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In my Ph.D. thesis "On the geometry and parametrization of almost invariant subspaces and observer theory" I consider the set of almost conditioned invariant subspaces of fixed dimension for a given fixed linear finite-dimensional time-invariant observable control system in state space form. Almost conditioned invariant subspaces were introduced by Willems. They generalize the concept of a conditioned invariant subspace requiring the invariance condition to hold only up to an arbitrarily small deviation in the metric of the state space. One of the goals of the theory of almost conditioned invariant subspaces was to identify the subspaces appearing as limits of sequences of conditioned invariant subspaces. An example due to {\"O}zveren, Verghese and Willsky, however, shows that the set of almost conditioned invariant subspaces is not big enough. I address this question in a joint paper with Helmke and Fuhrmann (Towards a compactification of the set of conditioned invariant subspaces, Systems and Control Letters, 48(2):101-111, 2003). Antoulas derived a description of conditioned invariant subspaces as kernels of permuted and truncated reachability matrices of controllable pairs of the appropriate size. This description was used by Helmke and Fuhrmann to construct a diffeomorphism from the set of similarity classes of certain controllable pairs onto the set of tight conditioned invariant subspaces. In my thesis I generalize this result to almost conditioned invariant subspaces describing them in terms of restricted system equivalence classes of controllable triples. Furthermore, I identify the controllable pairs appearing in the kernel representations of conditioned invariant subspaces as being induced by corestrictions of the original system to the subspace. Conditioned invariant subspaces are known to be closely related to partial observers. In fact, a tracking observer for a linear function of the state of the observed system exists if and only if the kernel of that function is conditioned invariant. In my thesis I show that the system matrices of the observers are in fact the corestrictions of the observed system to the kernels of the observed functions. They in turn are closely related to partial realizations. Exploring this connection further, I prove that the set of tracking observer parameters of fixed size, i.e. tracking observers of fixed order together with the functions they are tracking, is a smooth manifold. Furthermore, I construct a vector bundle structure for the set of conditioned invariant subspaces of fixed dimension together with their friends, i.e. the output injections making the subspaces invariant, over that manifold. Willems and Trentelman generalized the concept of a tracking observer by including derivatives of the output of the observed system in the observer equations (PID-observers). They showed that a PID-observer for a linear function of the state of the observed system exists if and only if the kernel of that function is almost conditioned invariant. In my thesis I replace PID-observers by singular systems, which has the advantage that the system matrices of the observers coincide with the matrices appearing in the kernel representations of the subspaces. In a second approach to the parametrization of conditioned invariant subspaces Hinrichsen, M{\"u}nzner and Pr{\"a}tzel-Wolters, Fuhrmann and Helmke and Ferrer, F. Puerta, X. Puerta and Zaballa derived a description of conditioned invariant subspaces in terms of images of block Toeplitz type matrices. They used this description to construct a stratification of the set of conditioned invariant subspaces of fixed dimension into smooth manifolds. These so called Brunovsky strata consist of all the subspaces with fixed restriction indices. They constructed a cell decomposition of the Brunovsky strata into so called Kronecker cells. In my thesis I show that in the tight case this cell decomposition is induced by a Bruhat decomposition of a generalized flag manifold. I identify the adherence order of the cell decomposition as being induced by the reverse Bruhat order.
