Rigid and Non-rigid Point-based Medical Image Registration

The primary goal of this dissertation is to develop point-based rigid and non-rigid image registration methods that have better accuracy than existing methods. We first present point-based PoIRe, which provides the framework for point-based global rigid registrations. It allows a choice of different search strategies including (a) branch-and-bound, (b) probabilistic hill-climbing, and (c) a novel hybrid method that takes advantage of the best characteristics of the other two methods. We use a robust similarity measure that is insensitive to noise, which is often introduced during feature extraction. We show the robustness of PoIRe using it to register images obtained with an electronic portal imaging device (EPID), which have large amounts of scatter and low contrast. To evaluate PoIRe we used (a) simulated images and (b) images with fiducial markers; PoIRe was extensively tested with 2D EPID images and images generated by 3D Computer Tomography (CT) and Magnetic Resonance (MR) images. PoIRe was also evaluated using benchmark data sets from the blind retrospective evaluation project (RIRE). We show that PoIRe is better than existing methods such as Iterative Closest Point (ICP) and methods based on mutual information. We also present a novel point-based local non-rigid shape registration algorithm. We extend the robust similarity measure used in PoIRe to non-rigid registrations adapting it to a free form deformation (FFD) model and making it robust to local minima, which is a drawback common to existing non-rigid point-based methods. For non-rigid registrations we show that it performs better than existing methods and that is less sensitive to starting conditions. We test our non-rigid registration method using available benchmark data sets for shape registration. Finally, we also explore the extraction of features invariant to changes in perspective and illumination, and explore how they can help improve the accuracy of multi-modal registration. For multimodal registration of EPID-DRR images we present a method based on a local descriptor defined by a vector of complex responses to a circular Gabor filter.

A Rapid and Sensitive High-Throughput Screening Method to Identify Compounds Targeting Protein–Nucleic Acids Interactions

DNA-binding and RNA-binding proteins are usually considered ‘undruggable’ partly due to the lack of an efficient method to identify inhibitors from existing small molecule repositories. Here we report a rapid and sensitive high-throughput screening approach to identify compounds targeting protein–nucleic acids interactions based on protein–DNA or protein–RNA interaction enzyme-linked immunosorbent assays (PDI-ELISA or PRI-ELISA). We validated the PDI-ELISA method using the mammalian highmobility- group protein AT-hook 2 (HMGA2) as the protein of interest and netropsin as the inhibitor of HMGA2–DNA interactions. With this method we successfully identified several inhibitors and an activator for HMGA2–DNA interactions from a collection of 29 DNA-binding compounds. Guided by this screening excise, we showed that netropsin, the specific inhibitor of HMGA2–DNA interactions, strongly inhibited the differentiation of the mouse pre-adipocyte 3T3-L1 cells into adipocytes, most likely through a mechanism by which the inhibition is through preventing the binding of HMGA2 to the target DNA sequences. This method should be broadly applicable to identify compounds or proteins modulating many DNA-binding or RNA-binding proteins.

Delay-Sensitive Service Request Scheduling for Cloud Computing

Cloud computing realizes the long-held dream of converting computing capability into a type of utility. It has the potential to fundamentally change the landscape of the IT industry and our way of life. However, as cloud computing expanding substantially in both scale and scope, ensuring its sustainable growth is a critical problem. Service providers have long been suffering from high operational costs. Especially the costs associated with the skyrocketing power consumption of large data centers. In the meantime, while efficient power/energy utilization is indispensable for the sustainable growth of cloud computing, service providers must also satisfy a user's quality of service (QoS) requirements. This problem becomes even more challenging considering the increasingly stringent power/energy and QoS constraints, as well as other factors such as the highly dynamic, heterogeneous, and distributed nature of the computing infrastructures, etc. In this dissertation, we study the problem of delay-sensitive cloud service scheduling for the sustainable development of cloud computing. We first focus our research on the development of scheduling methods for delay-sensitive cloud services on a single server with the goal of maximizing a service provider's profit. We then extend our study to scheduling cloud services in distributed environments. In particular, we develop a queue-based model and derive efficient request dispatching and processing decisions in a multi-electricity-market environment to improve the profits for service providers. We next study a problem of multi-tier service scheduling. By carefully assigning sub deadlines to the service tiers, our approach can significantly improve resource usage efficiencies with statistically guaranteed QoS. Finally, we study the power conscious resource provision problem for service requests with different QoS requirements. By properly sharing computing resources among different requests, our method statistically guarantees all QoS requirements with a minimized number of powered-on servers and thus the power consumptions. The significance of our research is that it is one part of the integrated effort from both industry and academia to ensure the sustainable growth of cloud computing as it continues to evolve and change our society profoundly.

Development of a New Client-Server Architecture for Context Aware Mobile Computing

This dissertation studies the context-aware application with its proposed algorithms at client side. The required context-aware infrastructure is discussed in depth to illustrate that such an infrastructure collects the mobile user’s context information, registers service providers, derives mobile user’s current context, distributes user context among context-aware applications, and provides tailored services. The approach proposed tries to strike a balance between the context server and mobile devices. The context acquisition is centralized at the server to ensure the usability of context information among mobile devices, while context reasoning remains at the application level. Hence, a centralized context acquisition and distributed context reasoning are viewed as a better solution overall. The context-aware search application is designed and implemented at the server side. A new algorithm is proposed to take into consideration the user context profiles. By promoting feedback on the dynamics of the system, any prior user selection is now saved for further analysis such that it may contribute to help the results of a subsequent search. On the basis of these developments at the server side, various solutions are consequently provided at the client side. A proxy software-based component is set up for the purpose of data collection. This research endorses the belief that the proxy at the client side should contain the context reasoning component. Implementation of such a component provides credence to this belief in that the context applications are able to derive the user context profiles. Furthermore, a context cache scheme is implemented to manage the cache on the client device in order to minimize processing requirements and other resources (bandwidth, CPU cycle, power). Java and MySQL platforms are used to implement the proposed architecture and to test scenarios derived from user’s daily activities. To meet the practical demands required of a testing environment without the impositions of a heavy cost for establishing such a comprehensive infrastructure, a software simulation using a free Yahoo search API is provided as a means to evaluate the effectiveness of the design approach in a most realistic way. The integration of Yahoo search engine into the context-aware architecture design proves how context aware application can meet user demands for tailored services and products in and around the user’s environment. The test results show that the overall design is highly effective,providing new features and enriching the mobile user’s experience through a broad scope of potential applications.

