Engineered Living Materials(ELMs) is a newly emerging field of biotechnology at the interface of synthetic biology and traditional material science. Over the past few years, several kinds of novel ELMs were developed. These materials, derived from organisms including bacteria, fungi and plants, have potential applications in therapeutics, electronics, constructions and environmental remediation. We invented an novel method that enables bacteria to from cohesive thin films through cell surface display of associative proteins. In this thesis, we will first demonstrate that we can genetically encode the mechanical properties of living bacterial films by controlling amino acid sequences of artificial proteins displayed at cell surface. Later, we will show that we can generate bacterial-matrix composite by displaying enzymes and peptides at the cell surface.
\r\n\r\nIn Chapter 1, we review the development of ELMs and existing examples of ELMs. The fundamental definition of ELMs and trends in ELMs development will be presented. Bacterial based ELMs, created either by encapsulating bacteria of interests into a synthetic polymeric matrix or by boosting the natural biosynthetic pathways of biopolymers and mineralization in bacteria will be the major part of discussion. The goal of this chapter is to provide context and background of ELMs research.
\r\n\r\nIn Chapter 2, we discuss the design and preparation method of our own ELM. The process of how we come up with growing bacterial films on perforated polycarbonate membranes and development of suction coating method will be presented. By using model SpyTag-SpyCatcher bacterial assembly system, we unraveled the principles behind making cohesive bacterial films from a single bacterial colony.
\r\n\r\nIn Chapter 3, we discuss controlling bacterial films\u2019 mechanical properties through genetic manipulation. Engineered bacteria displaying artificial unstructured Elastin-like-peptides (ELPs) at cell surface can form cohesive, soft and yielding films with tens of kPa value of Young\u2019s moduli. By merely adding a cysteine at the N-terminal part of the ELP, the engineered bacteria can form relative tough, non-yielding films with 3 times higher Young\u2019s moduli due to formation of intercellular covalent disulfide bond. Apart from having enhanced mechanical strength, such films containing covalent intercellular interactions have abilities to self-heal within 24 hours after being cut into halves.
\r\n\r\nIn chapter 4, we discuss a strategy based on stimulated Raman scattering microscopy to monitor phosphatase-catalyzed mineralization of engineered living bacterial films in situ. Real-time label-free imaging elucidates the mineralization process, quantifies both the organic and inorganic components of the material as functions of time, and reveals spatial heterogeneity at multiple scales. In addition, we correlate the mechanical performance of films with the extent of mineralization.
\r\n\r\nIn chapter 5, we discuss the ability of bacterial protein surface display system to catalyze artificial extracellular matrix formation. We demonstrated that heme-containing peroxidase Apex2 can be fused with autotransporter protein previous described in Chapter 2, 3 and 4, successfully displayed at cell surface and remain functional at catalyzing formation of polymer polyaniline (PANI) in the presence of hydrogen peroxide and aniline monomers at physiological pH. Similarly, by displaying multiple kinds peptide known to mediate silica deposition, we can coat bacteria with silica of different morphologies without reducing the viabilities of bacteria.
\r\n\r\nIn Chapter 6, we discuss the future directions of engineered living materials developed in previous chapters. We propose methods to further improve the mechanical strength of bacterial films, to find \u201csweet-spot\u201d of biomineralization, and to develop artificial hydrophobin.
", "doi": "10.7907/6cqr-vq43", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16362", "collection": "thesis", "collection_id": "16362", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04292024-055507772", "type": "thesis", "title": "Altering Framework Topology and Heteroatom Distributions of Molecular Sieves by Designed Organic Structure-Directing Agents", "author": [ { "family_name": "Park", "given_name": "Youngkyu", "orcid": "0000-0001-7328-7565", "clpid": "Park-Youngkyu" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The growing demand for chemical production combined with the urgent need to mitigate the accelerated climate and environmental changes motivates efforts to create highly efficient and selective catalysts and adsorbents. Zeolites and molecular sieves are a key class of materials for addressing these needs because of their high activity and selectivity with catalytic reactions. Additionally, they can show superior adsorption properties because of their structure and surface polarity that can also give shape selectivity with molecules smaller than ca. 1 nanometer. Further advancements in molecular sieve properties will rely on advancements in preparation methods. To this end, the research results presented here explore synthetic approaches for controlling the framework topology and the heteroatom incorporation within silicate-based molecular sieves by means of the strategic design of their organic structure-directing agents (OSDAs).
\r\n\r\nPart I presents the synthesis of STW-type germanosilicate molecular sieves with high-silica framework compositions and the enrichment of chirality. A chiral OSDA is computationally designed based on the predicted stabilization energy toward the pure-silica STW framework. An improved synthesis route for both enantiomers of the OSDA is developed. The enantiopure OSDA is capable of crystallizing a high-silica STW-type germanosilicate molecular sieve that shows distinct framework compositions from previously reported germanium-rich STW. The enantiomeric enrichment of powdered samples without occluded enantiopure OSDAs is characterized by the dynamical refinement of microcrystal electron diffraction data. The high-silica, enantiomerically enriched STW exhibits the framework stability upon thermal treatment and the enantioselective adsorption of 2-butanol. The results in Part I demonstrate the design strategy of OSDAs for crystallizing stable, enantio-enriched molecular sieves for enantioselective chemical separations and catalysis.
\r\n\r\nIn Part II, the distribution of heteroatoms incorporated within borosilicate molecular sieves is studied with regard to its control by cationic OSDAs. To aid in the characterization of the heteroatom sites within borosilicate molecular sieves, the relationship between the 11B NMR chemical shift and the local geometry of boron within tetrahedrally coordinated silicate frameworks is first investigated. From crystalline borosilicate minerals with highly ordered, tetrahedrally coordinated boron atoms, it is revealed that the chemical shifts from 11B NMR linearly correlate with the local geometric parameters. Further studies on the borosilicate molecular sieves that possess more open space and wider angles suggest that the correlation between the average bond angles and 11B NMR chemical shifts can be employed for the entire class of three-dimensional, crystalline borosilicates. Two structurally similar quaternary ammonium OSDAs with different locations of positive charge are designed and synthesized. MWW-type borosilicate molecular sieves are crystallized by both OSDAs, and the quaternary ammonium moieties in the two OSDAs are found to interact with boron species with significantly different 11B NMR chemical shifts. Using the correlation developed here, the characterization results demonstrate that the heteroatom siting within the molecular sieve framework can be selectively altered by tailoring the OSDA structure in terms of the position of positive charge.
", "doi": "10.7907/d1xj-kn25", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:16362", "collection": "thesis", "collection_id": "16362", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04292024-055507772", "type": "thesis", "title": "Altering Framework Topology and Heteroatom Distributions of Molecular Sieves by Designed Organic Structure-Directing Agents", "author": [ { "family_name": "Park", "given_name": "Youngkyu", "orcid": "0000-0001-7328-7565", "clpid": "Park-Youngkyu" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" }, { "family_name": "Stoltz", "given_name": "Brian M.", "orcid": "0000-0001-9837-1528", "clpid": "Stoltz-B-M" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The growing demand for chemical production combined with the urgent need to mitigate the accelerated climate and environmental changes motivates efforts to create highly efficient and selective catalysts and adsorbents. Zeolites and molecular sieves are a key class of materials for addressing these needs because of their high activity and selectivity with catalytic reactions. Additionally, they can show superior adsorption properties because of their structure and surface polarity that can also give shape selectivity with molecules smaller than ca. 1 nanometer. Further advancements in molecular sieve properties will rely on advancements in preparation methods. To this end, the research results presented here explore synthetic approaches for controlling the framework topology and the heteroatom incorporation within silicate-based molecular sieves by means of the strategic design of their organic structure-directing agents (OSDAs).
\r\n\r\nPart I presents the synthesis of STW-type germanosilicate molecular sieves with high-silica framework compositions and the enrichment of chirality. A chiral OSDA is computationally designed based on the predicted stabilization energy toward the pure-silica STW framework. An improved synthesis route for both enantiomers of the OSDA is developed. The enantiopure OSDA is capable of crystallizing a high-silica STW-type germanosilicate molecular sieve that shows distinct framework compositions from previously reported germanium-rich STW. The enantiomeric enrichment of powdered samples without occluded enantiopure OSDAs is characterized by the dynamical refinement of microcrystal electron diffraction data. The high-silica, enantiomerically enriched STW exhibits the framework stability upon thermal treatment and the enantioselective adsorption of 2-butanol. The results in Part I demonstrate the design strategy of OSDAs for crystallizing stable, enantio-enriched molecular sieves for enantioselective chemical separations and catalysis.
\r\n\r\nIn Part II, the distribution of heteroatoms incorporated within borosilicate molecular sieves is studied with regard to its control by cationic OSDAs. To aid in the characterization of the heteroatom sites within borosilicate molecular sieves, the relationship between the 11B NMR chemical shift and the local geometry of boron within tetrahedrally coordinated silicate frameworks is first investigated. From crystalline borosilicate minerals with highly ordered, tetrahedrally coordinated boron atoms, it is revealed that the chemical shifts from 11B NMR linearly correlate with the local geometric parameters. Further studies on the borosilicate molecular sieves that possess more open space and wider angles suggest that the correlation between the average bond angles and 11B NMR chemical shifts can be employed for the entire class of three-dimensional, crystalline borosilicates. Two structurally similar quaternary ammonium OSDAs with different locations of positive charge are designed and synthesized. MWW-type borosilicate molecular sieves are crystallized by both OSDAs, and the quaternary ammonium moieties in the two OSDAs are found to interact with boron species with significantly different 11B NMR chemical shifts. Using the correlation developed here, the characterization results demonstrate that the heteroatom siting within the molecular sieve framework can be selectively altered by tailoring the OSDA structure in terms of the position of positive charge.
", "doi": "10.7907/d1xj-kn25", "publication_date": "2024", "thesis_type": "phd", "thesis_year": "2024" }, { "id": "thesis:15248", "collection": "thesis", "collection_id": "15248", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05312023-220301021", "primary_object_url": { "basename": "ling_bill_thesis_final3.pdf", "content": "final", "filesize": 20171760, "license": "other", "mime_type": "application/pdf", "url": "/15248/1/ling_bill_thesis_final3.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Acoustic Biomolecules for Diagnostic Ultrasound Imaging", "author": [ { "family_name": "Ling", "given_name": "Bill", "orcid": "0000-0002-1276-7204", "clpid": "Ling-Bill" } ], "thesis_advisor": [ { "family_name": "Shapiro", "given_name": "Mikhail G.", "orcid": "0000-0002-0291-4215", "clpid": "Shapiro-M-G" } ], "thesis_committee": [ { "family_name": "Ismagilov", "given_name": "Rustem F.", "orcid": "0000-0002-3680-4399", "clpid": "Ismagilov-R-F" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Chan", "given_name": "Warren C. W.", "orcid": "0000-0001-5435-4785", "clpid": "Chan-Warren-C-W" }, { "family_name": "Shapiro", "given_name": "Mikhail G.", "orcid": "0000-0002-0291-4215", "clpid": "Shapiro-M-G" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Nanotechnology has enabled significant breakthroughs in the early detection and treatment of disease, but many of these advances rely on expensive and less-accessible imaging modalities. Ultrasound, on the other hand, is a noninvasive imaging modality that stands out for its universal availability, cost-effectiveness, and safety. However, harnessing the benefits of nanomaterials for ultrasound has been challenging due to the size and stability constraints of typical ultrasound contrast agents. Recently, an innovative solution has emerged in the form of gas vesicles (GVs), a class of air-filled protein nanostructures found in certain aquatic microbes. These promising next-generation ultrasound contrast agents offer a crucial bridge between nanotechnology and ultrasonography.
\r\n\r\nIn this thesis, we investigate the in vivo behavior of GVs, explore their potential applications as nanodiagnostic agents, and consider key factors for their future clinical deployment. In Chapter 2, we examine the interactions of GVs with blood components, focusing on imaging performance and immunogenicity. In Chapter 3, we show that intravenously injected GVs are cleared by liver-resident macrophages and subsequently undergo lysosomal degradation. We leverage this finding to develop an ultrasound-based method for visualizing cellular degradative processes and demonstrate its potential as a liver disease diagnostic. In Chapter 4, we introduce bicone GVs, the smallest known ultrasound contrast agent. We show that these sub-80 nm particles can penetrate tumors, deliver potent ultrasound-induced mechanical effects, and are readily engineered for molecular targeting, extended circulation time, and payload conjugation.
\r\n\r\nTogether, these findings highlight the tremendous potential of GVs as injectable nanomaterials for ultrasound imaging, laying the foundation for future studies to further refine the design and application of these agents.
", "doi": "10.7907/va8g-tb47", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15139", "collection": "thesis", "collection_id": "15139", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04142023-055704455", "primary_object_url": { "basename": "Faisal Alshafei - PhD Thesis - FINAL V1.pdf", "content": "final", "filesize": 13075550, "license": "other", "mime_type": "application/pdf", "url": "/15139/1/Faisal Alshafei - PhD Thesis - FINAL V1.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Enhancing the Ethylene and Propylene Selectivities in the Methanol-to-Olefins Reaction by Exploiting the Intricate Relationship between Framework Topology and Acidity", "author": [ { "family_name": "Alshafei", "given_name": "Faisal H.", "orcid": "0000-0003-1808-1374", "clpid": "Alshafei-Faisal-H" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis describes and presents results from several related projects within the theme of molecular sieve synthesis and catalysis. The early part of the thesis focuses on understanding the link between cage size/dimension and acidity (i.e., acid site density and strength) in the methanol-to-olefins (MTO) reaction. This relationship between cage size and acidity, once identified and investigated, is exploited in the latter parts of the thesis to rationally design materials that are able to steer the light olefins product distribution toward either more ethylene or propylene in a significant improvement over SAPO-34 (CHA), the commercial catalyst.
\r\n \r\nIn Chapters 2, 44 zeolites and silicoaluminophosphates (SAPOs) belonging to five frameworks (AEI, CHE, LEV, SWY, and ERI) with a wide range of Si/Al=4-31 and Si/(Al+P)=0.04-0.3, are synthesized and characterized using a myriad of techniques. Their MTO behavior is then systematically investigated to rationalize the effect of cage dimensions on the olefins product distribution as a function of acid site density and strength. The results from this study show that changes in acid site density and strength play a secondary role to the dominating influence of cage architecture on product distribution in AEI- and CHA-type molecular sieves. Decreasing the cage size, in going from AEI and CHA to LEV, SWY, and ERI, however, results in substantial changes in the ethylene-to-propylene ratio (E/P) as a function of acidity. These changes are attributed to differences in the identity and concentration of the hydrocarbon-pool (HP) species that form, particularly in early stages of the reaction.
\r\n \r\nIn Chapters 3 and 4, ERI-type molecular sieves (e.g., SSZ-98, UZM-12, ERI-type zeolites, and SAPO-17) are thoroughly investigated as promising methanol-to-ethylene materials due to their narrow cage size. Specifically, numerous ERI-type molecular sieves are synthesized using several organic structure-directing agents (OSDAs) with varied Si/Al or Si/T-atoms ratios. The list of ERI-related materials synthesized and tested in MTO included a new disordered SAPO, denoted as CIT-16P, which upon thermal treatment in air transforms to SAPO-17 (ERI). The reaction results show that decreasing the Si/Al (or increasing the Si/T) ratio, irrespective of other material properties, improves the E/P of ERI-type molecular sieves (E/P=1.1-1.9) over CHA-type molecular sieves (E/P=0.82-0.85) in MTO. Dissolution-extraction experiments reveal that the rapid formation of cyclic intermediates and the shift in their composition toward less-methylated methylbenzenes and methylnaphthalenes are found to be key to enhancing the ethylene selectivity in ERI-type molecular sieves.
