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Characterization of the multi-zinc finger transcriptionfactor Trps1 during chondrocyte differentiation
No full textTrps1 ist ein Multi-Zinkfinger Transkriptionsfaktor, der regulatorische Funktionen während der Chondrozyten Proliferation und Differenzierung hat. Mutationen in der Trps1 Gensequenz resultieren in Defekten der Knochenentwicklung, wie Missbildungen des Gesichts, Kleinwuchs und einem frühzeitigen Verschluss der Wachstumsfuge. Wie Trps1 während der enchondralen Ossifikation regulatorische Funktionen ausübt, ist bisher nicht genau bekannt. Um die Funktion von Trps1 aufzuschlüsseln, wurden Co-Immunpräzipitations-Interaktionsstudien (Co-IP) durchgeführt. Es konnte gezeigt werden, dass Trps1 endogen auf Proteinebene mit Hdac4, Hdac6 und Hsp90 interagiert.
Mittels Gelfiltrationsanalysen der Proteinkomplexe in Zelllysaten konnte gezeigt werden, dass Trps1 nicht als Monomer vorliegt, sondern nur in größeren Komplexen zwischen 307 und 687 kDa vorkommt und Überschneidungen mit Hdac1, Hdac4 und Hdac6 Proteinen hat, so dass vermutet werden kann, dass diese Proteine gemeinsam in Transkriptionskomplexen vorliegen können.
In einer massenspektrometrischen Analyse von Trps1 Co-IPs wurden neue potentielle Interaktoren des Trps1 Proteins identifiziert. Diese sind der Transkriptionsfaktor SUPT6H, das Nukleäre Körper Protein SP110, die RNA Helikase P110, sowie weitere Proteine der Hitze Schock Gruppe, wie Hsp70 und DnaJ.
Die Analyse der H3K9 und H3K18 Acetylierung und der Hdac Aktivität in Zellkulturen und Proteinextrakte aus Extremitäten verdeutlicht eine aktivierende Wirkung von Trps1 auf die Hdac Aktivität. Ein Verlust von Trps1 resultiert somit in hyperacetyliertem Chromatin. Diese Hyperacetylierung kann zu, in Trps1-/- Mäusen bekannten, itosedefekten führen.
Eine Hdac Inhibition, mittels TSA und NaB, während der Differenzierung der chondrogenen ATDC5 Zelllinie resultiert in einer stärkeren und beschleunigten Differenzierung. Eine Analyse der H3K9 Acetylierung während der Differenzierung zeigt jedoch einen Anstieg der Acetylierung nach sieben Tagen und anschließend einen Abfall der Acetylierung unabhängig von der Hdac Inhibition. Entweder wird für eine beschleunigte Differenzierung, durch Hdac Inhibition, nur ein Puls in der ersten Woche benötigt, oder die Inhibitoren wirken nicht auf die Histonedeacetylierung, sondern auf die Deacetylierung anderer Proteine wie z.B. Runx2, das ebenfalls von Hdacs deacetyliert werden kann. Somit könnte der Anstieg in der Acetylierung ein sekundärer Effekt sein, der durch die beschleunigte Differenzierung verursacht wird, die wiederum durch eine Deacetylierung anderer Proteine ausgelöst wurdeTrps1 is a multi-zinc finger transcription factor, regulating chondrocyte proliferation and differentiation. Mutations in the Trps1 gene sequence results in defects of bone formation, like malformations of the facial bones, dwarfism and a premature closure of the growth plate. But how Trps1 is regulating the endochondral ossification is not exactly known so far. To elucidate the details of Trps1 function, Co-Immunoprecipitation (Co-IP) interaction studies were performed. In this study could be shown, that endogenous Trps1 interacts on protein level with endogenous Hdac4, Hdac6 and Hsp90. Gelfiltration experiments with protein complexes of cell lysates show that Trps1 elutes not as a monomer but in higher order complexes between 307 and 687 kDa. Hdac1, Hdac4 and Hdac6 elute partly in the same fractions, so that it can be assumed that these proteins could act together in the same transcription complexes.
The analysis of H3K9 and H3K18 acetylation and Hdac activity in cell cultures and mouse limb extracts points up an activating Trps1 action on Hdac activity. Trps1 deficiency results in hyperacetylated chromatin. This could lead to defects in mitosis, which are common in Trps1-/- mice.
In a mass spectrometric analysis of Trps1 Co-IPs new potential Trps1 interacting proteins could be identified. These are the transcription factor SUPT6H, the Nuclear Body Protein SP110, the RNA Helicase P110, as well as proteins of the heat shock group like Hsp70 and DnaJ.
Hdac inhibition, due to TSA and NaB treatment, during differentiation of chondrogenic ATDC5 cells results in a stronger and faster differentiation. But the analysis of the H3K9 acetylation during the differentiation process showed, despite Hdac inhibition, the acetylation is enhanced in the first week, only. From the second week on the acetylation is steadily reduced. Either the Hdac inhibition pulse is only needed in the first week for an accelerated differentiation, or the inhibitors act by deacetylating other proteins like Runx2, which can be deacetylated by Hdacs. So the enhanced acetylation in the first week could be a secondary effect due to an enhanced differentiation, which resulted from deacetylation of other proteins
Large-scale applications and scalability for problems in the mechanics of soft biological tissues in arterial wall structures
No full textDer Zugriff auf den Volltext ist gesperrt, neue Version unter DuEPublico-ID 37999
An MPI-parallel Newton-Krylov-FETI-DP solver based on FEAP is presented together with applications to nonlinear problems
in the quasi-static biomechanics of soft biological tissues.
The formulation is based on highly nonlinear hyperelastic anisotropic and poly-convex models. High-resolution computations of the wall stresses in patient-specific arterial wall structures subjected to an interior normal pressure in the physiological regime of the blood pressure (up to 500 [mmHg]) are reported together with results on strong
scalability. The weak scalability of Newton-Krylov-FETI-DP is
investigated for up to 140 million degrees of freedom using 4096 processor cores on a Cray XT6m supercomputer in a series of simple tension tests. An implementation of a new FEAP-interface called libfw is presented which allows for the flexible unified integration of FEAP into other software packages, e.g., into LifeV. The modifications done to FEAP
are dissected and discussed in detail as a case study in order to illustrate possible approaches for the integration of different code components or applications in similar scenarios
Automated analysis of software artefacts - a use case in e-assessment
No full textAutomated grading and feedback generation for programming and modeling exercises has become a usual means of supporting teachers and students at universities and schools. Tools used in this context engage general software engineering techniques for the analysis of software artefacts. Experiences with the current state-of-the-art show good results, but also a gap between the potential power of such techniques and the actual power used in current e-assessment systems. This thesis contributes to closing this gap by developing and testing approaches that are more universal than the currently used approaches and provide novel means of feedback generation. It can be shown that these approaches can be used effectively and efficiently for the mass validation of exercises, and that they result in a high feedback quality according to students' perception
Identification and molecular characterization of resistance mechanisms against cellular immune effectors to optimize cancer immunotherapies
No full textEs existieren zahlreiche Immuntherapien um malignen Erkrankungen zu begegnen. Ihnen gemein ist, dass der Erfolg einer solchen Therapie von der Sensitivität gegenüber den eingesetzten Immuneffektoren und deren zytotoxischen Mechanismen abhängt. Deswegen haben wir ein Modell entwickelt, mit dem molekulare Resistenzmechanismen von Tumorzellen gegenüber antigenspezifischen zytotoxischen T-Zellen in vitro und in vivo untersucht werden können. Als Tumormodell dienten dabei murine Fibroblasten, welche mit dem adenoviralen Onkogen E1A transformiert wurden und das Epitop Ad5E1A234-243 im murinen H2-Db MHC-Klasse-I Kontext präsentieren (E1A-MEF). Als korrespondierende Immuneffektoren verwendeten wir E1A-spezifische, T-Zellrezeptor transgene zytotoxische T-Zellen (ZTL). Mit Hilfe dieses Systems konnten wir drei verschiedene Faktoren identifizieren, welche zu einer Resistenz gegenüber antigenspezifischen ZTL beitragen. In Vorarbeiten wurde ein erstes Kandidatengen, die Cyclooxygenase-2 (COX-2), identifiziert. Dieses Enzym, welches für die Produktion des Gewebshormons Prostaglandin E2 verantwortlich ist, wurde bereits im Zusammenhang mit der Tumorentstehung und der Resistenzbildung in der Literatur beschrieben. In unserem murinen Immuntherapiemodell führte die COX-2-Überexpression zu einer Resistenz gegenüber ZTLs in vitro, die sich in einer deutlichen Steigerung des klonogenen Überlebens der Tumorzellen nach Ko-Kultur mit antigenspezifischen ZTLs darstellte. Ebenfalls konnte gezeigt werden, dass die Überlebenszeit von Mäusen mit COX-2-exprimierenden Tumoren nach adoptivem Transfer mit E1A-spezifischen ZTLs deutlich verkürzt war. In einem Modell für Immunsurveillance zeigten COX-2 exprimierende Tumore ein deutlich schnelleres Wachstum, so dass gezeigt werden konnte, dass COX-2 auch zu einer spezifischen Immunresistenz in vivo führt. In weiterführenden Experimenten wurde festgestellt, dass die vermehrte COX-2 Expression die Sekretion von Interferon-gamma durch antigenspezifische T-Zellen reduziert und damit die Sensitivität von Tumorzellen vermindert wird. Die exogene Zugabe von Interferon-gamma konnte die COX-2-vermittelte Immunresistenz überwinden. COX-2 ist damit ein Beispiel für einen zell-autonomen Resistenzmechanismus gegenüber spezifischen Immuneffektoren.
