Amyotrophic lateral sclerosis (ALS) is a devastating, progressive, and fatal neurodegenerative disease. Despite the fact that ALS is the most common motor neuron disease in adulthood, there is no effective treatment for the disease. Although most ALS cases (90-95%) are sporadic (sALS), the remaining cases (5-10%) are dominantly inherited and referred to as familial ALS (fALS). Because sALS and fALS show indistinguishable disease symptoms, a common disease mechanism has been proposed. After the discovery of the link between fALS and mutants of cytosolic Cu/Zn superoxide dismutase (SOD1), over 140 mutations in SOD1 have been identified to account for ~20% of fALS. The location of these mutants are scattered throughout the primary and tertiary structures of the protein. It is widely accepted that fALS-linked mutations in SOD1 result in a gain of toxic function to cause the disease, rather than a loss of physiological function, although the nature of the toxic mechanism remains unclear. SOD1 is a -rich, homodimeric metalloenzyme that catalyzes the dismutation of superoxide radicals to O2 and H2O2. The protein is ubiquitously expressed and the mature form of SOD1 (holo SOD1) contains one catalytic Cu ion, one structural Zn ion, one intra-molecular disulfide bond (between C57 and C146) and two free Cys residues (C6 and C111) per 153 residue subunit. Analogous to many different human diseases in which protein aggregation is a hallmark, aggregation of Cu/Zn superoxide dismutase (SOD1) is implicated in the pathogenesis of ALS. This thesis reports the first observation of aggregation of the most abundant form of SOD1 in vivo, the native, metallated (holo) dimer, under physiologically relevant conditions (37 °C and pH 7.8). The medical relevance of aggregates is demonstrated by structural and tinctorial analyses as well as the novel observation of binding of an anti-SOD1 antibody that specifically recognizes pathological aggregates in ALS. Additionally, ALS-associated SOD1 mutations promote aggregation but are not required, supporting a common mechanism in familial and sporadic ALS. The aggregation is characterized by a lag phase, which is diminished by self- and cross-seeding where heterogeneous nucleation is the underlying mechanism. Moreover, multiple pathways of aggregation are elucidated including dimer dissociation and metal loss. It is shown that if holo SOD1 loses more Zn ions than Cu ions, the aggregation profiles have shorter duration and lower final intensity, whereas when holo SOD1 loses more Cu ions than Zn ions, the aggregation profiles have longer duration and higher intensity. Taken together, the data in this thesis establish a valuable system for understanding SOD1 aggregation and toxicity mechanisms which can be used for developing therapeutic strategies targeting protein aggregation.

Data exploration is considered one of the major processes that enables the user to analyze massive amount of data in order to find the most important and relevant informa- tion needed. Aggregation and Ranking are two of the most frequently used tools in data exploration. The interaction between ranking and aggregation has been studied widely from different perspectives. In this thesis, a comprehensive survey about this interaction is studied. Holistic Ranking Aggregation which is a new interaction is introduced. Finally, various algorithms are proposed to efficiently process ad-hoc holistic ranking aggregation for both monotone and generic scoring functions.

Many chromophoric organics and polymers are highly emissive in their dilute solutions but become weakly luminescent in the high concentration and solid film states due to the induced £k−£k interactions of the intimately-contact chromophores. Therefore, it is practically important to develop fluorescent organic and polymeric materials with enhanced emission in their aggregated states (so called aggregated-induced emission, AIE). In this study, organic compound 2,4-diphenylquinoline (DPQ) with inherent quinoline ring and polymeric poly(vinyl diphenylquinoline) (PVQ) with pendant quinoline group were prepared and their AIE-phenomena were characterized. To prove the reported point that restriction of intramolecular rotation (RIR) is the main cause for AIE effect, DPQ and PVQ were further incorporated with organic strong acid of camphorsulfonic acid (CSA). Through the favorable acid-base interaction between the sulfonic acid in CSA and the nitrogen atom of the quinoline ring in DPA (or CSA), ionic complex of DPQ-CSA (and PVQ-CSA) was easily prepared and their response toward AIE properties were studied. Through the enhanced RIR by the complexation of bulky CSA with the central quinoline ring, the resulting DPQ-CSA (and PVQ-CSA) complex was proved to have better AIE-effect compared to the pristine DPQ (and PVQ). RIR mechanism can be indirectly proved in this case. We study the AIE on micelle topics of the block copolymer. We choose the poly(styrene-block-tertbutylstyrene) (PS-b-PBS) as our block copolymer. To synthesize the PS-b-PBS, we can successfully get the new block copolymer PVQ-b-PBS. PVQ-b-PBS was similarly blended with the CSA. In the block copolymer micelles, choose the selective solvent to get the different micelles and observe the diverse on the luminescence. Finally, we analyzed compositions and conformations by atomic force microscopy (AFM) and transmission electron microscopy (TEM).