\r\n \r\nIn Chapter 5, several SAT-type molecular sieves are investigated as promising methanol-to-propylene catalysts. This effort entails the synthesis of CIT-17, an SAT SAPO-type molecular sieve, which is isostructural to STA-2 (MgAPO-SAT). Following the successful synthesis of CIT-17, the MTO behavior of several SAT-type molecular sieves (MgAPO, CoAPO, and SAPO) are investigated in MTO. The combination of low acidity of CIT-17 and unique structural features of the narrow SAT-cage lead to a catalytic pathway and mechanism that predominantly favors propylene (propylene-to-ethylene ratios (P/E) of 2-4.2; propylene selectivity of 40-50%). Indeed, CIT-17 achieves one of the highest P/E ratio values reported for this class of materials.
", "doi": "10.7907/btcj-w948", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:15139", "collection": "thesis", "collection_id": "15139", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04142023-055704455", "primary_object_url": { "basename": "Faisal Alshafei - PhD Thesis - FINAL V1.pdf", "content": "final", "filesize": 13075550, "license": "other", "mime_type": "application/pdf", "url": "/15139/1/Faisal Alshafei - PhD Thesis - FINAL V1.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Enhancing the Ethylene and Propylene Selectivities in the Methanol-to-Olefins Reaction by Exploiting the Intricate Relationship between Framework Topology and Acidity", "author": [ { "family_name": "Alshafei", "given_name": "Faisal H.", "orcid": "0000-0003-1808-1374", "clpid": "Alshafei-Faisal-H" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Manthiram", "given_name": "Karthish", "orcid": "0000-0001-9260-3391", "clpid": "Manthiram-Karthish" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis describes and presents results from several related projects within the theme of molecular sieve synthesis and catalysis. The early part of the thesis focuses on understanding the link between cage size/dimension and acidity (i.e., acid site density and strength) in the methanol-to-olefins (MTO) reaction. This relationship between cage size and acidity, once identified and investigated, is exploited in the latter parts of the thesis to rationally design materials that are able to steer the light olefins product distribution toward either more ethylene or propylene in a significant improvement over SAPO-34 (CHA), the commercial catalyst.
\r\n \r\nIn Chapters 2, 44 zeolites and silicoaluminophosphates (SAPOs) belonging to five frameworks (AEI, CHE, LEV, SWY, and ERI) with a wide range of Si/Al=4-31 and Si/(Al+P)=0.04-0.3, are synthesized and characterized using a myriad of techniques. Their MTO behavior is then systematically investigated to rationalize the effect of cage dimensions on the olefins product distribution as a function of acid site density and strength. The results from this study show that changes in acid site density and strength play a secondary role to the dominating influence of cage architecture on product distribution in AEI- and CHA-type molecular sieves. Decreasing the cage size, in going from AEI and CHA to LEV, SWY, and ERI, however, results in substantial changes in the ethylene-to-propylene ratio (E/P) as a function of acidity. These changes are attributed to differences in the identity and concentration of the hydrocarbon-pool (HP) species that form, particularly in early stages of the reaction.
\r\n \r\nIn Chapters 3 and 4, ERI-type molecular sieves (e.g., SSZ-98, UZM-12, ERI-type zeolites, and SAPO-17) are thoroughly investigated as promising methanol-to-ethylene materials due to their narrow cage size. Specifically, numerous ERI-type molecular sieves are synthesized using several organic structure-directing agents (OSDAs) with varied Si/Al or Si/T-atoms ratios. The list of ERI-related materials synthesized and tested in MTO included a new disordered SAPO, denoted as CIT-16P, which upon thermal treatment in air transforms to SAPO-17 (ERI). The reaction results show that decreasing the Si/Al (or increasing the Si/T) ratio, irrespective of other material properties, improves the E/P of ERI-type molecular sieves (E/P=1.1-1.9) over CHA-type molecular sieves (E/P=0.82-0.85) in MTO. Dissolution-extraction experiments reveal that the rapid formation of cyclic intermediates and the shift in their composition toward less-methylated methylbenzenes and methylnaphthalenes are found to be key to enhancing the ethylene selectivity in ERI-type molecular sieves.
\r\n \r\nIn Chapter 5, several SAT-type molecular sieves are investigated as promising methanol-to-propylene catalysts. This effort entails the synthesis of CIT-17, an SAT SAPO-type molecular sieve, which is isostructural to STA-2 (MgAPO-SAT). Following the successful synthesis of CIT-17, the MTO behavior of several SAT-type molecular sieves (MgAPO, CoAPO, and SAPO) are investigated in MTO. The combination of low acidity of CIT-17 and unique structural features of the narrow SAT-cage lead to a catalytic pathway and mechanism that predominantly favors propylene (propylene-to-ethylene ratios (P/E) of 2-4.2; propylene selectivity of 40-50%). Indeed, CIT-17 achieves one of the highest P/E ratio values reported for this class of materials.
", "doi": "10.7907/btcj-w948", "publication_date": "2023", "thesis_type": "phd", "thesis_year": "2023" }, { "id": "thesis:14350", "collection": "thesis", "collection_id": "14350", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08312021-211824138", "primary_object_url": { "basename": "Holman_Elizabeth_2021_thesisfull_final.pdf", "content": "final", "filesize": 3885043, "license": "other", "mime_type": "application/pdf", "url": "/14350/1/Holman_Elizabeth_2021_thesisfull_final.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "Developing Technologies for Real-Time Whole-Organism Imaging via FTIR Spectromicroscopy", "author": [ { "family_name": "Holman", "given_name": "Elizabeth Anne", "orcid": "0000-0002-5158-4689", "clpid": "Holman-Elizabeth-Anne" } ], "thesis_advisor": [ { "family_name": "Sternberg", "given_name": "Paul W.", "orcid": "0000-0002-7699-0173", "clpid": "Sternberg-P-W" }, { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" }, { "family_name": "Sternberg", "given_name": "Paul W.", "orcid": "0000-0002-7699-0173", "clpid": "Sternberg-P-W" }, { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "FTIR spectromicroscopy heavily resides in the domain of cell-based and tissue-based studies when focusing on its direct application to biological systems. The goal of the reported graduate research is to extend FTIR spectromicroscopy to multicellular whole-organism imaging, ideally for non-invasive, non-destructive, and label-free spatiochemical imaging of biological model Caenorhabditis elegans (C. elegans). With modern optics, detector, and light source technologies implemented at synchrotron facilities, this thesis focuses on exploring the feasibility of multicellular whole-organism imaging while identifying challenges and presenting working solutions for them.
", "doi": "10.7907/es4r-kq84", "publication_date": "2022", "thesis_type": "phd", "thesis_year": "2022" }, { "id": "thesis:13964", "collection": "thesis", "collection_id": "13964", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09232020-234052730", "primary_object_url": { "basename": "Kempler _ Thesis _ Revised2.pdf", "content": "final", "filesize": 19760134, "license": "other", "mime_type": "application/pdf", "url": "/13964/73/Kempler _ Thesis _ Revised2.pdf", "version": "v17.0.0" }, "type": "thesis", "title": "High-Aspect Ratio Structures in Light-Absorbers and Electrocatalysts for Solar Fuels Devices", "author": [ { "family_name": "Kempler", "given_name": "Paul Andrew", "orcid": "0000-0003-3909-1790", "clpid": "Kempler-Paul-Andrew" } ], "thesis_advisor": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "orcid": "0000-0001-5245-0538", "clpid": "Lewis-N-S" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Seinfeld", "given_name": "John H.", "orcid": "0000-0003-1344-4068", "clpid": "Seinfeld-J-H" }, { "family_name": "Giapis", "given_name": "Konstantinos P.", "orcid": "0000-0002-7393-298X", "clpid": "Giapis-K-P" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "orcid": "0000-0001-5245-0538", "clpid": "Lewis-N-S" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Solar fuels devices produce hydrogen fuel from water and sunlight and address a critical societal need for inexpensive, long-duration energy storage. Such devices are prepared from combinations of light-absorbing semiconductors and catalysts to sunlight to drive thermodynamically uphill reactions. This dissertation puts forth strategies for controlling the three-dimensional structure of semiconductors, electrocatalysts, and the film of gas bubbles evolved on the top and bottom of a solar fuels device. High-aspect ratio features led to unexpected effects in semiconductor/electrocatalyst assemblies. Optical losses were decoupled from the mass-loading of cobalt phosphide and copper electrocatalysts integrated onto silicon microwire photocathodes for the photoelectrochemical generation of hydrogen and hydrocarbons, respectively. Anti-reflective silicon microcone arrays were patterned with continuous films of Pt or CoP particles with minimal reflection losses due to the catalyst films. Transparent metal films were prepared from nanostructured metal phosphides, a class of earth-abundant hydrogen evolution catalysts. Silicon microwire array (photo)electrode surfaces were used to force bubbles away from electrocatalyst surfaces, even when oriented against gravity, leading to sustained operation in the absence of external convection.
", "doi": "10.7907/xpty-9891", "publication_date": "2021", "thesis_type": "phd", "thesis_year": "2021" }, { "id": "thesis:13614", "collection": "thesis", "collection_id": "13614", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01102020-003449091", "type": "thesis", "title": "Resistance is Futile: Physical Science, Systems Biology and Single-Cell Analysis to Understanding the Plastic and Heterogeneous Nature of Melanoma and Their Role in Non-Genetic Drug Resistance", "author": [ { "family_name": "Su", "given_name": "Yapeng", "orcid": "0000-0002-6305-8467", "clpid": "Su-Yapeng" } ], "thesis_advisor": [ { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Baltimore", "given_name": "David L.", "clpid": "Baltimore-D-L" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" }, { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Baltimore", "given_name": "David L.", "clpid": "Baltimore-D-L" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Melanoma is the most deadly form of skin cancer due to its great metastatic potential. Targeted therapy that inhibits the BRAF-V600E driver mutation has shown impressive initial responses in melanoma patients. However, drug resistance, as the universal phenomenon for any cancer therapy, always limits treatment efficacy and compromises outcomes. As the early-step of resistance development, non-genetic mechanisms enable cancer cells to transition into a drug-resistant state in as early as a few days after drug treatment without alteration of the genome. This early mechanism is, to a large extent, due to the heterogeneous and highly plastic nature of tumor cells. Therefore, it imperative to understand the plastic and heterogeneous nature of the melanoma cells in order to identify combination therapies that can overcome resistance.
\r\n\r\nIn this thesis, we investigate these two fundamental natures of non-genetic drug resistance using BRAF inhibition of BRAF-mutant melanomas as the model system. These melanoma cells undergo multi-step, reversible drug-induced cell-state transitions from the original sensitive phenotype to a drug-resistant one.
\r\n\r\nWe first conducted bulk analysis to characterize the detailed kinetics of the entire transition from drug-sensitive state towards drug-resistant state, revealing expression changes of thousands of genes and extensive chromatin remodeling. A 3-step computational biology approach greatly simplified the complexity and revealed that the whole cell-state transition was controlled by a gene module activated within just the first three days of drug treatment, with the RelA transcription factor driving chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes towards resistance. From there, a detailed mechanism connecting tumor epigenetic plasticity with non-genetic drug resistance was resolved through in-depth molecular biology experiments. The mechanism was validated in clinical patient samples.
\r\n\r\nWe further investigated heterogeneity by moving from bulk cellular studies to single-cell analysis. The single-cell view further revealed that two driving forces from both cell-state interconversions and phenotype-specific drug selection control the cell-state transition dynamics. The single-cell studies also pinpointed the signaling network hub, RelA, as the driver molecule of the initiation of the adaptive transition. These two competing driving forces were further quantitatively modeled via a thermodynamic-inspired surprisal analysis and a modified Fokker-Planck-type kinetic model.
\r\n\r\nFinally, using integrated single-cell proteomic and metabolic technology I developed to characterize the early-stage signaling and metabolic changes upon initial drug responses, we further identified two distinct paths connecting drug-sensitive and drug-tolerant states. Melanoma cells exclusively traverse one of the two paths depending on the level of MITF in the drug-na\u00efve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities and are independently druggable.
\r\n\r\nIn total, this thesis combines and synergizes various physical science and systems biology approaches together with several unique single-cell technologies and analysis to obtain a deep and comprehensive understanding of non-genetic drug resistance in cancer. The findings from this thesis provide several novel insights into the rational design of effective combination therapy for overcoming the development of resistance in response to cancer treatments.
", "doi": "10.7907/78ZP-Y270", "publication_date": "2020", "thesis_type": "phd", "thesis_year": "2020" }, { "id": "thesis:11328", "collection": "thesis", "collection_id": "11328", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12232018-185711169", "type": "thesis", "title": "Computational Heterogeneous Electrochemistry \u2013 From Quantum Mechanics to Machine Learning", "author": [ { "family_name": "Huang", "given_name": "Yufeng", "orcid": "0000-0002-0373-2210", "clpid": "Huang-Yufeng" } ], "thesis_advisor": [ { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "thesis_committee": [ { "family_name": "Miller", "given_name": "Thomas F.", "clpid": "Miller-T-F" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Because of coulomb interactions and complex surface morphologies, rigorous methods for heterogeneous electrochemical catalysis were not well-established. Thus, for different types of electrochemical systems, a specific strategy must be adapted. In this thesis, we first used the cluster model to study the chemistry on a 1D chain of MoS2 edges. Then, a rigorous grand canonical potential kinetics (GCP-K) method was developed for general crystalline systems. Starting from quantum mechanical calculations, the method gave rise to a different picture from the traditional description given by the Butler-Volmer kinetics. Next, we studied the chemical selectivity of CO2 reduction on polycrystalline copper nanoparticles. Because of the complexity of the reaction sites, we combined the reactive force field, density functional theory, and machine learning method to predict the reactive sites on 20,000 sites on a roughly 200,000-atom nanoparticle. Such a strategy opens up new way to understand chemistries on a much wider range of complex structures that were impossible to study theoretically. Lastly, we formulated a machine learning force field strategy using atomic energies for amorphous systems. We have shown that such a method can be used to reproduce quantum mechanical accuracies for molecular dynamics. This method will enable the accurate study of the dynamics of heterogeneous systems during electrochemical reactions. In summary, we have developed quantum chemical methods and machine learning strategies to reformulate rigorous ways to study a wide range of heterogeneous electrochemical catalysts.
", "doi": "10.7907/MCGV-Y790", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11702", "collection": "thesis", "collection_id": "11702", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06072019-032220561", "type": "thesis", "title": "I. Shape Selectivity of Small-pore Molecular Sieves for the Methanol-to-Olefins Reaction and II. Synthesis and Topotactic Transformation of Germanosilicate CIT-13", "author": [ { "family_name": "Kang", "given_name": "Jong Hun", "orcid": "0000-0002-4197-9070", "clpid": "Kang-Jong-Hun" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Rossman", "given_name": "George Robert", "clpid": "Rossman-G-R" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis presents research results from two projects involving molecular sieves. These investigations concern their synthesis, characterization and use as heterogeneous catalysis.
