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Background and aims. Tumor suppressor genes are often located in frequently deleted chromosomal regions of colorectal cancers (CRCs). In contrast to microsatellite stable (MSS) tumors, only few loss of heterozygosity (LOH) studies were performed in microsatellite instable (MSI) tumors, because MSI carcinomas are generally considered to be chromosomally stable and classical LOH studies are not feasible due to MSI. The single nucleotide polymorphism (SNP) array technique enables LOH studies also in MSI CRC. The aim of our study was to analyse tissue from MSI and MSS CRC for the existence of (frequently) deleted chromosomal regions and tumor suppressor genes located therein. Methods and results. We analyzed tissues from 32 sporadic CRCs and their corresponding normal mucosa (16 MSS and 16 MSI tumors) by means of 50K SNP array analysis. MSS tumors displayed chromosomal instability that resulted in multiple deleted (LOH) and amplified regions and led to the identification of MTUS1 (8p22) as a candidate tumor suppressor gene in this region. Although the MSI tumors were chromosomally stable, we found several copy neutral LOHs (cnLOH) in the MSI tumors; these appear to be instrumental in the inactivation of the tumor suppressor gene hMLH1 and a gene located in chromosomal region 6pter-p22. Discussion. Our results suggest that in addition to classical LOH, cnLOH is an important mutational event in relation to the carcinogenesis of MSS and MSI tumors, causing the inactivation of a tumor suppressor gene without copy number alteration of the respective region; this is crucial for the development of MSI tumors and for some chromosomal regions in MSS tumors.
Bildverarbeitungsanwendungen stellen besondere Ansprüche an das ausführende Rechensystem. Einerseits ist eine hohe Rechenleistung erforderlich. Andererseits ist eine hohe Flexibilität von Vorteil, da die Entwicklung tendentiell ein experimenteller und interaktiver Prozess ist. Für neue Anwendungen tendieren Entwickler dazu, eine Rechenarchitektur zu wählen, die sie gut kennen, anstatt eine Architektur einzusetzen, die am besten zur Anwendung passt. Bildverarbeitungsalgorithmen sind inhärent parallel, doch herkömmliche bildverarbeitende eingebettete Systeme basieren meist auf sequentiell arbeitenden Prozessoren. Im Gegensatz zu dieser "Unstimmigkeit" können hocheffiziente Systeme aus einer gezielten Synergie aus Software- und Hardwarekomponenten aufgebaut werden. Die Konstruktion solcher System ist jedoch komplex und viele Lösungen, wie zum Beispiel grobgranulare Architekturen oder anwendungsspezifische Programmiersprachen, sind oft zu akademisch für einen Einsatz in der Wirtschaft. Die vorliegende Arbeit soll ein Beitrag dazu leisten, die Komplexität von Hardware-Software-Systemen zu reduzieren und damit die Entwicklung hochperformanter on-Chip-Systeme im Bereich Bildverarbeitung zu vereinfachen und wirtschaftlicher zu machen. Dabei wurde Wert darauf gelegt, den Aufwand für Einarbeitung, Entwicklung als auch Erweiterungen gering zu halten. Es wurde ein Entwurfsfluss konzipiert und umgesetzt, welcher es dem Softwareentwickler ermöglicht, Berechnungen durch Hardwarekomponenten zu beschleunigen und das zu Grunde liegende eingebettete System komplett zu prototypisieren. Hierbei werden komplexe Bildverarbeitungsanwendungen betrachtet, welche ein Betriebssystem erfordern, wie zum Beispiel verteilte Kamerasensornetzwerke. Die eingesetzte Software basiert auf Linux und der Bildverarbeitungsbibliothek OpenCV. Die Verteilung der Berechnungen auf Software- und Hardwarekomponenten und die daraus resultierende Ablaufplanung und Generierung der Rechenarchitektur erfolgt automatisch. Mittels einer auf der Antwortmengenprogrammierung basierten Entwurfsraumexploration ergeben sich Vorteile bei der Modellierung und Erweiterung. Die Systemsoftware wird mit OpenEmbedded/Bitbake synthetisiert und die erzeugten on-Chip-Architekturen auf FPGAs realisiert.
