b-amyloid is derived from amyloid precursor protein (APP) and tightly associated with the pathogenesis of Alzheimer¡¦s disease (AD). Structurally, APP belongs to type I transmembrane protein family and is composed of a large glycosylated extracellular component, a single membrane-spanning region, and a short cytoplasmic domain. Although physiological function of APP remains unclear, the proteolytic processing of APP by b secretase and g secretase gives rise to the production and secretion of b-amyloid. The C-terminus of APP is believed to participate in the intracellular trafficking of APP and signal transduction via interacting with adaptors and signaling proteins, respectively. Three phosphorylation sites (Thr654, Ser655 and Thr668, numbering for APP695 isoform) and several functional motifs in the cytoplasmic domain of APP have been identified and demonstrated that the phosphorylation can indeed affect APP metabolism including: the rate of secretion, endocytosis and b-amyloid production. In this study, we focused on how APP binding protein1 and the phosphorylation affect on APP metabolism. The reasons are as following: (1) Among many APP associated proteins, APP binding protein 1 (APPBP1) is involved in S-M checkpoint regulation. (2) Recent evidence indicates that aberrantly activation of mitotic events may play an important role in development of AD. Since progression through mitosis is regulated by Cdc2 that has been demonstrated to phosphorylate APP on Thr668-Pro669, the phosphorylation of APP at Thr668 may play the important role in regulating APP metabolism and may also relate to AD development. (3) Moreover, protein phosphorylation induces the conformational change and affects the protein- protein interaction. Phosphorylation of Ser / Thr-Pro motif is a central mechanism controlling progression of the cell cycle, including mitosis. Proline residues provide a potential backbone switch in the polypeptide chain controlled by the cis / trans isomerization. Pin1 is an important mitotic regulator and a highly specific peptidyl-prolyl cis / trans isomerases (PPIase) that catalyzes the isomerization of phosphorylated Ser / Thr-Pro bonds. Our unpublished data have shown that Pin1 can bind to the phosphorylated Thr668-Pro669 APP peptide with high affinity (20 nM) that suggested that Pin1 may interact and regulate mitotic APP. Taken together, these data suggested that the interaction of APP and APPBP1 or Pin1 may affect the APP metabolism and its physiological function. This study investigated the hypothesis above and revealed includes the following results (i) the subcellular localization of the C-terminus of APP and APPBP1; (ii) the interaction between APPBP1 and the C-terminus of APP in vivo and in vitro; (iii) Thr668 of APP is the Cdc2 phosphorylation site; (iv) the binding of APPBP1 to the C-terminus of APP reduces the phosphorylation of APP by Cdc2; (v) the phosphorylation at Thr668 can abolish the interaction between APPBP1 and the C-terminus of APP; (vi) the C-terminus of APP is one of the caspase 3 targets; (vii) the phosphorylation of APP at Thr668 also reduces the caspase 3 activity forward to the C-terminus of APP cleavage; (viii) both APPBP1 and Pin1 can inhibit the C-terminus of APP cleavage by caspase 3 that suggested two novel mechanisms to regulate APP metabolism.

Understanding the mechanism of zeolite nucleation and crystallization will enable the zeolite science community to tune zeolite properties during synthesis in order to accommodate the purposes of various applications. Thus there has been considerable research effort in "deciphering" the mechanism by studying the growth course of tetrapropylammonium (TPA)-mediated silicalite-1 using several techniques, such as dynamic light scattering (DLS), small-angle X-ray/neutron scattering (SAXS/SANS), and nuclear magnetic resonance (NMR). While these studies have generated a more comprehensive picture on the silicalite-1 growth mechanism, the general application of the mechanism and how it could be applied to other zeolite systems have not been addressed. This work initially tried to apply the insights developed from the TPAsilicalite- 1 clear solution synthesis by investigating the nanoparticles formation and zeolite growth in several tetraethyl orthosilicate (TEOS)-organocation-water solutions heated at 368 K using SAXS. The results are in contrast to TEOS-TPAOH-water mixtures that rapidly form silicalite-1 at 368 K. These results imply that the developed TPA-silicalite-1 nucleation and crystallization mechanism is not universally applicable to other zeolite systems and TPA-silicalite-1 itself could be a special case. With this in mind, the next goal of this work uses in situ SAXS to revisit silicalite-1 growth kinetics prepared by using several TPA-mimic organocations and some asymmetric geometry organocations. The results clearly show the TPA cation is an extraordinarily efficient structure-directing agent (SDA) due to its moderate hydrophobicity and perfect symmetric geometry. Any perturbation of the hydrophobicity and symmetry of SDA leads to a deterioration of zeolite growth. This work further investigates the influences of alcohol identity and content on silicalite-1 growth from clear solutions at 368 K using in situ SAXS. Several tetraalkyl orthosilicates (Si(OR)4, R = Me, Pr, and Bu) are used as the alternative silica sources to TEOS in synthesizing silicalite-1. Increasing the alcohol identity hydrophobicity or lowering the alcohol content enhances silicalite-1 growth kinetics. This implies that the alcohol identity and content do affect the strength of 1) hydrophobic hydration of the SDA and 2) the water-alcohol interaction, through changing the efficiency of the interchanges between clathrated water molecules and solvated silicate species.

