Laserthermoschockversuche - Durchführung und Auswertung für unterschiedliche Hochleistungskeramiken

In dieser Arbeit wurde eine Laserstrahl-Thermoschockanlage grundlegend für die Durchführung von Aufheizthermoschockversuchen an verschiedenen Hochleistungskeramiken weiterentwickelt. Die Anlage wurde hinsichtlich der Versuchstechnik dahingehend erweitert, dass Versuche an Luft und erstmals auch im Vakuum möglich sind, wobei die Probenerwärmung kontinuierlich und sehr rasch durch eine vom Probeninneren ausgehende spiralförmige Laserstrahlführung erfolgt. Die Bestimmung der zeit- und ortsaufgelösten Temperaturverteilung mit Hilfe einer Hochfrequenz-Infrarotkamera stellt durch die Auswahl von vier Keramiken mit unterschiedlichen thermischen und optischen Eigenschaften einen hohen Anspruch an die Messtechnik. Eine Möglichkeit für die pyrometrische Hochgeschwindigkeits-Temperaturmessung von Proben mit großen Temperaturgradienten sowie wellenlängen- und temperaturabhängigen Transmissions- und Absorptionsverhalten wurde im Rahmen dieser Arbeit entwickelt und wird detailliert vorgestellt. Dazu gehören die Erstellung einer universellen Kalibrierprozedur sowie die Korrektur der Messdaten hinsichtlich verschiedener Rauscheffekte und messtechnischer Artefakte. Das Temperaturprofil kann mit dieser Technik mit guter Genauigkeit bestimmt und ausgewertet werden. Die Temperatur wird auf der gesamten Probenoberfläche erfasst und die Temperaturerhöhung im Laserspot wird damit ebenfalls ermittelt. Die zusätzliche Installation der Schallemissionsmessung erlaubt eine exakte Bestimmung des Zeitpunkts des Probenversagens. Mit diesen Weiterentwicklungen können nun Keramiken mit optisch und thermisch stark variierenden Eigenschaften in verschiedenen Medien untersucht werden. Der sich einstellende Temperaturgradient in der Probe ist für die Ausbildung von Druckspannungen im Probeninneren und Zugspannungen im kalten Randbereich der Probe verantwortlich. Beim Erreichen einer kritischen, versagensrelevanten Spannung tritt eine Schädigung der Probe auf, wobei der Laserspot eine, die Bruchursache darstellende lokale Temperatur- und daraus folgende Spannungsüberhöhung in der Nähe des jeweiligen Verweilortes verursacht. Die Bestimmung der sich einstellenden Spannungen wurde von einem eindimensionalen Ansatz zur Berechnung der Tangential- und Radialspannungen erstmals auf eine zweidimensionale, auf der Finite-Elemente-Methode basierende Berechnung erweitert. Die Streuung der versagensrelevanten Spannungen wird statistisch erfasst und bewertet. Die als Stand der Technik anerkannte Weibullstatistik wurde auf die Anforderungen des Thermoschockversuches angepasst bzw. weiterentwickelt. Hierbei wird in Form von Hüllkurven berücksichtigt, dass das belastete Volumen jeder Probe während des Versuches einem örtlich und zeitlich inhomogenen Spannungszustand unterliegt. Dies stellt eine Erweiterung der statistischen Weibull-Analyse dar, die auf der Annahme konstanter Prüfvolumina basiert. Neben dem versagensrelevanten Spannungszustand kann nun auch die bei Versagen gespeicherte elastische Energie berechnet werden, die sehr gut mit sich ausbildenden Bruchmustern korreliert. Basierend auf der Kenntnis des Spannungszustandes und der gespeicherten elastischen Energie wurden verschiedene Versagenskriterien abgeleitet. Aus einer vergleichenden Gegenüberstellung dieser Versagenskriterien für die untersuchten Hochleistungskeramiken wird das am besten geeignete, mit vertretbarem Aufwand bestimmbare Kriterium abgeleitet. Damit steht experimentell eine universelle Methode zur Verfügung, medienabhängige Thermoschockversuche an unterschiedlichen Keramiken durchzuführen und auszuwerten. Die so ermittelte Thermoschockfestigkeit und deren Streuung kann zur Auslegung von keramischen Bauteilen herangezogen werden.In this thesis, a laser beam thermal shock rig was fundamentally enhanced to realize heating-up thermal shock tests on different advanced ceramics. The testing technique of the rig was extended with respect to testing media, i.e. testing in vacuum is possible now in addition to air. Heating takes place continuously and very rapidly by a laser beam, which moves helically from the center of the sample to the outside. The measurement of the time and space resolved temperature distribution was realized by using a high performance infrared camera. The investigation of four different advanced ceramics with dissimilar optical and thermal properties represented a challenging task regarding measuring instrumentation. A procedure to apply pyrometric high-speed temperature measurements to samples with high thermal gradients as well as wavelength and temperature dependent transmission and absorption behavior was developed and is presented in detail. This includes the generation of a universal calibration procedure as well as the correction of the measured data with respect to different noise effects and measuring artifacts. The temperature profile can be determined and evaluated with good accuracy by this approach. The temperature is recorded on the complete specimen surface and the temperature increase in the laser spot is detected as well. The additional installation of the acoustic emission measurement allows the exact determination of the moment of specimen failure. With these advancements, ceramics with strong variations in optical and thermal properties can be investigated now in different media. The induced temperature gradient results in the development of compressive stresses in the hot sample interior and of tensile stresses in the cold rim. Damage of the sample occurs when reaching a critical failure relevant stress. The laser spot represents the rupture cause due to a local rising of the temperature and, consequently, a stress rise close to its dwell point. The determination of the resulting stresses was extended for the first time from a one dimensional approach calculating the tangential and radial stresses to a two dimensional calculation, which is based on the Finite-Element-Method. The scatter of the failure stress was statistically determined and assessed. The statistics of Weibull, which is accepted as a state-of-the-art approach, was adapted and further developed, respectively, for the requirements of thermal shock tests. The loaded volume of each sample during the experiment is subjected to a spatio-temporal inhomogeneous stress condition, which is taken into account in terms of an envelope. This represents an expansion of the statistics of Weibull, which assumes a constant sample volume. In addition to the failure relevant stresses, it is possible now to calculate the stored elastic energy at failure, which correlates very well with the observed fracture pattern. Based on the calculated stress state and the stored elastic energy, different failure criteria were derived. After a contrasting juxtaposition of these failure criteria of the investigated advanced ceramics, the most suitable criterion was proposed, which can be applied with justifiable effort. Thus, a universal method to perform and evaluate media dependent thermal shock experiments on ceramics is available now. Such thermal shock resistance data as well as their scatter can be used to design ceramic components.Doktorandenprogramm der Bundesanstalt für Materialforschung und -prüfun