This work presents the analysis, 3D modeling and interpretation of gravity and aeromagnetic data of Jordan and Middle East. The potential field data delineate the location of the major faults, basins, swells, anticlines, synclines and domes in Jordan. The surface geology of Jordan and the immediate area east of the Rift is dominated by two large basins, the Al-Jafr basin in the south and the Al-Azraq-Wadi as Sirhan basin to the northeast. These two basins strike southeast-northwest and are separated by an anticlinal axis, the Kilwah-Bayir swell. The Karak Wadi El Fayha fault system occurs along the western flank of the swell. The Swaqa fault occurs on the southwest hinge of Al-Azraq basin and the Fuluq fault occurs on its northeast hinge. In the south west of Jordan, Wadi Utm-Quwaira and Disi-Mudawara fault zones are shown clearly in the aeromagnetic and gravity maps. The previous major faults are well correlated with the structural map of Jordan published by Bender (1968). 3D modeling of gravity data in the Dead Sea basin (DSB) was used together with existing geological and geophysical information to give a complete structural picture of the basin. The 3D models of the DSB show that the internal structure of the Dead Sea basin (DSB) is controlled by longitudinal faults and the basin is developed as a full graben bounded by sub-vertical faults along its long sides. In the northern planes of the 3D model, the accumulation of Quaternary (salt and marl) and Mesozoic (pre-rift) sediments are thinner than in the central and southern planes of the model. In the northern planes, the thickness of the Quaternary sediments is about 4 km, 5 km in the southern planes and it exceeds 8 km in the central planes of the DSR. The thickness of the pre-rift sediments reaches 10-12 km in the northern and southern planes and exceeds 15 km in the central planes of the DSR. The planes of the 3D models show that the depth to the crystalline basement under the eastern shoulders of the DSR is shallower than those beneath the western shoulders. It is about 3-5 km beneath the eastern shoulders and 7-9 km under the western shoulder of the DSR. The gravity anomaly maps of residual and first derivative gravity delineate the subsurface basins of widely varying size, shape, and depth along the Rift Valley. The basins are created by the combination of the lateral motion along a right-tending step over and normal faulting along the opposite sides. Al Bakura basin occupies the upper Jordanian River valley and extends into the southern Tiberias Lake. Bet Shean basin to the south of Al Bakura basin plunges asymmetrically toward the east. The Damia basin, comprising the central Jordan Valley and Jericho areas to the north of the Dead Sea is shallow basin (~600-800m deep). The Lisan basin is the deepest basin in the Rift. The 3D gravity models indicate a maximum of ~12 km of basin fill. Three basins are found in Wadi Araba area, Gharandal, Timna (Qa'-Taba) and Aqaba (Elat) basin. The three basins become successively wider and deeper to the south. The three regional gravity long E-W profiles (225 km) from the Mediterranean Sea crossing the Rift Valley to the east to the Saudi Arabia borders, show the positive correlation between topography and free air anomaly and strong negative Bouguer anomaly under the central part of the Dead Sea Basin (DSB) and normal regional Bouguer anomaly outside of the DSB in the transform valley. Depth to the top of the bedrock in the under ground of Jordan was calculated from potential field data. The basement crops out in the south west of Jordan and becomes deeper to northwards and eastwards to be about ~ 8 km below ground surface in the Risha area.
The first goal of this study was to develop cell lines with a stable expression of bio-fluorescent topo II and topo I. This was successfully achieved using a bicistronic vector system. Control experiments showed that proteins of expected size were expressed, and that GFP-tagged topos I, IIa, and IIb were active in the cells and fully integrated in the endogenous pools of the enzymes. These cell-lines provided a novel tool for investigating the cell biology of human DNA topoisomerases. Our most important finding was, that both types of mammalian topoisomerases are entirely mobile proteins that are in continuous and rapid flux between all compartments of the nucleus and between the cytososl and the chromosomes of mitotic cells. This was particularly surprising with regard to topo II, which is considered to be a structural component of the nuclear matrix and the chromosome scaffold. We must conclude that if this was the case, then these architectural structures appear to be much more dynamic than believed until now. In this context it should also be mentioned, that the alignment of topo II with the central axes of the chromosome arms, which has until now been considered a hall-mark of the enzyme’s association with the chromosomal scaffold, is not seen in vivo and can be demonstrated to be to some extent an artefact of immunohistochemistry. Furthermore, we show that the two isoforms of topo II (a and b) have a different localisation during mitotic cell division, supporting the general concept that topo II functions at mitosis are exclusively assigned to the a-form, whereas at interphase the two isoenzymes work in concert. Despite unrestricted mobility within the entire nuclear space, topoisomerases I and II impose as mostly nucleolar proteins. We show that this is due to the fact that in the nucleoli they are moving slower than in the nucleoplasm. The decreased nucleolar mobility cannot be due to DNA-interactions, because compounds that fix topoisomerases to the DNA deplete them from the nucleoli. Interestingly, the subnucleolar distribution of topoisomerases I and II was complementary. The type II enzyme filled the entire nucleolar space, but excluded the fibrial centers, whereas topo I accumulated at the fibrial centers, an allocation directed by the enzyme’s N-terminus. During mitosis, it also mediates association with the nucleolar organising regions of the acrocentric chromosomes. Thus, topo I stays associated with the rDNA during the entire cell-cycle and consistently colocalizes there with RNA-polymerase I. Finally, we show that certain cancer drugs believed to act by stabilising covalent catalytic DNA-intermediates of topoisomerases, do indeed immobilize the enzymes in living cells. Interestingly, these drugs do not target topoisomerases in the nucleoli but only in the nucleoplasm.
