2010 UMKC Dissertations - Access Restricted to UMKC
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Item Functional Sorting of Evolutionary Effects in Protein Domains(University of Missouri--Kansas City, 2010) Yang, Ming, 1977-; Wyckoff, Gerald J.One of the most important questions in evolutionary genetics is whether a gene of interest is under positive selection, negative selection or neutral evolution. Although there are numerous existed methods and statistical tests to detect the action of positive selection, almost all of them heavily rely on the availability of enough within-species polymorphism data and between-species divergence data. But for the comparatively more conservative protein domain data, the absence of enough variations makes these general methods incompetent. The other problem lies at the difficulty of discerning the difference between positive selection and relaxation of functional constraint; both processes generally increase the rate of amino acid change relative to synonymous changes within coding regions, and unless the amino acid rate is overwhelmingly high across an entire gene, the signature of positive selection can be obscured.Two different kinds of methods to tackle the above problems were proposed. The first method utilizes the pattern of phylogenetic trees. Through the case study of the evolutionary analysis of the human hemopexin protein domain family, it is hypothesized that two family members hemopexin (HPX) and matrix metalloproteinase 12 (MMP12) genes might have been under positive selection. These two genes were further systematically sequenced within other six primate species; positive selections were detected by H-test. The tree parameters including average family distance, distances between tree members, tree symmetry, and numbers of changes along the branches were checked. Based on multiple linear regression analysis, three tree parameters were utilized to construct an equation for identification of family members under selection, which significantly deviate from the prediction line. These prediction lines essentially represent the neutral theory in a phylogenetic way. A more practical and valuable question can be asked is what part or which amino acids of a protein may be under selection, as this might help to pinpoint the targets with critical functional significance. One of the critical differences between the functional gene and its corresponding pseudogene is that the non-functional version of the gene tends to become simpler in terms of sequence complexity. This provides an independent variable for assessment of functional change. The information theory was applied to measure the change of information content (entropy) within a sequence. Combining this variable with the likelihood of amino acid change, a two dimensional plane is divided into four quadrants. Each of them will represent a different evolutionary mode. This method can sort the functional meaning of variations to each amino acid level. The phylogenetic method is a family-wise method and has a lower computational requirement. While the second method is a more refined one, it is more computationally intensive. Thus they can complement each other to satisfy diverse analysis requirements.Item Nutrient Transporter targeted Delivery of HIV Protease Inhibitors(University of Missouri--Kansas City, 2011-01-20) Luo, Shuanghui, 1970-; Mitra, Ashim K., 1954-HIV/AIDS has become one of the greatest threats to human health. Although inclusion of protease inhibitors (PIs) in HAART has greatly slowed the disease progression and improved the outcome of clinical treatment, the eradication of HIV/AIDS remains as a major medical challenge. Saquinavir (Saq) is the first anti-HIV PI approved by FDA. Despite of its high anti-HIV potency, its therapeutic efficacy is very limited due to its low oral absorption and bioavailability, which is attributed to extensive cellular efflux mediated by P-gp and first-pass metabolism mediated by CYP3A4. The objective of this dissertation is to develop novel Saq vitamin prodrugs targeting influx nutrient transporters and circumvent the P-gp mediated efflux as well as CYP3A4 mediated metabolism thus improving the absorption and bioavailability of Saq. First, two vitamin transport systems including sodium-dependent multivitamin transporter (SMVT) and sodium-dependent vitamin C transporter (SVCT), which are responsible for the uptake and transport of biotin and ascorbic acid (AA), were investigated using in vitro cell culture models. The carrier-mediated vitamin uptake and transport mechanisms were delineated. It was found that the uptake of biotin and AA was saturable with Km of 13.0 µM and 83.2 µM, respectively. The uptake processes were sodium, pH and temperature dependent. Both SMVT and SVCT dominantly located at apical membrane of the polarized cells. Subsequently, two vitamin prodrugs of Saq, Biotin-Saq and ascorbic-succinic-saquinavir (AA-Su-Saq), were synthesized and evaluated. The stability, cytotoxicity and metabolic kinetics of the prodrugs, and the interactions between the prodrugs and influx/efflux transport proteins were studied. The results indicated that the vitamin prodrugs were nontoxic and more metabolically stable than Saq. The prodrugs were recognized by vitamin transporters and showed less affinity to P-gp. The prodrug modification significantly decreased efflux and metabolism and improved the absorptive permeability and oral bioavailability of Saq. In conclusion, the influx nutrient transporters i.e. SMVT and SVCT can be targeted to improve the delivery of poorly absorbed drugs such as anti-HIV PIs. Finally, the effect of common buffer component HEPES on the uptake and transport of P-gp substrates was carefully examined. It was found out that HEPES in the cell growth medium and experimental buffer may affect the ATP-dependent cellular influx and efflux processes, which may provide some mechanistic insight into possible reasons for inconsistencies reported from various laboratories.Item Volatility-Aware Query Processing in Peer-to-Peer Systems(University of Missouri--Kansas City, 2010) Landeras, Francisco Jose; Kumar, Vijay, 1946-Peer-to-Peer (P2P) paradigm has been recognized as a disruptive technology that can aggregate enormous storage and processing resources for information sharing and distributed computing. This paradigm has received significant attention in both academic and industry. However, most of the effort has been focused on developing efficient searching mechanisms to locate the relevant data in the P2P network, and relatively little effort has been placed on improving P2P query processing. It is highly desirable to post more expressive and complex queries using a high-level declarative query language to support rich schema-based applications. To achieve this, conventional distributed query processing (CDQP) has been adopted to correlate and combine data across large number of scattered, autonomous, heterogeneous, and evolving peers. Although, CDQP permits decentralized schema-based query processing, we argue that two critical issues remain to be addressed to provide efficient P2P query processing: coping with highly transient populations of peers, and the dynamicity of P2P systems. CDQP assumes peers participating in a query plan are always present during query execution. Furthermore, it uses the compile-then-execute approach whose effectiveness relies heavily on the detail statistics available at compile time, and queries being executed in a relative stable environment. Unfortunately, these assumptions do not hold in P2P systems since peers join and leave the network in an ad hoc fashion, and P2P is a highly unpredictable and changeable environment. This makes the query optimizer more likely to produce sub-optimal query execution plans, and harder to guarantee query result completeness.This research concentrates on addressing both limitations in the context of peers' volatility from different viewpoints. First, we proposed a new adaptive P2P query processing architecture based on adaptation loop model that merges the merits of proactive and reactive methods to support a variety of plan-based adaptive query techniques. Next, we developed a model to better capture and predict the peers' availability in the system. Then, we proposed new volatility-aware query optimization schemes and volatility-aware adaptive query execution schemes that integrate the peers' availability as a first class parameter in query optimization and execution. Finally, we did a detail performance study showing the superiority of our proposed schemes.