In dieser Arbeit wurden zwei weitere Resistenz vermittelnde Faktoren identifiziert: das ribosomale Protein S9 (RPS9) und der eukaryotische Elongationsfaktor 1B delta (EF1Bδ). Die Überexpression dieser beiden Gene führte sowohl zu einer Resistenz gegenüber antigenspezifischen T-Zellen als auch zu einer Resistenz gegenüber Apoptose induzierenden Stimuli. In dieser Arbeit beschreiben wir die Beteiligung von RPS9 und EF1Bδ an der Ausbildung eines Resistenzmechanismus gegenüber ZTLs und zytotoxischen Substanzen, welcher vermutlich durch die Aktivierung des MAP-Kinase Signalwegs verursacht wird.The efficacy of immune surveillance and antigen-specific cancer immunotherapy equally depends on the activation of a sustained immune response targeting cancer antigens and the susceptibility of cancer cells to immune effector mechanisms. A detailed understanding of the activation and regulation of cancer-specific immune reaction as well as the mechanisms determining the effector phase of immune elimination is crucial for successful implementation and improvement of such immunotherapies. Therefore, we have development an experimental system for unbiased identification of mechanisms that modulate the susceptibility of cancer to the cytotoxic effects of activated, antigen-specific T cells. This system is based on murine embryonic fibroblasts expressing the adenoviral epitope E1A to serve as cancer model (E1A-MEF) and E1A-specific, receptor-transgenic cytotoxic T cells as corresponding immune effectors. Using this system we have identified three different factors that confer resistance to cancer cell elimination by antigen-specific cytotoxic T cells (CTL). The first analyzed candidate is cyclooxygenase 2 (COX-2) which, when expressed in E1A-MEF, increased the clonogenic survival of the cancer cells when cocultured with antigen-specific T cells. COX-2 expressing tumors established in immune-deficient mice were less susceptible to adoptive immunotherapy with TCR-transgenic lymphocytes in vivo. The immune surveillance of COX-2 positive tumor cells in TCR-transgenic mice was less efficient, too. Mechanistically, COX-2 expression decreased the sensitivity of cancer cells to activated antigen-specific T cells by modulating the release of interferon-gamma. Addition of interferon-gamma sensitized COX-2 expressing E1A-MEF to tumor suppression by their respective cellular targets. Here we describe a first example of a cell-autonomous resistance mechanism that is specific for cellular immune effectors.
Two further identified factors that confer resistance to antigen-specific CTL are the ribosomal protein S9 (RPS9) and the eukaryotic elongation factor 1 delta (EF1Bδ). Expressing RPS9 and EF1Bδ in E1A-MEF caused an increased clonogenic survival of cells when cocultured with antigen-specific T cells. Furthermore, RPS9 and EF1Bδ expression mediated resistance to cytotoxic stimuli. Presumable, the resistance to cellular immune effectors and to apoptosis inducing drugs results from an activation of the MAP-kinase pathway. Here we describe the involvement of two factors belonging to the protein biosynthesis machinery in the development of resistance to cytotoxic stimuli as well as antigen-specific CTL
Wash out kinetics and efficacy of a modified lavage technique for pulmonary alveolar proteinosis
No full textWhole lung lavage (WLL) is the standard treatment for pulmonary alveolar proteinosis (PAP). This study aimed to provide data about kinetics of the protein wash out, to identify factors influencing the protein concentration in the recovered fluid, and to assess the efficacy of a modified lavage technique.
