A Graphic Review of the Free Speech Clause

This work acts as a spring board for the study of the Free Speech Clause of the First Amendment. It builds useful graphical representations of complex constitutional theories from the ground up, allowing students to follow both development and the application of these theories

DESIGN, SYNTHESIS AND EVALUATION OF BIVALENT INHIBITORS OF TREHALOSE-6-PHOSPHATE PHOSPHATASE

The D-glucose disaccharide α, α-D-trehalose is synthesized by a variety of bacteria, fungi, plants and invertebrates to support cell survival by functioning as a fuel, a metabolic regulator or a protectant against environmental stress. Five different trehalose biosynthetic pathways are known to exist, one of which, the OtsA/OtsB pathway is common among pathogenic bacteria and fungi and is also found in parasitic nematodes. Previously reported otsA and otsB gene knockout (or knockdown) experiments have shown that both pathway enzymes are essential for M. tuberculosis cell growth and host colonization. RNAi gene silencing carried out in the nematode model system Caenohabditis elegans revealed that the T6P phosphatase is essential. Based on these findings we concluded that trehalose-synthesizing pathogens are likely to be vulnerable to the action of small molecule inhibitors of T6P phosphatase. We designed a bi-module inhibitor prototype. Accordingly, the phosphate group of the trehalose 6-phosphate moiety was replaced by a phosphate mimetic for targeting the active site of the catalytic domain, and the glucose unit was modified for targeting the cap domain for induced cap closure over the active site. Sulfate proved to be the most effective warhead for the substrate-binding site. T6S binding was shown by using Single Angle X-ray Scattering (SAXS) analysis to induce cap closure. Using glucose-6-sulfate as the platform, a series of synthetic derivatives possessing \u27drug-like\u27 functions tethered to the glucose ring were evaluated. Of these first generation inhibitors 4-n-octylphenyl-α-D-glucopyranoside 6-sulfate proved to be the tightest binding T6PP competitive inhibitor. In parallel, we have used the glucose-6-sulfate as the scaffold in the design of active site-directed, irreversible inhibitors. From the adducts which were synthesized and tested for T6PP inactivation, 4-n-octylphenyl-2-(3-(flurosulfonyl) benzoylamino)-2-deoxy-α-D-glucopyranoside-6-sulfate was selected for further characterization, and subsequently shown to inactivate the T6PPs with stoichiometric covalent modification and reasonable efficiency. Bioinformatic analysis and site-directed mutagenesis methods were used to identify the modified residue, a stringently conserved lysine residue was identified. Based on this result, the design and synthesis of the second generation of irreversible inhibitors that are optimized this target site is planned for future work

Anisotropic Stimuli-Responsive Polymeric Nanoparticles: Synthesis and Characterization

This dissertation focuses on the design, synthesis and characterization of stimuli-responsive anisotropic nanoparticles with various morphologies. Size- and shape-tunable Janus nanoparticles consisting of poly(methyl methacrylate/n-butyl acrylate) (p(MMA/nBA)), poly(pentafluorostyrene/nBA) (p(PFS/nBA) and poly(2-(N,N′-dimethylamino) ethyl methacrylate/nBA) (p(DMAEMA/nBA)) phases were synthesized via consecutive seeded emulsion polymerization. These Janus nanoparticles are capable of changing size and morphology in response of temperature and/or pH changes, which may have potential applications as solid surfactants. Gibbous and inverse-gibbous nanoparticles were synthesized viacopolymerization of fluorinated monomers in the presence of pMMA or polystyrene (pSt) seed particles. The morphology of the gibbous nanoparticles can be controlled by polymerization conditions. Incorporation and copolymerization of methacrylic acid (pMAA) components results in pH-responsive gibbous nanoparticles with numerous size-tunable bulges. In addition, the gibbous and inverse-gibbous nanoparticles can be controlled to self-assemble in solutions but upon evaporation of solvents form two- and three-dimensional assemblies stabilized by electrostatic interactions and shape-matching topographies. Taking advantage of the heterogeneous nature of emulsion polymerization, surfactant free heterogeneous radical polymerization (SFHRP) was developed to synthesize ultra-high molecular weight amphiphilic block copolymers. This is one-step process of preparing block copolymer morphologies. The amphiphilic block copolymers can form thermochromic inverse micelles in organic solvents, capable of selectively scattering light as a function of temperature. The approach was also utilized to synthesize polymer nanowires via in-situ self-assembly of amphiphilic block copolymers. This kinetically controlled directional growth may lead to many industrial applications, including synthesis of other block copolymers, polymeric nanowire latexes and other morphologies

Bis(2,2′-bipyridine)bis­{μ3-cis-N-(2-carboxyl­atophen­yl)-N′-[3-(dimethyl­amino)prop­yl]oxamidato(3−)}­bis(per­chlorato)­tetra­nickel(II) methanol disolvate

In the title methanol disolvate complex, [Ni4(C14H16N3O4)2(ClO4)2(C10H8N2)2]·2CH3OH, the neutral tetra­nickel(II) system lies on a centre of inversion. The polyhedron around each Ni(II) atom is a square pyramid. The separations of the Ni atoms bridged by the oxamide and carboxyl groups are 5.227 (9) and 5.268 (6) Å, respectively. In the crystal structure, a two-dimensional supramolecular network structure involving O—H⋯O and C—H⋯O hydrogen bonding is observed

{μ-trans-N,N′-Bis[2-(2-hydroxy­ethyl­amino)eth­yl]oxamidato(2−)}bis­[picrato­nickel(II)]

The title complex, [Ni2(C6H2N3O7)2(C10H20N4O4)], contains a centrosymmetric binuclear unit in which the oxamide ligand (located on a centre of symmetry) acts in a bis-­tetra­dentate fashion and the picrate anion binds to nickel(II) in a bidentate mode. The NiII atom displays a distorted octa­hedral coordination with axial elongation. The binuclear mol­ecules are linked by inter­molecular N—H⋯O, O—H⋯O and C—H⋯O hydrogen bonds into a two-dimensonal supra­molecular network extending parallel to (100)