Heat shock protein 90 (Hsp90) is an essential and conserved chaperone, required for the conformational maturation and stability of many signaling kinases. We hypothesized that the functional pleiotropism of Hsp90 can be exploited during pharmacological inhibition causing simultaneous restraint of tumor growth as well as suppression of distant spread. Recognizing the lack of therapeutic options in advanced and metastatic squamous cell carcinomas (SCC) of the uterine cervix as well as the oral cavity, this dual concept was tested in corresponding cell lines and xenografts, and correlated with clinical data on client protein expression. Examination of the cell cycle response to Hsp90 inhibition revealed a G2/M-arrest in a panel of four cervical cancer cell lines and a contribution of abnormal mitosis to apoptosis induction in vitro. Although limited to intraperitoneal application, in vivo evidence of biological activity including heat shock response and decreased client kinase phosphorylation was seen with the geldanamycin derivative 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). Importantly, focal adhesion kinase (FAK) signaling and associated functional parameters were inhibited by the drug treatment. Functional significance of FAK as a client was confirmed using a molecular model based on FAK-related non-kinase (FRNK) expression. Dependency on FAK appeared to be a requirement for full response to FRNK as well as 17-DMAG, and was observed in the mesenchymal-like cervical cell line SiHa. FAK expression and E-cadherin loss were features found in both cervical and oral malignancies, but absent from normal mucosa of either anatomic site. Particularly high FAK expression was noted in oral SCC with sarcomatoid features. Thus, we conclude that Hsp90 inhibition has potential in the treatment of advanced and metastatic SCC of cervical and oral origin. The further examination of novel Hsp90-targeting compounds as well as strategies focused on other components of the Hsp90 chaperone complex seems warranted.

Loss of the renal microvasculature is a common feature of almost all forms of chronic kidney disease (CKD). Here we explored the role of the angiogenic chemokine stromal cell-derived factor-1-alpha (SDF-1) and its cognate receptor CXCR4 in experimental and human CKD. CXCR4 was present on endothelial cells and podocytes, while SDF-1 was detectable on podocytes, arteriolar smooth muscle cells, interstitial fibroblasts and occasional endothelial cells. CXCR4 mRNA was elevated in the kidneys of rats with CKD and chronic antagonism of CXCR4 accelerated renal decline and capillary loss. Acute SDF-1 infusion activated glomerular endothelial nitric oxide synthase (eNOS) in vivo, while functional response to SDF-1 was impaired in glomerular endothelial cells derived from eNOS-/- mice. Finally, CXCR4 mRNA was also found to be increased in biopsies of patients with secondary focal segmental glomerulosclerosis. These observations indicate that local eNOS-dependent SDF-1/CXCR4 signaling exerts a compensatory reno-protective effect in the setting of CKD.

Loss of the renal microvasculature is a common feature of almost all forms of chronic kidney disease (CKD). Here we explored the role of the angiogenic chemokine stromal cell-derived factor-1-alpha (SDF-1) and its cognate receptor CXCR4 in experimental and human CKD. CXCR4 was present on endothelial cells and podocytes, while SDF-1 was detectable on podocytes, arteriolar smooth muscle cells, interstitial fibroblasts and occasional endothelial cells. CXCR4 mRNA was elevated in the kidneys of rats with CKD and chronic antagonism of CXCR4 accelerated renal decline and capillary loss. Acute SDF-1 infusion activated glomerular endothelial nitric oxide synthase (eNOS) in vivo, while functional response to SDF-1 was impaired in glomerular endothelial cells derived from eNOS-/- mice. Finally, CXCR4 mRNA was also found to be increased in biopsies of patients with secondary focal segmental glomerulosclerosis. These observations indicate that local eNOS-dependent SDF-1/CXCR4 signaling exerts a compensatory reno-protective effect in the setting of CKD.

