Als Stand der Technik sind einfache, kreisförmige Verrundungen zur Reduktion von Kerbspannungen an Querschnittsübergängen bekannt, für die aus Tabellenwerken / Diagrammen in der Literatur die Formzahl einfach abgelesen werden kann. Die Effizienz der Spannungsreduktion solcher Lösungen ist jedoch sehr begrenzt. Ziel der Arbeit ist es daher, dem Konstrukteur bzw. Berechnungsingenieur ein Verfahren in die Hand zu geben, mit dem er für Standardquerschnittsübergänge und Standardlastfälle "Nicht-Kreiskerben" ohne teure und zeitaufwendige FEM-Analyse einfach durch Nutzung geeigneter Formzahldiagramme auslegen kann. Dabei sind sogar Formzahlen von nahezu eins möglich, d.h., in der "Kerbe" bleibt praktisch nur noch die Nennspannung übrig. Die Präsentation ist zweitgeteilt: Im ersten Teil werden die Arbeitsmethoden bzw. Softwarefunktionen und verwendeten Softwarewerkzeuge vorgestellt: Dies sind die Programme Creo Parametric als vollparametrisches CAD-Werkzeug und Creo Simulate als p-FEM-Programm der Parametric Technology Coprporation (PTC). Der zweite Teil der Präsentation beschreibt den Gültigkeitsbereich sowie die untersuchten Kerbgeometrien: Die einfache kreisförmige Verrundung als Stand der Technik, die Zwei-Radien-Kerbe, die Baud-Kurve, die Methode der Zugdreiecke nach Claus Mattheck, die elliptische Kerbe sowie die konische Rundung als generalisierte elliptische Kerbe. Es wird kurz eine Bibliothek vorgestellt, mit der solche Kerben einfach ausgelegt werden können, d.h. Ihre exakte Geometrie festgelegt sowie die zugehörige Formzahl αk bestimmt werden kann. / Circular (one-radius) fillets are known as state-of-the-art for reducing notch stresses at cross section transitions. The stress concentration factor Kt of such geometries can be read out from diagrams/tables given in the literature. However, the efficiency of stress reduction of circular notches is very limited. The goal of the work therefor is to present a method for the designer/analyst how to design non-circular notches/fillets just by using suitable Kt-diagrams without time-consuming and expensive FEM analyses. Kt-numbers of nearly one are possible, that means in the "notch" just the nominal stress appears and no stress concentration takes place. The presentation has two parts: Part one describes the working methods and software functions as well as software tools: Creo Parametric as fully-parametric CAD program and Creo Simulate as embedded p-FEM-tool from Parametric Technology Corporation (PTC) have been used. The second part describes the range of validity and the examined notch geometries: The one-radius fillet as state-of-the-art, the two-radii filet, the Baud-curve, the method of tensile triangles from Claus Mattheck, the standard elliptical fillet and the conical round as generalized elliptical fillet. A notch layout library is shortly presented that allows to design such fillets, that means exactly determine the notch geometry and the related stress concentration factor Kt.

Hybrid stepper motors are a common type of electric motor used throughout industry thanks to its low-cost, high torque at low speed and open loop positioning capabilities. However, a closed loop control is often required for industrial applications with high precision requirements. The closed loop control can also be used to lower the power consumption of the motor and ensure that stalls are avoided. It is quite common to utilise a large and costly position encoder or resolver to feedback the position signal to the control logic. This thesis has explored the possibility of using a low-cost position sensor based on Hall elements. Additionally, a sensorless estimation algorithm, using only stator winding measurements, has been investigated both as a competitive alternative and as a possible complement to the position sensor. The thesis work summarises and discusses previous research attempts to adequately measure or estimate and control the hybrid stepper motors position and load angle without using a typical encoder or resolver. Qualitative results have been produced through simulations prior to implementation and experimental testing. The readings from the position sensor is subject to noise, owing to its resolution and construction. The position signal has been successfully filtered, improving its accuracy from 0.56° to 0.25°. The output from the sensorless estimation algorithm is subject to non-linear errors caused by errors in phase voltage measurements and processing of velocity changes. However, the dynamics are reliable at constant speeds and could be used for position control.