Localized Surface Plasmon Resonance Biosensors for Real-Time Biomolecular Binding Study

Surface Plasmon Resonance (SPR) and localized surface plasmon resonance (LSPR) biosensors have brought a revolutionary change to in vitro study of biological and biochemical processes due to its ability to measure extremely small changes in surface refractive index (RI), binding equilibrium and kinetics. Strategies based on LSPR have been employed to enhance the sensitivity for a variety of applications, such as diagnosis of diseases, environmental analysis, food safety, and chemical threat detection. In LSPR spectroscopy, absorption and scattering of light are greatly enhanced at frequencies that excite the LSPR, resulting in a characteristic extinction spectrum that depends on the RI of the surrounding medium. Compositional and conformational change within the surrounding medium near the sensing surface could therefore be detected as shifts in the extinction spectrum. This dissertation specifically focuses on the development and evaluation of highly sensitive LSPR biosensors for in situ study of biomolecular binding process by incorporating nanotechnology. Compared to traditional methods for biomolecular binding studies, LSPR-based biosensors offer real-time, label free detection. First, we modified the gold sensing surface of LSPR-based biosensors using nanomaterials such as gold nanoparticles (AuNPs) and polymer to enhance surface absorption and sensitivity. The performance of this type of biosensors was evaluated on the application of small heavy metal molecule binding affinity study. This biosensor exhibited ~7 fold sensitivity enhancement and binding kinetics measurement capability comparing to traditional biosensors. Second, a miniaturized cell culture system was integrated into the LSPR-based biosensor system for the purpose of real-time biomarker signaling pathway studies and drug efficacy studies with living cells. To the best of our knowledge, this is the first LSPR-based sensing platform with the capability of living cell studies. We demonstrated the living cell measurement ability by studying the VEGF signaling pathway in living SKOV-3 cells. Results have shown that the VEGF secretion level from SKOV-3 cells is 0.0137 ± 0.0012 pg per cell. Moreover, we have demonstrated bevacizumab drug regulation to the VEGF signaling pathway using this biosensor. This sensing platform could potentially help studying biomolecular binding kinetics which elucidates the underlying mechanisms of biotransportation and drug delivery.

Effect of Arginine and Oscillatory Ca2+ on Vascular Response Mediated Via Nitric Oxide Signaling in Normal and Salt Sensitive Hypertensive Rat Mesenteric Arterioles

Hypertension, a major risk factor in the cardiovascular system, is characterized by an increase in the arterial blood pressure. High dietary sodium is linked to multiple cardiovascular disorders including hypertension. Salt sensitivity, a measure of how the blood pressure responds to salt intake is observed in more than 50% of the hypertension cases. Nitric Oxide (NO), as an endogenous vasodilator serves many important biological roles in the cardiovascular physiology including blood pressure regulation. The physiological concentrations for NO bioactivity are reported to be in 0-500 nM range. Notably, the vascular response to NO is highly regulated within a small concentration spectrum. Hence, much uncertainty surrounds how NO modulates diverse signaling mechanisms to initiate vascular relaxation and alleviate hypertension. Regulating the availability of NO in the vasculature has demonstrated vasoprotective effects. In addition, modulating the NO release by different means has proved to restore endothelial function. In this study we addressed parameters that regulated NO release in the vasculature, in physiology and pathophysiology such as salt sensitive hypertension. We showed that, in the rat mesenteric arterioles, Ca2+ induced rapid relaxation (time constants 20.8 ± 2.2 sec) followed with a much slower constriction after subsequent removal of the stimulus (time constants 104.8 ± 10.0 sec). An interesting observation was that a fourfold increase in the Ca2+ frequency improved the efficacy of arteriolar relaxation by 61.1%. Our results suggested that, Ca2+ frequency-dependent transient release of NO from the endothelium carried encoded information; which could be translated into different steady state vascular tone. Further, Agmatine, a metabolite of L-arginine, as a ligand, was observed to relax the mesenteric arterioles. These relaxations were NO-dependent and occurred via α-2 receptor activity. The observed potency of agmatine (EC50, 138.7 ± 12.1 µM; n=22), was 40 fold higher than L-arginine itself (EC50, 18.3 ± 1.3 mM; n = 5). This suggested us to propose alternative parallel mechanism for L-arginine mediated vascular relaxation via arginine decarboxylase activity. In addition, the biomechanics of rat mesentery is important in regulation of vascular tone. We developed 2D finite element models that described the vascular mechanics of rat mesentery. With an inverse estimation approach, we identified the elasticity parameters characterizing alterations in normotensive and hypertensive Dahl rats. Our efforts were towards guiding current studies that optimized cardiovascular intervention and assisted in the development of new therapeutic strategies. These observations may have significant implications towards alternatives to present methods for NO delivery as a therapeutic target. Our work shall prove to be beneficial in assisting the delivery of NO in the vasculature thus minimizing the cardiovascular risk in handling abnormalities, such as hypertension.