentivirus. This allowed us to study the partial loss-of-function of the target gene within the context of diabetes, directly seeing its effect on autoimmune mechanisms. In this thesis we examined two different genes in this manner, Ctla4 and Clec16a. A type 1 diabetes associated polymorphism in the CTLA4 gene had been found to alter the splicing ratio of its variants soluble CTLA-4 (sCTLA-4) and full length CTLA-4, the associated allele producing less sCTLA-4 than the protective allele. We mimicked this effect by specifically targeting the sCtla4 mRNA via lentiviral RNAi in the NOD model. As a result we could confirm the reduction of sCTLA-4 to accelerate type 1 diabetes development. Furthermore we could show a function of sCTLA-4 in regulatory T cells, more specifically at least partly in their ability to modulate costimulation by antigen presenting cells. The second candidate gene, Clec16a was targeted with the shRNA in a way that was designed to knock down most splice variants. As the gene function and the effect of the associated SUMMARY 10 polymorphism was unknown, we reasoned this method to be feasible to investigate its role in type 1 diabetes. The knockdown of Clec16a in NOD mice resulted in an almost complete protection from diabetes development that could be attributed to T cells dysfunction. However, as expression patterns and a study of the Drospophila orthologue suggested a possible role of CLEC16A in antigen presentation we also examined antigen presenting cells in the thymus and periphery. Although we did not detect any effect of the knockdown on peripheral antigen presenting cells, thymic epithelial cells were clearly affected by the loss of CLEC16A, rendering them more activated and shifting the ratio of cortical to medullary epithelial cells in favor of cortical cells. We therefore suggest a role of CLEC16A in the selection of T cells, that needs, however, to be further investigated. In this thesis we provided a feasible and fast method to study function of genes and even of single splice variants within the NOD mouse model. We demonstrate its usefulness on two candidate genes associated with type 1 diabetes by confirming and unraveling the cause of their connection to the disease.
It has been proposed that different features of a face provide a source of information for separate perceptual and cognitive processes. Properties of a face that remain rather stable over time, so called invariant facial features, yield information about a face’s identity, and changeable aspects of faces transmit information underlying social communication such as emotional expressions and speech movements. While processing of these different face properties was initially claimed to be independent, a growing body of evidence suggests that these sources of information can interact when people recognize faces with whom they are familiar. This is the case because the way a face moves can contain patterns that are characteristic for that specific person, so called idiosyncratic movements. As a face becomes familiar these idiosyncratic movements are learned and hence also provide information serving face identification. While an abundance of experiments has addressed the independence of invariant and variable facial features in face recognition, little is known about the exact nature of the impact idiosyncratic facial movements have on face recognition. Gaining knowledge about the way facial motion contributes to face recognition is, however, important for a deeper understanding of the way the brain processes and recognizes faces. In the following dissertation three experiments are reported that investigate the impact familiarity of changeable facial features has on processes of face recognition. Temporal aspects of the processing of familiar idiosyncratic facial motion were addressed in the first experiment via EEG by investigating the influence familiar facial movement exerts on event-related potentials associated to face processing and face recognition. After being familiarized with a face and its idiosyncratic movement, participants viewed familiar or unfamiliar faces with familiar or unfamiliar facial movement while their brain potentials were recorded. Results showed that familiarity of facial motion influenced later event-related potentials linked to memory processes involved in face recognition. The second experiment used fMRI to investigate the brain areas involved in processing familiar facial movement. Participants’ BOLD-signal was registered while they viewed familiar and unfamiliar faces with familiar or unfamiliar idiosyncratic movement. It was found that activity of brain regions, such as the fusiform gyrus, that underlie the processing of face identity, was modulated by familiar facial movement. Together these two experiments provide valuable information about the nature of the involvement of idiosyncratic facial movement in face recognition and have important implications for cognitive and neural models of face perception and recognition. The third experiment addressed the question whether idiosyncratic facial movement could increase individuation in perceiving faces from a different ethnic group and hence reduce impaired recognition of these other-race faces compared to own-race faces, a phenomenon named the own-race bias. European participants viewed European and African faces that were each animated with an idiosyncratic smile while their attention was either directed to the form or the motion of the face. Subsequently recognition memory for these faces was tested. Results showed that the own-race bias was equally present in both attention conditions indicating that idiosyncratic facial movement was not able to reduce or diminish the own-race bias. In combination the here presented experiments provide further insight into the involvement of idiosyncratic facial motion in face recognition. It is necessary to consider the dynamic component of faces when investigating face recognition because static facial images are not able to provide the full range of information that leads to recognition of a face. In order to reflect the full process of face recognition, cognitive and neural models of face perception and recognition need to integrate dynamic facial features as a source of information which contributes to the recognition of a face.
The Nucleotide Excision Repair (NER) pathway is able to remove a vast diversity of structurally unrelated DNA lesions and is the only repair mechanism in humans responsible for the excision of UV induced DNA damages. The NER mechanism raises two fundamental questions: 1) How is DNA damage recognition achieved discriminating damaged from non damaged DNA? 2) How is DNA incision regulated preventing endonucleases to cleave DNA non specifically but induce and ensure dual incision of damaged DNA? Thus, the aim of this work was to investigate the mechanisms leading from recognition to incision of damaged DNA. To decipher the underlying process of damage recognition in a prokaryotic model system, the intention of the first part of this work was to co crystallize the helicase UvrB form Bacillus caldotenax together with a DNA substrate comprising a fluorescein adducted thymine as an NER substrate. Incision assays were performed to address the question whether UvrB in complex with the endonuclease UvrC is able to specifically incise damaged DNA employing DNA substrates with unpaired regions at different positions with respect to the DNA lesion. The results presented here indicate that the formation of a specific pre incision complex is independent of the damage sensor UvrA. The preference for 5’ bubble substrate suggests that UvrB is able to slide along the DNA favorably in a 5’ → 3’ direction until it directly encounters a DNA damage on the translocating strand to then recruit the endonuclease UvrC. In the second part of this work, the novel endonuclease Bax1 from Thermoplasma acidophilum was characterized. Due to its close association to archaeal XPB, a potential involvement of Bax1 in archaeal NER has been postulated. Bax1 was shown to be a Mg2+ dependent, structure specific endonuclease incising 3’ overhang substrates in the single stranded region close to the ssDNA/dsDNA junction. Site directed mutagenesis of conserved amino acids was employed to identify putative active site residues of Bax1. In complex with the helicase XPB, however, incision activity of Bax1 is altered regarding substrate specificity. The presence of two distinct XPB/Bax1 complexes with different endonuclease activities indicates that XPB regulates Bax1 incision activity providing insights into the physical and functional interactions of XPB and Bax1.
This study was conducted to determine the influence of different stress factors on the honeybee Apis mellifera. The investigation was motivated by previous experiments that suggested the existence of an unspecific defense mechanism causing a generalized change of flight behavior after the onset of different diseases. This mechanism is thought to impede the ability of flight bees to return to their respective colonies thereby removing the disease from the colony over time. During the last years, the existence of such a “suicidal behavior” was supported by further studies. Thus, an unnoticed, potentially highly effective defense mechanism of social insects was revealed whose spectrum of activity and physiological basics require further investigation. Suggesting that the reaction by the bees is unspecific to different diseases as well as to other potential stress factors, this study was designed to investigate the influence of pathogens, insecticides, and different brood rearing temperatures on different parameters like lifespan, foraging activity, and foraging trip duration of worker bees.
Urinary tract infection (UTI) is one of the most serious health problems worldwide. It accounts for a million hospital visits annually in the United States. Among the many uropathogenic bacteria, uropathogenic Escherichia coli (UPEC) is the most common causative agent of UTI. However, not all E. coli that inhabit the urinary tract can cause UTI. Some of them thrive for long periods of time in the urinary bladder without causing overt symptoms of infection. This carrier state is called asymptomatic bacteriuria (ABU). E. coli ABU isolates can live in the host without inducing host response due to deletions, insertions and point mutations in the genome leading to the attenuation of virulence genes. They therefore behave in the same way as commensals. Since bacteria that inhabit the urinary tract are said to originate from the lower intestinal tract and ABU behave in a similar way as commensals, this study compared various phenotypic and genotypic characteristics of ABU and commensal E. coli fecal isolates. The two groups did not show a strict clustering with regards to phylogenetic lineage since there appears to be overlaps in their distribution in some clonal complexes. In addition, it was observed that the UPEC virulence genes were more frequently inactivated in ABU than in fecal isolates. Hence, ABU tend to have less functional virulence traits compared to the fecal isolates. The ABU model organism E. coli 83972 which is known not only for its commensal behavior in the urinary bladder but its ability to outcompete other bacteria in the urinary tract is currently being used as prophylactic treatment in patients who have recurrent episodes of UTI at the University Hospital in Lund, Sweden. The pilot studies showed that upon deliberate long-term colonization of the patients with E. coli 83972, they become protected from symptomatic UTI. In this study, the phenotypic and genotypic characteristics of eight re-isolates taken from initially asymptomatically colonized patients enrolled in the deliberate colonization study who reported an episode of symptoms during the colonization period were investigated. Two out of the eight re-isolates were proven to be a result of super infection by another uropathogen. Six re-isolates, on the other hand, were E. coli 83972. The urine re-isolates confirmed to be E. coli 83972 were phenotypically heterogeneous in that they varied in colony size as well as in swarming motility. Four of these re-isolates were morphologically homogenous and similar to the parent isolate E. coli 83972 whereas one of them appeared phenotypically heterogenous as a mixture of smaller and normal-sized colonies. Still another re-isolate phenotypically resembled small colony variants. Meanwhile, three of the six re-isolates did not differ from the parent isolate with regards to motility. On the other hand, three exhibited a markedly increased motility compared to the parent isolate. Transcriptome analysis demonstrated the upregulation of a cascade of genes involved in flagellar expression and biosynthesis in one of the three motile re-isolates. However, upon further investigation, it was found out that the expression of flagella had no effect on bacterial adhesion to host cells in vitro as well as to the induction of host inflammatory markers. Thus, this implies that the increased motility in the re-isolates is used by the bacteria as a fitness factor for its benefit and not as a virulence factor. In addition, among the various deregulated genes, it was observed that gene regulation tends to be host-specific in that there is no common pattern as to which genes are deregulated in the re-isolates. Taken together, results of this study therefore suggest that the use of E. coli 83972 for prophylactic treatment of symptomatic UTI remains to be very promising.
For the realization of a programmable logic device, or indeed any nanoscale device, we need a reliable method to probe the magnetization direction of local domains. For this purpose we extend investigations on the previously discovered tunneling anisotropic magneto resistance effect (TAMR) by scaling the pillar size from 100 µm down to 260 nm. We start in chapter 4 with a theoretical description of the TAMR effect and show experimental data of miniaturized pillars in chapter 5. With such small TAMR probes we are able to locally sense the magnetization on the 100 nm scale. Sub-micron TAMR and anisotropic magneto resistance (AMR) measurements of sub-millimeter areas show that the behavior of macroscopic (Ga,Mn)As regions is not that of a true macrospin, but rather an ensemble average of the behavior of many nearly identical macrospins. This shows that the magnetic anisotropies of the local regions are consistent with the behavior extracted from macroscopic characterization. A fully electrically controllable read-write memory device out the ferromagnetic semiconductor (Ga,Mn)As is presented in chapter 6. The structure consists of four nanobars which are connected to a circular center region. The first part of the chapter describes the lithography realization of the device. We make use of the sub-micron TAMR probes to read-out the magnetization state of a 650 nm central disk. Four 200 nm wide nanobars are connected to the central disk and serve as source and drain of a spin-polarized current. With the spin-polarized current we are able to switch the magnetization of the central disk by means of current induced switching. Injecting polarized holes with a spin angular momentum into a magnetic region changes the magnetization direction of the region due to the p-d exchange interaction between localized Mn spins and itinerant holes. The magnetization of the central disk can be controlled fully electrically and it can serve as one bit memory element as part of a logic device. In chapter 7 we discuss the domain wall resistance in (Ga,Mn)As. At the transition from nanobars to central disk we are able to generate 90° and 180° domain walls and measure their resistance. The results presented from chapter 5 to 7 combined with the preexisting ultracompact (Ga,Mn)As-based memory cell of ref. [Papp 07c] are the building blocks needed to realize a fully functioning programmable logic device. The work of ref. [Papp 07c] makes use of lithographically engineered strain relaxation to produce a structure comprised of two nanobars with mutually orthogonal uniaxial easy axes, connected by a narrow constriction. Measurements showed that the resistance of the constriction depends on the relative orientation of the magnetization in the two bars. The programmable logic device consists of two central disks connected by a small constriction. The magnetization of the two central disks are used as the input bits and the constriction serves as the output during the logic operation. The concept is introduced in the end of chapter 6 and as an example for a logic operation an XOR gate is presented. The functionality of the programmable logic scheme presented here can be straightforwardly extended to produce multipurpose functional elements, where the given geometry can be used as various different computational elements depending on the number of input bits and the chosen electrical addressing. The realization of such a programmable logic device is shown in chapter 8, where we see that the constriction indeed can serve as a output of the logic operation because its resistance is dependent on the relative magnetization state of both disks. Contrary to ref. [Papp 07c], where the individual magnetic elements connected to the constriction only have two non-volatile magnetic states, each disk in our scheme connected to the constriction has four non-volatile magnetic states. Switching the magnetization of a central disk with an electrical current does not only change the TAMR read-out of the respective disk, it also changes the resistance of the constriction. The resistance polar plot of the constriction maps the relative magnetization states of the individual disks. The presented device design serves as an all-electrical, all-semiconductor logic element. It combines a memory cell and data processing in a single monolithic paradigm.
We investigate transport measurements on all II-VI semiconductor resonant tunneling diodes (RTDs). Being very versatile, the dilute magnetic semiconductor (DMS) system (Zn,Be,Mn,Cd)Se is a perfect testbed for various spintronic device designs, as it allows for separate control of electrical and magnetic properties. In contrast to the ferromagnetic semiconductor (Ga,Mn)As, doping ZnSe with Mn impurities does not alter the electrical properties of the semiconductor, as the magnetic dopant is isoelectric in the ZnSe host.
Practical optimization problems often comprise several incomparable and conflicting objectives. When booking a trip using several means of transport, for instance, it should be fast and at the same time not too expensive. The first part of this thesis is concerned with the algorithmic solvability of such multiobjective optimization problems. Several solution notions are discussed and compared with respect to their difficulty. Interestingly, these solution notions are always equally difficulty for a single-objective problem and they differ considerably already for two objectives (unless P = NP). In this context, the difference between search and decision problems is also investigated in general. Furthermore, new and improved approximation algorithms for several variants of the traveling salesperson problem are presented. Using tools from discrepancy theory, a general technique is developed that helps to avoid an obstacle that is often hindering in multiobjective approximation: The problem of combining two solutions such that the new solution is balanced in all objectives and also mostly retains the structure of the original solutions. The second part of this thesis is dedicated to several aspects of systems of equations for (formal) languages. Firstly, conjunctive and Boolean grammars are studied, which are extensions of context-free grammars by explicit intersection and complementation operations, respectively. Among other results, it is shown that one can considerably restrict the union operation on conjunctive grammars without changing the generated language. Secondly, certain circuits are investigated whose gates do not compute Boolean values but sets of natural numbers. For these circuits, the equivalence problem is studied, i.\,e.\ the problem of deciding whether two given circuits compute the same set or not. It is shown that, depending on the allowed types of gates, this problem is complete for several different complexity classes and can thus be seen as a parametrized) representative for all those classes.