Hot sections of gas engine turbines require specialized materials to withstand extreme conditions present during engine operation. Nickel-base superalloys are typically used as blades and disks in the high pressure turbine section because they possess excellent fatigue strength, creep strength and corrosion resistance at elevated temperatures. Components undergo thermomechanical fatigue conditions as a result of transient engine operation. Sharp geometric features, such as cooling holes in blades or fir-tree connections in disks, act as local stress raisers. The material surrounding these features are potential sites of localized inelastic deformation and crack formation. To reduce customer costs associated with unnecessary overhauls or engine down-time, gas turbine manufacturers require accurate prediction methods to determine component endurances. The influence of stress concentration severity on thermomechanical fatigue crack formation is of particular importance as cracks often initiate in these hot spots. Circumferentially notched specimens were utilized to perform thermomechanical fatigue experiments on blade material CM247LC DS and disk material PM IN100. A parametric study on CM247LC DS was performed utilizing four notched specimens. Experimental results were coupled with finite element simulations utilizing continuum based constitutive models. The effects of applied boundary conditions on crack initiation life was studied in both alloys by performing experiments under remotely applied force and displacement boundary conditions. Finite element results were utilized to develop a life prediction method for notched components under thermomechanical fatigue conditions.

Hypoxia-inducible factor (HIF) is the master regulator of genes involved in adaptation to hypoxia. The stability and transcriptional activity of HIF are regulated by post-translational hydroxylations: prolyl hydroxylation by the prolyl hydroxylase domain-containing enzymes PHD1 – 3 earmarks HIF for proteasomal degradation, whilst asparaginyl hydroxylation by factor inhibiting HIF (FIH) blocks the interaction of HIF with the transcriptional coactivators p300/CBP. The PHDs and FIH hydroxylate HIF directly from molecular oxygen and are therefore oxygen sensors. Recent literature shows that FIH also hydroxylates a number of proteins containing an ankyrin-repeat domain (ARD). Together with reports suggesting that the PHDs are involved in HIF-independent pathways, this suggests that the HIF hydroxylases may have a wide range of non-HIF targets. This thesis describes my investigations into novel substrates of the HIF hydroxylases. This work has characterized the FIH-dependent hydroxylation of the ARD-containing protein Notch1, and defined a consensus sequence for hydroxylation that corresponds to the ankyrin-repeat consensus. Using this consensus potential sites of hydroxylation in a novel ARD FIH substrate, myosin phosphatase targeting subunit 1 (MYPT1), were identified then subsequently confirmed and characterized. Notch1 competes with HIF for FIH hydroxylation. My experiments show that this occurs because Notch1 is a more efficient substrate than HIF, whilst studies on MYPT1 and other proteins indicate that competitive inhibition of FIH may be a general property of ARDs. There are more than 300 ARD proteins in the human genome, and this thesis demonstrates that FIH may hydroxylate a significant percentage of these. In addition to the analysis of ARD hydroxylation a proteomic investigation into novel PHD3 substrates has identified two candidate proteins, suggesting that the PHDs may also have multiple targets. These results have important implications for oxygen sensing, and indicate that post-translational hydroxylation is likely to be a widespread modification in cell biology.

Transcription factors of the helix-loop-helix (HLH) gene family are widespread in the animal kingdom. Among them, members of HLH subfamilies such as ASCL, Neurogenin, NeuroD, COE, Atonal, Oligo, NSCL, Hairy/E(spl) and Hey (here referred to as neural HLH genes) have been shown to be fundamental for the development of the nervous system. They are expressed at different time periods of neuronal differentiation, from the specification of ectoderm towards a neural lineage, to the ultimate differentiation of neurons. Few HLH genes have been identified in the lamprey; however, considering the wide diversity of HLH gene subfamilies in metazoans, including vertebrates, it is very likely that lampreys possess a large repertoire of HLH genes in their genome. In the present study, the identification of several HLH genes in the lamprey genome, as well as the isolation and expression of different lamprey neural HLH genes is reported. As expected, a wide repertoire of HLH genes was identified in the sea lamprey (Petromyzon marinus) genome. On the other hand, the identification and expression analysis of different neural HLH genes of the ASCL, Neurogenin, COE and Hairy/E(spl) in the brook lamprey Lampetra planeri showed an overall conservation with other vertebrates, both at the sequence and expression pattern levels. In addition, novel features of the lamprey nervous system are revealed, such as the identification of possible new sensory cranial placodes in pharyngeal arches. Furthermore, these genes can serve as molecular markers for different cranial placodes and dorsal root ganglia (DRG), and their expression also highlights the presence of a ventricular zone in the brain and spinal cord, along with a complementary marginal zone. Finally, with the use of a Notch pathway inhibitor in developing L. planeri embryos, the regulation of expression of the isolated genes by the Notch signaling pathway was shown to be generally conserved between lampreys and gnathostomes in the spinal cord. This functional study also revealed that the lamprey spinal cord likely presents an independent developmental programme from the brain. All together, the present study shows that the analysis of neural HLH genes represents an excellent tool to understand the lamprey nervous system.

Multipotent haematopoietic stem cells (HSCs) supply the organism with mature blood cells of all lineages throughout adult life. These cells first originate in the dorsal aorta (DA) of the vertebrate embryo, and a multitude of signalling pathways regulate their specification in the embryo. The emergence of HSCs is dependent on appropriate arterial specification and vessel maturation, processes which are heavily dependent on Notch signalling. This arterial involvement of Notch obscures its later roles in HSC specification. The Notch ligand dll4 is crucially involved in arterial development in the mammalian embryo, while zebrafish embryos deficient for dll4 activity only exhibit minor arterial defects at the time of HSC emergence. Here, the zebrafish model has been exploited to reveal the first specific evidence for a role of dll4 in HSC specification. Dll4 is required for the expression of runx1, a transcription factor (TF) required for HSC specification, prior to any observed effects on vascular development. HSCs and all their derivatives are depleted in dll4 morphants. To disentangle the genetic requlatory cascade downstream of dll4 and upstream of runx1, RNA-seq was employed to discover downstream effectors of this signalling. Expression and functional screening of best candidate genes revealed seven genes with novel roles in HSC development. Foxc1b is a dll4 target predominantly mirroring the dll4 phenotype, and is thus likely to be the downstream effector of dll4, upstream of runx1. Interestingly, foxc1b also has a later dll4-independent role in HSC development, remarkably similar to that of cmyb. Taken together I show here for the first time a requirement of dll4 upstream of runx1 in HSC specification, mediated by foxc1b, followed by a later dll4-independent phase in HSC development.

Colorectal cancer (CRC) arises in part from the dysregulation of cellular proliferation, associated with the canonical Wnt pathway, and differentiation, effected by the Notch signalling network. In this thesis, we develop a mathematical model of ordinary differential equations (ODEs) for the coupled interaction of the Notch and Wnt pathways in cells of the human intestinal epithelium. Our central aim is to understand the role of such crosstalk in the genesis and treatment of CRC. An embedding of this model in cells of a simulated colonic tissue enables computational exploration of the cell fate response to spatially inhomogeneous growth cues in the healthy intestinal epithelium. We also examine an alternative, rule-based model from the literature, which employs a simple binary approach to pathway activity, in which the Notch and Wnt pathways are constitutively on or off. Comparison of the two models demonstrates the substantial advantages of the equation-based paradigm, through its delivery of stable and robust cell fate patterning, and its versatility for exploring the multiscale consequences of a variety of subcellular phenomena. Extension of the ODE-based model to include mutant cells facilitates the study of Notch-mediated therapeutic approaches to CRC. We find a marked synergy between the application of γ-secretase inhibitors and Hath1 stabilisers in the treatment of early-stage intestinal polyps. This combined treatment is an efficient means of inducing mitotic arrest in the cell population of the intestinal epithelium through enforced conversion to a secretory phenotype and is highlighted as a viable route for further theoretical, experimental and clinical study.