\r\n\r\nIn part I, the shape selectivity in the methanol-to-olefins (MTO) reaction is studied, and a new molecular sieve structure \u2013 MTO reaction selectivity relationship is developed. 17 zeolites and 13 phosphate-based molecular sieves having 14 selected cage-type/small-pore topologies (CHA, AFX, SFW, LEV, ERI, DDR, AEI, RTH, ITE, SAV, LTA, RHO, KFI, and UFI) are synthesized. The MTO reaction is performed using these catalysts at the same reaction conditions.
\r\n\r\nThe reaction results lead to the conclusion that the molecular sieve cage topology is the most important structural factor that primarily determines the olefin product distribution. For example, AEI and CHA are synthesized with four different elemental compositions (zeolite, SAPO, CoAPO, MgAPO). Regardless of differences in elemental compositions, very similar product distribution patterns are observed in each of the isostructural groups of molecular sieves. Additionally, other isostructural pairs of SAPOs and zeolites show similar product distributions.
\r\n\r\nThe reaction results from 14 topologies are grouped into four categories. Category I consists of CHA, AFX, SFW, and other GME-related topologies. Catalysts having these topologies show ethylene-to-propylene ratios close to one. Category II is a group of ERI and LEV which generate more ethylene than propylene. Category III is a group of DDR, AEI, RTH, ITE, and SAV which shows propylene selectivities higher than those of ethylene. Category IV is a group of LTA, RHO, KFI, and UFI which possess LTA-cages. These types of catalysts give high butylene selectivities.
\r\n\r\nThe concept of cage-defining ring and its size is introduced as a reliable geometric indicator on the basis of a hypothetical ellipsoid cage model. The cage-defining ring size can be easily calculated from crystallographic information which is available online. A strong correlation is found between the cage-defining ring sizes and the four categories of reaction behavior.
\r\n\r\nIn part II, an extra-large-pore germanosilicate molecular sieve CIT-13 with 14- and 10-ring pores is synthesized using monoquaternary, methylbenzylimidazolium-derivative OSDAs, and the synthesis conditions are optimized. Fluoride-free synthetic pathways for pure germanosilicate CIT-13 and isomorphous aluminum substitution in synthesis of aluminogermanosilicate CIT-13 are also described. The nature of disorder in the arrangement within CIT-13 framework is discussed, and its physicochemical properties compared to a UTL-type germanosilicate IM-12.
\r\n\r\nA comprehensive network of topotactic transformation and postsynthetic modification pathways starting from germanosilicate CIT-13 (Ge-CIT-13) is described. The moisture-mediated transformation of Ge-CIT-13 into another extra-large-pore CFI-type germanosilicate (Ge-CIT-5) is discovered, and the role of sorbed water in the transformation kinetics studied. The resultant Ge-CIT-5 is the first germanosilicate molecular sieve having a CFI topology, and the corresponding transformation is also the first inter-germanosilicate transformation occurring at room temperature. The microporosity of Ge-CIT-5 matched well with the reference pure-silica CIT-5 synthesized using the sparteine-type OSDA.
\r\n\r\nThe acid-delamination processes of Ge-CIT-13 and Ge-CIT-5 are investigated. Ge-CIT-13 can be transformed into two new frameworks, CIT-14 with 12- and 8-ring pores and CIT-15 with 10-ring pores, on the basis of an ADOR-type topotactic transformation. The inverse sigma transformation of Ge-CIT-13 directly into CIT-14 is also firstly described. The conventional acid-delamination of Ge-CIT-13 does not yield Ge-CIT-5. However, the CIT-15-type material is obtained via the base-delamination pathway from Ge-CIT-5. The postsynthetic alumination of Ge-CIT-13 and Ge-CIT-5 is also achievable.
\r\n", "doi": "10.7907/PG34-B728", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11720", "collection": "thesis", "collection_id": "11720", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06072019-161940566", "primary_object_url": { "basename": "grantz_amanda_2019_thesis.pdf", "content": "final", "filesize": 13534786, "license": "other", "mime_type": "application/pdf", "url": "/11720/1/grantz_amanda_2019_thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Aerosol Particle Measurements: Strategies for Health-Relevant Data Collection and Analysis", "author": [ { "family_name": "Grantz Pansing", "given_name": "Amanda", "clpid": "Grantz-Pansing-Amanda" } ], "thesis_advisor": [ { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "thesis_committee": [ { "family_name": "Seinfeld", "given_name": "John H.", "clpid": "Seinfeld-J-H" }, { "family_name": "Wennberg", "given_name": "Paul O.", "clpid": "Wennberg-P-O" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Particulate matter (PM) is an important component of outdoor and indoor air pollution that can cause significant harm to human health. The present work, organized into two parts, introduces strategies for optimizing the collection and analysis of airborne particle measurements to inform PM health-effect research.
\r\n\r\nPart I focuses on the fundamental aerosol data analysis task of interpreting indirect measurements of particle size to reveal the distribution of sizes of particles in a sampled aerosol. An approach to this aerosol data inversion problem is developed that shows improved particle size distribution recovery compared to other common approaches described in the literature. This inverse solution method incorporates cubic spline interpolation to represent the particle size distribution within a discrete linear model of the inverse problem while placing no constraints on the number or spacing of solution points. The inverse problem setup can then interface with three established numerical methods for solution computation. The accuracy of this procedure is demonstrated through analysis of test-case data for differential mobility analyzer systems. Source code and supporting documentation are also provided to encourage researchers to use and adapt this inversion algorithm for analyzing data collected from existing as well as potential future measurement systems.
\r\n\r\nPart II of this work focuses on the retrieval of health-relevant information from aerosol particle measurement data. The inversion analysis introduced in Part I is incorporated into an extended analysis procedure for evaluating the metrics of PM exposure and respiratory dose that can be obtained from different measurement systems. Applying this evaluation procedure to a range of existing and potential future measurement techniques reveals that full characterization of particle size distributions need not be time and resource intensive and should be pursued for the great benefits this information would provide to health studies. Not only can size distribution information permit lung tissue dose estimates through a set of relatively simple calculations, but a single set of size distribution data can be analyzed and reanalyzed to provide dose estimates for human populations of interest by applying the appropriate respiratory tract deposition profiles. The measurement evaluation procedure developed here reveals target criteria for the particle characterization necessary to provide sufficient exposure and dose information for health studies. The intent is not to eliminate the current measurements and standards, but to help direct future developments in health-related aerosol particle measurement design.
", "doi": "10.7907/Y730-W245", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:11513", "collection": "thesis", "collection_id": "11513", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05132019-140157302", "type": "thesis", "title": "Stereoselective Synthesis of Diazaheterocycles by Decarboxylative Asymmetric Allylic Alkylation", "author": [ { "family_name": "Sun", "given_name": "Alexander Wang", "orcid": "0000-0001-6639-4469", "clpid": "Sun-Alexander-Wang" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The Stoltz group has developed transition-metal catalyzed methods to synthesize quaternary and tetrasubstituted stereocenters over the past fourteen years. Using iridium, palladium, copper, and nickel, the group has synthesized a myriad cyclic and acylic quaternary motifs of incredible synthetic and medicinal utility. This thesis presents several projects that further expand the scope of Pd-catalyzed decarboxylative allylic alkylation and examine its applications to the synthesis of medicinally important small molecules. The synthesis of chiral gem-disubstituted five-, six-, and seven-membered diazaheterocycles is presented. Their utility as building blocks for complex medicinal compounds is highlighted. Then, we explore the utility of gem-disubstituted heterocycles in the context of medicinal chemistry.
", "doi": "10.7907/E2YS-GJ06", "publication_date": "2019", "thesis_type": "phd", "thesis_year": "2019" }, { "id": "thesis:10938", "collection": "thesis", "collection_id": "10938", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05252018-104854693", "primary_object_url": { "basename": "Dissertation - Final.pdf", "content": "final", "filesize": 7373482, "license": "other", "mime_type": "application/pdf", "url": "/10938/66/Dissertation - Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Cyclic Polyolefins via Ring-Expansion Metathesis Polymerization", "author": [ { "family_name": "Edwards", "given_name": "Julian Peter", "orcid": "0000-0001-9243-8197", "clpid": "Edwards-Julian-Peter" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The synthesis of cyclic polyolefins prepared using a supported, molecular ring-expansion metathesis polymerization catalyst is described. The synthesis of the catalysts, themselves, is described in detail. Additionally, thorough physical characterization of cyclic polymers with comparison to linear polymer analogues is reported.
", "doi": "10.7907/kmh1-y153", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:11033", "collection": "thesis", "collection_id": "11033", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06062018-180959061", "type": "thesis", "title": "Targeted Nanoparticle Delivery of Therapeutics Across the Blood-Brain and Blood-Tumor Barriers to Breast Cancer Brain Metastases", "author": [ { "family_name": "Wyatt", "given_name": "Emily Ann", "orcid": "0000-0002-7534-0582", "clpid": "Wyatt-Emily-Ann" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Shapiro", "given_name": "Mikhail G.", "clpid": "Shapiro-M-G" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "clpid": "Mazmanian-S-K" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Brain metastases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer are presenting an increasing problem in the clinic. While HER2-targeted therapies effectively control systemic disease, their efficacy against brain metastases is hindered by their inability to penetrate the blood-brain and blood-tumor barriers (BBB and BTB). One promising strategy to increase brain penetration of systemic therapeutics is to exploit endogenous transport systems at the BBB to shuttle drugs into the brain. Previous studies showed that gold nanoparticles designed to shed transferrin receptor (TfR)-targeting ligands under acidic conditions encountered during transcytosis of the BBB demonstrated increased accumulation in the brain. The focus of this work was to determine whether therapeutic, TfR-targeted nanoparticles using an improved acid-cleavable chemistry could be used to deliver therapeutically useful amounts of drug to the brain.
\r\n\r\nTo accomplish this goal, a new animal model of HER2-positive breast cancer brain metastasis was developed in an attempt to create a clinically representative, impermeable barrier to standard therapeutics. This new model establishes brain metastases by methods that more closely resemble the human disease, forming whole-body tumors that eventually metastasize to the brain. Brain metastases formed by this new methodology show no response to standard HER2-targeted agents, mimicking the clinical situation.
\r\n\r\nNext, efficacy and brain uptake of TfR-targeted, single-agent therapeutic nanoparticles were investigated in the newly developed model, as well as two common models from the literature. These nanoparticles show significant tumor growth delay and increased accumulation in both brain metastases and healthy brain tissue in all three models, highlighting their therapeutic potential. Additionally, non-BBB-penetrant small molecule and non-targeted nanoparticle therapeutics elicit a substantial antitumor response as well as brain tumor accumulation in the most commonly used literature model. In contrast, the new model and one gaining popularity in the literature provide for a more clinically relevant, impermeable barrier to non-BBB-penetrant agents, indicating that the method used to establish brain metastases can affect efficacy and brain uptake of therapeutics.
", "doi": "10.7907/5qpd-0736", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:10993", "collection": "thesis", "collection_id": "10993", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012018-005336099", "type": "thesis", "title": "Advancing the Protein-Catalyzed Capture Agent Technology to New Frontiers", "author": [ { "family_name": "McCarthy", "given_name": "Amy Michelle", "orcid": "0000-0003-3456-0383", "clpid": "McCarthy-Amy-Michelle" } ], "thesis_advisor": [ { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "thesis_committee": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "orcid": "0000-0003-1464-2461", "clpid": "Dougherty-D-A" }, { "family_name": "Peters", "given_name": "Jonas C.", "orcid": "0000-0002-6610-4414", "clpid": "Peters-J-C" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Protein-catalyzed capture (PCC) agents are a nascent synthetic aptamer technology that was first disclosed in 2009. In addition to reviewing the different classes of peptide-based aptamers in chapter 1, this thesis records efforts to advance the PCC technology in two ways. First, in chapter 2 the development of a barcoded-rapid assay platform (B-RAP) technology enables the parallel analysis of up to fifteen PCC agents at once as well as dramatically shortening the time required to characterize the binding affinity for a pool of ligands from weeks to a couple of days. Secondly, the capture agent technology was utilized to target difficult proteins. Kirsten rat sarcoma (KRas) protein is a GTPase that acts as a light switch for several important cellular signaling pathways. Oncogenic variants of KRas are responsible for driving roughly 20-25% of all cancers, but KRas is considered \u201cundruggable\u201d from a small molecule targeting point of view. We report the identification of PCC ligands that bind to conserved allosteric switches on KRas and inhibit the protein\u2019s GTPase enzymatic activity. The biomarker Plasmodium falciparum Histidine Rich Protein II (HRP2) presents an unusual challenge as it is a highly variable, unstructured and sticky protein. In chapter 3 we report on efforts to develop low nM binding capture agents against highly prevalent epitopes of HRP2, and the use of medicinal chemistry optimization to prepare structurally related variants of the lead capture agent for probing the structure-activity relationship and how it affects binding to HRP2.", "doi": "10.7907/HHP5-1Z83", "publication_date": "2018", "thesis_type": "phd", "thesis_year": "2018" }, { "id": "thesis:9903", "collection": "thesis", "collection_id": "9903", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08192016-131948034", "primary_object_url": { "basename": "Ji_Yuewei_2017_thesis_final.pdf", "content": "final", "filesize": 9644883, "license": "other", "mime_type": "application/pdf", "url": "/9903/1/Ji_Yuewei_2017_thesis_final.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Organic Structure Directing Agent Free Synthesis of Small Pore Zeolite Catalysts for the Methanol-to-Olefins Reaction\r ", "author": [ { "family_name": "Ji", "given_name": "Yuewei Lucy", "orcid": "0000-0002-6625-4252", "clpid": "Ji-Yuewei-Lucy" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Rossman", "given_name": "George Robert", "clpid": "Rossman-G-R" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Light olefins, ethylene and propylene, are two of the highest produced petrochemicals globally. The methanol-to-olefins (MTO) reaction is a promising route for making these chemicals from non-petroleum feedstocks such as natural gas and coal that has been successfully commercialized. The catalysts employed for this reaction are typically microporous molecular sieves with Br\u00f8nsted acidity, e.g., zeolites and silicoaluminophosphates, that generally require costly organic structure directing agents (OSDAs) to synthesize.
\r\n\r\nThis thesis explores an alternative, low cost method for synthesizing small pore zeolite catalysts for the MTO reaction without the use of OSDAs. Small pore zeolites are first synthesized in the absence of OSDAs. The resulting high-aluminum materials are then converted into useful catalysts via high temperature (500-800\u00b0C) steam treatments that extract a portion of the framework aluminum, thereby modifying the acid site concentration, pore structure and catalytic behavior of the materials. This synthesis method is demonstrated on three small pore zeolite structures that are prepared without using OSDAs: CHA, RHO and KFI. In the as-synthesized forms, these materials deactivate rapidly when evaluated as catalysts for the MTO reaction due to their high aluminum contents. Upon steam treatment, however, improved catalyst lifetimes and olefin selectivities are observed that are attributed to a decrease in the total Br\u00f8nsted acid site concentration and the creation of mesopores that facilitate transport of reactants and products.
\r\n\r\nImprovements in the activity were observed for all three of the zeolites chosen for investigation with CHA-type zeolites performing best, though differences in olefin selectivities were observed. Poisoning of acid sites located in the mesopores and on external surface of the steamed zeolites did not change the observed product distribution, suggesting that these differences do not arise from secondary reactions of olefins and instead may be attributed to differences in the pore structures.
\r\n\r\nOverall, the successful demonstration of this catalyst preparation method on three different zeolite structures suggests that it may be a useful route for converting any small pore zeolite that can be synthesized without using OSDAs into catalysts that may be useful for reactions like MTO.