Comprehensive 1000 year climatic history from an intermediate-depth ice core from the south dome of Berkner Island, Antarctica: methods, dating and first results

A 181 m deep ice core drilled in 1994/95 on the south dome of Berkner Island, Antarctica, was analyzed for stable isotopes, major ions and microparticle concentrations. Samples for ion chromatography were prepared by using a novel technique of filling decontaminated sample from a device for continuous ice-core melting directly into the sample vials. The core was dated through identification of volcanic horizons and interpolative layer counting. The core, together with a similar core from the north dome, reveals a 1000 year history of relatively stable climate. Temporal variations in the two cores deviate from each other owing to changing patterns of regional-scale circulation; the best correspondence between them is found for MSA(-). delta(18)O, accumulation rate and a sea-salt proxy show only negligible correlation, which suggests a complex meteorological setting. Increasing annual accumulation is observed for the last 100 years. A period of increased sea-salt concentrations started around AD 1405, as has also been observed in other cores. Microparticle concentrations are on average 1220 particles (>= 1.0 mu m diameter) mL(-1); they are enhanced from (AD) 1200 to 1350, possibly because of a higher atmospheric mineral dust load or because local volcanic activity was stronger than previously thought. Microparticles and NH4+ show marked but multiple and very irregular sub-annual peaks; long-term stacking of 1 year data intervals yields seasonal maxima in austral spring or mid-summer, respectively. Post-depositional redistribution was observed for MSA, NO3- and F- at volcanic horizons

Design and synthesis of inhibitors of the E3 ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 (SMURF1) as a treatment for lung remodeling in Pulmonary Arterial Hypertension (PAH)

Design and synthesis of inhibitors of the E3 ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 (SMURF1) as a treatment for lung remodeling in Pulmonary Arterial Hypertension (PAH) A series of selective SMURF1 ligase inhibitors have been identified, optimized for potency and properties to enable excellant rat pharmacokinetic properties. Furthermore compounds from the series have been shown to potently block the remodeling of vascular smooth muscle in the rat Hypoxia –Sugen model of PAH

Design of potent and selective covalent inhibitors of Bruton’s Tyrosine Kinase targeting an inactive conformation

Bruton’s tyrosine kinase (BTK) is a member of the TEC kinase family and is selectively expressed in a subset of immune cells. It is a key regulator of antigen receptor signaling in B cells and of Fc receptor signaling in mast cells and macrophages. A BTK inhibitor will likely have a positive impact on autoimmune diseases which are caused by autoreactive B cells and immune-complex driven inflammation. We report the design, optimization, and characterization of potent and selective covalent BTK inhibitors. Starting from the selective reversible inhibitor 3 binding to an inactive conformation of BTK, we designed covalent irreversible compounds by attaching an electrophilic warhead to reach Cys481. The first prototype 4 covalently modified BTK and showed an excellent kinase selectivity including several Cys-containing kinases, validating the design concept. In addition, this compound blocked FcγR-mediated hypersensitivity in vivo. Optimization of whole blood potency and metabolic stability resulted in compounds such as 8, which maintained the excellent kinase selectivity and showed improved BTK occupancy in vivo

Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Bruton’s tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in Phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren’s Syndrome