La plupart des côtes de la Terre reculent et 80% sont rocheuses. La prévision du recul des falaises littorales est primordiale afin d’anticiper les risques futurs pour les aménagements littoraux. Cependant, la compréhension de ce recul est difficile car de nombreux paramètres le contrôlent. Des expériences en canal à houle de petite échelle ont été effectuées où nous avons mis en place un massif de sable humide soumis à l’attaque des vagues par sapement. Le but est de comprendre comment l’effet des vagues contrôle l’érosion des falaises. La technique de mesure par ombroscopie a été employée et nous a permis de détecter la surface du sable et la surface libre en fonction du temps. Nous avons ainsi analysé l’influence du forçage des vagues (F, ξ) (où F est le flux d’énergie des vagues incidentes au large et ξ est le paramètre de similitude de “surf”) sur la vitesse de recul de la falaise et sur la profondeur des évènements d’effondrement. La vitesse de recul de la falaise augmente linéairement avec le flux d’énergie F. Les débris de falaise érodés changent la morphologie du fond, les types de morphologie du fond dépendent fortement du paramètre de similitude de “surf” au déferlement, ou encore du paramètre de Dean Ω. Des profils du fond instationnaires présentant une oscillation auto-entretenue de la barre sédimentaire ont été observés. Nous avons de plus étudié l’effet de la granulométrie du sable utilisé : pour un sable plus fin, la falaise est plus cohésive et s’effondre au cours d’évènements de plus grande ampleur. Etonnamment, le recul de la falaise est plus important pour du sable fin. Ceci est probablement dû à une modification de la morphologie du fond conduisant à une dissipation de l’énergie des vagues moins importante. Le volume de sable injecté dans le système a finalement été quantifié, la barre sédimentaire a d’abord été prélevée périodiquement et il a été observé que la vitesse de recul de la falaise vr est constante. Puis, la hauteur de falaise a été modifiée, le recul des falaises est plus important pour des petites falaises. Il semblerait que l’instationnarité d’un profil du fond se déclenche à partir d’un volume seuil de sable érodé. / Most of the Earth coasts recedes and 80 % are rocky. Prediction of sea-cliff recession is essential to anticipate future risks for coastal development. However, it is difficult to understand this recession because many parameters control it. In addition, both the space and time scales are too big for the different mechanisms of cliff erosion to be fully analysed. Experiments in a small-scale wave flume were conducted in which a massif made of wet sand is submitted to wave attack. The aim is to understand how cliff erosion is wave-controlled. The technique of shadow graph measurements was used to detect the time evolution of sand and water surfaces. We have analyzed the influence of wave forcing (F, ξ) (where F is the incident offshore wave energy flux and ξ is the surf similarity parameter) on the cliff recession rate and on collapse event size. The cliff recession rate increases linearly with the wave energy flux F. The eroded cliff materials change the bottom morphology ; the types of bottom morphology strongly depend on the surf similarity parameter at the breaker point, or the Dean parameter Ω. Bottom profiles characterized by unsteady self-sustained sandbar oscillation were observed. In addition, we studied how sand granulometry change the system evolution. Finer the sand is, more cohesive is the cliff and bigger are cliff collapses. Contrary to what was expected, cliff recession is more important for a finer sand : this could be due to a more dissipative bottom morphology built by fine sands. The sand volume within the system changes following cliff collapses and a sandbar removal during particular experiments. The cliff recession rate is constant when the sandbar is removed and decreases with cliff height. It seems that the unsteadiness of the bottom profile is activated when the volume of eroded sand exceeds a threshold value.