\r\n", "doi": "10.7907/Z9MG7MG0", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10279", "collection": "thesis", "collection_id": "10279", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06052017-104255604", "primary_object_url": { "basename": "BlumenfeldFinalThesis.pdf", "content": "final", "filesize": 19643366, "license": "other", "mime_type": "application/pdf", "url": "/10279/1/BlumenfeldFinalThesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Covalent Functionalization of Metal-Oxide Surfaces with Non-Traditional Ligands", "author": [ { "family_name": "Blumenfeld", "given_name": "Carl Michael", "clpid": "Blumenfeld-Carl-Michael" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" } ], "thesis_committee": [ { "family_name": "Rossman", "given_name": "George Robert", "orcid": "0000-0002-4571-6884", "clpid": "Rossman-G-R" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "orcid": "0000-0001-5245-0538", "clpid": "Lewis-N-S" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Herein detailed are the syntheses, properties, and applications of metal-oxide nanosubstrates\r\ncovalently functionalized with two classes of materials, inorganic macrocycles called\r\ncorroles, and genomic deoxyribonucleic acid (DNA). These products have found biomedical\r\napplications in tumor imaging and chemotherapeutic sequestration, respectively. Both\r\nclasses of prepared materials are the first of their kind.
\r\n\r\nCorroles are tetrapyrrolic macrocycles, which have found applications in tumor imaging and\r\ntreatment, catalysis, solar fuels, and energy conversion. The direct functionalization of\r\nmetal-oxides with inorganic macrocycles, including corroles, has largely revolved around\r\nthe formation of hydrogen bonding type interactions between the substrate and the ligand.\r\nHydrogen bonding motifs result in materials with only moderate stability due to solvent\r\ndissolution. In the first three chapters of this thesis, the scalable preparation of 5,10,15-\r\n(trispentafluorophenyl) corrole and its subsequent covalent functionalization of metal-oxide\r\nsurfaces are discussed.
\r\n\r\nChapter 1 details mechanistic elements of the oligomerization and oxidative cyclization of\r\n5,10,15-(trispentafluorophenyl) corrole from pentafluorobenzaldehyde and pyrrole. Prior to\r\nthis work the synthesis of triperfluoroaryl corroles was dangerously exothermic and could\r\nonly be carried out on milligram scale. Mechanistic insights led to a safe and scalable\r\nsynthesis of the desired corrole species, achieving a 17.0 % yield (4.58 g). A detailed\r\ndiscussion of the covalent functionalization of the surface of TiO2 with chlorosulfonated\r\nderivatives of 5,10,15-tris(pentafluorophenyl) corrole is presented in Chapter 2. The\r\nchlorosulfonated species investigated include the freebase, gallium, and aluminum corroles.\r\nHydroxyl groups on the metal-oxide react with the chlorosulfonyl groups of the corrole ring\r\nvia nucleophilic attack, resulting in the formation of sulfonic ester linkages. The aluminum\r\nspecies was further investigated as a potential near-infrared optical contrast agent. The\r\ndetails of this study, described in Chapter 3, include imaging experiments with immortalized\r\nhuman cancer lines and harvested mouse hepatocytes. This nanoconjugate exhibited low\r\ntoxicity and efficient cellular uptake.
\r\n\r\nConventional chemotherapy agents that target DNA are notorious for producing severe\r\nside-effects. Sequestering chemotherapeutics that enters systemic circulation, in a process\r\ndeemed \u201cChemoFiltration,\u201d is a strategy for reducing off-target toxicity. Materials capable\r\nof such activity have yet to be fully realized. Reported in Chapter 4 are the first methods\r\ncovalent attachments of genomic DNA to surfaces, namely magnetite (Fe3O4) nanoparticles,\r\nvia two separate strategies. These materials show efficacy in removing doxorubicin,\r\ncisplatin, and epirubicin from biologically relevant solutions. A device coated with this\r\nmaterial demonstrated in vivo activity in a porcine model.
", "doi": "10.7907/Z9FJ2DT7", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10195", "collection": "thesis", "collection_id": "10195", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05232017-150306598", "type": "thesis", "title": "Studies in Palladium-Catalyzed Allylic Alkylation: Enantioselective Total Syntheses of Structurally Diverse Alkaloids", "author": [ { "family_name": "Pritchett", "given_name": "Beau Patrick", "orcid": "0000-0001-9922-9160", "clpid": "Pritchett-Beau-Patrick" } ], "thesis_advisor": [ { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "thesis_committee": [ { "family_name": "Reisman", "given_name": "Sarah E.", "clpid": "Reisman-S-E" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Presented herein are three projects, all unified by the use of palladium-catalyzed, enantioconvergent, decarboxylative allylic alkylations to synthesize stereochemically rich, nitrogen-containing small molecules. The ubiquity of nitrogen in biologically active natural products and pharmaceutical ingredients necessitates perpetual exploration and development of relevant small molecules. Highly robust palladium-catalyzed allylic alkylation reactions of non-stabilized enolates enable the construction of sterically encumbered all-carbon quaternary and tetrasubstituted tertiary stereocenters present within such targets.
\r\n\r\nThe successful development of a novel substrate class for palladium-catalyzed allylic alkylation, namely dihydropyrido[1,2-a]indolones (DHPIs), has enabled divergent syntheses of multiple monoterpene indole alkaloids. By setting the C20 quaternary stereocenter present within these alkaloids at an early stage in the synthesis, the remaining stereocenters can be forged with exquisite levels of control. Critical to the success of this work was the identification of highly tunable and predictable cyclizations between an indole and a C2-tethered iminium moiety. Regiodivergent cyclizations were used to complete the first catalytic enantioselective total synthesis of (\u2013)-goniomitine, along with efficient formal syntheses of (+)-aspidospermidine and (\u2013)-quebrachamine. Stereodivergent cyclization strategies were then employed in total syntheses of (+)-limaspermidine and (+)-kopsihainanine A. Synthetic efforts toward the highly caged Kopsia alkaloids (\u2013)-kopsinine, (\u2013)-kopsinilam, and (\u2013)-kopsifoline G are also discussed.
\r\n\r\nLastly, the synthesis of challenging alpha-quaternary Mannich-type products was accomplished through a simple, elegant inversion of strategy. The chiral building blocks made available by this technology bear significant potential in the realm of medicinal chemistry. Furthermore, this work enabled rapid total syntheses of (\u2013)-isonitramine and (+)-sibirinine.
", "doi": "10.7907/Z9ZG6Q9Q", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10242", "collection": "thesis", "collection_id": "10242", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06012017-074605131", "primary_object_url": { "basename": "170531 Rapp_Thesis_May2017_Final.pdf", "content": "final", "filesize": 5582593, "license": "other", "mime_type": "application/pdf", "url": "/10242/1/170531 Rapp_Thesis_May2017_Final.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Diffusion and Molecular Association in Artificial Protein Hydrogels", "author": [ { "family_name": "Rapp", "given_name": "Peter Butterweck", "orcid": "0000-0002-9586-2126", "clpid": "Rapp-Peter-Butterweck" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "thesis_committee": [ { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "clpid": "Mazmanian-S-K" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Artificial proteins may be programmed to reversibly self-assemble into water-soluble networks, or \u201chydrogels\u201d, by encoding them with terminal coiled-coil forming domains. Such networks are model viscoelastic materials. The well-defined molecular structures adopted by proteins, combined with their facile preparation by recombinant synthesis, invite a careful exploration of the relationship between protein sequence and the resulting network properties.
\r\n\r\nThis work explores the relationship between network reorganization and diffusion from the perspective of single chains, using artificial elastin-like proteins as a model system. We make use of fluorescence recovery after photobleaching (FRAP), a classic biophysical technique, to measure chain mobilities as a function of network structure and probe architecture. Reversible network association is demonstrated to control the effective diffusivity of network-bound chains, and a novel mechanism of chain transport is proposed: the chains naturally partition into various bound states, and move by \u201chopping\u201d from site to site in between binding events.
\r\n\r\nA careful analysis of the equilibrium constants that control this partioning leads to the conclusion that the sequential binding of identical chain ends to the network is inherently asymmetric: the first association is always stronger than the second. This binding asymmetry is shown to arise from a strong entropic penalty for chain entry into the fully bound state due to local network structure. We derive a simple equation predicting the degree of binding asymmetry as a function of network geometry from equilibrium statistical mechanics. A large set of self-diffusivity measurements on a series of model telechelic proteins finds good agreement with this new theory. Generalized binding asymmetry for chains with many associative domains also holds.
\r\n\r\nFinally, the inherent viscoelasticity of the elastin-like network is found to couple with an entropically driven phase separation above a critical temperature set point. Relaxation of the viscoelastic stress throughout the process of phase domain segregation is found to induce highly dynamic phase patterns. The time evolution of these patterns illustrates that a delicate balance of surface tension and viscoelastic stress controls pattern formation in viscoelastic materials.
", "doi": "10.7907/Z9CV4FSF", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:9894", "collection": "thesis", "collection_id": "9894", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07202016-150438490", "primary_object_url": { "basename": "Marat Orazov PhD Thesis.pdf", "content": "final", "filesize": 4919027, "license": "other", "mime_type": "application/pdf", "url": "/9894/1/Marat Orazov PhD Thesis.pdf", "version": "v9.0.0" }, "type": "thesis", "title": "Development and Characterization of Catalytic Systems for Biomass-Derived Chemical Feedstocks", "author": [ { "family_name": "Orazov", "given_name": "Marat", "orcid": "0000-0003-1621-1331", "clpid": "Orazov-Marat" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Heterogeneous catalysis by Br\u00f8nsted and/or Lewis acid sites isolated within microporous environments is a topic that is perpetually growing in scope and importance. While Br\u00f8nsted acid sites in zeolites have been studied and applied extensively in the petrochemical industry, new opportunities for green processes based on renewable chemical feedstocks call for applications of new microporous materials that possess Lewis acid sites (e.g., zeotypes with framework Sn, Ti, Zr, or Hf). Characterization of such materials and the specific structures of the Lewis acid sites provides insights for rational catalyst design and application.
\r\n\r\nThis work provides experimental evidence for the identities of the active sites in Sn-Beta zeotype for the 1,2-intramolecular hydride shift (1,2-HS) reaction that results in D-glucose isomerization to D-fructose, and for the 1,2-intramolecular carbon shift (1,2-CS) reaction that results in D-glucose isomerization to D-mannose. Specifically, by selective poisoning experiments, the partially-hydrolyzed, \"open\" Sn site is shown to be the active site for the 1,2-HS reaction. The participation of the proximal silanol of such an open Sn site in the 1,2-HS reaction is demonstrated thorough alkali-exchange experiments. Such experiments also reveal that the active site for the 1,2-CS reaction is an open Sn site with a cation-exchanged proximal silanol.
\r\n\r\n1,2-CS catalysts, in general, are shown to also catalyze retro-aldol reactions of hexoses at moderate temperatures (ca. 100 \u00b0C), and to be compatible with microporous 1,2-HS catalysts in tandem catalytic schemes that enable production of alkyl lactates.
\r\n\r\nFinally, the Lewis acidity of framework Zn in zincosilicate microporous materials is demonstrated through probe-molecule infrared spectroscopy. One such material is then shown to catalyze Diels-Alder cycloaddition-dehydration reactions of oxygenated furans and ethylene. To the best of our knowledge, these materials are the first heterogeneous catalysts reported to catalyze the direct formation of terephthalate esters from ethylene and dimethyl 2,5-furandicarboxylate with appreciable selectivity.
\r\n", "doi": "10.7907/Z9X63JZZ", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:10141", "collection": "thesis", "collection_id": "10141", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04182017-134255198", "primary_object_url": { "basename": "Brand_Stephen_2017.pdf", "content": "final", "filesize": 62579051, "license": "other", "mime_type": "application/pdf", "url": "/10141/1/Brand_Stephen_2017.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "I. Tin Silsesquioxanes as Analogs for the Open and Closed Sites in Tin-Containing Zeotype Beta and II. Enantiomerically Enriched, Polycrystalline Molecular Sieves", "author": [ { "family_name": "Brand", "given_name": "Stephen Kramer", "orcid": "0000-0002-0894-401X", "clpid": "Brand-Stephen-Kramer" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The use of biomass as a resource to produce value-added products has garnered significant interest as a means of reducing reliance on fossil fuels. This task is complicated by the complex, highly functionalized nature of abundant biomass derivatives, such as glucose. Tin-containing zeolite Beta (Sn-Beta) has been investigated as a catalyst for isomerizing aldohexoses into ketohexoses through a Lewis acid mediated hydride shift (1,2-intramolecular hydride shift, 1,2-HS). Recent studies on the reactivities of Lewis base-doped and alkali-exchanged Sn-Beta samples have conclusively demonstrated that the open tin site performs the glucose isomerization reaction. With Lewis base doped Sn-Beta, glucose conversion is almost completely eliminated and product selectivity is shifted predominantly to mannose, formed through a 1,2-intramolecular carbon shift (1,2-CS). To understand the structure-activity relationships between the conditions of the active sites in the zeolite, three molecular models (tin silsesquioxanes) of the tin sites in the zeolite are synthesized. Two tin silsesquioxanes that contain an octahedral tin site with and without an adjacent silanol group are prepared and used as catalysts for the reaction of glucose. The catalyst that contains the adjacent silanol group selectively forms fructose through a 1,2-HS while the catalyst without the silanol group yields mannose through a 1,2-CS. These results provide further evidence for the nature of the active sites in Sn-Beta. A methyl-ligated tin silsesquioxane is experimentally and theoretically examined to examine possible reactivities at the closed site. This compound is an active glucose conversion catalyst that selectively produces mannose, although the rates of reaction are far below those obtained from Sn-Beta. Additionally, a hybrid quantum mechanical/molecular mechanics model is constructed, and the complete catalytic cycle is computationally examined via considering ring-opening, three distinct pathways for each hydride- and carbon-shift reaction, and ring-closing. The combined experimental and computational results suggest that there could be reaction pathways that involve Si-O-Sn cleavage that give much slower reaction rates than the open tin site in Sn-Beta.
\r\n\r\nZeolite and zeolite-like molecular sieves are being used in a large number of applications such as adsorption and catalysis. Achievement of the long-standing goal of creating a chiral, polycrystalline molecular sieve with bulk enantioenrichment would enable these materials to perform enantioselective functions. In part II of this thesis, the synthesis of enantiomerically enriched samples of a molecular sieve is reported. Enantiopure organic structure directing agents (OSDAs) are designed with the assistance of computational methods, and used to synthesize enantioenriched, polycrystalline molecular sieve samples of either enantiomer. Computational results correctly predicted which enantiomer is obtained, and enantiomeric enrichment is proven by high-resolution transmission electron microscopy. The enantioenriched and racemic samples of the molecular sieves are tested as adsorbents and heterogeneous catalysts. The enantioenriched molecular sieves show enantioselectivity for the ring opening reaction of epoxides and enantioselective adsorption of 2-butanol (R enantiomer of the molecular sieve shows opposite and approximately equal enantioselectivity from the S enantiomer of the molecular sieve, while the racemic sample of the molecular sieve shows no enantioselectivity).
