Thesis (Ph. D.)--Virginia Commonwealth University, 2007. / Prepared for: Dept. of Chemistry. Bibliography: leaf 146.

Thesis (Ph.D.)--York University, 2005. Graduate Programme in Chemistry. / Typescript. Includes bibliographical references. Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://proquest.umi.com/pqdweb?index=0&did=1163224921&SrchMode=1&sid=7&Fmt=2&VInst=PROD&VType=PQD&RQT=309&VName=PQD&TS=1195066319&clientId=5220

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

Thesis (Ph.D.)--University of California, Berkeley, 1963. / "UC-4 Chemistry" -t.p. "TID-4500 (19th Ed.)" -t.p. Includes bibliographical references (p. 125-127).

abstract: Single molecule identification is one essential application area of nanotechnology. The application areas including DNA sequencing, peptide sequencing, early disease detection and other industrial applications such as quantitative and quantitative analysis of impurities, etc. The recognition tunneling technique we have developed shows that after functionalization of the probe and substrate of a conventional Scanning Tunneling Microscope with recognition molecules ("tethered molecule-pair" configuration), analyte molecules trapped in the gap that is formed by probe and substrate will bond with the reagent molecules. The stochastic bond formation/breakage fluctuations give insight into the nature of the intermolecular bonding at a single molecule-pair level. The distinct time domain and frequency domain features of tunneling signals were extracted from raw signals of analytes such as amino acids and their enantiomers. The Support Vector Machine (a machine-learning method) was used to do classification and predication based on the signal features generated by analytes, giving over 90% accuracy of separation of up to seven analytes. This opens up a new interface between chemistry and electronics with immediate implications for rapid Peptide/DNA sequencing and molecule identification at single molecule level. / Dissertation/Thesis / Ph.D. Physics 2014

The regulated interaction of leukocyte with endothelium is of key importance during normal immune surveillance and leukocyte infiltration to sites of infection in the inflammatory response. This thesis is concerned with the structure and function of CD31 (platelet-endothelial cell adhesion molecule-1), one of the adhesion molecules implicated in these processes. Previous work has shown both in vivo and in vitro that CD31 is involved in the final step of leukocyte recruitment, transmigration across the endothelial monolayer. CD31 mediated adhesion is complex, since it is capable of mediating multiple adhesive interactions, both to itself (homophilic adhesion) and to other ligands (heterophilic adhesion). In order to study homophilic adhesion, an heterologous cell-protein assay was used in combination with recombinant chimeric CD31Fc fusion proteins, ICAM-3/CD31 chimeras and chimeras between human and murine CD31. These reagents located the homophilic binding site to the NH₂-terminal domains 1 and 2, but also define a non-binding accessory role for the membrane proximal domains. Using site-directed mutagenesis to target all of the exposed charged residues in domain 1 and a subset of charged residues in domain 2, five residues were identified, mutations in which resulted in inhibition of homophilic adhesion. These residues map to both faces of the domain 1 immunoglobulinlike fold, suggesting that each molecule of CD31 interacts with two others. A novel zipper model of homophilic adhesion involving CD31 lateral association analogous to that seen amongst cadherins is proposed on the basis of these results. Evidence for lateral association of CD31 to form dimers was obtained from biophysical, biochemical and molecular biology techniques. These show that Cd31 exists in an equilibrium between monomeric and dimeric forms both in solution as soluble recombinant protein, and at the cell surface. In solution the affinity of the interaction was calculated to lie in the range 12-14μM. A large panel of anti-CD31 monoclonal antibodies were generated and tested for their ability to effect homophilic adhesion. Inhibitory antibodies were identified, mapping throughout the extracellular domain, away from the ligand binding site. In addition possible stimulating antibodies mapping to the membrane proximal domains were also identified. This indicates that CDS 1 may be induced to undergo conformational changes which effect homophilic adhesion, and it is proposed that these conformational changes may be linked to the ability of CD31 to form laterally associated dimers. Using the reagents described above, a screen of haematopoietic cell lines identified a novel heterophilic interaction, which was shown to be mediated by the integrin αvβ3. Proteinprotein assays were used to confirm a direct physical association between CD31 and αvβ3, and to map the integrin binding site to the third immunoglobulin-like fold of CD31. The functional significance of this interaction was assessed in neutrophil transmigration assays, in which both anti-CD31 and anti-αvβ3 antibodies were found to partially inhibit neutrophil transmigration.

This thesis will present the synthesis, characterization and magnetic measurements of lanthanide complexes with varying nuclearities (Ln, Ln2, Ln3 and Ln4). EuIII, GdIII, TbIII, DyIII, HoIII and YbIII have been selected as the metal centers. Eight polydentate Schiff-base ligands have been synthesized with N- and mostly O-based coordination environments which chelate 7-, 8- or 9-coordinate lanthanide ions. The molecular structures were characterized by single crystal X-ray crystallography and the magnetic properties were measured using a SQUID magnetometer. Each chapter consists of crystal structures and magnetic measurements for complexes with the same nuclearity. There are eight DyIII SMMs in this thesis which are discrete molecules that act as magnets below a certain temperature called their blocking temperature. This phenomenon results from an appreciable spin ground state (S) as well as negative uni-axial anisotropy (D), both present in lanthanide ions owing to their f electron shell, generating an effective energy barrier for the reversal of the magnetization (Ueff). The ab initio calculations are also included for the SMMs with high anisotropic energy barriers to understand the mechanisms of slow magnetic relaxation in these systems.