Neste trabalho foi medida a tenacidade à fratura de quatro ligas fundidas com composição química base do aço AISI M2 – uma de composição química convencional (liga I), e as demais modificadas por adições de nitrogênio (liga II), cério (liga III) e antimônio (liga IV) – submetidas a tratamentos térmicos visando a decomposição do carboneto M2C, a esferoidização e engrossamento dos carbonetos produto M6C e MC, em altas temperaturas e por diversos tempos. A metodologia empregada nesta avaliação da tenacidade à fratura foi a dos corpos de prova curtos com entalhe chevron segundo ASTM E 1304-97, de forma a superar a necessidade do pré-trincamento por fadiga, procedimento de difícil controle e custoso em materiais como os aços rápidos temperados e revenidos. Verificou-se que a metodologia utilizada para obtenção e ensaio de corpos de prova chevron foi de fácil execução (comparada à metodologia convencional) permitindo grande número de experimentos. Para verificar a consistência dos resultados, em algumas condições, também se utilizou a metodologia convencional segundo a ASTM E 399-90, cujo pré-trincamento foi feito utilizando os procedimentos propostos por Harris e Dunegan. Os resultados obtidos para os aços fundidos foram correlacionados com os obtidos para outros aços rápidos convencionais (VM2, M2 Thyssen) e um aço rápido sinterizado (SINTER 23). A microestrutura foi caracterizada utilizando-se técnicas de ataques metalográficos diferenciais, metalografia quantitativa manual e computadorizada e microscopia eletrônica de varredura. A avaliação microestrutural indica que não ocorreu precipitação eutética do carboneto M6C, em nenhuma das ligas fundidas. O carboneto M2C apresenta morfologia tanto irregular (plaquetas – tipo 1) quanto regular-complexa (lamelas – tipo 2). As ligas I, III e IV, apresentaram a predominância da morfologia tipo 1 enquanto que a liga II modificada pelo nitrogênio, apresentou apenas a morfologia tipo 2. O carboneto MC apresentou-se com morfologia regular-complexa. Medidas do espaçamento interdendrítico indicam que não houve influência significativa dos elementos modificadores sobre este parâmetro. Ensaios de resistência à flexão, indicam pouca influência dos elementos modificadores, mas forte influência dos tratamentos térmicos sobre o limite de resistência à ruptura transversal do aço fundido. Em todas as ligas, a resistência à flexão cresceu com o tempo de tratamento a 1200°C, bem como com a temperatura de decomposição em tratamentos por 2 horas. Análise das fraturas por microscopia eletrônica de varredura indicou que o crescimento das trincas se deu na região interdendrítica. O aço convencional apresentou resistência à ruptura transversal muito superior à dos aços fundidos. Os ensaios de tenacidade à fratura apresentaram resultados compatíveis com a literatura para os aços AISI M2 convencional e SINTER 23. Os resultados obtidos para o aço fundido, indicam queda nos valores de tenacidade à fratura nos materiais tratados a 1050°C com o avanço do tempo de tratamento; pouca variação dos valores com o tempo nas amostras tratadas a 1150°C; e aumento significativo da tenacidade à fratura com o tempo de tratamento a 1200°C. Os valores de tenacidade obtidos para os aços rápidos fundidos foram mais elevados que os obtidos para os materiais trabalhados e para o material sinterizado. / Fracture Toughness of four cast alloys with chemical composition based on the High-Speed Steel AISI M2 were measured. One of the alloys (alloy I) had the conventional AISI M2 composition, while the other three were modified by the addition of N (alloy II), Ce (alloy III) and Sb (alloy IV). The cast alloys were heat-treated in order to promote the decomposition of the M2C carbide as well as spheroidize and coarsen the product M6C e MC carbides. The method chosen for measuring fracture toughness was based on the use of short rod and bar chevron notched samples, according to ASTM E1304 – 97, in order to evade the need for fatigue pre-cracking, notoriously difficult for High Speed Steels quenched and tempered. The chevron-notch method proved straightforward and allowed for successful testing a great number of specimens. Conventional compact sample fracture toughness, according to ASTM E 399-90, with pre-cracking obtained using Harris-Dunegan drop-weight procedure, was used to validate the results. The results for cast alloys were compared with conventionally produced High Speed Steels (VM2, M2 Thyssen) and with a powder metallurgy High Speed Steel (SINTER 23). Microstructural characterization was performed using selective etching of polished surfaces, manual and automated quantitative metallography and SEM. Microstructural evaluation of as-cast alloys showed that there was no eutectic precipitation of M6C carbides. The M2C carbides show an irregular eutectic morphology (Type 1- plates) as well as a regular-complex eutectic morphology. Measurements of interdendritic spacing did not detect any effect of the modification. The bending test rupture strengths did not vary with the addition of modifying elements, but increased with the time and temperature of decomposition, spheroidization and coarsening of carbides. Rupture strengths increased with the heat-treatment time at 1200°C as well as with increasing temperatures for 2 h heat-treatments. SEM examination of the fracture surfaces showed that crack preferential growth path was interdendritical. Conventional High Speed Steels tested in bending presented better results for the rupture strength than cast steels. Fracture toughness results for M2 conventional steels and for the SINTER 23 steel were similar to the results from the literature. Fracture toughness results obtained for cast steels diminished with increasing decomposition time at 1050°C, did not change much with increasing decomposition time at 1150°C, increased markedly withy increasing decomposition times at 1200°C. The fracture toughness results for the as-cast steels were higher than the results obtained for the wrought steels and for the powder metallurgy steel.

A roller coaster manufacturer became aware that improperly heat treated track couplings were sent to a construction site for assembly. Concerns were that suspect couplings might not meet the engineering specifications and could be vulnerable to sudden failure. A testing company in Oak Ridge, TN that specializes in in-situ and laboratory mechanical testing was contacted by the manufacturer for help in this endeavor. The construction company elected to enlist a local testing firm to perform field tests on the components instead of the company in Oak Ridge. The test methods used are incapable of providing quantitative results that could be measured to the engineering specifications, making it unlikely to identify anything but the worst material conditions. This study is an example that the need for accurate analysis is very important. The manufacturer reported that 60 couplings were replaced, but it is presently unknown how many should have been replaced.