Heat shock protein 90 (Hsp90) is an essential and conserved chaperone, required for the conformational maturation and stability of many signaling kinases. We hypothesized that the functional pleiotropism of Hsp90 can be exploited during pharmacological inhibition causing simultaneous restraint of tumor growth as well as suppression of distant spread. Recognizing the lack of therapeutic options in advanced and metastatic squamous cell carcinomas (SCC) of the uterine cervix as well as the oral cavity, this dual concept was tested in corresponding cell lines and xenografts, and correlated with clinical data on client protein expression. Examination of the cell cycle response to Hsp90 inhibition revealed a G2/M-arrest in a panel of four cervical cancer cell lines and a contribution of abnormal mitosis to apoptosis induction in vitro. Although limited to intraperitoneal application, in vivo evidence of biological activity including heat shock response and decreased client kinase phosphorylation was seen with the geldanamycin derivative 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). Importantly, focal adhesion kinase (FAK) signaling and associated functional parameters were inhibited by the drug treatment. Functional significance of FAK as a client was confirmed using a molecular model based on FAK-related non-kinase (FRNK) expression. Dependency on FAK appeared to be a requirement for full response to FRNK as well as 17-DMAG, and was observed in the mesenchymal-like cervical cell line SiHa. FAK expression and E-cadherin loss were features found in both cervical and oral malignancies, but absent from normal mucosa of either anatomic site. Particularly high FAK expression was noted in oral SCC with sarcomatoid features. Thus, we conclude that Hsp90 inhibition has potential in the treatment of advanced and metastatic SCC of cervical and oral origin. The further examination of novel Hsp90-targeting compounds as well as strategies focused on other components of the Hsp90 chaperone complex seems warranted.

In optical imaging system, misfocus occurs because of a nonaccuate focal length. In recent years, the improvement for misfocus problem has caught much attention in researches. This thesis is aimed to explore the misfocus improvement and analysis. Lens plays an important role in optical image system. It can focus light at one point. The distance between the focal point and the lens is called focal length. Focal length is determined by the object distance and the image distance. As light is focused farther out of the focal point, the image will blur. It is called misfocus. The general method to improve misfocus image is done by post-processing. In 1995, wave-front coding was first proposed by Dowski and Cathey. They placed the phase mask in front of the lens, and then emphasized on the processing. In recent years, more and more researches work on this field. In this thesis, a one ring phase mask is designed by modulating the phase difference in the ring to make the improvement better. Research before wave-front coding in order to achieve a closed optical transfer function for different degrees of misfocus, but we hope the phase mask can provide immediate improvement. This idea can be applied to real-time video monitoring.

The cytoskeleton is a diverse, multi-protein framework that plays a fundamental role in many cellular activities including mitosis, cell division, intracellular transport, cell motility, muscle contraction, and the regulation of cell polarity and organization. Furthermore, cytoskeletal filaments have been implicated in the pathogenesis of a wide variety of diseases including cancer, blood disease, cardiovascular disease, inflammatory disease, neurodegenerative disease, and problems with skin, nail, cornea, hair, liver and colon. Increasing evidence suggests that the distribution and organization of the cytoskeleton in living cells are affected by mechanical stresses and the cytoskeleton determines cell stiffness. We developed a fully nonlinear, constrained mixture model for adherent cells that allows one to account separately for the contributions of the primary structural constituents of the cytoskeleton and extended a prior solution from the finite elasticity literature for use in a sub-class of atomic force microscopy (AFM) studies of cell mechanics. The model showed that the degree of substrate stretch and the geometry of the AFM tip dramatically affect the measured cell stiffness. Consistent with previous studies, the model showed that disruption of the actin filaments can reduce the stiffness substantially, whereas there can be little contribution to the overall cell stiffness by the microtubules or intermediate filaments. To investigate the effect of mechanical stretching on cytoskeletal remodeling and cell stiffness, we developed a simple cell-stretching device that can be combined with an AFM and confocal microscopy. Results demonstrate that cyclic stretching significantly and rapidly alters both cell stiffness and focal adhesion associated vinculin and paxillin, suggesting that focal adhesion remodeling plays a critical role in cell stiffness by recruiting and anchoring F-actin. Finally, we estimated cytoskeletal remodeling by synthesizing data on stretch-induced dynamic changes in cell stiffness and focal adhesion area using constrained mixture approach. Results suggest that the acute increase in stiffness in response to an increased cyclic stretch was probably due to an increased stretch of the original filaments whereas the subsequent decrease back towards normalcy was consistent with a replacement of the highly stretched original filaments with less stretched new filaments.