This dissertation describes the single-molecule magnet (SMM) behaviour of f-block cyclooctatetraenyl sandwich complexes. Chapter one introduces the concepts that dictate SMM behavior particularly in f-elements. The emphasis is to understand the origin of magnetic behaviour and the properties that make lanthanide elements particularly interesting to explore. Current strategies used to predict such behaviour are discussed and a literature review on the subject is provided. Chapter Two describes the magnetic properties of eight isostructural lanthanide sandwich complexes utilizing 1,4-bis(trimethylsilyl)cyclooctatetraenyl dianion as the ligand, [Li(DME)3][LnIII(COT”)2] (Ln = Ce, Nd, Gd, Tb, Dy, Ho, Er, Tb, COT” = 1,4-bis(trimethylsilyl)cyclooctatetraenyl dianion, DME = dimethoxyethane). The complexes display a wide range of magnetic behaviour. The best performing SMM was the erbium complex, which had a blocking temperature of 8 K. Investigating different lanthanide ions with the same ligand enabled us to evaluate our findings in relation to current models used to predict SMM behaviour in lanthanide complexes. Chapter three extends the discussion of lanthanide sandwich complexes to include higher symmetry cyclooctatetraenyl complexes of ErIII and DyIII, [K(18-C-6)][LnIII(COT)2] (18-C-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane, COT = cyclooctatetraene).The change in symmetry evoked by removing the trimethylsyl- (TMS) groups on the ligand greatly influenced the magnetic properties of both complexes. Ab initio calculations revealed that the magnetic relaxation in the ErIII complex occurs via the second excited state which contributes to the very high blocking temperature of 10 K in this complex. Chapter four presents an organometallic building block approach to create triple decker lanthanide COT” complexes of GdIII, DyIII and ErIII with a molecular formula of LnIII2(COT”)3. Synthetically, we couple together the sandwich complexes discussed in Chapter 2 by oxidatively removing one ligand to produce linear complexes where the two metals are bridged by an aromatic COT” ligand. The magnetic properties of all complexes are compared to their respective mononuclear analogs. Most interesting is the unprecedented 4 K increase in blocking temperature of the triple decker ErIII analog compared to the ErIII mononuclear sandwich complex discussed in Chapter 2. This increase is due to a ferromagnetic dipole-dipole interaction between the ErIII ions through the COT” ring. The aromatic bridging ligand provides a GdIII - GdIII interaction of J = -0.448(1) cm-1. Chapter five extends the discussion of magnetic exchange coupling to include linear K2(THF)4[LnIII2(COT)4] (Ln = Gd, Dy, Er, COT = cyclooctatetraenyl dianion, THF = tetrahydrofuran) complexes of GdIII, DyIII and ErIII. Each complex is composed of two LnCOT2 units bridged linearly by a potassium ion. The magnetic interaction between metal ions is much weaker than in the triple decker complexes discussed in Chapter 4, with a GdIII-GdIII interaction of J = − 0.007(4) cm–1. The magnetic properties of the quadruple decker complexes were compared to their mononuclear equivalents (Chapter 3). Surprisingly, the ErIII complex showed an increase in magnetic blocking temperature over its mononuclear analog despite the large ErIII-ErIII separation of 8.819 Å. Ab initio calculations revealed that this increase is due to single ion effects, most likely an increase in symmetry. Chapter six deviates from lanthanide magnetism to study the magnetic properties of uranium sandwich complexes with multiple ligand systems and oxidation states. Prior to this study the SMM behaviour of uranium sandwich complexes was unknown. We report the synthesis, structure and magnetic properties of both uranium-COT” sandwich complexes and uranium-cycloheptatrienyl complexes with oxidation states spanning (III)-(V). None of the complexes showed zero-field SMM behaviour, indicating a sandwichtype ligand is not appropriate for harnessing the SMM character in uranium. We compared the slow magnetic relaxation of isostructural and valence isoelectronic uranium and neodymium complexes. The improved energy barrier in the uranium complex further motivates the use of uranium in SMM design due to its large spin-orbit coupling.

Indiana University-Purdue University Indianapolis (IUPUI) / Despite therapeutic advancements, prostate cancer remains the second most common cause of cancer-related mortality in men. Docetaxel is the first cytotoxic agent to show modest improvements in overall survival rate in patients with metastatic prostate cancer. Unfortunately, over half of these patients do not respond to treatment and ultimately all develop resistance. The mechanism mediating docetaxel resistance remains unknown. Survivin has a classical biological role in cancer, in fact survivin has been shown to be overexpressed in almost every solid tumor and is associated with drug resistance and clinically aggressive disease. In these studies I demonstrate that docetaxel resistant cells have overexpression of survivin compared to sensitive parental cells, knockdown of survivin decreases docetaxel resistance, and stable overexpression of survivin increases resistance to docetaxel. The data in these studies suggest that survivin is likely implicated in docetaxel resistance and treatment with a direct survivin inhibitor may sensitize resistant cells to docetaxel. To this end the evaluation and optimization of two different backbones of survivin inhibitors was performed. One such inhibitor identified is LQZ-7-3 which decreases survivin level via proteasome degradation, leads to apoptosis of cells, and showed efficacy in a prostate cancer xenograft model in vivo when given in an oral formulation. LQZ- 7-3 showed strong specificity to survivin versus other IAP family members at the protein level. Another inhibitor, LQZ-7F-1, demonstrated nanomolar inhibition of cancer cell growth and similar effects on survivin. Both compounds synergized with docetaxel in vitro warranting future in vivo efficacy studies as a combinatorial therapy. Overall, our findings indicate survivin is a significant contributor to docetaxel resistance in metastatic prostate cancer at the molecular level and survivin inhibitors may prove efficacious as a new therapy to sensitize cancer cells to chemotherapies.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13214号 / 論医博第2164号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 安達 泰治, 教授 江藤 浩之 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM