The potential of human 20S proteasome inhibitors continues to be of interest for anticancer chemotherapy and the recent FDA approval of bortezomib (Velcade) validates the proteasome as a target for cancer chemotherapy. Salinosporamide A, a marine unique bicycle [3.2.0] Beta-lactone-containing natural product, is not only a potent nanomolar inhibitor of the human proteasome but also active against bortezomibresistant multiple myeloma cells. The racemic and asymmetric syntheses of salinosporamide A and derivatives were targeted. In this dissertation, we successfully accomplished the shortest route to date with only a 9-step total synthesis of (–)-salinosporamide A. The conciseness of this strategy arises from the key bis-cyclization of a Beta-keto tertiary amide, amenable to gram scale, constructs both the Gamma-lactam and the fused-Beta-lactone in one operation with high enantiopurity, which was enabled by A^1,3-strain. Several derivatives were synthesized and their inhibition activity toward chymotripsin-like, caspase-like, and trypsin-like of the human 20S proteasome was evaluated. This dissertation also included a successfully optimized Organic Syntheses procedure for asymmetric synthesis of (1S,5R)-6-oxaspiro[bicyclo[3.2.0]heptane-3,2'- [1,3]dioxolan]-7-one via the nucleophile-catalyzed aldol-lactonization.

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L’analyse de la fonction systolique longitudinale par speckletracking permet d’analyser les mouvements de déformations du myocarde ainsi que la fonction systolique longitudinale ventriculaire gauche. Le Strain Longitudinal Global (SLG) est le paramètre le plus étudié en cardiologie et s’intéresse aux déformations du grand axe du ventricule gauche. Il n’existe pas de données sur le SLG chez les patients atteints d’une pathologie cérébrale aiguë placés sous ventilation mécanique, alors que les cardiopathies de stress ont été largement décrites dans ce contexte. Nous avons évalué le SLG chez des patients atteints d’hémorragie sous-arachnoïdienne par rupture d’anévrysme. Il existait plus de 30% de cardiopathies de stress évaluée par le SLG, alors que la fraction d’éjection ventriculaire gauche était normale. Chez les patients traumatisés crâniens, nous avons observé une absence de cardiopathies de stress, avec un SLG conservé. Néanmoins nous ne pouvons exclure que les anomalies constatées sont liées aux variations des conditions de charge secondaires à la ventilation mécanique. Nous avons testé l’effet de la ventilation mécanique invasive après anesthésie générale au bloc opératoire sur le SLG, ainsi que les effets du lever de jambe passif. Au décours de l’anesthésie générale, il existe une altération modeste mais significative du SLG. Après une épreuve de lever de jambe passif, l’altération du SLG est persistante. En conclusion, les altérations du SLG témoignant d’une cardiopathie de stress, sont spécifiques en neuroréanimation, mais l’analyse du SLG doit prendre en compte les variations rapides de conditions de charge. / .Speckle-tracking echography allows the analysis of left ventricular strain movements and longitudinal systolic function. Global Longitudinal Strain (GLS) is the most studied parameter in cardiology and provides data regarding strain movements of the left ventricle in the long axis. There are no data regarding SLG in neurocritical care patients undergoing invasive mechanical ventilation, although stress cardiomyopathy has been numerously described in this context. We have studied GLS in patients with aneurysmal subarachnoid haemorrhage. We identified over 30% of stress cardiomyopathy with GLS along with preserved left ventricular ejection fraction. In patients with traumatic brain injury, GLS was preserved implying the absence of stress cardiomyopathy. However, we could not rule out that GLS alterations were the consequences of the variations in the loading conditions of the left ventricle, because of mechanical ventilation. We tested these effects in patients undergoing invasive mechanical ventilation with general anaesthesia in the operating room. We also tested the effects of passive leg raising. After general anaesthesia, we witnessed a moderate but significant GLS impairment. After a passive leg raising test, GLS impairment was still present. In definite, GLS’s modifications are specific of the neurocritical care setting and imply the existence of stress cardiomyopathy, but GLS analysis must consider rapid modifications of the loading conditions.

Pathological phenomena often change the mechanical properties of the tissue. Therefore, estimation of tissue mechanical properties can be of clinical importance. Ultrasound elastography is a well-established strain estimation technique. Until recently, mainly 1D elastography algorithms have been developed. A few 2D algorithms have also been developed in the past. Both of these two types of technique ignore the tissue motion in the elevational direction, which could be a significant source of decorrelation in the RF data. In this thesis, a 3D elastography algorithm that estimates all the three components of tissue displacement is implemented and tested statistically. In this research, displacement fields of mechanical models are simulated. RF signals are then generated based on these displacement fields and used as the input of elastography algorithms. To evaluate the image quality of elastograms, absolute error, SNRe, CNRe and CNRasse are computed. The SNRe, CNRe and CNRasse values are investigated not only under different strain conditions, but also in different frame locations, which forms 3D strain filters. A statistical comparison between image qualities of the 3D technique and 2D technique is also provided. The results of this study show that the 3D elastography algorithm outperforms the 2D elastography algorithm in terms of image quality and robustness, especially under high strain conditions. This is because that the 3D algorithm estimates the elevational displacement, while the 2D technique only estimates the axial and lateral deformation. Since the elevational displacement could be an important source for the decorrelation in the RF data, the 3D technique is more effective and robust compared with the 2D technique.

Two strains (NCm 9897 and 9898; strains A and B respectively) of a Pseudomonas· species have been shown to display antifungal and antibacterial activity on solid media. Biochemical tests indicate that the organisms may be two distinct strains of a new species. Cell morphology was studied using scanning electron microscopy. Chemically defined media, established for the organisms, indicate non-fastidous characteristics. Four liquid media, able to elicit antibiotic production from Strain A have been developed: a chemically defined medium (antibacterial), a chemically defined medium and a complex medium (antifungal) and a chemically defined medium (antibacterial and antifungal). Nitrogen and magnesium limitation significantly increased yields. Magnesium content in a medium (without a magnesium salt component) and in whole cell samples grown in the said medium were assessed using atomic absorption spectroscopy and elemental analysis respectively. Optimization experiments for antibacterial and antifungal activity, assessed by a disc diffusion assay, increased yields, in 250 ml conical flasks by a factor of X9 and 109% respectively. A 6 litre laboratory-scale fermentor was used for larger batch cultivations . Procedures for extraction of the active compounds from the biological matrices were . developed leading to the isolation of one antibacterial compound, ABl (yellow crystalline) and three antifungal compounds, AFl, AF2 and AF3 (pale yellow and amorphous). Structure determination of ABl, involving mass spectrometry, IR/UV spectroscopy, lH-NMR and x-ray diffraction, indicated it to be 1.6 dimethyl pyrimido[5,4-e ]-1,2,4- triazine-5,7(IH,6H)-dione (Xanthothricin; Toxoflavin), a toxic metabolite previously detected in foods contaminated with Ps. cocovenenans. Selective media, developed ' for Strain A and Strain B, did not support growth of Ps. cocovenenans. Preliminary structural analysis suggests that AFl may possess a mono-substituted ring system with CHz chain and a terminal hydroxyl group; that AF2 may belong to the polyene group of antifungal antibiotics and that AF3 may be an aliphatic ketone with hydroxyl group . Agar diffusion, minimum inhibitory concentration, assays for the compounds, indicate activity to be in the ~gml range for sensitive microorganisms. Antibiotic challenge against test microorganisms suggest bacteriostatic activity for ABl, fungistatic activity for AFl and AF3 and fungicidal activity for AF2.

Master of Science / Civil Engineering / Dunja Peric / The conventional triaxial test is the primary laboratory test for determining the shear strength of soils. Geotechnical field conditions such as long earth dams, long embankments, long retaining walls, strip foundations, tunnels, and buried pipelines often experience plane strain states of stress. However, stress strain and load deformation responses in plane strain loading differ considerably from responses observed in the conventional triaxial test. Research has shown that soils loaded in a plane strain state are far more sensitive to imperfections than soils tested in a conventional triaxial device. Plane strain loading leads to material instability manifested as sudden localized failure, resulting in decreased load-carrying capacity of the soil and compromised geotechnical and civil infrastructures. Although previous studies have mostly focused on granular materials, this research investigated the plane strain response of clay. An undrained plane strain compression test program was devised to investigate the effects of past stress history and strain rates on strain localization in kaolin clay. Experiments were carried out in a plane strain (or biaxial) device at Northwestern University, Evanston, Illinois. Because the device was heavily internally instrumented, strain localization progress was closely monitored throughout each biaxial test. Clay response in the biaxial test demonstrated three phases: (1) a homogenous response, (2) the onset and propagation of strain localization, and (3) the evolution of strain localization as a shear band. The duration of each phase was determined for each test, and a Lagrange strain tensor was used to obtain the evolution of volumetric and shear strains at the level of a shear band for three tests. Results revealed the development of large strains in these mesoscale structures. Furthermore, evolution of Mohr-Coulomb effective shear strength parameters was traced throughout the propagation and evolution phases by using two different methods. It showed that in clay samples, unlike in granular materials, the post-peak plateau, which is reached by deviatoric stress, corresponds to friction values that are significantly lower than the critical state values. Other researchers who used scanning electron microscope and anisotropy of magnetic susceptibility detected a significant reorientation of clay particles inside shear bands. Their findings combined with findings in this study lead to the conclusion that the sub-meso scale mechanism responsible for large shear strains and a severe reduction in effective friction is a significant reorientation of clay particles inside shear band.

This thesis presents a theoretical description and experimental testing of two polarimetric fiber-optic strain sensors. 'The first .of these is an intrinsic sensor in which a single mode optical fiber acts as the sensing element. This sensor exhibited low strain sensitivity and high cross-sensitivity to temperature. The second sensor was of the extrinsic type, A single polarization maintaining fiber was used to deliver and collect light from the sensing element, which a was piece of photoelastic sheet PS-1. This type of sensor exhibited large dynamic range of 1:1350, resolution of 0.59ps, and strain sensitivity of the normalized signal of0.00219pe+1. / Thesis / Master of Engineering (ME)

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