In this study I investigate the role of Schwann cell and axon-derived trophic signals as modifiers of axonal integrity and sprouting in motoneuron disease and diabetic neuropathy (DNP). The first part of this thesis focuses on the role of the Schwann-cell-derived ciliary neurotrophic factor (CNTF) for compensatory sprouting in a mouse model for mild spinal muscular atrophy (SMA). In the second part, the role of the insulin-like growth factor 1 (IGF-1) and its binding protein 5 (IGFBP-5) is examined in the peripheral nerves of patients with DNP and in two corresponding mouse models. Proximal SMA is caused by homozygous loss or mutation of the SMN1 gene on human chromosome 5. The different forms of SMA can be divided into four groups, depending on the levels of SMN protein produced from a second SMN gene (SMN2) and the severity of the disease. Patients with milder forms of the disease, type III and type IV SMA, normally reach adulthood and regularly show enlargement of motor units, signifying the reinnervation of denervated muscle fibers. However, the underlying mechanisms are not understood. Smn+/- mice, a model of type III/IV SMA, are phenotypically normal, but they reveal progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. The progressive loss of spinal motor neurons reaches 50% at 12 months but muscle strength is not reduced. The first evidence for axonal sprouting as a compensatory mechanism in these animals was the more than 2-fold increase in amplitude of single motor unit action potentials (SMUAP) in the gastrocnemius muscle. Confocal analysis confirmed pronounced sprouting of innervating motor axons. As CNTF is highly expressed in Schwann cells and known to be involved in sprouting, its role for this compensatory sprouting response and the maintenance of muscle strength in Smn+/- mice was investigated. Deletion of CNTF in this mouse model results in reduced sprouting and decline of muscle strength in Smn+/- Cntf-/- mice. These findings indicate that CNTF is necessary for a sprouting response and thus enhances the size of motor units in skeletal muscles of Smn+/- mice. DNP afflicting motor and sensory nerve fibers is a major complication in diabetes mellitus. The underlying cellular mechanisms of motor axon degeneration are poorly understood. IGFBP-5, an inhibitory binding protein for IGF-1, is highly upregulated in peripheral nerves in patients with DNP. The study investigates the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP-5 in motor axons. These mice develop motor axonopathy similar to that seen in DNP. Motor axon degeneration is also observed in mice in which the IGF-1 receptor (IGF-1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF-1 on IGF-1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP-5 in diabetic nerves reduces the availability of IGF-1 for IGF-1R on motor axons leading to progressive neurodegeneration, and thus offers novel treatment strategies.
Polarity and migration are essential for T cell activation, homeostasis, recirculation and effector function. To address how T cells coordinate polarization and migration when interacting with dendritic cells (DC) during homeostatic and activating conditions, a low density collagen model was used for confocal live-cell imaging and high-resolution 3D reconstruction of fixed samples. During short-lived (5 to 15 min) and migratory homeostatic interactions, recently activated T cells simultaneously maintained their amoeboid polarization and polarized towards the DC. The resulting fully dynamic and asymmetrical interaction plane comprised all compartments of the migrating T cell: the actin-rich leading edge drove migration but displayed only moderate signaling activity; the mid-zone mediated TCR/MHC induced signals associated with homeostatic proliferation; and the rear uropod mediated predominantly MHC independent signals possibly connected to contact-dependent T cell survival. This “dynamic immunological synapse” with distinct signaling sectors enables moving T cells to serially sample antigen-presenting cells and resident tissue cells and thus to collect information along the way. In contrast to homeostatic contacts, recognition of the cognate antigen led to long-lasting T cell/DC interaction with T cell rounding, disintegration of the uropod, T cell polarization towards the DC, and the formation of a symmetrical contact plane. However, the polarity of the continuously migrating DC remained intact and T cells aggregated within the DC uropod, an interesting cellular compartment potentially involved in T cell activation and regulation of the immune response. Taken together, 3D collagen facilitates high resolution morphological studies of T cell function under realistic, in vivo-like conditions.