Samples from 180 WLLs of 42 adult PAP patients were collected. 110 WLL were performed according to the classical technique. In 70 WLL repeated manual ventilation was applied during the procedure. Spectrophotometry was used to measure the protein concentration in the recovered fluid.
The initial protein concentration in the recovered fluid was 460 mg/dL, the final concentration was 26 mg/dL, and the total amount of removed proteins during a lavage was 17.5 g. A history of dust exposure was associated with a higher residual protein concentration in the recovered fluid (p=0.00013). The amount of removed proteins correlated inversely with the diffusing capacity of the lung for carbon monoxide (DLCO) (p=0.001) and the partial pressure of oxygen in the blood (PaO2) (p=0.004). The modified technique removed a greater amount of proteins than the classical technique and prolonged the time to relapse (p=0.011).
The exposure to dust seems to influence the kinetics of the protein wash out. Applying manual ventilation during the procedure can enhance the efficacy of WLL
High Performance CMOS Range Imaging
No full textDiese Arbeit fokussiert sich auf die Modellierung, Charakterisierung und Optimierung von Rauschen um den Entwurf von hochperformanten CMOS-Bildsensoren im Allgemeinen und von distanzgebenden Bildsensoren im Speziellen zu unterstützen. CMOS Bildsensorik ist bekannt dafür, den CCD-Sensoren bezüglich Flexibilität überlegen zu sein, aber modifizierter Prozesse zu bedürfen um vergleichbare Leistung in Parametern wie Rauschen, Dynamik oder Empfindlichkeit zu erreichen. Rauschen wird als einer der wichtigsten Parameter erachtet, da es die erreichbare Genauigkeit maßgeblich limitiert und nicht korrigiert werden kann. Diese Thesis präsentiert einen Überblick über die weit gefächerte Theorie des Rauschens und fügt ihr eine Methodik hinzu die Rauschperformance von zeitlich abgetasteten Systemen zu schätzen. Eine Charakterisierung der verfügbaren Bauelemente des verwendeten 0:35 µm 2P4M CMOS-Prozesses wurde durchgeführt und anhand heuristischer Betrachtungen und dem Kenntnisstand der Rausch-Theorie evaluiert. Diese fundamentalen Untersuchungen werden als Grundlage erachtet, die Vorhersagbarkeit der Rauschperformance von z.B. Bildsensoren zu verbessern. Rauschquellen von Fotodetektoren wurden in der Vergangenheit erforscht, wobei viele mit der Einführung der PPD minimiert werden konnten. Üblicherweise sind die verbleibenden dominanten Rauschquellen das Resetrauschen und das Rauschen der Ausleseschaltung. Um Letzteres zu verbessern, wurde eine neuartige JFET-basierte Auslesestruktur entwickelt, welche im Vergleich zu verfügbaren Standard-MOSFETs eine um ca. Faktor 100 verbesserte Rauschperformance für niedrige Frequenzen aufweist. ToF wird als eine Schlüssel-Technologie erachtet, die neue Applikationen z.B. in Machine Vision, Automobil, Surveillance und Unterhaltungselektronik ermöglicht. Das konkurrierende CW-Verfahren ist bekannt dafür, anfällig bzgl. Störungen z.B. durch Hintergrundbestrahlung zu sein. Das PM-ToF-Prinzip wird als eine vielversprechende Methode für widrige Bedingungen erachtet, die allerdings eines schnellen Fotodetektors bedarf. Diese Arbeit trug zu zwei Generationen von LDPD basierten ToF-Bildsensoren bei und präsentiert eine alternative Implementierung des MSI-PM-ToF Verfahrens. Es wurde nachgewiesen, dass diese eine wesentlich bessere Performance bzgl. Geschwindigkeit, Linearität, Dunkelstrom und Matching bietet. Ferner bietet diese Arbeit ein nichtlineares und zeitvariantes Modell des realisierten Sensorprinzips, welches ungewünschte Phänomene wie die endliche Ladungsträgergeschwindigkeit und eine parasitäre Fotoempfindlichkeit der Speicherknoten berücksichtigt, um Großsignal-, Sensitivitäts- und Rauschperformance erforschen zu können. Es wurde gezeigt, dass das Modell gegen ein "Standard"-Modell konvergiert und die Messungen gut nachbildet. Letztlich wurde die Auswirkung dieser ungewünschten Phänomene auf die Performance der Distanzmessung präsentiert.This work is dedicated to CMOS based imaging with the emphasis on the noise modeling, characterization and optimization in order to contribute to the design of high performance imagers in general and range imagers in particular. CMOS is known to be superior to CCD due to its flexibility in terms of integration capabilities, but typically has to be enhanced to compete at parameters as for instance noise, dynamic