Plant growth and survival depend on photosynthesis in the leaves. This involves the uptake of carbon dioxide from the atmosphere and the simultaneous capture of light energy to produce organic molecules, which enter metabolism and are converted to many other compounds which then serve as building blocks for biomass growth. Leaves are organs specialised for photosynthetic carbon dioxide fixation. The function of leaves involves many trade-offs which must be optimised in order to achieve effective use of resources and maximum photosynthesis. It is known that the morphology of leaves adjusts to the growth environment of plants and this is important for optimising their function for photosynthesis. However, it is unclear how this adjustment is regulated. The general aim of the work presented in this thesis is to understand how leaf growth and morphology are regulated in the model species Arabidopsis thaliana. Special attention was dedicated to the possibility that there might be internal metabolic signals within the plant which affect the growth and development of leaves. In order to investigate this question, leaf growth and development must be considered beyond the level of the single organ and in the context of the whole plant because leaves do not grow autonomously but depend on resources and regulatory influences delivered by the rest of the plant. Due to the complexity of this question, three complementary approaches were taken. In the first and most specific approach it was asked whether a proposed down-stream component of sucrose signalling, trehalose-6-phosphate (Tre-6-P), might influence leaf development and growth. To investigate this question, transgenic Arabidopsis lines with perturbed levels of Tre-6-P were generated using the constitutive 35S promoter to express bacterial enzymes involved in trehalose metabolism. These experiments also led to an unanticipated project concerning a possible role for Tre-6-P in stomatal function, which is another very important function in leaves. In a second and more general approach it was investigated whether changes in sugar levels in plants affect the morphogenesis of leaves in response to light. For this, a series of metabolic mutants impaired in central metabolism were grown in one light environment and their leaf morphology was analysed. In a third and even more general approach the natural variation in leaf and rosette morphological traits was investigated in a panel of wild Arabidopsis accessions with the aim of understanding how leaf morphology affects leaf function and whole plant growth and how different traits relate to each other. The analysis included measurements of leaf morphological traits as well as the number of leaves in the plant to put leaf morphology in a whole plant context. The variance in plant growth could not be explained by variation in photosynthetic rates and only to a small degree by variation in rates of dark respiration. There were four key axes of variation in rosette and leaf morphology – leaf area growth, leaf thickness, cell expansion and leaf number. These four processes were integrated in the context of whole plant growth by models that employed a multiple linear regression approach. This then led to a theoretical approach in which a simple allometric mathematical model was constructed, linking leaf number, leaf size and plant growth rate together in a whole plant context in Arabidopsis.
Regulation of gene transcription plays a major role in mediating cellular responses and physiological behavior in all known organisms. The finding that similar genes are often regulated in a similar manner (co-regulated or "co-expressed") has directed several "guilt-by-association" approaches in order to reverse-engineer the cellular transcriptional networks using gene expression data as a compass. This kind of studies has been considerably assisted in the recent years by the development of high-throughput transcript measurement platforms, specifically gene microarrays and next-generation sequencing. In this thesis, I describe several approaches for improving the extraction and interpretation of the information contained in microarray based gene expression data, through four steps: (1) microarray platform design, (2) microarray data normalization, (3) gene network reverse engineering based on expression data and (4) experimental validation of expression-based guilt-by-association inferences. In the first part test case is shown aimed at the generation of a microarray for Thellungiella salsuginea, a salt and drought resistant close relative to the model plant Arabidopsis thaliana; the transcripts of this organism are generated on the combination of publicly available ESTs and newly generated ad-hoc next-generation sequencing data. Since the design of a microarray platform requires the availability of highly reliable and non-redundant transcript models, these issues are addressed consecutively, proposing several different technical solutions. In the second part I describe how inter-array correlation artifacts are generated by the common microarray normalization methods RMA and GCRMA, together with the technical and mathematical characteristics underlying the problem. A solution is proposed in the form of a novel normalization method, called tRMA. The third part of the thesis deals with the field of expression-based gene network reverse engineering. It is shown how different centrality measures in reverse engineered gene networks can be used to distinguish specific classes of genes, in particular essential genes in Arabidopsis thaliana, and how the use of conditional correlation can add a layer of understanding over the information flow processes underlying transcript regulation. Furthermore, several network reverse engineering approaches are compared, with a particular focus on the LASSO, a linear regression derivative rarely applied before in global gene network reconstruction, despite its theoretical advantages in robustness and interpretability over more standard methods. The performance of LASSO is assessed through several in silico analyses dealing with the reliability of the inferred gene networks. In the final part, LASSO and other reverse engineering methods are used to experimentally identify novel genes involved in two independent scenarios: the seed coat mucilage pathway in Arabidopsis thaliana and the hypoxic tuber development in Solanum tuberosum. In both cases an interesting method complementarity is shown, which strongly suggests a general use of hybrid approaches for transcript expression-based inferences. In conclusion, this work has helped to improve our understanding of gene transcription regulation through a better interpretation of high-throughput expression data. Part of the network reverse engineering methods described in this thesis have been included in a tool (CorTo) for gene network reverse engineering and annotated visualization from custom transcription datasets.