Transforming-Growth-Factor-beta1 (TGF-b1) is a multifunctional cytokine that regulates cell growth and differentiation in many types of cells. TGF-b1 is especially known to exert a variety of regulatory functions in the immune system, such as T cell differentiation and T cell function. Signal transduction of TGF-b1 is mediated by phosphorylation of receptorassociated Smad proteins (R-Smads). R-Smads are phosphorylated by the activated type I receptor, which is itself phosphorylated by the high affinity type II receptor upon ligand binding. The phosphorylated R-Smads then associate with Co-Smads. Heterooligomers of R- and Co-Smads translocate into the nucleus where they regulate transcription of target genes in concert with other transcription factors such as CBP/p300 or AP-1. Recent findings suggest that the pleiotropic effects of TGF-b1 are conferred by crosstalks to other signal transduction pathways such as the MAP-kinases or the STAT-pathway. Here we describe the effect of long-term exposure to TGF-b1 on the effector function of differentially stimulated primary murine splenocytes and purified primary murine CD8+ cytotoxic T cells. Long-term exposure to TGF-b1 results in non-responsiveness to TGF-b1- induced Smad2 phosphorylation. This is seen either by no phosphorylation or sustained phosphorylation of Smad2. Furthermore, we observed a strong correlation between sustained Smad2 phosphorylation and resistance to TGF-b1 mediated growth inhibition. In contrast, splenocyte cultures strongly growth inhibited by TGF-b1 showed no Smad2 phosphorylation. Lytic activity of these cultures, however, was found to be suppressed regardless of proliferation properties and Smad2 phosphorylation pattern. We also describe that a functional MEK-1 pathway is a prerequisite for rendering murine splenocytes unresponsive to TGF-b1 mediated growth inhibition, and that inhibition of the MEK-1 cascade alters the Smad2 phosphorylation pattern. In addition, we show that resistance to TGF-b1 mediated growth inhibition correlates with the activation of the JNK pathway. However, the resistant phenotype was found unable to be reverted upon administration of exogeneous IFNg and/or aCD28 antibody. In human or mouse T cell lines, however, the described correlation between the type of stimulation and TGF-b growth resistance or growth sensitivity is not present. Thus, this correlation is specific for primary T cells. We also cloned a chimeric dominantnegative TGF-b receptor which is coupled to a suicide gene, in order to render T cells resistant to TGF-b mediated effects.These findings shed light on how TGF-b1 mediates its immunosuppressive role, and may help to gain knowledge of averting these TGF-b1 effects in the course of tumor therapy.
The thesis consists of two major parts. The first part contains a theoretical-experimental study of confocal micro-Raman spectroscopy on hybrid polymer coatings and an application of this spectroscopic method on PDMS-membranes. The theoretical-experimental study includes the application of a model that describes the influence of the refraction effect on the focus length on confocal Raman experiments, and the development of a new model that additionally takes into account the effect of diffraction on the focus dimensions. A parallel comparison between these two theoretical approaches and experimental data has been also drawn and a better agreement between theory and experiment was observed, when both refraction and diffraction effects were considered. Further, confocal resonance micro-Raman spectroscopy has been applied to characterise the diffusion processes of pharmacologically relevant molecules (b-carotene dissolved in dimethylsulfoxide) through a polydimethylsiloxane (PDMS)-membrane. The diffusion rate as a function of the measurement depth and diffusion time as well as the concentration gradient under a steady flux have been determined. The measurements shown that the confocal micro-Raman technique is a powerful tool to investigate the kinetics of diffusion processes within a membrane before the steady state has been reached. The second part of the thesis contains infrared and Raman spectroscopic studies of copper and iron doped B2O3-Bi2O3 glass systems. These studies were performed to obtain specific data regarding their local structure and the role played by dopant ions on boron and bismuthate units. The changes of B2O3 and Bi2O3 structural units due to the relaxation of the amorphous structure, which was induced in these samples by the thermal treatment, were also evidenced.