range or spectral response. Temporal noise is an important topic, since it is one of the most crucial parameters that ultimately limits the performance and cannot be corrected. This thesis gathers the widespread theory on noise and extends the theory by a non-rigorous but potentially computing efficient algorithm to estimate noise in time sampled systems. The available devices of the 0:35 µm 2P4M CMOS process were characterized for their low-frequency noise performance and mutually compared by heuristic observations and a comparison to the state of research. These investigations set the foundation for a more rigorous treatment of noise exhibition and are thus believed to improve the predictability of the performance of e.g. image sensors. Many noise sources of CMOS APS have been investigated in the past and most of them can be minimized by usage of a PPD as a photodetector. Remaining dominant noise sources typically are the reset noise and the noise from the readout circuitry. In order to improve the latter, an alternative JFET based readout structure is proposed that was designed, manufactured and measured, proving the superior low-frequency noise performance of approximately a factor of 100 compared to standard MOSFETs. ToF is one key technology to enable new applications in e.g. machine vision, automotive, surveillance or entertainment. The competing CW principle is known to be prone to errors introduced by e.g. high ambient illuminance levels. The PM ToF principle is considered to be a promising method to supply the need for depth-map perception in harsh environmental conditions, but requires a high-speed photodetector. This work contributed to two generations of LDPD based ToF range image sensors and proposed a new approach to implement the MSI PM ToF principle. This was verified to yield a significantly faster charge transfer, better linearity, dark current and matching performance. A non-linear and time-variant model is provided that takes into account undesired phenomena such as finite charge transfer speed and a parasitic sensitivity to light when the shutters should remain OFF, to allow for investigations of large-signal characteristics, sensitivity and precision. It was demonstrated that the model converges to a standard photodetector model and properly resembles the measurements. Finally the impact of these undesired phenomena on the range measurement performance is demonstrated
Bimetallic Silver-Gold-Nanoparticles - Synthesis, Characterization and cellbiological investigations
No full textThe aim of this thesis was to establish syntheses of Ag-Au-nanoparticles in aqueous media with subsequent characterization of the nanoparticles as well as their cytotoxicity.
Based on the prominent Turkevich-method and comparable syntheses of Ag-Au-nanoparticles, citrate-stabilized spherical Ag-Au-nanoparticles were prepared in nine different compositions by co-reduction of suitable silver- and gold-precursors with tri-sodium citrate. Due to a lack of stability the particles were functionalized with poly(vinylpyrrolidone), which furthermore made a purification of the nanoparticles by ultracentrifugation possible. The experimental Ag:Au compositions were examined by AAS and showed good agreement with the theoretical values. Based on UV-Vis-analyses of the surface plasmon resonance of the particles, a high degree of alloying was determined.
Due to significant differences in the size of the citrate-stabilized nanoparticles with different compositions, polydispersity and poor stability, a stronger reducing agent, i.e. a mixture of tri-sodium citrate and tannic acid, was used to modify the synthesis. The reduction of Au3+ and Ag+ with a mixture of citrate and tannic acid led to spherical Ag-Au-nanoparticles with improved monodispersity and stability which could be purified by ultracentrifugation. The theoretical Ag:Au-composition was verified by AAS. Compared to the citrate-stabilized particles, the citrate/tannin-stabilized particles were smaller but showed a gradual trend in particle size that was dependent on the silver content. A functionalization of the Ag-Au-nanoparticles with PVP and TPPTS was carried out and verified by means of colloidal and spectroscopical analyses. Although a high degree of alloying was detected by UV-Vis spectroscopy, HR-TEM (HAADF, STEM) showed that the distribution of silver and gold inside individual ~12 nm Ag:Au-50:50-particles was not statistical.