In this thesis different algorithms for the solution of generalized Nash equilibrium problems with the focus on global convergence properties are developed. A globalized Newton method for the computation of normalized solutions, a nonsmooth algorithm based on an optimization reformulation of the game-theoretic problem, and a merit function approach and an interior point method for the solution of the concatenated Karush-Kuhn-Tucker-system are analyzed theoretically and numerically. The interior point method turns out to be one of the best existing methods for the solution of generalized Nash equilibrium problems.
There is such vast amount of visual information in our surroundings at any time that filtering out the important information for further processing is a basic requirement for any visual system. This is accomplished by deploying attention to focus on one source of sensory inputs to the exclusion of others (Luck and Mangun 2009). Attention has been studied extensively in humans and non human primates (NHPs). In Drosophila, visual attention was first demonstrated in 1980 (Wolf and Heisenberg 1980) but this field remained largely unexplored until recently. Lately, however, studies have emerged that hypothesize the role of attention in several behaviors but do not specify the characteristic properties of attention. So, the aim of this research was to characterize the phenomenon of visual attention in wild-type Drosophila, including both externally cued and covert attention using tethered flight at a torque meter. Development of systematic quantifiable behavioral tests was a key aspect for this which was not only important for analyzing the behavior of a population of wild-type flies but also for comparing the wild-type flies with mutant flies. The latter would help understand the molecular, genetic, and neuronal bases of attention. Since Drosophila provides handy genetic tools, a model of attention in Drosophila will serve to the greater questions about the neuronal circuitry and mechanisms involved which might be analogous to those in primates. Such a model might later be used in research involving disorders of attention. Attention can be guided to a certain location in the visual field by the use of external cues. Here, using visual cues the attention of the fly was directed to one or the other of the two visual half-fields. A simple yet robust paradigm was designed with which the results were easily quantifiable. This paradigm helped discover several interesting properties of the cued attention, the most substantial one being that this kind of external guidance of attention is restricted to the lower part of the fly’s visual field. The guiding cue had an after-effect, i.e. it could occur at least up to 2 seconds before the test and still bias it. The cue could also be spatially separated from the test by at least 20° and yet attract the attention although the extent of the focus of attention (FoA) was smaller than one lower visual half-field. These observations excluded the possibility of any kind of interference between the test and the cue stimuli. Another interesting observation was the essentiality of continuous visibility of the test stimulus but not the cue for effective cuing. When the contrast of the visual scene was inverted, differences in response frequencies and cuing effects were observed. Syndirectional yaw torque responses became more frequent than the antidirectional responses and cuing was no longer effective in the lower visual field with inverted contrast. Interestingly, the test stimulus with simultaneous displacement of two stripes not only effectuated a phasic yaw torque response but also a landing response. A 50 landing response was produced in more than half of the cases whenever a yaw torque response was produced. Elucidation of the neuronal correlates of the cued attention was commenced. Pilot experiments with hydroxyurea (HU) treated flies showed that mushroom bodies were not required for the kind of guidance of attention tested in this study. Dopamine mutants were also tested for the guidance of attention in the lower visual field. Surprisingly, TH-Gal4/UAS-shits1 flies flew like wild-type flies and also showed normal optomotor response during the initial calibration phase of the experiment but did not show any phasic yaw torque or landing response at 18 °C, 25 °C or 30 °C. dumb2 flies that have almost no D1 dopamine receptor dDA1 expression in the mushroom bodies and the central complex (Kim et al. 2007) were also tested and like THGal4/ UAS-shits1 flies did not show any phasic yaw torque or landing response. Since the dopamine mutants did not show the basic yaw torque response for the test the role of dopamine in attention could not be deduced. A different paradigm would be needed to test these mutants. Not only can attention be guided through external cues, it can also be shifted endogenously (covert attention). Experiments with the windows having oscillating stripes nicely demonstrated the phenomenon of covert attention due to the production of a characteristic yaw torque pattern by the flies. However, the results were not easily quantifiable and reproducible thereby calling for a more systematic approach. Experiments with simultaneous opposing displacements of two stripes provide a promising avenue as the results from these experiments showed that the flies had a higher tendency to deliver one type of response than when the responses would be produced stochastically suggesting that attention increased this tendency. Further experiments and analysis of such experiments could shed more light on the mechanisms of covert attention in flies.
By the end of the year 2011, both the CMS and ATLAS experiments at the Large Hadron Collider have recorded around 5 inverse femtobarns of data at an energy of 7 TeV. There are only vague hints from the already analysed data towards new physics at the TeV scale. However, one knows that around this scale, new physics should show up so that theoretical issues of the standard model of particle physics can be cured. During the last decades, extensions to the standard model that are supposed to solve its problems have been constructed, and the corresponding phenomenology has been worked out. As soon as new physics is discovered, one has to deal with the problem of determining the nature of the underlying model. A first hint is of course given by the mass spectrum and quantum numbers such as electric and colour charges of the new particles. However, there are two popular model classes, supersymmetric models and extradimensional models, which can exhibit almost equal properties at the accessible energy range. Both introduce partners to the standard model particles with the same charges and thus one needs an extended discrimination method. From the origin of these partners arises a relevant difference: The partners constructed in extradimensional models have the same spin as their standard model partners while in Supersymmetry they differ by spin 1/2.\\ These different spins have an impact on the phenomenology of the two models. For example, one can exploit the fact that the total cross sections are affected, but this requires a very good knowledge of the couplings and masses involved. Another approach uses angular distributions depending on the particle spins. A prevailing method based on this idea uses the invariant mass distribution of the visible particles in decay chains. One can relate these distributions to the spin of the particle mediating the decay since it reflects itself in the highest power of the invariant mass $\sff$ of the adjacent particles. In this thesis we first study the influence of higher than dimension 4 operators on spin determination in such decay chains. We write down the relevant dimension 5 and 6 operators and calculate their contributions to the invariant mass distribution. We discuss how they affect the determination of spin and couplings.\\ We then address two scenarios which do not involve decay chains in the usual sense. In three body decays, the method pointed out above cannot be applied since it can only be used if the mediating particle is produced on-shell. For off-shell decays, which are important e.g. in split-Supersymmetry or split-Universal Extra Dimensions, the narrow width approximation cannot be made which previously led to the simple relation between spin and the highest power of $\sff$. We work out a strategy for these three body decays that can distinguish between the different spin scenarios. The method relies on the fact that the differential decay width $d\Gamma /d\sff$ can be rewritten in this limit as a global phase space function and a polynomial in $\sff$. The coefficients in this polynomial are functions of masses and couplings and we show that they have distinct signs or ratios depending on the spins involved in the decay. We test the strategy in a series of Monte Carlo studies and discuss the influence of the intermediate particle's mass. In the last part we consider a topology with very short decay chains. Again one cannot use the relation between spin and invariant mass. We investigate one variable that has been invented for the discrimination of Supersymmetry and Universal Extra Dimensions in the high energy limit which reduces the problem to the underlying production process. We show how this variable can also be used in new physics scenarios where the high energy limit is not a viable approximation. We include all possible spin scenarios with renormalizable interactions and study in detail the influence of the involved masses and couplings on the discrimination power of this variable. We find for example that the scenario containing the supersymmetric case is well distinguishable from most other spin scenarios.