Quantum well infrared photodetectors (QWIP) utilize quantum wells of large bandgap materials to detect infrared radiation. When compared to conventional low bandgap LWIR photodetectors, the QWIP technology offers largest format thermal imagers with much better uniformity. The theoretical part of this study includes the development of a QWIP ensemble Monte Carlo simulator. Capture paths of electrons to quantum wells are simulated in detail. For standard AlGaAs/GaAs QWIPs, at medium and high E-fields L valley quantum well (QW) is a trap for electrons which causes higher capture probability when compared with InP/InGaAs and GaAs/InGaAs QWIPs. The results suggest that high photoconductive gain observed in InP/InGaAs and GaAs/InGaAs QWIPs is not due to good transport properties of binary barrier material but due to higher &amp / #61511 / -L valley energy separation. The experimental part of the study includes the fabrication and characterization of InP/InGaAs and InP/InGaAsP QWIPs and 640x512 FPAs with the main objective of investigating the feasibility of these material systems for QWIPs. The InP/InGaAs and InP/InGaAsP QWIP detectors showed specific detectivity values above 1x1010 cm.Hz1/2/W (70K, f/2, background limited). The devices offer higher allowable system noise floor when compared with the standard AlGaAs/GaAs QWIP technology. It is also experimentally shown that for strategic applications LWIR InP based QWIPs have advantages over the standard QWIP technology. The InP/InGaAs 640x512 QWIP FPA reached 36 mK average NETD value at 70 K with f/1.5 optics and 10 ms integration time. The InP/InGaAsP QWIP on the other hand yielded 38 mK NETD histogram peak at 70 K with f/1.5 optics and 5 ms integration time on 320x256 window of the 640x512 FPA.

Numerous studies have shown that culture is a critical factor affecting leadership perceptions. Although these studies provide useful information about cultural differences, they overlook the fundamental difference between East Asians and Westerners, a holistic view versus an analytic view. In addition, these studies are based on methodologies in which verbal or pictorial stimuli are presented by researchers under conditions of high capacity, which does not allow other representational differences to be observed. This study investigates leadership representations in South Korea and the United States based on hypotheses about fundamental differences in social cognitive processing among South Koreans and Americans, as revealed in spontaneously generated visual productions. The results suggest that South Koreans have a holistic view, whereas Americans have an analytic view of leadership representations. Implications and future directions for research on cultural differences in leadership representations are discussed.

This thesis focuses on the construction and role of benchmark quality computations in the area of non-covalent interactions. We have provided a detailed error analysis of focal-point schemes commonly used in benchmark quality computations, as well as provide error and speedup analysis of commonly used approximations to these methods. An analysis of basis set effects on higher-order corrections to MP2/CBS has been carried out, providing the community error bounds on future benchmarks. We demonstrate how these high-level computations can elucidate a better understanding of non-bonded interactions in chemistry as well as provide high-quality reference data to refit existing methods against to increase the overall accuracy of the method.

<p>The problem of spatial disorientation during flight of aircraft is briefly described, as are definitions of the phenomenon. Traditional countermeasure efforts that are often directed towards changes in the central visual field are reconsidered in favour of presentation of information in the peripheral visual field. It is proposed to use optic flow to support spatial orientation, as well as to omit such information from the central visual field. An experiment was conducted, and results showed that forward visual flow gave very important spatial information. The flow could be cropped to a certain degree in the periphery (horizontally), as well as parts of the central presentation could be omitted without decreasing effects in the experiment. Implications relevant to possible implementations in aircraft are discussed.</p>