The thesis contains two major parts. The first part deals with structural investigations on different coordination compounds performed by using infrared absorption and FT-Raman spectroscopy in combination with density functional theory calculations. In the first section of this part the starting materials Ph2P-N(H)SiMe3 and Ph3P=NSiMe3 and their corresponding [(MeSi)2NZnPh2P-NSiMe3]2 and Li(o-C6H4PPh2NSiMe3)]2·Et2O complexes have been investigated in order to determine the influence of the metal coordination on the P–N bond length. In the next section the vibrational spectra of four hexacoordinated silicon(IV) and germanium(IV) complexes with three symmetrical bidentate oxalato(2-) ligands have been elucidated. Kinetic investigations of the hydrolysis of two of them, one with silicon and another one with germanium, have been carried out at room temperature and at different pH values and it was observed that the hydrolysis reaction occurs only for the silicon compound, the fastest reaction taking place at acidic pH. In the last section of this part, the geometric configurations of some hexacoordinated silicon(IV) complexes with three unsymmetrical bidentate hydroximato(2-) ligands have been determined. The second part of the thesis contains vibrational investigations of some biologically active molecules performed by means of Raman spectroscopy together with theoretical simulations. The SER spectra of these molecules at different pH values have also been analysed and the adsorption behaviour on the metal surface as well as the influence of the pH on the molecule-substrate interaction have been established.
Transplantation is now firmly established as a therapeutic approach to extend and improve the life of patients in the final stages of organ failure. It has been demonstrated that transplantation between genetically non-identical individuals leads to the activation of the recipient’s alloimmune response as a major determinant of transplant outcome. T cell recognition of foreign MHC molecules plays a key role in initiating and sustaining allograft rejection. To prevent the risk of rejection, patients are given immunosuppressive drugs, which are non-specific and have major side-effects (infections, malignancies). It has been shown that the alloreactive T cells specifically recognize donor MHC-derived peptides. This implies that it may be possible to develop antigen-specific strategies in order to modulate the alloimmune response by peptide analogues and specifically altered peptide ligands. The purpose of this study was to explore the potential of “recipient-adapted” analogues from the dominant MHC class I peptide to modulate the alloimmune response. Beside the significant role of donor dominant determinants in the rejection process, we tested seven 13-to-24-mer peptides from the Wistar-Furth MHC class I molecule (WF, RT1.Au) for their possible immunogenicity in a fully MHC-mismatched WF to Lewis (LEW, RT1l) rat strain combination. Secondly, the immunodominant allopeptide was selected to generate analogues in order to investigate their modulatory capacity. All peptides were tested in vitro in a standard proliferation assay and in vivo using a heterotopic heart transplantation model. Our findings show that five peptides (P1-P5) were able to induce specific T cell proliferation in LEW responders. Furthermore, we found a hierarchical distribution of the determinants: peptide P1 as a good candidate for the immunodominant determinant, while P2, P3, P4, and P5 as subdominant epitopes and the other two peptides, P6 and P7, as non-immunogenic determinants of WF MHC class I molecule. Furthermore, the dominance of P1 was confirmed by the strong proliferation induced after immunization with a mixture of peptides in the presence of P1. This hierarchical distribution of the proliferative response correlated with the cytokine production. Peptide P1, comprising only 3 allogeneic amino acids (L5, L9, and T10) induced the strongest T cell proliferation and produced high levels of cytokines, especially IL-2 and IFN-g. In addition, the immunodominance of peptide P1 was confirmed by the significant reduction in the allograft survival time in comparison to the non-immunized control animals. Since the TCR Vß repertoire of rejected graft-infiltrating cells in rejected allografts was similar to the profile observed after in vitro restimulation of P1-primed T cells, we concluded that peptide P1 is able to activate the alloreactive T cell population. Our results demonstrate the particular role of the dominant peptide P1 (residues 1-19) in the allograft rejection in WF to LEW rat strain combination. In the second set of experiments, we investigated the fine specificity of the dominant peptide P1-activated T cells using peptide analogues from P1. The “recipient-adapted” analogues were designed by changing the allogeneic RT1.Au amino acids (L5, L9, T10) one-by-one with the correspondent syngeneic RT1.Al amino acids (M5, D9, I10) in the sequence of peptide P1. The six peptide analogues (A1.1-A1.6) consisting of either one or two allogeneic amino acids were able to induce a specific T cell proliferative response and cytokine production. Analogue A1.5 with only one allogeneic amino acid (L5) was of particular interest because it induced a low T cell proliferation and high cytokine levels, especially IL-4 and IL-10. In addition, immunization with A1.5 did not influence the allograft survival time in comparison to the non-immunized LEW recipients. A1.5 was the only analogue able to down-regulate the proliferation of P1-primed T cells. Our results reveal that A1.5 is an MHC competitor as confirmed by the in vitro MHC competition assay and the inhibition of the negative effect of P1 on the allograft survival time when recipients were immunized with a mixture of P1 and A1.5. These findings suggest that it is possible to design peptide analogues, such as A1.5, which do not stimulate the dominant peptide P1-specific T cell population and even more, are able to block its presentation in the MHC molecule. In all, the results indicate that the specific suppression of indirect allorecognition can be achieved by using peptide analogues of the dominant allopeptide.
Transforming growth factor-ß (TGF-ß) is a multifunctional cytokine that is engaged in regulating versatile cellular processes that are pivotal for development and homeostasis of most tissues in multicellular organisms. TGF-ß signal transduction is initially propagated by binding of TGF-ß to transmembrane serine/threonine kinase receptors, designated TßRI and TßRII. Upon activation, the receptors phosphorylate Smad proteins which serve as downstream mediators that enter the nucleus and finally trigger transcriptional responses of specific genes. During the past years, it became evident that signaling cascades do not proceed in a linear fashion but rather represent a complex network of numerous pathways that mutually influence each other. Along these lines, members of the TGF-ß superfamily are attributed to synergize with neurotrophins. Together, they mediate neurotrophic effects in different populations of the nervous system, suggesting that an interdependence exists between TGF-ßs on the one hand and neurotrophins on the other. In the present work, the crosstalk of NGF and TGF-ß/Smad signaling pathways is characterized in rat pheochromocytoma cells (PC12) which are frequently used as a model system for neuronal differentiation. PC12 cells were found to be unresponsive to TGF-ß due to limiting levels of TßRII. However, stimulation with NGF results in initiation of Smad-mediated transcription independent of TGF-ß. Binding of NGF to functional TrkA receptors triggers activation of Smad3. This NGF-dependent Smad activation occurs by a mechanism which is different from being induced by TGF-ß receptors in that it provokes a different phosphorylation pattern of R-Smads. Together with an inferior role of TßRI, Smad3 is proposed to serve as a substrate for cellular kinases other than TßRI. Based on the presented involvement of components of both, the MAPK/Erk and the TAK1/MKK6 cascade, signal mediators of these pathways rank as candidates to mediate direct activation of Smad3. Smad3 is subsequently translocated to the nucleus and activates transcription in a Smad4-dependent manner. Negative regulation is provided by Smad7 which was found to act as a potent inhibitor of Smad signaling not only in TGF-ß- but also in NGF-mediated cascades. The potential of NGF to activate the Smad pathway independent of TGF-ß might be of special importance in regulating expression of genes that are essential for the development and function of neuronal cells or of other NGF-sensitive cells, in particular those which are TGF-ß-resistant.