\r\n", "doi": "10.7907/Z96T0JPX", "publication_date": "2017", "thesis_type": "phd", "thesis_year": "2017" }, { "id": "thesis:9185", "collection": "thesis", "collection_id": "9185", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10012015-132559997", "primary_object_url": { "basename": "2015 - Alexander M Sutherland Thesis - Technology for Single Cell Protein Analysis in Immunology and Cancer Prognostics.pdf", "content": "final", "filesize": 7315760, "license": "other", "mime_type": "application/pdf", "url": "/9185/1/2015 - Alexander M Sutherland Thesis - Technology for Single Cell Protein Analysis in Immunology and Cancer Prognostics.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Technology for Single Cell Protein Analysis in Immunology and Cancer Prognostics", "author": [ { "family_name": "Sutherland", "given_name": "Alexander Muir", "clpid": "Sutherland-Alexander-Muir" } ], "thesis_advisor": [ { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "clpid": "Mazmanian-S-K" }, { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The first chapter of this thesis deals with automating data gathering for single cell microfluidic tests. The programs developed saved significant amounts of time with no loss in accuracy. The technology from this chapter was applied to experiments in both Chapters 4 and 5.
\r\n\r\nThe second chapter describes the use of statistical learning to prognose if an anti-angiogenic drug (Bevacizumab) would successfully treat a glioblastoma multiforme tumor. This was conducted by first measuring protein levels from 92 blood samples using the DNA-encoded antibody library platform. This allowed the measure of 35 different proteins per sample, with comparable sensitivity to ELISA. Two statistical learning models were developed in order to predict whether the treatment would succeed. The first, logistic regression, predicted with 85% accuracy and an AUC of 0.901 using a five protein panel. These five proteins were statistically significant predictors and gave insight into the mechanism behind anti-angiogenic success/failure. The second model, an ensemble model of logistic regression, kNN, and random forest, predicted with a slightly higher accuracy of 87%.
\r\n\r\nThe third chapter details the development of a photocleavable conjugate that multiplexed cell surface detection in microfluidic devices. The method successfully detected streptavidin on coated beads with 92% positive predictive rate. Furthermore, chambers with 0, 1, 2, and 3+ beads were statistically distinguishable. The method was then used to detect CD3 on Jurkat T cells, yielding a positive predictive rate of 49% and false positive rate of 0%.
\r\n\r\nThe fourth chapter talks about the use of measuring T cell polyfunctionality in order to predict whether a patient will succeed an adoptive T cells transfer therapy. In 15 patients, we measured 10 proteins from individual T cells (~300 cells per patient). The polyfunctional strength index was calculated, which was then correlated with the patient's progress free survival (PFS) time. 52 other parameters measured in the single cell test were correlated with the PFS. No statistical correlator has been determined, however, and more data is necessary to reach a conclusion.
\r\n\r\nFinally, the fifth chapter talks about the interactions between T cells and how that affects their protein secretion. It was observed that T cells in direct contact selectively enhance their protein secretion, in some cases by over 5 fold. This occurred for Granzyme B, Perforin, CCL4, TNFa, and IFNg. IL- 10 was shown to decrease slightly upon contact. This phenomenon held true for T cells from all patients tested (n=8). Using single cell data, the theoretical protein secretion frequency was calculated for two cells and then compared to the observed rate of secretion for both two cells not in contact, and two cells in contact. In over 90% of cases, the theoretical protein secretion rate matched that of two cells not in contact.
", "doi": "10.7907/Z9PK0D3K", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9689", "collection": "thesis", "collection_id": "9689", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04282016-162609209", "primary_object_url": { "basename": "Clark_Andrew J_Thesis_04292016_Final.pdf", "content": "final", "filesize": 7462710, "license": "other", "mime_type": "application/pdf", "url": "/9689/1/Clark_Andrew J_Thesis_04292016_Final.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Delivery of Targeted Nanoparticles Across the Blood-Brain Barrier Using a Detachable Targeting Ligand", "author": [ { "family_name": "Clark", "given_name": "Andrew James", "orcid": "0000-0003-4240-7119", "clpid": "Clark-Andrew-James" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Beauchamp", "given_name": "Jesse L.", "clpid": "Beauchamp-J-L" }, { "family_name": "Shapiro", "given_name": "Mikhail G.", "clpid": "Shapiro-M-G" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Chronic diseases of the central nervous system are poorly treated due to the inability of most therapeutics to cross the blood-brain barrier. The blood-brain barrier is an anatomical and physiological barrier that severely restricts solute influx, including most drugs, from the blood to the brain. One promising method to overcome this obstacle is to use endogenous solute influx systems at the blood-brain barrier to transport drugs. Therapeutics designed to enter the brain through transcytosis by binding the transferrin receptor, however, are restricted within endothelial cells. The focus of this work was to develop a method to increase uptake of transferrin-containing nanoparticles into the brain by overcoming these restrictive processes.
\r\n\r\nTo accomplish this goal, nanoparticles were prepared with surface transferrin molecules bound through various liable chemical bonds. These nanoparticles were designed to shed the targeting molecule during transcytosis to allow increased accumulation of nanoparticles within the brain.
\r\n\r\nTransferrin was added to the surface of nanoparticles through either redox or pH sensitive chemistry. First, nanoparticles with transferrin bound through disulfide bonds were prepared. These nanoparticles showed decreased avidity for the transferrin receptor after exposure to reducing agents and increased ability to enter the brain in vivo compared to those lacking the disulfide link.
\r\n \r\nNext, transferrin was attached through a chemical bond that cleaves at mildly acidic pH. Nanoparticles containing a cleavable link between transferrin and gold nanoparticle cores were found to both cross an in vitro model of the blood-brain barrier and accumulate within the brain in significantly higher numbers than similar nanoparticles lacking the cleavable bond. Also, this increased accumulation was not seen when using this same strategy with an antibody to transferrin receptor, indicating that behavior of nanoparticles at the blood-brain barrier varies depending on what type of targeting ligand is used.
\r\n\r\nFinally, polymeric nanoparticles loaded with dopamine and utilizing a superior acid-cleavable targeting chemistry were investigated as a potential treatment for Parkinson\u2019s disease. These nanoparticles were capable of increasing dopamine quantities in the brains of healthy mice, highlighting the therapeutic potential of this design. Overall, this work describes a novel method to increase targeted nanoparticle accumulation in the brain.
\r\n", "doi": "10.7907/Z9WH2MZ6", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9817", "collection": "thesis", "collection_id": "9817", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05312016-151045544", "primary_object_url": { "basename": "Thesis Final.pdf", "content": "final", "filesize": 19681606, "license": "other", "mime_type": "application/pdf", "url": "/9817/1/Thesis Final.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "An Experimental and Technoeconomic Study of Silicon Microwire Arrays for Fuel Production Using Solar Energy", "author": [ { "family_name": "Shaner", "given_name": "Matthew Reed", "orcid": "0000-0003-4682-9757", "clpid": "Shaner-Matthew-Reed" } ], "thesis_advisor": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" }, { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" } ], "thesis_committee": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" }, { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "JCAP" }, { "literal": "div_chem" } ], "abstract": "Direct solar energy conversion is one of few sustainable energy resources able to wholly satisfy global energy demand; however, utility scale adoption and reliance are currently limited by the lack of a cost effective energy storage technology. The production of fuel from sunlight (solar fuels) enables solar energy storage in chemical bonds, a volumetrically and gravimetrically dense form compatible with current infrastructure worldwide. Hydrogen production via water splitting is a first generation solar fuel targeted herein that is currently used for hydrocarbon up-grading and fertilizer production and could further be utilized in combustion cycles and/or fuel cells for electricity and heat production and transportation.
\r\n\r\nThis thesis presents achievements that form the foundation for Si microwire array based solar water splitting devices beginning with a tandem junction device design using Si microwire arrays as the architectural motif and one of many active components. Si microwire arrays have potential advantages over two dimensional planar device architectures such as minimized resistance losses, lower semiconductor material usage, and embedment in a polymeric membrane enabling a flexible device.
\r\n\r\nExperimental fabrication and characterization of this tandem junction device design was realized in the form of a np+-Si microwire array coated by either tungsten oxide (WO3) or titanium dioxide (TiO2) as the second tandem semiconductor. The Si/TiO2 device demonstrated the highest performance with an expected solar-to-hydrogen efficiency of 0.39%. To achieve these demonstrations new processing methods were needed and developed for formation of the np+-Si microwire array homojunction and formation of a low resistance contact between the p+-Si and second semiconductor using sputtered tin- doped indium oxide (ITO) and spray pyrolyzed fluorine-doped tin oxide (FTO).
\r\n\r\nAnother achievement includes demonstration of the longest known (>2200 hours) photoanode stability for water oxidation using a np+-Si microwire array coated with an in-house developed amorphous TiO2 protection layer and NiCrOx electrocatalyst. Additionally, the Si microwire array architecture was used to enable decoupling of semiconductor light absorption and catalytic activity, two performance metrics that ideally are maximized simultaneously. However, all previous demonstrations have shown anti-correlation between these performance metrics because planar architectures are subject to a trade-off where adding electrocatalyst increases catalytic activity, but decreases semiconductor light absorption and vice versa.
\r\n\r\nFinally, a techno-economic analysis of solar water splitting production facilities was performed to assess economic competitiveness because this is the ultimate metric by which all energy production technologies are currently evaluated. This analysis suggests that a hydrogen production facility that is cosmetically similar to current solar panel installations with hydrogen collection from distributed tilted panels is unlikely to achieve cost competitiveness with fossil fuel derived hydrogen due to the balance of systems costs alone. A cost of CO2 greater than ~$800 (ton CO2)-1 was estimated to be necessary for the least expensive base-case solar-to-hydrogen system to reach price parity with hydrogen derived from steam reforming of methane priced at $3 (MM BTU)-1 ($1.39 (kg H2)-1). Direct CO2 reduction systems were also explored and resulted in even larger challenges than hydrogen production. Accordingly, major facility wide breakthroughs are required to obtain viable economic costs for solar hydrogen production, but the barriers to achieve cost-competitiveness with existing large-scale thermochemical processes for CO2 reduction are even greater.
", "doi": "10.7907/Z98C9T7Z", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9758", "collection": "thesis", "collection_id": "9758", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05252016-151033826", "primary_object_url": { "basename": "Thesis (Full).pdf", "content": "final", "filesize": 16638040, "license": "other", "mime_type": "application/pdf", "url": "/9758/104/Thesis (Full).pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Tools For Spatiotemporally Specific Proteomic Analysis In Multicellular Organisms", "author": [ { "family_name": "Yuet", "given_name": "Kai P.", "orcid": "0000-0002-1381-8923", "clpid": "Yuet-Kai-P" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Sternberg", "given_name": "Paul W.", "clpid": "Sternberg-P-W" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Sternberg", "given_name": "Paul W.", "clpid": "Sternberg-P-W" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Shapiro", "given_name": "Mikhail G.", "clpid": "Shapiro-M-G" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The emergence of mass spectrometry-based proteomics has revolutionized the study of proteins and their abundances, functions, interactions, and modifications. However, in a multicellular organism, it is difficult to monitor dynamic changes in protein synthesis in a specific cell type within its native environment. In this thesis, we describe methods that enable the metabolic labeling, purification, and analysis of proteins in specific cell types and during defined periods in live animals. We first engineered a eukaryotic phenylalanyl-tRNA synthetase (PheRS) to selectively recognize the unnatural L-phenylalanine analog p-azido-L-phenylalanine (Azf). Using Caenorhabditis elegans, we expressed the engineered PheRS in a cell type of choice (i.e. body wall muscles, intestinal epithelial cells, neurons, pharyngeal muscles), permitting proteins in those cells -- and only those cells -- to be labeled with azides. Labeled proteins are therefore subject to \"click\" conjugation to cyclooctyne-functionalized affnity probes, separation from the rest of the protein pool and identification by mass spectrometry. By coupling our methodology with heavy isotopic labeling, we successfully identified proteins -- including proteins with previously unknown expression patterns -- expressed in targeted subsets of cells. While cell types like body wall or pharyngeal muscles can be targeted with a single promoter, many cells cannot; spatiotemporal selectivity typically results from the combinatorial action of multiple regulators. To enhance spatiotemporal selectivity, we next developed a two-component system to drive overlapping -- but not identical -- patterns of expression of engineered PheRS, restricting labeling to cells that express both elements. Specifically, we developed a split-intein-based split-PheRS system for highly efficient PheRS-reconstitution through protein splicing. Together, these tools represent a powerful approach for unbiased discovery of proteins uniquely expressed in a subset of cells at specific developmental stages.", "doi": "10.7907/Z9VD6WDH", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9714", "collection": "thesis", "collection_id": "9714", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05092016-155820873", "primary_object_url": { "basename": "DorothyPan_Thesis_Edits2.pdf", "content": "final", "filesize": 20115454, "license": "other", "mime_type": "application/pdf", "url": "/9714/1/DorothyPan_Thesis_Edits2.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Development of a Cationic Mucic Acid Polymer-Based Nanoparticle siRNA Delivery System", "author": [ { "family_name": "Pan", "given_name": "Dorothy Weichi", "orcid": "0000-0003-4066-7750", "clpid": "Pan-Dorothy-Weichi" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Campbell", "given_name": "Judith L.", "clpid": "Campbell-J-L" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Cancer chemotherapy has advanced from highly toxic drugs to more targeted treatments in the last 70 years. Chapter 1 opens with an introduction to targeted therapy for cancer. The benefits of using a nanoparticle to deliver therapeutics are discussed. We move on to siRNA in particular, and why it would be advantageous as a therapy. Specific to siRNA delivery are some challenges, such as nuclease degradation, quick clearance from circulation, needing to enter cells, and getting to the cytosol. We propose the development of a nanoparticle delivery system to tackle these challenges so that siRNA can be effective.
\r\n\r\nChapter 2 of this thesis discusses the synthesis and analysis of a cationic mucic acid polymer (cMAP) which condenses siRNA to form a nanoparticle. Various methods to add polyethylene glycol (PEG) for stabilizing the nanoparticle in physiologic solutions, including using a boronic acid binding to diols on mucic acid, forming a copolymer of cMAP with PEG, and creating a triblock with mPEG on both ends of cMAP. The goal of these various pegylation strategies was to increase the circulation time of the siRNA nanoparticle in the bloodstream to allow more of the nanoparticle to reach tumor tissue by the enhanced permeation and retention effect. We found that the triblock mPEG-cMAP-PEGm polymer condensed siRNA to form very stable 30-40 nm particles that circulated for the longest time \u2013 almost 10% of the formulation remained in the bloodstream of mice 1 h after intravenous injection.
\r\n\r\nChapter 3 explores the use of an antibody as a targeting agent for nanoparticles. Some antibodies of the IgG1 subtype are able to recruit natural killer cells that effect antibody dependent cellular cytotoxicity (ADCC) to kill the targeted cell to which the antibody is bound. There is evidence that the ADCC effect remains in antibody-drug conjugates, so we wanted to know whether the ADCC effect is preserved when the antibody is bound to a nanoparticle, which is a much larger and complex entity. We utilized antibodies against epidermal growth factor receptor with similar binding and pharmacokinetics, cetuximab and panitumumab, which differ in that cetuximab is an IgG1 and panitumumab is an IgG2 (which does not cause ADCC). Although a natural killer cell culture model showed that gold nanoparticles with a full antibody targeting agent can elicit target cell lysis, we found that this effect was not preserved in vivo. Whether this is due to the antibody not being accessible to immune cells or whether the natural killer cells are inactivated in a tumor xenograft remains unknown. It is possible that using a full antibody still has value if there are immune functions which are altered in a complex in vivo environment that are intact in an in vitro system, so the value of using a full antibody as a targeting agent versus using an antibody fragment or a protein such as transferrin is still open to further exploration.
\r\n\r\nIn chapter 4, nanoparticle targeting and endosomal escape are further discussed with respect to the cMAP nanoparticle system. A diboronic acid entity, which gives an order of magnitude greater binding (than boronic acid) to cMAP due to the vicinal diols in mucic acid, was synthesized, attached to 5kD or 10kD PEG, and conjugated to either transferrin or cetuximab. A histidine was incorporated into the triblock polymer between cMAP and the PEG blocks to allow for siRNA endosomal escape. Nanoparticle size remained 30-40 nm with a slightly negative ca. -3 mV zeta potential with the triblock polymer containing histidine and when targeting agents were added. Greater mRNA knockdown was seen with the endosomal escape mechanism than without. The nanoparticle formulations were able to knock down the targeted mRNA in vitro. Mixed effects suggesting function were seen in vivo.
\r\n\r\nChapter 5 summarizes the project and provides an outlook on siRNA delivery as well as targeted combination therapies for the future of personalized medicine in cancer treatment.
\r\n", "doi": "10.7907/Z9VM497J ", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:9083", "collection": "thesis", "collection_id": "9083", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08062015-163035886", "primary_object_url": { "basename": "Schmidt thesis v5 proofreader comments.pdf", "content": "final", "filesize": 3880387, "license": "other", "mime_type": "application/pdf", "url": "/9083/1/Schmidt thesis v5 proofreader comments.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Imidazolium-Based Organic Structure Directing Agents for the Synthesis of Microporous Materials", "author": [ { "family_name": "Schmidt", "given_name": "Joel Edward", "orcid": "0000-0002-0039-2863", "clpid": "Schmidt-Joel-Edward" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Rossman", "given_name": "George Robert", "clpid": "Rossman-G-R" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The central theme of this thesis is the use of imidazolium-based organic structure directing agents (OSDAs) in microporous materials synthesis. Imidazoliums are advantageous OSDAs as they are relatively inexpensive and simple to prepare, show robust stability under microporous material synthesis conditions, have led to a wide range of products, and have many permutations in structure that can be explored. The work I present involves the use of mono-, di-, and triquaternary imidazolium-based OSDAs in a wide variety of microporous material syntheses. Much of this work was motivated by successful computational predictions (Chapter 2) that led me to continue to explore these types of OSDAs. Some of the important discoveries with these OSDAs include the following: 1) Experimental evaluation and confirmation of a computational method that predicted a new OSDA for pure-silica STW, a desired framework containing helical pores that was previously very difficult to synthesize. 2) Discovery of a number of new imidazolium OSDAs to synthesize zeolite RTH, a zeolite desired for both the methanol-to-olefins reaction as well as NOX reduction in exhaust gases. This discovery enables the use of RTH for many additional investigations as the previous OSDA used to make this framework was difficult to synthesize, such that no large scale preparations would be practical. 3) The synthesis of pure-silica RTH by topotactic condensation from a layered precursor (denoted CIT-10), that can also be pillared to make a new framework material with an expanded pore system, denoted CIT-11, that can be calcined to form a new microporous material, denoted CIT-12. CIT-10 is also interesting since it is the first layered material to contain 8 membered rings through the layers, making it potentially useful in separations if delamination methods can be developed. 4) The synthesis of a new microporous material, denoted CIT-7 (framework code CSV) that contains a 2-dimensional system of 8 and 10 membered rings with a large cage at channel intersections. This material is especially important since it can be synthesized as a pure-silica framework under low-water, fluoride-mediated synthesis conditions, and as an aluminosilicate material under hydroxide mediated conditions. 5) The synthesis of high-silica heulandite (HEU) by topotactic condensation as well as direct synthesis, demonstrating new, more hydrothermally stable compositions of a previously known framework. 6) The synthesis of germanosilicate and aluminophosphate LTA using a triquaternary OSDA. All of these materials show the diverse range of products that can be formed from OSDAs that can be prepared by straightforward syntheses and have made many of these materials accessible for the first time under facile zeolite synthesis conditions. ", "doi": "10.7907/Z96H4FBM", "publication_date": "2016", "thesis_type": "phd", "thesis_year": "2016" }, { "id": "thesis:8893", "collection": "thesis", "collection_id": "8893", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05272015-172038281", "primary_object_url": { "basename": "AmyFu2015_Thesis.pdf", "content": "final", "filesize": 22043453, "license": "other", "mime_type": "application/pdf", "url": "/8893/1/AmyFu2015_Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Mitigating Scarring and Inflammation during Corneal Wound Healing using Nanofiber-Hydrogel Scaffolds", "author": [ { "family_name": "Fu", "given_name": "Amy Hau Yu", "clpid": "Fu-Amy-Hau-Yu" } ], "thesis_advisor": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" } ], "thesis_committee": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Shapiro", "given_name": "Mikhail G.", "clpid": "Shapiro-M-G" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Due to the universal lack of donor tissue, there has been emerging interest in engineering materials to stimulate living cells to restore the features and functions of injured organs. We are particularly interested in developing materials for corneal use, where the necessity to maintain the tissue\u2019s transparency presents an additional challenge. Every year, there are 1.5 \u2013 2 million new cases of monocular blindness due to irregular healing of corneal injuries, dwarfing the approximately 150,000 corneal transplants performed. The large gap between the need and availability of cornea transplantation motivates us to develop a wound-healing scaffold that can prevent corneal blindness.
\r\n\r\nTo develop such a scaffold, it is necessary to regulate the cells responsible for repairing the damaged cornea, namely myofibroblasts, which are responsible for the disordered and non-refractive index matched scar that leads to corneal blindness. Using in vitro assays, we identified that protein nanofibers of certain orientation can promote cell migration and modulate the myofibroblast phenotype. The nanofibers are also transparent, easy to handle and non-cytotoxic. To adhere the nanofibers to a wound bed, we examined the use of two different in situ forming hydrogels: an artificial extracellular matrix protein (aECM)-based gel and a photo-crosslinkable heparin-based gel. Both hydrogels can be formed within minutes, are transparent upon gelation and are easily tunable.
\r\n\r\nUsing an in vivo mouse model for epithelial defects, we show that our corneal scaffolds (nanofibers together with hydrogel) are well-tolerated (no inflammatory response or turbidity) and support epithelium regrowth. We developed an ex vivo corneal tissue culture model where corneas that are wounded and treated with our scaffold can be cultured while retaining their ability to repair wounds for up to 21 days. Using this technique, we found that the aECM-based treatment induced a more favorable wound response than the heparin-based treatment, prompting us to further examine the efficacy of the aECM-based treatment in vivo using a rabbit model for stromal wounds. Results show that treated corneas have fewer myofibroblasts and immune cells than untreated ones, indicating that our corneal scaffold shows promise in promoting a calmer wound response and preventing corneal haze formation.
\r\n", "doi": "10.7907/Z9Q81B00", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8855", "collection": "thesis", "collection_id": "8855", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05112015-143241169", "primary_object_url": { "basename": "M_Deimund_Thesis_Corrected.pdf", "content": "final", "filesize": 112843968, "license": "other", "mime_type": "application/pdf", "url": "/8855/11/M_Deimund_Thesis_Corrected.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "I. Nickel-Exchanged Zincosilicate Catalysts for the Oligomerization of Propylene and II. Organic SDA-Free Catalysts for the Methanol-to-Olefins Reaction", "author": [ { "family_name": "Deimund", "given_name": "Mark Austin", "clpid": "Deimund-Mark-Austin" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Nickel-containing catalysts are developed to oligomerize light olefins. Two nickel-containing zincosilicates (Ni-CIT-6 and Ni-Zn-MCM-41) and two nickel-containing aluminosilicates (Ni-HiAl-BEA and Ni-USY) are synthesized as catalysts to oligomerize propylene into C3n (C6 and C9) products. All catalysts oligomerize propylene, with the zincosilicates demonstrating higher average selectivities to C3n products, likely due to the reduced acidity of the Zn heteroatom.
\r\n\r\nTo test whether light alkanes can be incorporated into this oligomerization reaction, a supported homogeneous catalyst is combined with Ni-containing zincosilicates. The homogeneous catalyst is included to provide dehydrogenation/hydrogenation functions. When this tandem catalyst system is evaluated using a propylene/n-butane feed, no significant integration of alkanes are observed.
\r\n\r\nNi-containing zincosilicates are reacted with 1-butene and an equimolar propylene/1-butene mixture to study other olefinic feeds. Further, other divalent metal cations such as Mn2+, Co2+, Cu2+, and Zn2+ are exchanged onto CIT-6 samples to investigate stability and potential use for other reactions. Co-CIT-6 oligomerizes propylene, albeit less effectively than Ni-CIT-6. The other M-CIT-6 samples, while not able to oligomerize light olefins, may be useful for other reactions, such as deNOx.
\r\n\r\nMolecular sieves are synthesized, characterized, and used to catalyze the methanol-to-olefins (MTO) reaction. The Al concentration in SSZ-13 samples is varied to investigate the effect of Al number on MTO reactivity when compared to a SAPO-34 sample with only isolated Si Br\u00f8nsted acid sites. These SSZ-13 samples display reduced transient selectivity behavior and extended reaction lifetimes as Si/Al increases; attributable to fewer paired Al sites. MTO reactivity for the higher Si/Al SSZ-13s resembles the SAPO-34 sample, suggesting that both catalysts owe their stable reaction behavior to isolated Br\u00f8nsted acid sites.
\r\n\r\nZeolites CHA and RHO are prepared without the use of organic structure-directing agents (OSDAs), dealuminated by steam treatments (500\u00b0C-800\u00b0C), and evaluated as catalysts for the MTO reaction. The effects of temperature and steam partial pressure during steaming are investigated. X-ray diffraction (XRD) and Ar physisorption show that steaming causes partial structural collapse of the zeolite, with degradation increasing with steaming temperature. 27Al MAS NMR spectra of steamed materials reveal the presence of tetrahedral, pentacoordinate, and hexacoordinate aluminum.
\r\n\r\nProton forms of as-synthesized CHA (Si/Al=2.4) and RHO (Si/Al=2.8) rapidly deactivate under MTO testing conditions (400\u00b0C, atmospheric pressure). CHA samples steamed at 600\u00b0C performed best among samples tested, showing increased olefin selectivities and catalyst lifetime. Acid washing these steamed samples further improved activity. Reaction results for RHO were similar to CHA, with the RHO sample steamed at 800\u00b0C producing the highest light olefin selectivities. Catalyst lifetime and C2-C3 olefin selectivities increase with increasing reaction temperature for both CHA-type and RHO-type steamed samples.
", "doi": "10.7907/Z9XK8CG9", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8866", "collection": "thesis", "collection_id": "8866", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05182015-163742452", "primary_object_url": { "basename": "JJ PACHECO PHD THESIS_MAY 2015_Final.pdf", "content": "final", "filesize": 3537043, "license": "other", "mime_type": "application/pdf", "url": "/8866/1/JJ PACHECO PHD THESIS_MAY 2015_Final.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "New Catalysts for the Renewable Production of Monomers for Bioplastics", "author": [ { "family_name": "Pacheco", "given_name": "Joshua Joseph", "clpid": "Pacheco-Joshua-Joseph" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Terephthalic acid (PTA) is one of the monomers used for the synthesis of the polyester, polyethylene terephthalate (PET), that is used for the large-scale manufacture of synthetic fibers and plastic bottles. PTA is largely produced from the liquid-phase oxidation of petroleum-derived p-xylene (PX). However, there are now ongoing worldwide efforts exploring alternative routes for producing PTA from renewable, biomass resources.
\r\n\r\nIn this thesis, I present a new route to PTA starting from the biomass-derived platform chemical, 5-hydroxymethylfurfural (HMF). This route utilizes new, selective Diels-Alder-dehydration reactions involving ethylene and is advantageous over the previously proposed Diels-Alder-dehydration route to PTA from HMF via 2,5-dimethylfuran (DMF) since the H2 reduction of HMF to DMF is avoided. Specifically, oxidized derivatives of HMF are reacted as is, or after etherification-esterification with methanol, with ethylene over solid Lewis acid catalysts that do not contain strong Br\u00f8nsted acids in order to synthesize intermediates of PTA and its equally important diester, dimethyl terephthalate (DMT). The partially oxidized HMF, 5-(hydroxymethyl)furoic acid (HMFA) is reacted with high pressure ethylene over a pure-silica molecular sieve catalyst containing framework tin (Sn-Beta) to produce the Diels-Alder-dehydration product, 4-(hydroxymethyl)benzoic acid (HMBA), with ~30% selectivity at ~20% yield. If HMFA is protected with methanol to form methyl 5-(methoxymethyl)furan-2-carboxylate (MMFC), MMFC can react with ethylene in the presence of a pure-silica molecular sieve containing framework zirconium (Zr-Beta) to produce methyl 4-(methoxymethyl)benzenecarboxylate (MMBC) with >70% selectivity at >20% yield. HMBA and MMBC can then be oxidized to produce PTA and DMT, respectively. When Lewis acid containing mesoporous silica (MCM-41) and amorphous silica, or Br\u00f8nsted acid containing zeolites (Al-Beta), are used as catalysts, a significant decrease in selectivity/yield of the Diels-Alder-dehydration product is observed.
\r\n\r\nAn investigation to elucidate the reaction network and side products in the conversion of MMFC to MMBC was performed, and the main side products are found to be methyl 4-formylcyclohexa-1,3-diene-1-carboxylate and the ethylene Diels-Alder adduct of this cyclohexadiene. These products presumably form by a different dehydration pathway of the MMFC/ethylene Diels-Alder adduct and should be included when determining the overall selectivity to PTA or DMT since, like MMBC, these compounds are precursors to PTA or DMT.
\r\n\r\nFundamental physical and chemical information on the ethylene Diels-Alder-dehydration reactions catalyzed by the Lewis acid-containing molecular sieves was obtained. Madon-Boudart experiments using Zr-Beta as catalyst show that the reaction rates are limited by chemical kinetics only (physical transport limitations are not present), all the Zr4+ centers are incorporated into the framework of the molecular sieve, and the whole molecular sieve crystal is accessible for catalysis. Apparent activation energies using Zr-Beta are low, suggesting that the overall activation energy of the system may be determined by a collection of terms and is not the true activation energy of a single chemical step.
