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In this thesis hard probes are studied in the partonic transport model BAMPS (Boltzmann Approach to MultiParton Scatterings). Employing Monte Carlo techniques, this model describes the 3+1 dimensional evolution of the quark gluon plasma phase in ultra-relativistic heavy-ion collisions by propagating all particles in space and time and carrying out their collisions according to the Boltzmann equation. Since hard probes are produced in hard processes with a large momentum transfer, the value of the running coupling is small and their interactions should be describable within perturbative QCD (pQCD). This work focuses on open heavy flavor, but also addresses the suppression of light parton jets, in particular to highlight differences due to the mass. For light partons, radiative processes are the dominant contribution to their energy loss. For heavy quarks, we show that also binary interactions with a running coupling and an improved Debye screening matched to hard-thermal-loop calculations play an important role. Furthermore, the impact of the mass in radiative interactions, prominently named the dead cone effect, and the interplay with the Landau-Pomeranchuk-Migdal (LPM) effect are studied in great detail. Since the transport model BAMPS has access to all medium properties and the space time information of heavy quarks, it is the ideal tool to study the dissociation and regeneration of J/psi mesons, which is also investigated in this thesis.
Panama is a megadiverse country that together with Costa Rica constitutes Lower Central America (LCA). Western Panama's Cordillera Central accounts for the eastern part of the LCA highlands shared between these countries. The aim of the present study is to compile the most complete and updated picture possible of the taxonomy, diversity, and distribution of reptiles that occur from 500 m asl upwards along the Talamanca and Tabasará ranges. These two continuous mountain ridges account for the western two-thirds of the Cordillera Central between the Costa Rican border and 81°W Including specimens collected four own research travels, I morphologically examined more than 1800 specimens, analyzed 16S and/or COI barcodes of 300 specimens, and performed a thorough search in literature and databases to obtain locality records for specimens and species occurrences. My complete occurrence dataset comprises 14620 georeferenced occurrence records in three quality categories. Conceivable occurrences of species not yet documented from a given area are evaluated on the basis of existing data either as "plausible" or "possible". I provide all datasets which I generated for this study in Appendices. The previously published descriptions of Dactyloa ginaelisae Lotzkat, Hertz, Bienentreu & Köhler 2013, Norops benedikti (Lotzkat, Bienentreu, Hertz & Köhler 2011), Sibon perissostichon Köhler, Lotzkat & Hertz 2010, and Sibon noalamina Lotzkat, Hertz & Köhler 2012 are included in the present work. In the course of integrative taxonomic analyses, I classify 15 genealogical lineages revealed by DNA barcoding within 7 anole species as Deep Conspecific Lineages (DCLs) because they lack consistent morphological differences to their nominal conspecifics. I provisionally classify 18 mitochondrial lineages found within six other anole species as Unconfirmed Genealogical Lineages (UGLs) pending adequate analyses of their morphological variation. I regard the two additional UGLs Celestus sp. and Geophis sp. and the two Confirmed Genealogical Lineages (CGLs) Lepidoblepharis sp. 1 and 2 to represent undescribed species. My taxonomic analyses yield the hitherto most comprehensive survey of the variability exhibited by dozens of reptile species in western Panama. The 16S and/or COI barcodes I provide represent 65 species recognized herein and constitute the first DNA barcode reference library for LCA reptiles. The reptile fauna of Panama comprises 265 species, including the four UGLs and CGLs mentioned above and characterized for the first time in this study, as well as Dendrophidion crybelum Cadle 2012 whose presence in the country I consider plausible. My occurrence dataset reveals that 160 of these species have been documented to occur in my study area. Adding the 20 species whose occurrence therein I consider plausible, I report the total species richness of the Talamanca and Tabasará ranges as comprising 180 species representing 81 genera in 25 families. With 178.8 species per 10 000 km2, the relative species richness of the area is extremely high even in a tropical context. In view of their overall documented distribution, I regard the presence of 27 additional species in my study area as possible. For the 180 species occurring in my study area I provide standardized species accounts that, together with the taxonomic results, for the first time permit the doubtless identification of all 180 species, and illustrate 168 of these with color photographs. Concerning biogeography, my georeferenced dataset yields noteworthy distribution extensions for many species. Moreover, I present the hitherto most comprehensive, detailed, and reproducible assessments of the distribution patterns, historical origins, and conservation as well as of the occurrence among physiographic regions, climatic and altitudinal belts, political subdivisions, and protected areas, for my study area's reptile fauna. With 65 species, more than a third of the fauna is endemic to LCA. Among these, 42 Talamancan highland endemics are restricted to the LCA highlands, in the case of 16 small-scale highland endemics with documented ranges spanning less than 100 km. I assess many of these endemics as endangered. The fact that several of these species do not occur in any protected area renders the establishment of additional conservation areas necessary, especially in the central Serranía de Tabasará. Distributional range boundaries shared among different clades of highland anoles indicate physiographic and climatic barriers that may have effected in situ speciation within these lineages. As the largest study on Panamanian reptile diversity assembled to date, the present dissertation considerably increases our knowledge on the reptiles along the Cordillera Central and beyond, and thus constitutes a solid basis for future studies.