This theses deals with the syntheses and the coordination behaviour of polyimidosulfur anions like S(NR)32–, S(NR)42–, RS(NR)2– or RS(NR)3–, the nitrogen analogues of the well known oxo-anions SO32–, SO42–, RSO2– and RSO3–. The first aim was the synthesis of a triimidosulfite with three different NR-substituents, a so called asymmetrical triimidosulfite. In all reactions, that have been carried out to obtain a triimidosulfite with three (or two) different residues at nitrogen, the final product was always the dilithium sulfide adduct. The syntheses of chiral alkylenediimidosulfites was successful. Similar to Corey’s S-ylides (R2(O)S+––CR2) and Wittig’s phosphonium ylides (R3P+––CR2) these molecules contain a positively charged sulfur atom next to a carbanionic centre. The structures of the alkylenediimidosulfites are not influenced by the different substituents at nitrogen and carbon, respectively. In each case a doublecubic structure is received. The first members of a completely new class of compounds were synthesised: the aryl-bis-(diimidosulfinates). In this compounds two SN2 units are connected via a heteroaromatic linker, containing a potential donor centre in metal coordination. They represent, like the known alkyldiimidosulfinates, dipodal monoanionic ligands. In the field of sulfur (VI) chemistry the syntheses of aryltriimidosulfonates were successful. Hitherto it was believed, that only spatial less demanding lithium organics could be added to a S=N double bond in S(NtBu)3. This assumption was confirmed by the fact that methyl- and phenylacetylene-triimidosulfonate were the only known alkylsulfonates. Nevertheless, the addition of several lithiumheteroarenes to sulfurtriimide worked without difficulties. If the shape of the nucleophile permits to slot in between the NtBu substituents and to approach the electrophilic sulfur in the sulfurtriimide from the side rather than in an orthogonal angle, the addition reaction works smoothly. Although the steric demand of the tris(tert.-butyl)triimidosulfonate unit is very high, the synthesis of thiophene-bis-(triimidosulfonate) worked. The sulfonate moieties function as dipodal ligands.
Characterization of memories and ignorant (S6KII) mutants in operant conditioning in the heat-box
(2002)
Learning and memory processes of operant conditioning in the heat-box were analysed. Age, sex, and larval desity were not critical parameters influencing memory, while low or high activity levels of flies were negatively correlated with their performance. In a search for conditioning parameters leading to high retention scores, intermittent training was shown to give better results than continuous training. As the memory test is the immediate continuation of the conditioning phase just omitting reinforcement, we obtain a memory which consists of two components: a spatial preference for one side of the chamber and a stay-where-you-are effect in which the side preference is contaminated by the persistence of heat avoidance. Intermittent training strengthens the latter. In the next part, memory retention was investigated. Flies were trained in one chamber and tested in a second one after a brief reminder training. With this direct transfer, memory scores reflect an associative learning process in the first chamber. To investigate memory retention after extended time periods, indirect transfer experiments were performed. The fly was transferred to a different environment between training and test phases. With this procedure an after-effect of the training was still observed two hours later. Surprisingly, exposure to the chamber without conditioning also lead to a memory effect in the indirect transfer experiment. This exposure effect revealed a dispositional change that facilitates operant learning during the reminder training. The various memory effects are independent of the mushroom bodies. The transfer experiments and yoked controls proved that the heat-box records an associative memory. Even two hours after the operant conditioning procedure, the fly remembers that its position in the chamber controls temperature. The cAMP signaling cascade is involved in heat-box learning. Thus, amnesiac, rutabaga, and dunce mutants have an impaired learning / memory. Searching for, yet unknown, genes and signaling cascades involved in operant conditioning, a Drosophila melanogaster mutant screen with 1221 viable X-chromosome P-element lines was performed. 29 lines with consistently reduced heat avoidance/ learning or memory scores were isolated. Among those, three lines have the p[lacW] located in the amnesiac ORF, confirming that with the chosen candidate criteria the heat-box is a useful tool to screen for learning and /or memory mutants. The mutant line ignP1 (8522), which is defective in the gene encoding p90 ribosomal S6 kinase (S6KII), was investigated. The P-insertion of line ignP1 is the first Drosophila mutation in the ignorant (S6KII) gene. It has the transposon inserted in the first exon. Mutant males are characterized by low training performance, while females perform well in the standard experiment. Several deletion mutants of the ignorant gene have been generated. In precise jumpouts the phenotype was reverted. Imprecise jumpouts with a partial loss of the coding region were defective in operant conditioning. Surprisingly, null mutants showed wild-type behavior. This might indicate an indirect effect of the mutated ignorant gene on learning processes. In classical odor avoidance conditioning, ignorant null mutants showed a defect in the 3-min, 30-min, and 3-hr memory, while the precise jumpout of the transposon resulted in a reversion of the behavioral phenotype. Deviating results from operant and classical conditioning indicate different roles for S6KII in the two types of learning.