In this thesis I studied psychological aspects in the behaviour of Drosophila, and especially Drosophila larvae. After an introduction where I present the general scientific context and describe the mechanisms of olfactory perception as well as of classical and operant conditioning, I present the different experiments that I realised during my PhD. Perception The second chapter deals with the way adult Drosophila generalise between single odours and binary mixtures of odours. I found that flies perceive a mixture of two odours as equally similar to the two elements composing it; and that the intensity as well as the physico-chemical nature of the elements composing a mixture affect the degree of generalisation between this mixture and one of its elements. These findings now call for further investigation on the physiological level, using functional imaging. Memory The third chapter presents a series of experiments in Drosophila larvae in order to define some characteristics of a new protocol for classical aversive learning which involves associating odours with mechanical disturbance as a punishment. The protocol and the first results should open new doors for the study of classical conditioning in Drosophila larvae, by allowing the comparison between two types of aversive memory (gustatory vs. mechanical reinforcement), including a comparison of their neurogenetic bases. It will also allow enquiries into the question whether these respective memories are specific for the kind of reinforcer used. Agency The fourth chapter documents our attempts to establish operant memory in Drosophila larvae. By analysing the first moments of the test, I could reveal that the larvae modified their behaviour according to their previous operant training. However, this memory seems to be quickly extinguished during the course of the test. We now aim at repeating these results and improving the protocol, in order to be able to systematically study the mechanisms allowing and underlying operant learning in Drosophila larvae. In the fifth chapter, I use the methods developed in chapter four for an analysis of larval locomotion. I determine whether larval locomotion in terms of speed or angular speed is affected by a treatment with the “cognitive enhancer” Rhodiola rosea, or by mutations in the Synapsin or SAP47 genes which are involved in the formation of olfactory memory. I also characterize the modifications induced by the presence of gustatory stimuli in the substrate on which the larvae are crawling. This thesis thus brings new elements to the current knowledge of Drosophila
The nicotinic acetylcholine receptor of skeletal muscle is one of the best-investigated synaptic proteins and often serves as model for the entire family of pentameric ligand gated ion channels (pLGICs). Receptors of this superfamily share a common architecture. After binding the agonist the characteristic C-loop structure closes around the ligand-binding site and triggers a wave of conformational changes that spread through the protein and finally result in the opening of the channel gate. As shown before, high-resolution single channel data can hardly be described by simple kinetic mechanisms (Parzefall et al., 1998, Hallermann et al., 2005). Recent advances in the field of kinetic modelling on receptor currents demonstrate that the introduction of additional short lived shut states in kinetic schemes enhances the quality of estimates of reaction rates. The additional shut states that immediately follow ligand bound states in the mechanism are suggested to resemble the closing movement of the C-loop (Lape et al., 2008; Mukhtasimova et al., 2009). It has not been described yet whether and how the structural differences of the 2 binding sites of the receptor influence the opening behaviour. To address this question, high-resolution single channel recordings, in combination with agonists that are known to exhibit different binding site selectivity, were performed. Thereby, a detailed description of the binding site dependent generation of channel currents is possible. At the embryonic mouse-muscle receptor used in this study the ligand binding sites are located at the α-γ and α-δ subunit interfaces. By allocation of opening characteristics to the α-δ and α-γ sites it is possible to show the binding site dependent activation of distinct kinetic states. Furthermore, it will be shown that the recently introduced short-lived shut states are sufficient to describe high-resolution single channel data. Finally an enhanced kinetic mechanism based on the ‘primed states’ model, published in 2009 by Mukhtasimova et al., will be presented. In this model the structurally diverse α-δ and α-γ binding sites elicit different kinetic channel characteristics. Thus the complex high-resolution kinetic characteristics of the embryonic receptor can be described coherently.