Alzheimer disease is characterized by the initial degeneration of a subset of cholinergic neurons. This pattern of degeneration can be triggered by overexpression of the amyloid precursor protein (APP) gene in humans. Interestingly, APP is widely expressed; it is therefore unclear why only certain cholinergic neurons are vulnerable to degeneration. We show that widespread expression of the human APP gene in the nematode Caenorhabditis elegans also induces age-dependent apoptotic degeneration of select cholinergic neurons. Identical results were obtained by overexpressing the orthologous worm gene apl-1. The pattern of neurodegeneration matched the cell-autonomous accumulation of APP protein in vulnerable neurons and could be activated cell-non-autonomously by distinct portions of APP. Vulnerability to APP accumulation and degeneration depended inversely on the level of ASK1/p38MAPK innate-immune signaling in cholinergic neurons. Lastly, we identify a compound P7C3 that blocks entrance to apoptosis caused by APP or immunodeficiency. Our results suggest that immunosenescence sculpts the cellular pattern of neurodegeneration by APP. / text

Jadomycins are secondary metabolites produced by Streptomyces venezuelae ISP5230 VS1099 in response to conditions of stress such as heat or ethanol shock. They have been shown to exhibit antibiotic and anticancer activity. Unique structural features of the jadomycins include a rare 2,6-dideoxysugar, L-digitoxose, and an oxazolone ring with an amino acid component. Previous studies have revealed that jadomycin derivatives can be produced by altering the amino acid in S. venezuelae ISP5230 VS1099 culture media which becomes incorporated into the oxazolone ring. One jadomycin from a proteogenic amino acid and three new jadomycins from non-proteogenic amino acids have been successfully produced on a large scale (4 mg/L to 12 mg/L, 2 L) and characterized using mass spectrometry, infrared spectroscopy, UV-visible spectroscopy, and nuclear magnetic resonance spectroscopy. One of these contains a terminal alkyne functionality and has been used in cycloaddition reactions with various azides to produce a library of triazole-containing jadomycins.

Osteocytes (resident bone cells) are believed to sense loading-induced interstitial fluid flow in bone and transduce the signals to osteoclasts (bone resorption cells) and osteoblasts (bone formation cells) to regulate bone remodeling. Recent studies have shown that bone disuse causes osteocyte apoptosis, which precedes osteoclast activity at the local remodeling site. Although osteoclast precursors are known to travel via the circulation, the specific mechanism by which they are transported to the remodeling site is unclear. We hypothesized that lack of fluid flow induces osteocyte apoptosis. Furthermore, we hypothesized that osteocyte populations containing apoptotic osteocytes secrete cytokines that: 1) promote angiogenesis, and 2) activate the endothelium to promote osteoclast precursor adhesion to the endothelium such that osteoclast precursors can be delivered closer and directly to the remodeling site. In our in vitro studies, we found that lack of oscillatory fluid flow (mimicking mechanical disuse) promotes osteocyte apoptosis. In addition, osteocyte populations containing apoptotic cells promote endothelial cell proliferation, migration, and tubule formation. Inhibition of the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), abrogated osteocyte apoptosis-mediated angiogenesis. Furthermore, we found that osteocyte populations containing apoptotic cells secrete cytokines that promoted osteoclast precursor adhesion. Upon further investigation, we found that apoptotic osteocytes secreted elevated levels of inflammatory cytokine interleukin 6 (IL-6), and its soluble receptor, sIL-6R. We demonstrated that both IL-6 and sIL-6R are required to activate the endothelium to express ICAM-1. Inhibition of ICAM-1 and IL-6 by blocking antibodies abolished apoptotic osteocyte-mediated osteoclast precursor adhesion. Our findings suggest for the first time that osteocytes communicate to endothelial cells directly to mediate angiogenesis and osteoclast precursor adhesion. Results from this study may assist in a better understanding of osteoclast precursor recruitment at the initial onset of bone resorption.

Due to its unique characteristics, carbon fiber is one of the leading materials for light weight, high strength and stiffness applications in composite materials. The development of carbon fibers approaching theoretical strengths and stiffness is a continuing process which has led to improved mechanical and physical properties over the recent years. Improvements in carbon fiber properties are directly dependent on the quality of the precursor fiber. Research and development of PAN precursor fiber requires extensive experimentation to determine how processing conditions affect the structure and properties of the precursor fibers. Therefore, it is the goal of this thesis to analyze the results of varying coagulation rates on fiber shape, density and porosity, to determine the effect of cross-sectional shape, density, and fiber diameter on the tensile strength of the fiber, and to investigate the most effective method for the reduction of fiber diameter. Results indicate a low temperature, high solvent concentration coagulating bath leads to a rounder cross section with lower void content. Reduction in fiber diameter was found to increase tensile strength while increased molecular orientation experienced during high draw down ratios led to an increase in fiber modulus.

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: pp. 135-148.

Thesis (M.Sc.) - Carleton University, 2006. / Includes bibliographical references (p. 106-118). Also available in electronic format on the Internet.

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Bibliography: p. 97-121.

Thesis (Ph.D.) -- University of Rhode Island, 2008. / Typescript. Includes bibliographical references (leaves 141-159).