To overcome poor treatment response of pediatric high-risk acute lymphoblastic leukemia (ALL), novel treatment strategies are required to reactivate programmed cell death in this malignancy. Therefore, we take advantage of using small-molecule antagonists of Inhibitor of apoptosis (IAP) proteins, so called Smac mimetics such as BV6, which are described to overcome apoptosis resistance and thereby sensitize tumor cells for several apoptotic stimuli. To address the question whether redox alterations can sensitize leukemic cells for Smac mimetic-mediated cell death, we interfered with the cellular redox status in different ALL cell lines. Here, we show for the first time that redox alterations, mediated by the glutathione depleting agent Buthioninesulfoximine (BSO), prime ALL cells for BV6-induced apoptosis. Besides ALL cell lines, BV6/BSO cotreatment similarly synergizes in cell death induction in patient-derived primary leukemic samples. In contrast, the combination treatment does not exert any cytotoxicity against peripheral blood lymphocytes (PBLs) or mesenchymal stroma cells (MSCs) from healthy donors, suggesting some tumor selectivity of this treatment. We also identify the underlying molecular mechanism of the novel synergistic drug interaction of BSO and BV6. We demonstrate that both agents act in concert to increase reactive oxygen species (ROS) production, lipid peroxidation and finally apoptotic cell death. Enhanced ROS levels in the combination treatment account for cell death induction, since several ROS scavengers, like NAC, MnTBAP and Trolox attenuate BSO/BV6-induced apoptosis. BSO/BV6-induced ROS can be mainly classified as lipid peroxides, since the vitamin E derivate α-Tocopherol as well as Glutathione peroxidase 4 (GPX4), which both specifically reduce lipid-membrane peroxides, prevent lipid peroxidation, caspase activation and cell death induction. Vice versa, GPX4 knockdown and pharmacological inhibition of GPX4 by RSL3 or Erastin enhance BV6-induced cell death. Importantly, cell death induction critically depends on the formation of a complex consisting of RIP1/FADD/Caspase-8, since all complex components are required for ROS production, lipid peroxidation and cell death induction. Taken together, we demonstrate that BSO and BV6 cooperate to induce ROS production and lipid peroxidation which are eventually required for caspase activation and cell death execution. Collectively, findings of this study indicate that BV6-induced apoptosis is mediated via redox alterations offering promising new treatment strategy to overcome apoptosis resistance in ALL.
Immune cells are key players in several physiological and pathophysiological events such as acute and chronic inflammation, atherosclerosis and cancer. Especially in acute inflammation, macrophages are indispensable for the switch from the acute inflammatory phase to the resolution phase. Not only the phagocytosis of apoptotic cells, but especially the surrounding cytokines and mediators are able to switch macrophage polarization from inflammatory- to anti-inflammatory phenotypes. Within this cytokine environment, sphingosine-1-phosphate (S1P) plays an important role for immune cell activation, polarization and migration.
Tumor development usually follows predictable paths where tumor cells acquire common characteristics and features known as the hallmarks of cancer. Recently, additional characteristics have been added to these hallmarks since solid tumors are composed of a very heterogeneous population of transformed, formerly normal tissue cells and stromal cells, e.g. immune cells and fibroblasts. Compelling evidence suggests that stromal cells and tumor cells maintain a symbiotic relationship to build up the tumor microenvironment and to fuel tumor growth. In cancer therapies, common features of tumors such as unrestricted cell growth, suppression of immunological responses, and the ability to form new blood vessels (angiogenesis) have emerged as the main targets of interest. The lipid mediator prostaglandin E2 (PGE2) is known to promote all these features and thus, is connected to cancer progression in general. Its synthesis is triggered in response to stress factors or during inflammation. Inducible PGE2 production relies on the enzymes cyclooxygenase 2 (COX-2) and microsomal prostanglandin E synthase 1 (mPGES-1), which are simultaneously expressed in response to a variety of different stimuli and are functionally coupled. Inhibition of COX-2 with non-steroidal antiinflammatory drugs (NSAIDs) for cancer treatment is, however, limited by cardiovascular risks, since selective COX-2 inhibition disrupts the prostacyclin/thromboxane balance. Therefore targeting mPGES-1 downstream of COX-2 for PGE2 inhibition was evaluated in this work in different steps of carcinogenesis. Knockdown of mPGES-1 in DU145 prostate cancer cells revealed that the mPGES-1 status did not affect growth of monolayer tumor cells, but significantly impaired 3D growth of multi-cellular tumor spheroids (MCTS). Spheroid formation induced COX-2 in DU145 and other prostate cancer spheroids. High levels of PGE2 were detected in supernatants of DU145 MCTS as opposed to monolayer DU145 cells. Pharmacological inhibition of COX-2 and mPGES-1 confirmed the pivotal role of PGE2 for DU145 MCTS growth. Besides promoting spheroid growth, MCTS-derived PGE2 also inhibited cytotoxic T lymphocyte (CTL) activation. When investigating the mechanisms of COX-2 induction during spheroid formation, the typical tumor microenvironmental factors such as glucose deprivation, hypoxia or tumor cell apoptosis failed to enhance COX-2. Interestingly, when interfering with apoptosis in DU145 spheroids, the pan-caspase inhibitor Z-VAD-FMK triggered a Summary 12 shift towards necrosis, thus enhancing COX-2 expression. Coculturing