\r\n", "doi": "10.7907/Z9N58JBZ", "publication_date": "2015", "thesis_type": "phd", "thesis_year": "2015" }, { "id": "thesis:8028", "collection": "thesis", "collection_id": "8028", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11182013-104133647", "primary_object_url": { "basename": "Pirogovsky-Paul_PhD_Thesis_Final.pdf", "content": "final", "filesize": 8751475, "license": "other", "mime_type": "application/pdf", "url": "/8028/1/Pirogovsky-Paul_PhD_Thesis_Final.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Intramolecular Conflict: Conformation and Self-Assembly of Architecturally Complex Macromolecules in Solution", "author": [ { "family_name": "Pirogovsky", "given_name": "Paul Peter", "clpid": "Pirogovsky-Paul-Peter" } ], "thesis_advisor": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" } ], "thesis_committee": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The solution behavior of linear polymer chains is well understood, having been the subject of intense study throughout the previous century. As plastics have become ubiquitous in everyday life, polymer science has grown into a major field of study. The conformation of a polymer in solution depends on the molecular architecture and its interactions with the surroundings. Developments in synthetic techniques have led to the creation of precision-tailored polymeric materials with varied topologies and functionalities. In order to design materials with the desired properties, it is imperative to understand the relationships between polymer architecture and their conformation and behavior. To meet that need, this thesis investigates the conformation and self-assembly of three architecturally complex macromolecular systems with rich and varied behaviors driven by the resolution of intramolecular conflicts. First we describe the development of a robust and facile synthetic approach to reproducible bottlebrush polymers (Chapter 2). The method was used to produce homologous series of bottlebrush polymers with polynorbornene backbones, which revealed the effect of side-chain and backbone length on the overall conformation in both good and theta solvent conditions (Chapter 3). The side-chain conformation was obtained from a series of SANS experiments and determined to be indistinguishable from the behavior of free linear polymer chains. Using deuterium-labeled bottlebrushes, we were able for the first time to directly observe the backbone conformation of a bottlebrush polymer which showed self-avoiding walk behavior. Secondly, a series of SANS experiments was conducted on a homologous series of Side Group Liquid Crystalline Polymers (SGLCPs) in a perdeuterated small molecule liquid crystal (5CB). Monodomain, aligned, dilute samples of SGLCP-b-PS block copolymers were seen to self-assemble into complex micellar structures with mutually orthogonally oriented anisotropies at different length scales (Chapter 4). Finally, we present the results from the first scattering experiments on a set of fuel-soluble, associating telechelic polymers. We observed the formation of supramolecular aggregates in dilute (\u22640.5wt%) solutions of telechelic polymers and determined that the choice of solvent has a significant effect on the strength of association and the size of the supramolecules (Chapter 5). A method was developed for the direct estimation of supramolecular aggregation number from SANS data. The insight into structure-property relationships obtained from this work will enable the more targeted development of these molecular architectures for their respective applications. ", "doi": "10.7907/0DXJ-3H18", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8451", "collection": "thesis", "collection_id": "8451", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05302014-220000101", "type": "thesis", "title": "Density Functional Theory Embedding for Correlated Wavefunctions", "author": [ { "family_name": "Goodpaster", "given_name": "Jason Daniel", "clpid": "Goodpaster-Jason-Daniel" } ], "thesis_advisor": [ { "family_name": "Miller", "given_name": "Thomas F.", "clpid": "Miller-T-F" } ], "thesis_committee": [ { "family_name": "Miller", "given_name": "Thomas F.", "clpid": "Miller-T-F" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Methods that exploit the intrinsic locality of molecular interactions show significant promise in making tractable the electronic structure calculation of large-scale systems. In particular, embedded density functional theory (e-DFT) offers a formally exact approach to electronic structure calculations in which the interactions between subsystems are evaluated in terms of their electronic density. In the following dissertation, methodological advances of embedded density functional theory are described, numerically tested, and applied to real chemical systems.
\r\n\r\nFirst, we describe an e-DFT protocol in which the non-additive kinetic energy component of the embedding potential is treated exactly. Then, we present a general implementation of the exact calculation of the non-additive kinetic potential (NAKP) and apply it to molecular systems. We demonstrate that the implementation using the exact NAKP is in excellent agreement with reference Kohn-Sham calculations, whereas the approximate functionals lead to qualitative failures in the calculated energies and equilibrium structures.
\r\n\r\nNext, we introduce density-embedding techniques to enable the accurate and stable calculation of correlated wavefunction (CW) in complex environments. Embedding potentials calculated using e-DFT introduce the effect of the environment on a subsystem for CW calculations (WFT-in-DFT). We demonstrate that WFT-in-DFT calculations are in good agreement with CW calculations performed on the full complex.
\r\n\r\nWe significantly improve the numerics of the algorithm by enforcing orthogonality between subsystems by introduction of a projection operator. Utilizing the projection-based embedding scheme, we rigorously analyze the sources of error in quantum embedding calculations in which an active subsystem is treated using CWs, and the remainder using density functional theory. We show that the embedding potential felt by the electrons in the active subsystem makes only a small contribution to the error of the method, whereas the error in the nonadditive exchange-correlation energy dominates. We develop an algorithm which corrects this term and demonstrate the accuracy of this corrected embedding scheme.
", "doi": "10.7907/RX3S-GH65", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8112", "collection": "thesis", "collection_id": "8112", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03062014-172332538", "primary_object_url": { "basename": "Wei_Wei_2014_thesis.pdf", "content": "final", "filesize": 10594762, "license": "other", "mime_type": "application/pdf", "url": "/8112/1/Wei_Wei_2014_thesis.pdf", "version": "v10.0.0" }, "type": "thesis", "title": "Microfluidics-Based Single-Cell Functional Proteomics Microchip for Portraying Protein Signal Transduction Networks within the Framework of Physicochemical Principles, with Applications in Fundamental and Translational Cancer Research", "author": [ { "family_name": "Wei", "given_name": "Wei", "orcid": "0000-0002-1018-7708", "clpid": "Wei-Wei" } ], "thesis_advisor": [ { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" } ], "thesis_committee": [ { "family_name": "Johnson", "given_name": "William L.", "clpid": "Johnson-W-L" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" }, { "family_name": "Greer", "given_name": "Julia R.", "clpid": "Greer-J-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" } ], "local_group": [ { "literal": "div_eng" } ], "abstract": "Single-cell functional proteomics assays can connect genomic information to biological function through quantitative and multiplex protein measurements. Tools for single-cell proteomics have developed rapidly over the past 5 years and are providing unique opportunities. This thesis describes an emerging microfluidics-based toolkit for single cell functional proteomics, focusing on the development of the single cell barcode chips (SCBCs) with applications in fundamental and translational cancer research.
\r\n\r\nThe microchip designed to simultaneously quantify a panel of secreted, cytoplasmic and membrane proteins from single cells will be discussed at the beginning, which is the prototype for subsequent proteomic microchips with more sophisticated design in preclinical cancer research or clinical applications. The SCBCs are a highly versatile and information rich tool for single-cell functional proteomics. They are based upon isolating individual cells, or defined number of cells, within microchambers, each of which is equipped with a large antibody microarray (the barcode), with between a few hundred to ten thousand microchambers included within a single microchip. Functional proteomics assays at single-cell resolution yield unique pieces of information that significantly shape the way of thinking on cancer research. An in-depth discussion about analysis and interpretation of the unique information such as functional protein fluctuations and protein-protein correlative interactions will follow.
\r\n\r\nThe SCBC is a powerful tool to resolve the functional heterogeneity of cancer cells. It has the capacity to extract a comprehensive picture of the signal transduction network from single tumor cells and thus provides insight into the effect of targeted therapies on protein signaling networks. We will demonstrate this point through applying the SCBCs to investigate three isogenic cell lines of glioblastoma multiforme (GBM).
\r\n\r\nThe cancer cell population is highly heterogeneous with high-amplitude fluctuation at the single cell level, which in turn grants the robustness of the entire population. The concept that a stable population existing in the presence of random fluctuations is reminiscent of many physical systems that are successfully understood using statistical physics. Thus, tools derived from that field can probably be applied to using fluctuations to determine the nature of signaling networks. In the second part of the thesis, we will focus on such a case to use thermodynamics-motivated principles to understand cancer cell hypoxia, where single cell proteomics assays coupled with a quantitative version of Le Chatelier's principle derived from statistical mechanics yield detailed and surprising predictions, which were found to be correct in both cell line and primary tumor model.
\r\n\r\nThe third part of the thesis demonstrates the application of this technology in the preclinical cancer research to study the GBM cancer cell resistance to molecular targeted therapy. Physical approaches to anticipate therapy resistance and to identify effective therapy combinations will be discussed in detail. Our approach is based upon elucidating the signaling coordination within the phosphoprotein signaling pathways that are hyperactivated in human GBMs, and interrogating how that coordination responds to the perturbation of targeted inhibitor. Strongly coupled protein-protein interactions constitute most signaling cascades. A physical analogy of such a system is the strongly coupled atom-atom interactions in a crystal lattice. Similar to decomposing the atomic interactions into a series of independent normal vibrational modes, a simplified picture of signaling network coordination can also be achieved by diagonalizing protein-protein correlation or covariance matrices to decompose the pairwise correlative interactions into a set of distinct linear combinations of signaling proteins (i.e. independent signaling modes). By doing so, two independent signaling modes \u2013 one associated with mTOR signaling and a second associated with ERK/Src signaling have been resolved, which in turn allow us to anticipate resistance, and to design combination therapies that are effective, as well as identify those therapies and therapy combinations that will be ineffective. We validated our predictions in mouse tumor models and all predictions were borne out.
\r\n\r\nIn the last part, some preliminary results about the clinical translation of single-cell proteomics chips will be presented. The successful demonstration of our work on human-derived xenografts provides the rationale to extend our current work into the clinic. It will enable us to interrogate GBM tumor samples in a way that could potentially yield a straightforward, rapid interpretation so that we can give therapeutic guidance to the attending physicians within a clinical relevant time scale. The technical challenges of the clinical translation will be presented and our solutions to address the challenges will be discussed as well. A clinical case study will then follow, where some preliminary data collected from a pediatric GBM patient bearing an EGFR amplified tumor will be presented to demonstrate the general protocol and the workflow of the proposed clinical studies.
\r\n", "doi": "10.7907/Z9WS8R7G", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8001", "collection": "thesis", "collection_id": "8001", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10192013-181502465", "primary_object_url": { "basename": "Ming-Hsin_Wei_2014_thesis.pdf", "content": "final", "filesize": 6936655, "license": "other", "mime_type": "application/pdf", "url": "/8001/1/Ming-Hsin_Wei_2014_thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Synthesis and Potency of Long End-Associative Polymers for Mist Control", "author": [ { "family_name": "Wei", "given_name": "Ming-Hsin", "clpid": "Wei-Ming-Hsin" } ], "thesis_advisor": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" } ], "thesis_committee": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Sarohia", "given_name": "Virendra", "clpid": "Sarohia-V" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Long linear polymers that are end-functionalized with associative groups were studied as additives to hydrocarbon fluids to mitigate the fire hazard associated with the presence of mist in a crash scenario. These polymers were molecularly designed to overcome both the shear-degradation of long polymer chains in turbulent flows, and the chain collapse induced by the random placement of associative groups along polymer backbones. Architectures of associative groups on the polymer chain ends that were tested included clusters of self-associative carboxyl groups and pairs of hetero-complementary associative units.
\r\n\r\nLinear polymers with clusters of discrete numbers of carboxyl groups on their chain ends were investigated first: an innovative synthetic strategy was devised to achieve unprecedented backbone lengths and precise control of the number of carboxyl groups on chain ends (N). We found that a very narrow range of N allows the co-existence of sufficient end-association strength and polymer solubility in apolar media. Subsequent steady-flow rheological study on solution behavior of such soluble polymers in apolar media revealed that the end-association of very long chains in apolar media leads to the formation of flower-like micelles interconnected by bridging chains, which trap significant fraction of polymer chains into looped structures with low contribution to mist-control. The efficacy of very long 1,4-polybutadiene chains end-functionalized with clusters of four carboxyl groups as mist-control additives for jet fuel was further tested. In addition to being shear-resistant, the polymer was found capable of providing fire-protection to jet fuel at concentrations as low as 0.3wt%. We also found that this polymer has excellent solubility in jet fuel over a wide range of temperature (-30 to +70\u00b0C) and negligible interference with dewatering of jet fuel. It does not cause an adverse increase in viscosity at concentrations where mist-control efficacy exists.
\r\n\r\nFour pairs of hetero-complementary associative end-groups of varying strengths were subsequently investigated, in the hopes of achieving supramolecular aggregates with both mist-control ability and better utilization of polymer building blocks. Rheological study of solutions of the corresponding complementary associative polymer pairs in apolar media revealed the strength of complementary end-association required to achieve supramolecular aggregates capable of modulating rheological properties of the solution.
\r\n\r\nBoth self-associating and complementary associating polymers have therefore been found to resist shear degradation. The successful strategy of building soluble, end-associative polymers with either self-associative or complementary associative groups will guide the next generation of mist-control technology.
", "doi": "10.7907/Z91834FW", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8241", "collection": "thesis", "collection_id": "8241", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05192014-100254158", "primary_object_url": { "basename": "Bermejo-Deval_R, 06-13-2014.pdf", "content": "final", "filesize": 5287603, "license": "other", "mime_type": "application/pdf", "url": "/8241/1/Bermejo-Deval_R, 06-13-2014.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Reaction of Glucose Catalyzed by Framework and Extraframework Tin Sites in Zeolite Beta", "author": [ { "family_name": "Bermejo-Deval", "given_name": "Ricardo", "clpid": "Bermejo-Deval-Ricardo" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Agapie", "given_name": "Theodor", "clpid": "Agapie-T" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The isomerization of glucose into fructose is a large-scale reaction for the production of high-fructose corn syrup, and is now being considered as an intermediate step in the possible route of biomass conversion into fuels and chemicals. Recently, it has been shown that a hydrophobic, large pore, silica molecular sieve having the zeolite beta structure and containing framework Sn4+ (Sn-Beta) is able to isomerize glucose into fructose in aqueous media. Here, I have investigated how this catalyst converts glucose to fructose and show that it is analogous to that achieved with metalloenzymes. Specifically, glucose partitions into the molecular sieve in the pyranose form, ring opens to the acyclic form in the presence of the Lewis acid center (framework Sn4+), isomerizes into the acyclic form of fructose and finally ring closes to yield the furanose product. Akin to the metalloenzyme, the isomerization step proceeds by intramolecular hydride transfer from C2 to C1. Extraframework tin oxides located within hydrophobic channels of the molecular sieve that exclude liquid water can also isomerize glucose to fructose in aqueous media, but do so through a base-catalyzed proton abstraction mechanism. Extraframework tin oxide particles located at the external surface of the molecular sieve crystals or on amorphous silica supports are not active in aqueous media but are able to perform the isomerization in methanol by a base-catalyzed proton abstraction mechanism. Post-synthetic exchange of Na+ with Sn-Beta alters the glucose reaction pathway from the 1,2 intramolecular hydrogen shift (isomerization) to produce fructose towards the 1,2 intramolecular carbon shift (epimerization) that forms mannose. Na+ remains exchanged onto silanol groups during reaction in methanol solvent, leading to a near complete shift in selectivity towards glucose epimerization to mannose. In contrast, decationation occurs during reaction in aqueous solutions and gradually increases the reaction selectivity to isomerization at the expense of epimerization. Decationation and concomitant changes in selectivity can be eliminated by addition of NaCl to the aqueous reaction solution. Thus, framework tin sites with a proximal silanol group are the active sites for the 1, 2 intramolecular hydride shift in the isomerization of glucose to fructose, while these sites with Na-exchanged silanol group are the active sites for the 1, 2 intramolecular carbon shift in epimerization of glucose to mannose. ", "doi": "10.7907/6AYX-9086", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:8446", "collection": "thesis", "collection_id": "8446", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05302014-140200007", "primary_object_url": { "basename": "Su_Judith_2014_thesis.pdf", "content": "final", "filesize": 98921756, "license": "other", "mime_type": "application/pdf", "url": "/8446/1/Su_Judith_2014_thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Label-Free Detection of Single Molecule Using Microtoroid Optical Resonators", "author": [ { "family_name": "Su", "given_name": "Tsu-Te Judith", "clpid": "Su-Tsu-Te-Judith" } ], "thesis_advisor": [ { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" } ], "thesis_committee": [ { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" }, { "family_name": "Phillips", "given_name": "Robert B.", "orcid": "0000-0003-3082-2809", "clpid": "Phillips-R" }, { "family_name": "Vahala", "given_name": "Kerry J.", "orcid": "0000-0003-1783-1380", "clpid": "Vahala-K-J" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Bjorkman", "given_name": "Pamela J.", "orcid": "0000-0002-2277-3990", "clpid": "Bjorkman-P-J" } ], "local_group": [ { "literal": "Kavli Nanoscience Institute" }, { "literal": "div_bbe" } ], "abstract": "Being able to detect a single molecule without the use of labels has been a long standing goal of bioengineers and physicists. This would simplify applications ranging from single molecular binding studies to those involving public health and security, improved drug screening, medical diagnostics, and genome sequencing. One promising technique that has the potential to detect single molecules is the microtoroid optical resonator. The main obstacle to detecting single molecules, however, is decreasing the noise level of the measurements such that a single molecule can be distinguished from background. We have used laser frequency locking in combination with balanced detection and data processing techniques to reduce the noise level of these devices and report the detection of a wide range of nanoscale objects ranging from nanoparticles with radii from 100 to 2.5 nm, to exosomes, ribosomes, and single protein molecules (mouse immunoglobulin G and human interleukin-2). We further extend the exosome results towards creating a non-invasive tumor biopsy assay. Our results, covering several orders of magnitude of particle radius (100 nm to 2 nm), agree with the 'reactive' model prediction for the frequency shift of the resonator upon particle binding. In addition, we demonstrate that molecular weight may be estimated from the frequency shift through a simple formula, thus providing a basis for an ``optical mass spectrometer'' in solution. We anticipate that our results will enable many applications, including more sensitive medical diagnostics and fundamental studies of single receptor-ligand and protein-protein interactions in real time. The thesis summarizes what we have achieved thus far and shows that the goal of detecting a single molecule without the use of labels can now be realized.", "doi": "10.7907/EHWP-DH17", "publication_date": "2014", "thesis_type": "phd", "thesis_year": "2014" }, { "id": "thesis:7498", "collection": "thesis", "collection_id": "7498", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03062013-145838327", "primary_object_url": { "basename": "Wiley PhD Thesis.pdf", "content": "final", "filesize": 77779507, "license": "other", "mime_type": "application/pdf", "url": "/7498/1/Wiley PhD Thesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Design of Nanoparticles that Cross the Blood-Brain Barrier by Receptor Mediated Transcytosis", "author": [ { "family_name": "Wiley", "given_name": "Devin Thomas", "clpid": "Wiley-Devin-Thomas" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Webster", "given_name": "Paul", "clpid": "Webster-P" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The primary objective of my thesis work is to establish a set of design criteria for nanoparticles whose purpose is to safely and efficiently access the brain after systemic injection. Nanoparticles that can access the brain may be able to deliver therapeutic molecules to the brain that otherwise would be excluded by the blood-brain barrier.