We propose dynamic aggregation of virtual tags in TLB to increase its coverage and improve the overall miss ratio during address translation. Dynamic aggregation exploits both the spatial and temporal locality inherent in most application programs. To support dynamic aggregation, we introduce the use of ternary-CAM (TCAM) cells at the second-level TLB. The modified TLB architecture results in an increase of TLB reach without additional CAM entries. We also adopt bulk prefetching concurrently with aggregation technique to enhance the benefits due to spatial locality. The performance of the proposed TLB architecture is evaluated using SPEC2000 benchmarks concentrating on those that show high data TLB miss ratios. Simulation results indicate a reduction in miss ratios between 59% and 99.99% for all the considered bench-marks except for one benchmark, which has a reduction of 10%. We show that the L2 TLB when enhanced using TCAM cells is an attractive solution to high miss ratios exhibited by applications.

Luminescent properties of the dye molecules can be influenced by the environments as well as intermolecular interactions. Suitable control the aggregation can be useful for optoelectronic device applications. In this thesis, we investigate the spectroscopic properties of dye molecule, DiI_C18, in solutions. Solvents and concentrations are used to control the degree of aggregation. Absorption and emission are used to probe the properties. We use water, methanol, and ethylene glycol as key solvents to control the aggregation effects, especially the methanol solution mixing with water. As the concentration increased, the change of the absorption spectra are observed, which is caused by the aggregation between molecules. Two types of aggregations: head-to-tail structure and parallel structure, are proposed. Head-to-tail structure behaves red-shifted spectrum, and a corresponding shorter decay lifetime. On the contrary, parallel structure aggregation exhibits blue-shifted absorption spectrum and a longer fluorescence lifetime. Both structures are observed at different period after mixing. Only monomer exists in the methanol solution, even at high concentration. However, after missing with water, parallel structure aggregates are formed. Head-to-tail structure aggregates are formed after a much longer period, usually several hours after the mixing. These aggregates not only have different photo-physical properties. After high light intensity illumination, parallel structures are easier to turn into non-fluorescent structures, while head-to-tail structures last a longer period. Monomer structures exhibit the longest period. This provides additional evidence for the formation of different structures in the mixing solutions.

Thesis (Ph.D.)--University of Delaware, 2009. / Principal faculty advisor: Christopher J. Roberts, Dept. of Chemical Engineering. Includes bibliographical references.

Zugl.: Göttingen, Univ., Diss., 2008

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 164-170).

Many neuro-degenerative and metabolic diseases like Parkinson’s and Alzheimer’s are attributed to the effect of mis-folded and aggregated state of proteins in cells. This suggests that the phenomenon of in vivo protein aggregation may be relatively common, perhaps more than currently appreciated. In this study, we aimed to decipher the cause behind an intriguing and potentially related phenomenon observed in yeast cells - a widespread reorganization of hundreds of cytosolic proteins into punctate foci under starvation conditions. The key question that emerges is whether this phenomenon represents organization of proteins into functional assemblies or catastrophic aggregation. This thesis supports the aggregation hypothesis and provides evidence of its role in shaping the dynamics of cellular proteomes. We have been able to demonstrate that the proteins forming foci share a high propensity to aggregate and that these foci may represent sites of homogenous protein aggregation, structures which are typically associated with chaperones. A link between the formation of foci to the yeast aging process has also been established. With evidence correlating protein aggregation propensities to the cellular energy state, we have extended the current "living on the edge" hypothesis (which demonstrates an inverse correlation between protein expression levels and their aggregation propensities). For a specific case of the "purinosome", which is inferred to be a functional enzyme complex responsible for purine biosynthesis, we have shown that the observations may be explained alternatively as a generic protein aggregation phenomenon. This study highlights a systems approach to studying cellular proteins, which can corroborate or provide an alternative explanation to inferences drawn from traditional reductionistic analysis. / text