viable DU145 monolayer cells with isolated heat-shocked-treated necrotic DU145 cells, but not with necrotic cell supernatants, induced COX-2 and PGE2, confirming the impact of necrosis for MCTS growth and CTL inhibition. As mentioned, in vivo tumors are very heterogenous mixtures of tumor cells and stromal cells e.g. immune cells. Hence, the interaction of the immune system with tumors was investigated in further experiments. When coculturing MCF-7 breast cancer spheroids with human peripheral blood mononuclear cells (PBMCs), only low levels of PGE2 were detected, since MCF-7 cells did not upregulate COX-2 during spheroid formation and did not induce PGE2 production by PBMCs. Under inflammatory conditions, by adding the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) to cocultures, PGE2 production was triggered, spheroid sizes were reduced, and numbers of high levels of granzyme B expressing (GrBhi) CTLs were increased, while CD80 expression by tumor-associated phagocytes was also elevated. Inhibition of CD80 but not CD86 diminished numbers of GrBhi CTLs and attenuated spheroid lysis. To determine the role of ctivation-induced PGE2 production, use of the COX-2 inhibitor celecoxib and the experimental mPGES-1 inhibitor C3 further increased CD80 expression. Addition of PGE2, the prostaglandin E2 (EP2) receptor agonist butaprost, and the phosphodiesterase 4 (PDE4) inhibitor rolipram reduced LPS/C3-triggered CD80 expression, confirming the impact of COX- 2/mPGES-1-derived PGE2 on shaping phagocyte phenotypes in an EP2/cAMP-dependent manner. In a spontaneous breast cancer model (MMTV-PyMT), mPGES-1-deficiency significantly delayed tumor growth in mice, confirming an overall protumorigenic role of mPGES-1 in breast cancer development in vivo. However in tumors of mPGES-1-/- mice, tumor-infiltrating phagocytes expressed low levels of CD80 similar to their wildtype counterparts. These data suggest that the immunosuppressive microenvironment does not allow for immunostimulatory effects by mPGES-1 inhibition without an activating stimulus. Evidences in this study recommend the application of mPGES-1 inhibitors for treating cancer diseases, since mPGES-1 promotes tumor growth in multiple steps of carcinogenesis, ranging from well-characterized effects of tumor cell growth to immune suppression of CTL activity and phagocyte polarization. Regarding the latter, blunting PGE2 during immune activation may limit the tumor-favoring features of inflammation and improve the efficiency of TLR4 based immune therapies.
In mitochondria, biogenesis of oxidase is a crucial process involving the participation of an array of assembly factors. Studying the process of biogenesis in eukaryotes is highly complicated due to the presence and partaking of two genetic systems. Employing a bacterial model such as Paracoccus denitrificans that utilizes only one genetic system enables easy studying of the assembly process. The aa3 cytochrome c oxidase of P. denitrificans shows high structural and functional homology to its mitochondrial counterpart despite its simple subunit composition. The assembly of the core subunits I and II that house the active redox centers (heme a, and heme a3.CuB centre in subunit I; and the binuclear CuA centre in subunit II) along with the chaperons responsibly for their incorporation form the crux of this work. This work concentrates particularly on CtaG, a chaperone previously speculated to be involved in the delivery of copper to the CuB center in subunit I. As the full length structure of CtaG or its structural homologues have not been solved, attempts were made to obtain high-diffracting crystals of CtaG by heterologously expressing it in E. coli. Growth media, expression strains and induction parameters were some of the conditions screened in order to obtain optimal yield. Additives, pH and detergent were screened to yield a homogeneous preparation of CtaG. Crystallization trials were conducted by employing the sitting drop, vapour diffusion, method and later the bicelles were employed. Preliminary crystals obtained were further optimized employing seeding, detergent and additives, to improve diffraction. The diffraction improved from 30 Å to 15 Å. BN PAGE (Blue Native Polyacrylamide Gel Electrophoresis) analysis and cross-linking studies were undertaken to decipher the oligomeric condition of CtaG. Both the methods indicate that the protein is a dimer under native conditions. To study the importance of CtaG in the process of oxidase assembly, two deletion mutants were obtained from the lab; one with only ctaG deleted and the other with ctaG and most of the upstream ORF. The effect of the deletion was assayed on the assembly and activity of oxidase. The deletion mutants showed residual activity of approx. 20 %, while displaying a very low heme signal (both in membranes and in purified COX). In order to exclude polar effects arising due to gene manipulation, complementation strains were prepared, reintroducing ctaG alone into both the deletion strains. Complementation strains, where only ctaG was deleted and re-introduced assayed for COX activity showed a restoration in activity to approx. 70 %. Further, calculating the heme:protein ratio, the deletion strains displayed a value of 7 nmol/mg of oxidase which was increased to wild type levels of 16 nmol/mg in the complementation strains. To further confirm the absence of the copper in subunit I, total reflection X-ray fluorescence spectroscopy analysis was carried out, which showed a decrease in the copper content in the deletion strain, restored on complementation. The strain lacking in the ORF and ctaG when complemented with ctaG alone illustrated no increase in activity or heme signal in comparison to that of the deletion strain. These point at a possible role for ORF in the assembly of COX, which is still absent in the complementation strains. To further characterize the ORF, a series of bioinformatical analysis was carried out, the results from which were insufficient to characterize the ORF conclusively. In order to enlist the proteins involved in the biosynthesis of COX, two independent approaches were employed. Two-dimensional gel examinations of solubilised membranes from untreated and cross-linked cells were analyzed by Western blotting. The CtaG-COX interaction was observed in untreated membranes, which was additionally strengthened by cross-linking. To further confirm this association, pull-down assays were done employing protein A coated magnetic beads coated with different antibodies and incubated with solubilised membranes derived from untreated or cross-linked cells. The elutions were assayed by Western blotting and confirmed for the CtaG-COX interaction. These fractions were further analysed by mass spectrometry to identify other chaperons involved in biogenesis of oxidase. Along with CtaG, I also noticed Sco, Surf1c and other factors involved in the recruitment and transport of heme (CtaB, CtaA, and Ccm proteins). Interestingly, protein components of both ribosomal subunits and protein translocation factors were observed, which indicated a co-translational approach for co-factor insertion into COX.
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor and third leading cause of cancer-related death worldwide. Most cases arise as a consequence of underlying liver disease, e.g. developed from chronic hepatitis B or C infectionsalcohol abuse or obesity, and are most often associated with liver cirrhosis. Hypoxiand the hypoxia inducible factors (HIF)-1α and -2α promote tumor progression of HCC, not only affecting tumor cell proliferation and invasion, but also angiogenesis and lymphangiogenesis and thus, increasing the risk of metastasis.
HCC is characterized as one of the most vascularized solid tumors. While HIF-1α and HIF-2α are frequently up-regulated in HCC only HIF-2α is correlated with high patientlethality. HIF-dependent regulation of HCC angiogenesis is controversially discussed.VEGFA, for example, as the most prominent factor inducing tumor angiogenesis represents not only a HIF-1 target, but also a HIF-2 target gene in HCC. This questions whether both isoforms have overlapping functions in regulating the angiogenic switch in HCC.
Besides angiogenesis also tumor-associated lymphangiogenesis significantly influences patient survival in HCC. Lymphatic spread is an important clinical determinant for the prognosis of HCC, but little is known how lymphangiogenesis is controlled in this context. To date, mainly HIF-1α was positively correlated with olymphatic invasion and metastasis in HCC, while a defined role of HIF-2α is missing. Thus, although HIF-1α and HIF-2α are structurally alike and regulate overlapping but not identical sets of target genes, they promote highly divergent outcomes in cancer progression and may even have counteracting roles. The aim of my work was to characterize the specific role of HIF-1α and HIF-2α in the angiogenic switch and lymphangiogenesis induction during HCC development.
Therefore, I created a stable knockdown of HIF-1α and HIF-2α in HepG2 cells and generated cocultures of HepG2 spheroids and embryonic bodies derived from embryonic mouse stem cells as an in vitro tumor model mimicking the cancer microenvironment to analyze which HIF isoform has key regulatory functions in HCC (lymph)angiogenesis. In cocultures with a HIF-2α knockdown angiogenesis was attenuated but lymphangiogenesis increased, while the knockdown of HIF-1α was without effect. Microarray analysis identified plasminogen activator inhibitor 1 (PAI-1)and insulin-like growth factor binding protein 1 (IGFBP1) as HIF-2 target genes.However, prominent angiogenic and lymphangiogenic factors such as VEGFs, PDGFB, ANG and their receptors were not regulated in a HIF-dependent manner. As PAI-1 was linked to angiogenesis in literature and IGF-signaling, which is negatively regulated by IGFBP-1, was correlated with lymphangiogenesis, I decided to investigate their HIF-2α-dependent influence on HCC (lymph)angiogenesis. The knockdown of PAI-1 in HepG2 cells also lowered angiogenesis in PAI-1k/d cocultures similar to the HIF-2α k/d phenotype. PAI-1 as the potent inhibitor of tPA and uPA, both inducing the conversion of plasminogen to plasmin, also inhibits plasmin directly. Therefore, I assumed an increase of plasmin in HIF-2α k/d and PAI-1 k/d cocultures as a result of the reduced PAI-1 levels. Blocking plasmin with aprotinin in HIF-2α k/d cocultures restored angioge nesis, suggesting that HIF-2α increases PAI-1 to lower concentrations of active plasmin, thereby supporting angiogenesis. In further experiments I could exclude PAI-1 to reduce angiogenesis by inducing plasmin-mediated apoptosis of differentiating stem cells in PAI-1 k/d and HIF-2α k/d cocultures, but demonstrated an increase of VEGFA165 degradation in these cocultures, suggesting plasmin-catalyzed proteolysis of VEGF as an additional layer of regulation required to explain the angiogenic phenotype. Besides the pivotal role of PAI-1 in angiogenesis I also investigated its potentialinfluence in lymphangiogenesis. Indeed, the knockdown of PAI-1 reduced lymphaticstructures and implied an important but opposing role in lymphangiogenesis comparedto induced lymphangiogenesis in HIF-2α k/d cocultures. However, blocking plasmin again with aprotinin in HIF-2α k/d cocultures restored lymphangiogenesis to the level of control virus, which indicates a divergent lymphangiogenic role of plasmin in PAI-1 k/d and HIF-2α k/d cocultures, possibly because of other essential pathways masking the lymphangiogenic effects of PAI-1 in HIF-2α k/d cocultures.
HIF-2α resulting in reduced IGFBP1 expression induced the differentiation of stem cells toward a lymphatic cell type and significantly enhanced the assembly of human dermal lymphatic endothelial cells into tubes. These data point the first time to an important impact of HIF-2 in the regulatin of lymphangiogenesis in vitro by inducing IGFBP1 and thus, scavenging IGF-1. Furthermore, matrigel plug assays to investigate the in vivorelevance of these observations confirmed HIF-2α as a crucial factor in the regulation of lymphangiogenesis in vivo
In conclusion, this work provides evidence that HIF-2α is a key regulator of angiogenesis and lymphangiogenesis in HCC by regulating PAI-1 and IGFBP1. HIF-2α positively influences the angiogenic switch via PAI-1 and negatively affects lymphangiogenesis via IGFBP1 expression. Targeting HIF-2α in HCC to reduce tumor angiogenesis should be approached carefully, as it might be overcome by induced lymphangiogenesis and metastasis.
Efficient algorithms for object recognition are crucial for the newly robotics and computer vision applications that demand real-time and on-line methods. Some examples are autonomous systems, navigating robots, autonomous driving. In this work, we focus on efficient semantic segmentation, which is the problem of labeling each pixel of an image with a semantic class.
Our aim is to speed-up all of the parts of the semantic segmentation pipeline. We also aim at delivering a labeling solution on a time budget, that can be decided on-the-fly. For this purpose, we analyze all the components of the semantic segmentation pipeline, and identify the computational bottleneck of each of them. The different components of the pipeline are over-segmenting the image with local regions, extracting features and classify the local regions, and the final inference of the image labeling with semantic classes. We focus on each of these steps.
First, we introduce a new superpixel algorithm to over-segment the image. Our superpixel method runs in real-time and can deliver a solution at any time budget. Then, for feature extraction, we focus on the framework that computes descriptors and encodes them, followed by a pooling step. We see that the encoding step is the bottleneck, for computational efficiency and performance. We present a novel assignment-based encoding formulation, that allows for the design of a new, very efficient, encoding. Finally, the image labeling output is obtained modeling the dependencies with a Conditional Random Field (CRF). In semantic image segmentation, the computational cost of instantiating the potentials is much higher than MAP inference. We introduce Active MAP inference to on-the-fly select a subset of potentials to be instantiated in the energy function, leaving the rest as unknown, and to estimate the MAP labeling from such incomplete energy function.
We perform experiments on all proposed methods for the different parts of the semantic segmentation pipeline. We show that our superpixel extraction achieves higher accuracy than state-of-the-art on standard superpixel benchmark, while it runs in real-time. We test our feature encoding on standard image classification and segmentation benchmarks, and we show that our method achieves competitive results with the state-of-the-art, and requires less time and memory. Finally, results for semantic segmentation benchmark show that Active MAP inference achieves similar levels of accuracy but with major efficiency gains.
The cones of nonnegative polynomials and sums of squares arise as central objects in convex algebraic geometry and have their origin in the seminal work of Hilbert ([Hil88]). Depending on the number of variables n and the degree d of the polynomials, Hilbert famously characterizes all cases of equality between the cone of nonnegative polynomials and the cone of sums of squares. This equality precisely holds for bivariate forms, quadratic forms and ternary quartics ([Hil88]). Since then, a lot of work has been done in understanding the difference between these two cones, which has major consequences for many practical applications such as for polynomial optimization problems. Roughly speaking, minimizing polynomial functions (constrained as well as unconstrained) can be done efficiently whenever certain nonnegative polynomials can be written as sums of squares (see Section 2.3 for the precise relationship). The underlying reason is the fundamental difference that checking nonnegativity of polynomials is an NP-hard problem whenever the degree is greater or equal than four ([BCSS98]), whereas checking whether a polynomial can be written as a sum of squares is a semidefinite feasibility problem (see Section 2.2). Although the complexity status of the semidefinite feasibility problem is still an open problem, it is polynomial for fixed number of variables. Hence, understanding the difference between nonnegative polynomials and sums of squares is highly desirable both from a theoretical and a practical viewpoint.