For the citrate/tannin mixture the influence of the amount of reducing agent on the resulting particle size was examined. As it was expected, a lesser quantity of reducing agent led to larger nanoparticles, while an increase in the amount of reducing agent used led to significantly smaller particles. With a 1.5-fold increase in reducing agent concentration Ag:Au-nanoparticles with nine different compositions and particle sizes of ~ 7 nm could be synthesized and functionalized with PVP. Interestingly there was almost no trend in particle size observable. TEM- and XRD-studies showed that the nanoparticles synthesized with a 1.5-fold amount of citrate/tannin were nanocrystalline and not twinned. Furthermore a distinct compression of the unit cell was observed, leading to a deviation from Vegard’s law and the emergence of microstrain in the crystal lattice of the nanoparticles.
Cellbiological studies revealed a toxic effect of the nanoparticles towards HeLa-cells and hMSCs which was dependent on the total metal concentration and the silver content of the nanoparticles. However, the dependence on the silver ratio was not linear, as particles with a silver content of below 50 mol% showed only a slight toxic effect while Ag:Au-80:20-nanoparticles exerted higher toxicity than Ag:Au-90:10- and pure Ag-nanoparticles after an incubation time of 24 h (total metal concentration hMSCs: 50 µg mL-1, HeLa-cells: 50 µg mL-1 and 100 µg mL-1).
In addition to Ag-Au-nanoparticles in the size range of ~10 nm, ultrasmall cluster-like Ag:Au-nanoparticles were synthesized via simultaneous reduction of Au3+ and Ag+ with sodium borohydride in the presence of thiol-ligands, i.e. 11-mercaptoundecanoic acid and dihydrolipoic acid. With 11-MUA as ligand, monodisperse, quasispherical nanoparticles were synthesized, that could be purified by precipitation and redispersion. The 11-MUA-Ag-Au-nanoparticles had a mean diameter of about 2 nm, independent of their Ag:Au-composition. The theoretical ratio of Ag and Au was confirmed by AAS. By 1H-NMR and ATR analyses it was revealed, that the ligand was bound to the particle surface with the thiol-group. 11-MUA-Ag-Au-particles with a composition between Ag:Au-10:90 and Ag:Au-60:40 showed notable autofluorescent properties with emission in the visible range. The color of the emission seemed to depend on the silver content of the nanoparticles and showed a red shift with increasing Ag:Au-ratio. Cellbiological studies revealed a rather low toxicity of the particles towards HeLa-cells with cell viabilities mostly above 50 % after incubation for 24 h with a total metal concentration of 50 µg mL-1. Only nanoparticles with a very high silver content exerted stronger toxic effects. Uptake studies with autofluorescent 11-MUA-Ag-Au-nanoparticles indicated, that the particles accumulated mainly on the cell membrane and presumably in endosomal vesicles
Entwicklung eines CMOS-integrierten massensensitiven Sensors zur Anwendung in der Biologie
No full textGegenstand der vorliegenden Arbeit ist die Charakterisierung eines kapazitiven massensensitiven Drucksensors auf sein Resonanzverhalten und sein Auflösungsvermögen. Dafür wird ein Messsystem entwickelt, das den Sensor elektrostatisch zur Resonanz anregt und die Resonanzfrequenzen elektrisch misst. Das Resonanzverhalten wird mit unterschiedlichen Messmethoden verglichen. Das Auflösungsvermögen des Sensors wird mit Variation der elektrischen Spannungen optimiert und mit dünnen Goldschichten und Partikeln im Pikogrammbereich bestimmt.
Zusätzlich wird der Sensor biochemisch beschichtet und auf seine Selektivität untersucht. Dazu gehört der Nachweis der spezifischen Bindung mit Proteinen und Antikörpern auf dem Sensor.