Das Fremdwort im Deutschen
(2011)
Hepatic insulin resistance is a major contributor to hyperglycemia in metabolic syndrome and type II diabetes. It is caused in part by the low-grade inflammation that accompanies both diseases, leading to elevated local and circulating levels of cytokines and cyclooxygenase (COX) products such as prostaglandin E-2 (PGE(2)). In a recent study, PGE(2) produced in Kupffer cells attenuated insulin-dependent glucose utilization by interrupting the intracellular signal chain downstream of the insulin receptor in hepatocytes. In addition to directly affecting insulin signaling in hepatocytes, PGE(2) in the liver might affect insulin resistance by modulating cytokine production in non-parenchymal cells. In accordance with this hypothesis, PGE(2) stimulated oncostatin M (OSM) production by Kupffer cells. OSM in turn attenuated insulin-dependent Akt activation and, as a downstream target, glucokinase induction in hepatocytes, most likely by inducing suppressor of cytokine signaling 3 (SOCS3). In addition, it inhibited the expression of key enzymes of hepatic lipid metabolism. COX-2 and OSM mRNA were induced early in the course of the development of non-alcoholic steatohepatitis (NASH) in mice. Thus, induction of OSM production in Kupffer cells by an autocrine PGE(2)-dependent feed-forward loop may be an additional, thus far unrecognized, mechanism contributing to hepatic insulin resistance and the development of NASH.
Simulations of strong ground motion within the Santiago de Chile Metropolitan area were carried out by means of 3-D deterministic wave propagation tool based on the spectral element method. The simulated events take into account the pronounced interface between the low-velocity sedimentary basin and the bedrock as well as topography of the area. To verify our model we simulated a regional earthquake recorded by a dense network installed in the city of Santiago for recording aftershock activity after the 2010 February 27 Maule main shock. The results proof the alluvial basin amplification effects and show a strong dependence of spectral amplification in the basin on the local site conditions. Moreover, we studied the seismic response due to a hypothetical M(w) = 6.0 event occurring along the active San Ramon Fault, which is crossing the eastern edge of the city. The scenario earthquakes exhibit that an unfavourable interaction between fault rupture, radiation mechanism and complex geological and topographic conditions in the near-field region may give rise to large values of peak ground velocity in the basin. Finally, 3-D numerical predictions of ground motion are compared with the one computed according to ground motion prediction equations selected among the next generation attenuation relationships, in terms of ground motion peak values and spectral acceleration. The comparison underlines that the 3-D scenario simulations predict a significantly higher level of ground motion in the Santiago basin, especially over deep alluvial deposits. Moreover, also the location of the rupture nucleation largely influences the observed shaking pattern.
Characterizing the local site response in large cities is an important step towards seismic hazard assessment. To this regard, single station seismic noise measurements were carried out at 146 sites in the northern part of Santiago de Chile. This extensive survey allowed the fundamental resonance frequency of the sedimentary cover, derived from horizontal-to-vertical (H/V) spectral ratios, to be mapped. By inverting the spectral ratios under the constraint of the thickness of the sedimentary cover, known from previous gravimetric measurements, local S-wave velocity profiles have been retrieved. After interpolation between the individual profiles, the resulting high resolution 3D S-wave velocity model allows the entire area, as well as deeper parts of the basin, to be represented in great detail. Since one lithology shows a great scatter in the velocity values only a very general correlation between S-wave velocity in the uppermost 30 m (v(s)(30)) and local geology is found. Local S-wave velocity profiles can serve as a key factor in seismic hazard assessment, since they allow an estimate of the amplification potential of the sedimentary cover. Mapping the intensity distribution of the 27 February 2010 Maule, Chile, event (Mw = 8.8) the results indicate that local amplification of the ground motion might partially explain the damage distribution and encourage the use of the low cost seismic noise techniques for the study of seismic site effects.
Inhalt: - Kurzzusammenfassung - I. Introduction - II. Current challenges to the United Nations Human Rights Programme - III. The Secretary General’s Reform report “In larger Freedom” and its impact for the human rights programme - IV. The High Commissioner’s Plan of Action of May 2005 - V. Negotiations on the establishment of the Human Rights Council and first Council activities - VI. Reform of the treaty body system and debates over the creation of a unified standing treaty body