This work is concerned with two topics at the intersection of convex algebraic geometry and optimization.
We develop a new method for the optimization of polynomials over polytopes. From the point of view of convex algebraic geometry the most common method for the approximation of polynomial optimization problems is to solve semidefinite programming relaxations coming from the application of Positivstellensätze. In optimization, non-linear programming problems are often solved using branch and bound methods. We propose a fused method that uses Positivstellensatz-relaxations as lower bounding methods in a branch and bound scheme. By deriving a new error bound for Handelman's Positivstellensatz, we show convergence of the resulting branch and bound method. Through the application of Positivstellensätze, semidefinite programming has gained importance in polynomial optimization in recent years. While it arises to be a powerful tool, the underlying geometry of the feasibility regions (spectrahedra) is not yet well understood. In this work, we study polyhedral and spectrahedral containment problems, in particular we classify their complexity and introduce sufficient criteria to certify the containment of one spectrahedron in another one.
Tympanal hearing organs of insects emit distortion-product otoacoustic emissions (DPOAEs) which are indicative of nonlinear mechanical sound processing. General characteristics of insect DPOAEs are comparable to those measured in vertebrates, despite distinct differences in ear anatomy. DPOAEs appear during simultaneous stimulation with two pure tones (f1<f2) as additional spectral peaks at frequencies of nf1-(n-1)f2 and nf2-(n-1)f1, with the 2f1-f2 emission being the most prominent one. Insect DPOAEs are highly vulnerable to manipulations that interfere with the animal's physiological state and disappear after death. First evidence from locusts suggested that scolopidial mechanoreceptors might play a role in frequency-specific DPOAE generation (Möckel et al. 2007). The overall aim of this thesis was to determine the source of sensitive, nonlinear hearing at high frequencies and of DPOAE generation in tympanal organs of insects.
The first project of the present thesis involved general characteristics of DPOAE generation in the bushcricket Mecopoda elongata and the selective exclusion of the scolopidial mechanoreceptors using the neuroactive insectizide pymetrozine (Möckel et al. 2011). Pymetrozin appears to act highly effective and selectively on chordotonal organs, without affecting other sensory organs that lack scolopidial receptors. Pymetrozine solutions were applied as closely as possible to the scolopidia via a cuticle opening in the tibia, distally to the organ. Applications at concentrations between 10-3 and 10-7 M led to a pronounced and irreversible decrease of DPOAE amplitudes. Both this study on bushcrickets (Möckel et al. 2011) and an earlier one on locusts (Möckel et al. 2007) hence indicate the involvement of scolopidia in DPOAE generation in insects, by using complementary methods (pharmacological versus mechanical manipulation) and different animal models.
The second project of the present thesis investigated the temperature-dependence of DPOAEs in the locust Locusta migratoria (Möckel et al. 2012). The suggested biological origin of acoustic two-tone distortions in insects should involve metabolic processes, whose temperature-dependence would directly affect the DPOAE generation. Body temperature shifts resulted in reversible, level- and frequency-dependent effects on the 2f1–f2 emission. Using low f2 frequencies of up to 10 kHz, a body temperature increase (median +8–9°C) led to an upward shift of DPOAE amplitudes of approximately +10 dB, whereas a temperature decrease (median –7°C) was followed by a reduction of DPOAE amplitudes by 3 to 5 dB. Both effects were only present in the range of the low-level component of DPOAE growth functions below f2 stimulus levels of approximately 30-40 dB SPL. Emissions induced by higher stimulus levels and frequencies (e.g. 12 and 18 kHz) remained unaffected by any temperature shifts. The Arrhenius activation energy of the underlying cellular component amounted to 34 and 41 kJmol-1 (for growth functions measured with 8 and 10 kHz as f2, respectively). Such activation energy values provide a hint that an intact dynein-tubulin system within the scolopidial receptors could play an essential part in the DPOAE generation in tympanal organs.
The third project of this thesis demonstrated mechanical DPOAE analogs in the tympanum's vibration pattern during two-tone stimulation in the locust Schistocerca gregaria, using laser Doppler vibrometry (Möckel et al. 2014). DPOAE generation crucially relies on the integrity of the scolopidial mechanoreceptors (Möckel et al. 2007, 2011), which in locusts, directly attach to the tympanal membrane. During two-tone stimulation, DPOAEs were shown to mechanically emerge at the tympanum region where the auditory mechanoreceptors are attached. Those emission-coupled vibrations differed remarkably from tympanum waves evoked by external pure tones of the same frequency, in terms of wave propagation, energy distribution, and location of amplitude maxima. In contrast to traveling wave-like characteristics of externally evoked vibrations, intrinsically generated waves were locally restricted to the region around the high frequency receptors’ attachment position. The mechanical gradient of the tympanal membrane that leads to direction-dependent properties probably avoids the spreading of these locally evoked waves, which are then reflected and occur only in restricted areas as standing waves. Selective inactivation of mechanoreceptors by mechanical lesions did not affect the tympanum's response to external pure tones, but abolished the emission's displacement amplitude peak. These findings provide evidence that tympanal auditory receptors, comparable to the situation in mammals, comprise the required nonlinear response characteristics, which during two-tone stimulation lead to additional, highly localized deflections of the tympanum.
This thesis is structured into 7 chapters:
• Chapter 2 gives an overview of the ultrashort high intensity laser interaction with matter. The laser interaction with an induced plasma is described, starting from the kinematics of single electron motion, followed by collective electron effects and the ponderamotive motion in the laser focus and the plasma transparency for the laser beam. The three different mechanisms prepared to accelerate and propagate electrons through matter are discussed. The following indirect acceleration of protons is explained by the Target Normal Sheath Acceleration (TNSA) mechanism. Finally some possible applications of laser accelerated protons are explained briefly.
• Chapter 3 deals with the modeling of geometry and field mapping of magnetic lens. Initial proton and electron distributions, fitted to PHELIX measured data are generated, a brief description of employed codes and used techniques in simulation is given, and the aberrations at the solenoid focal spot is studied.
• Chapter 4 presents a simulation study for suggested corrections to optimize the proton beam as a later beam source. Two tools have been employed in these suggested corrections, an aperture placed at the solenoid focal spot as energy selection tool, and a scattering foil placed in the proton beam to smooth the radial energy beam profile correlation at the focal spot due to chromatic aberrations. Another suggested correction has been investigated, to optimize the beam radius at the focal spot by lens geometry controlling.
• Chapter 5 presents a simulation study for the de-neutralization problem in TNSA caused by the fringing fields of pulsed magnetic solenoid and quadrupole. In this simulation, we followed an electrostatic model, wherethe evolution of both, self and mutual fields through the pulsed magnetic solenoid could be found, which is not the case in the quadrupole and only the growth of self fields could be found. The field mapping of magnetic elements is generated by the Matlab program, while the TraceWin code is employed to study the tracking through magnetic elements.
• Chapter 6 describes the PHELIX laser parameters at GSI with chirp pulse amplification technique (CPA), and Gafchromic Radiochromic film RCF) as a spatial energy resolver film detector. The results of experiments with laser proton acceleration, which were performed in two experimental areas at GSI (Z6 area and PHELIX Laser Hall (PLH)), are presented in section 6.3.
• Chapter 7 includes the main results of this work, conclusions and gives a perspective for future experimental activities.
A multiple filter test for the detection of rate changes in renewal processes with varying variance
(2014)
The thesis provides novel procedures in the statistical field of change point detection in time series.
Motivated by a variety of neuronal spike train patterns, a broad stochastic point process model is introduced. This model features points in time (change points), where the associated event rate changes. For purposes of change point detection, filtered derivative processes (MOSUM) are studied. Functional limit theorems for the filtered derivative processes are derived. These results are used to support novel procedures for change point detection; in particular, multiple filters (bandwidths) are applied simultaneously in oder to detect change points in different time scales.
The work presented in this thesis is devoted to two classes of mathematical population genetics models, namely the Kingman-coalescent and the Beta-coalescents. Chapters 2, 3 and 4 of the thesis include results concerned with the first model, whereas Chapter 5 presents contributions to the second class of models.
Natural products (NPs) have been a rich source for pharmaceutically used anti-infectives and other drugs. However, the application of anti-infectives inevitably causes the development of resistant and multiresistant pathogens, which have to be treated with novel anti-infectives. The industrial research for novel anti-infectives has been concentrating on members of the bacterial Actinomycetales for a long time. Due to several reasons, e.g. the rediscovery of already known NPs, pharmaceutical companies abandoned their NP-research and focused on drug development based on combinatorial chemistry. However, the limited structural diversity of merely synthetic compound libraries has not been a fruitful source for bioactive compounds. Hence the discovery of novel bioactive NPs as a source for anti-infectives is still of economical and humanitarian interest and will remain to be an important branch of research in the future. One strategy to circumvent the rediscovery of bioactive NPs is the analysis of yet unexplored bacterial taxa. Based on this assumption, this work aimed at the discovery of novel NPs from the entomopathogenic bacterial genera Xenorhabdus and Photorhabdus and other promising taxa, as well as the investigation of their biosynthesis. ...
Acceleration of Biomedical Image Processing and Reconstruction with FPGAs
Increasing chip sizes and better programming tools have made it possible to increase the boundaries of application acceleration with reconfigurable computer chips. In this thesis the potential of acceleration with Field Programmable Gate Arrays (FPGAs) is examined for applications that perform biomedical image processing and reconstruction. The dataflow paradigm was used to port the analysis of image data for localization microscopy and for 3D electron tomography from an imperative description towards the FPGA for the first time.
After the primitives of image processing on FPGAs are presented, a general workflow is given for analyzing imperative source code and converting it to a hardware pipeline where every node processes image data in parallel. The theoretical foundation is then used to accelerate both example applications. For localization microscopy, an acceleration of 185 compared to an Intel i5 450 CPU was achieved, and electron tomography could be sped up by a factor of 5 over an Nvidia Tesla C1060 graphics card while maintaining full accuracy in both cases.
This thesis presents experimental studies of proton capture and fragmentation reactions with heavy-ion storage rings. In one experiment, the 96Ru(p, γ)97Rh cross sections near the Gamow window have been measured at the ESR of GSI. In the other experiment, the measurement of the fragmentation yields has been carried out at the CSRe of IMP.
It is essential to determine the cross sections of (γ, p) or (p, γ) reactions for p-process network calculations. However, only very few of the required cross sections have been measured and thus most of them rely solely on Hauser-Feshbach model predictions. The predictions of the model have always very large uncertainties because of the not well-known input parameters. These parameters can be constrained by experiments. Compared to the traditional activation technique, a novel method using a storage ring has been developed to measure the cross sections of (p, γ) reactions in inverse kinematics.
This proton capture experiment has been performed at the ESR, where the circulating 96Ru44+ ions interacted with a hydrogen gas target at 9, 10 and 11 MeV/u. The nuclear reaction products of (p, p), (p, α), (p, n) and (p, γ) reactions were registered by position sensitive detectors. A Geant4 simulation code has been developed to distinguish the (p, γ) reaction products unambiguously from the background reactions. In this work, a relative normalization method has been utilized to accurately determine the cross sections of the (p, γ) reaction. The 96Ru(p, γ)97Rh cross section in the Gamow window of the p process is sensitive to two parameters, i.e., the γ-ray strength function and the optical model potential, while it is mainly sensitive to the γ-ray strength function in the energy region of our experiment. Therefore, our experimental (p, γ) cross sections near 10 MeV/u have been used to directly constrain the γ-ray strength function used in the model. Furthermore, the proton potential has also been constrained by combining our results with additional experimental data for this reaction in the lower energy region. The constrained model has been used to calculate the reaction rate over a wide temperature range, which is an extremely important input for astrophysical calculations.
The yields of fragments produced by 78Kr fragmentation reactions have been measured at the CSRe for the Tz = −1/2 and Tz = 1/2 nuclei along or close to the paths of αp- and rp-processes. The measured yields present a significant odd-even staggering effect for Tz = −1/2 nuclides but they are small for Tz = 1/2 nuclides.
The magnitude of this effect for four consecutive yields has been quantified using a third-order difference formula. It is found that the largest odd-even staggering is reached near the closed shells Z = 20 and Z = 28. Our experimental results could also compared with the data from other experiments with different projectile-target combinations. All these experimental data strongly support the closed shells Z = 20 and Z = 28 for the Tz = −1/2 nuclei.
This thesis serves two main purposes:
1. The introduction of a novel experimental method to investigate phase change dynamics of supercooled liquids
2. First-time measurements for the crystallization behaviour for hydrogen isotopes under various conditions
1) The new method is established by the synergy of a liquid microjet of ~ 5 µm diameter and a scattering technique with high spatial resolution, here linear Raman spectroscopy. Due to the high directional stability and the known velocity of the liquid filament, its traveling axis corresponds to a time axis static in space. Utilizing evaporative cooling in a vacuum environment, the propagating liquid cools down rapidly and eventually experiences a phase transition to the crystalline state. This temporal evolution is probed along the filament axis, ultimately resulting in a time resolution of 10 ns. The feasibility of this approach is proven successfully within the following experiments.
2) A main object of study are para-hydrogen liquid filaments. Raman spectra reveal a temperature gradient of the liquid across the filament. This behaviour can quantitatively be reconstructed by numerical simulations using a layered model and is rooted in the effectiveness of evaporative cooling on the surface and a finite thermal conductivity. The deepest supercoolings achieved are ~ 30% below the melting point, at which the filament starts to solidify from the surface towards the core. With a crystal growth velocity extracted from the data the appropriate growth mechanism is identified. The crystal structure that initially forms is metastable and probably the result of Ostwald’s rule of stages. Indications for a transition within the solid towards the stable equilibrium phase support this interpretation.
The analog isotope ortho-deuterium is evidenced to behave qualitatively similar with quantitative differences being mass related.
In further measurements, isotopic mixtures of para-hydrogen and ortho-deuterium are investigated. It is found that the crystallization process starts earlier and lasts significantly longer compared to the pure substances with the maximum values between 20-50% ortho-deuterium content. A solely temperature based explanation for this effect can be excluded. The difference in the quantum character and hence effective size of the isotopes suggests a strong influence of the progressing liquid-solid-interface. Small dilutions of each para-hydrogen and ortho-deuterium with neon show an even more extended crystallization process compared to above isotopic mixtures. Additionally, the crystal is strongly altered in favor of the equilibrium lattice structure of neon.