Das Messsystem wurde durch Integration der Ausleseschaltung miniaturisiert und durch Integration der Fluidik automatisiert. Hierfür wurde die Ausleseschaltung auf den Sensorchip integriert und das Resonanzverhalten wurde mit dem des diskreten Sensors verglichen. Eine vollautomatische und programmierbare Fluidik wird entwickelt, die Flüssigkeiten auf den Sensor dispensiert, spült, trocknet und die Messung wieder aufnimmt. Der Sensor mit integrierter Elektronik wird in das Messsystem mit Fluidik integriert und im Spülprozess getestet. Zusätzlich wird eine Mikrofluidik mit
Kapillarpumpe für den Sensor entwickelt, um das Probenvolumen zu reduzieren und das gesamte Messsystem zu miniaturisieren.The present work shows the characterisation of a capacitive mass-sensitive pressure sensor on resonance behaviour and resolution. For this, a measurement system is developed, which electrostatically excites the sensor and electrically measures the resonance frequencies. The resonance behaviour is compared with different measurement methods. The resolution is optimized by varying the electrical voltages and is determined with thin gold layers and particles in the picogram range.
Additionally, the sensor is coated with a biochemical layer and is analyzed for ist selectivity. This includes the detection of the specific binding of proteins and antibodies onto the sensor.
The measurement system is miniaturized by the integration of a readout circuit and is automatized by the integration of a fluidic system. The readout circuit is integrated on the sensor chip and the resonance behaviour is compared to the behaviour of the discrete sensor. A programmable fluidic is developed by dispensing liquids, rinsing, drying and measuring the frequency automatically. The sensor with integrated readout circuit is integrated into the fluidic system and tested by rinsing and drying. In addition, a microfluidic system with a capillary pump is developed to reduce the sample volume and to miniaturize the entire measurement system
Analyzing hidden and indirect factors for rising health expenditure
No full textThis thesis comprises four studies on different topics in health economics that all potentially contribute to rising health expenditure: Consequences of demographic change, technological progress, changing trends in awareness for diseases and inefficiencies on health insurance markets. The problems of demographic change are twofold: (i) In an aging society there are less persons in working age that contribute to social pay-as-you-go insurance systems. This decreases the financial base of social insurances while (ii) the share of non-working (older and retired) persons, who do not contribute but benefit from social insurances, increases. Against this background, analyzing consequences of informal caregiving recently gained attention. The first study sheds light on the consequences of the double burden of caregiving and full-time work for caregiver’s health status. It is shown empirically that the double burden deteriorates both, mental and physical health of the caregiver. The second study focuses on indirect consequences of technological progress in medicine which arise from an option value that comes along with technological progress. In a discrete choice experiment it is analyzed whether an option value of future therapies changes risk preferences and leads to an increased demand for marginally effective and risky therapies. It is found that the option value changes risk acceptance and thereby potentially increases demand for such treatments resulting in increasing health expenditure. The third study empirically analyzes spillover effects of insecure job conditions on the health status of spouses. Mental diseases recently gained public attention resulting in an increased number of diagnoses which contributes to rising health expenditure. Therefore, analyzing consequences of a not yet studied facet of unemployment gives insight into mechanisms that deteriorate mental conditions. It is found that perceived fear of job loss worsens the mental health status of spouses. The fourth study uses a laboratory experiment to analyze how consumers choose health insurance. Efficient consumer choice is necessary to encourage competition between insurers and to reach an efficient allocation. It is found that heuristics help individuals to increase individual decision quality. Thereby, the quality measure is based on individual cumulative prospect theory values which are in addition found to explain a substantial amount of observed insurance choices
A parallel Newton-Krylov-FETI-DP Solver based on FEAP: Large-scale applications and scalability for problems in the mechanics of soft biological tissues in arterial wall structures
No full textAn MPI-parallel Newton-Krylov-FETI-DP solver based on FEAP is presented together with applications to nonlinear problems in the quasi-static biomechanics of soft biological tissues. The formulation is based on highly nonlinear hyperelastic anisotropic and poly-convex models. High-resolution computations of the wall stresses in patient-specific arterial wall structures subjected to an interior normal pressure in the physiological regime of the blood pressure (up to 500 [mmHg]) are reported together with results on strong scalability. The weak scalability of Newton-Krylov-FETI-DP is investigated for up to 140 million degrees of freedom using 4096 processor cores on a Cray XT6m supercomputer in a series of simple tension tests. An implementation of a new FEAP-interface called libfw is presented which allows for the flexible unified integration of FEAP into other software packages, e.g., into LifeV. The modifications done to FEAP are dissected and discussed in detail as a case study in order to illustrate possible approaches for the integration of different code components or applications in similar scenarios