\r\n\r\nE. coli glycoprotein 96 (Ecgp96) is explored as a candidate receptor on the blood-brain barrier that could potentially facilitate nanoparticle-receptor mediated transcytosis into the brain. Results from studies utilizing PET/CT, SPECT/CT, MRI, Xenogen fluorescence imaging, and confocal microscopy conclude that Ecgp96 is observed in the blood-brain barrier endothelial cells, but is not accessible from the blood of adult or neonatal mice under normal, non-pathological conditions.
\r\n\r\nTransferrin receptor is a well-characterized receptor on the blood-brain barrier that is accessible from the blood and known to transcytose transferrin. I focused on this receptor and on synthesizing and characterizing a well-defined set of transferrin containing gold nanoparticles of various sizes and transferrin compositions that would be investigated during in-vivo studies. Nanoparticle sizes were measured by DLS and nanoparticle tracking analysis. Zeta potentials were also measured. Nanoparticle transferrin content was directly measured by labeling transferrin with 64Cu and measuring the nanoparticle associated gamma activity. The nanoparticle binding avidities to mouse transferrin receptors were ranked by a silver enhancement fluorescence-based method using the mouse Neruo2A cell line.
\r\n\r\nEach nanoparticle formulation was systemically injected into mice, and localization in the mouse brain was observed by silver enhancement light microscopy, and TEM. The quantitation of the gold was determined by ICP-MS. Nanoparticles with large amounts of transferrin remain strongly attached to brain endothelial cells, while nanoparticles with less transferrin are capable of both interacting with transferrin receptor on the luminal side of the blood-brain barrier and detaching from transferrin receptor on the brain side of the blood-brain barrier. These results highlight the fact that the nanoparticle avidity must be tuned to maximize the number of nanoparticles exiting the endothelial cells and entering the brain tissue. Lanthanum nitrate perfusion-fixation studies demonstrate that the nanoparticle formulations investigated do not degrade the blood-brain barrier integrity and enter the brain by transferrin receptor-mediated transcytosis. The results from these studies provide initial design criteria for creating nanoparticle therapeutics for delivery to the brain from systemic administrations.
\r\n", "doi": "10.7907/DKRM-S631", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7320", "collection": "thesis", "collection_id": "7320", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12102012-132511810", "primary_object_url": { "basename": "Abrecht-PHDThesis.pdf", "content": "final", "filesize": 1819276, "license": "other", "mime_type": "application/pdf", "url": "/7320/1/Abrecht-PHDThesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Thermodynamic Properties of Organometallic Dihydrogen Complexes for Hydrogen Storage Applications", "author": [ { "family_name": "Abrecht", "given_name": "David Gregory", "clpid": "Abrecht-David-Gregory" } ], "thesis_advisor": [ { "family_name": "Fultz", "given_name": "Brent T.", "clpid": "Fultz-B-T" } ], "thesis_committee": [ { "family_name": "Fultz", "given_name": "Brent T.", "clpid": "Fultz-B-T" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "Resnick Sustainability Institute" }, { "literal": "div_chem" } ], "abstract": "The mechanism and thermodynamic properties of hydrogen binding to the solid-state complexes [M(CO)dppe2][BArF24] (M = Mn, Re, Tc) and [M'Hdppe2][NTf2] (M' = Fe, Ru, Os) were investigated experimentally and computationally over the temperature range 298K-373K and pressure range 0-2800 torr, based on the Sieverts method. The bulk absorption behavior was found to be accurately described by Langmuir isotherms. Enthalpy and entropy values of ΔH° = -52.2 kJ/mol and ΔS° = -99.6 J/mol-K were obtained experimentally for hydrogen absorption onto [Mn(CO)dppe2][BArF24] from the Langmuir equilibrium constant, and values obtained from electronic structure calculations using the LANL2DZ-ECP basis set were found to successfully reproduce both the pressure-temperature-composition behavior and the thermodynamic values to within 5% of those obtained through experiment. Results from simulations for all complexes yielded large enthalpy values similar to metal hydride formation enthalpies for all complexes studied, and the substitution of the metal center reproduced qualitative binding strength trends of 5d>3d>4d consistent with those previously reported for the group 6 metals.
\r\n\r\nX-ray diffraction patterns and Mössbauer spectra were taken to determine the thermal decomposition pathway for [FeH(η2-H2)dppe2][NTf2]. Simulations at the B3LYP/TZVP level of theory and experimental Mössbauer spectra confirmed the direct thermal decomposition from singlet-state [FeH(η2-H2)dppe2][NTf2] to triplet-state [FeHdppe2][NTf2] under vacuum conditions at 398K. Evaluation of the partial quadrupole splitting values of Q(H2) = -0.245 mm/s from Mössbauer spectroscopy significantly differ from typical values obtained for hydrides, indicating an underutilized mechanism for identification of dihydrogen ligands. Singlet-state thermodynamic values from simulation were consistent with experimental observations for Ru and Os, and ruthenium complexes were found to have thermodynamic properties within appropriate ranges for hydrogen storage applications. Simulated thermodynamic values for Fe complexes were found to significantly underestimate experimental behavior, demonstrating the importance of the magnetic spin state of the molecule to hydrogen binding properties.
", "doi": "10.7907/z9057cvb", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7873", "collection": "thesis", "collection_id": "7873", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06072013-160243112", "primary_object_url": { "basename": "LH_thesis_final.pdf", "content": "final", "filesize": 116038390, "license": "other", "mime_type": "application/pdf", "url": "/7873/1/LH_thesis_final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Towards Conditional RNAi : Shape and Sequence Transduction with Small Conditional RNAs", "author": [ { "family_name": "Hochrein", "given_name": "Lisa Marie", "clpid": "Hochrein-Lisa-Marie" } ], "thesis_advisor": [ { "family_name": "Pierce", "given_name": "Niles A.", "clpid": "Pierce-N-A" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Pierce", "given_name": "Niles A.", "clpid": "Pierce-N-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Rossi", "given_name": "John J.", "clpid": "Rossi-J-J" }, { "family_name": "Burnett", "given_name": "John", "clpid": "Burnett-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "RNA interference (RNAi) is a powerful biological pathway allowing for sequence-specific knockdown of any gene of interest. While RNAi is a proven tool for probing gene function in biological circuits, it is limited by being constitutively ON and executes the logical operation: silence gene Y. To provide greater control over post-transcriptional gene silencing, we propose engineering a biological logic gate to implement \u201cconditional RNAi.\u201d Such a logic gate would silence gene Y only upon the expression of gene X, a completely unrelated gene, executing the logic: if gene X is transcribed, silence independent gene Y. Silencing of gene Y could be confined to a specific time and/or tissue by appropriately selecting gene X.
\r\n\r\nTo implement the logic of conditional RNAi, we present the design and experimental validation of three nucleic acid self-assembly mechanisms which detect a sub-sequence of mRNA X and produce a Dicer substrate specific to gene Y. We introduce small conditional RNAs (scRNAs) to execute the signal transduction under isothermal conditions. scRNAs are small RNAs which change conformation, leading to both shape and sequence signal transduction, in response to hybridization to an input nucleic acid target. While all three conditional RNAi mechanisms execute the same logical operation, they explore various design alternatives for nucleic acid self-assembly pathways, including the use of duplex and monomer scRNAs, stable versus metastable reactants, multiple methods of nucleation, and 3-way and 4-way branch migration.
\r\n\r\nWe demonstrate the isothermal execution of the conditional RNAi mechanisms in a test tube with recombinant Dicer. These mechanisms execute the logic: if mRNA X is detected, produce a Dicer substrate targeting independent mRNA Y. Only the final Dicer substrate, not the scRNA reactants or intermediates, is efficiently processed by Dicer. Additional work in human whole-cell extracts and a model tissue-culture system delves into both the promise and challenge of implementing conditional RNAi in vivo.
", "doi": "10.7907/NTZT-8Q67", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7618", "collection": "thesis", "collection_id": "7618", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04182013-113509606", "primary_object_url": { "basename": "FULL THESIS-DCM.pdf", "content": "final", "filesize": 60147657, "license": "other", "mime_type": "application/pdf", "url": "/7618/37/FULL THESIS-DCM.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Improving the Biological Activity of Pyrrole-Imidazole Polyamides ", "author": [ { "family_name": "Montgomery", "given_name": "David Church", "clpid": "Montgomery-David-Church" } ], "thesis_advisor": [ { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Dervan", "given_name": "Peter B.", "clpid": "Dervan-P-B" }, { "family_name": "Campbell", "given_name": "Judith L.", "clpid": "Campbell-J-L" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "DNA is nature\u2019s blueprint, holding within it the genetic code that defines the structure and function of an organism. A complex network of DNA-binding proteins called transcription factors can largely control the flow of information from DNA, so modulating the function of transcription factors is a promising approach for treating many diseases. Pyrrole-imidazole (Py-Im) polyamides are a class of DNA-binding oligomers, which can be synthetically programmed to bind a target sequence of DNA. Due to their unique shape complementarity and a series of favorable hydrogen bonding interactions that occur upon DNA-binding, Py-Im polyamides can bind to the minor groove of DNA with affinities comparable to transcription factors. Previous studies have demonstrated that these cell-permeable small molecules can enter cell nuclei and disrupt the transcription factor-DNA interface, thereby repressing transcription. As the use of Py-Im polyamides has significant potential as a type of modular therapeutic platform, the need for polyamides with extremely favorable biological properties and high potency will be essential. Described herein, a variety of studies have been performed aimed at improving the biological activity of Py-Im polyamides. To improve the biological potency and cellular uptake of these compounds, we have developed a next-generation class of polyamides bearing aryl-turn moieties, a simple structural modification that allows significant improvements in cellular uptake. This strategy was also applied to a panel of high-affinity cyclic Py-Im polyamides, again demonstrating the remarkable effect minor structural changes can have on biological activity. The solubility properties of Py-Im polyamides and use of formulating reagents with their treatment have also been examined. Finally, we describe the study of Py-Im polyamides as a potential artificial transcription factor.", "doi": "10.7907/28SH-6Z27", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7293", "collection": "thesis", "collection_id": "7293", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11282012-141927745", "primary_object_url": { "basename": "Thesis_BhaweYashodhan.pdf", "content": "final", "filesize": 24883515, "license": "other", "mime_type": "application/pdf", "url": "/7293/1/Thesis_BhaweYashodhan.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "I: Solid Materials for Low Temperature Thermochemical Water Splitting. II: Structure-Property Relationships on the Zeolite Catalyzed Conversion of Methanol to Light Olefins", "author": [ { "family_name": "Bhawe", "given_name": "Yashodhan", "clpid": "Bhawe-Yashodhan" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Miller", "given_name": "Thomas F.", "clpid": "Miller-T-F" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis describes two separate projects. The first part of the thesis involves the synthesis of materials for enabling thermochemical water splitting at temperatures below 1000\u00baC, while the second part focuses on the structure-property relationships for the catalytic conversion of methanol-to-olefins.
\r\n\r\nIn the first project, metal oxide clusters are impregnated in a silica support and tested as catalysts for the thermochemical splitting of water at temperatures below 1000\u00baC. These supported catalysts are able to do either the oxidation or reduction half cycle, but not both. Thermodynamic analyses reveal that for most common metal / metal oxide pairs, a thermochemical water splitting cycle can not occur in two steps below 1000\u00baC. Thus, a multi-step thermochemical cycle is developed using Mn3O4 and Na2CO3. This new cycle can be closed at temperatures that do not exceed 850\u00baC. Additionally, three metal spinels (Mn, Fe and Co based) are investigated with three alkali metal carbonates (Li, Na and K) for both thermochemical water splitting and thermochemical CO2 reduction. The manganese, sodium system is found to be the optimal combination for water splitting.
\r\n\r\nThe second project explores the effects that zeolite structure has on the product selectivity in the methanol-to-olefins (MTO) reaction. After first ensuring that literature results on the more common MTO catalysts could be reproduced, the effects of several zeolite structure features on product selectivity are elucidated. Structural features such as channel width and channel eccentricity, cage size (tested on the LEV, CHA and AFX frameworks) and framework composition (tested on the LEV, AEI, CHA and AFX frameworks) are explored. It is found that the product selectivity does not have a strong correlation with channel width and eccentricity. Ethylene selectivity did increase with a reduction in cage size, while propylene selectivity is a maximum with the CHA cage. The most consistent theme noted is that between the aluminosilicates (zeolites) and the silicoaluminophosphates (SAPOs), the effect of temperature on the C3=/C2= is the same (if the aluminosilicate shows an increase in C3=/C2= with an increase in temperature, so does the silicoaluminophosphate, etc.).
", "doi": "10.7907/05FG-JG39", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7443", "collection": "thesis", "collection_id": "7443", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01262013-020116009", "primary_object_url": { "basename": "Han Thesis.pdf", "content": "final", "filesize": 52470821, "license": "other", "mime_type": "application/pdf", "url": "/7443/1/Han Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Development of Targeted, Polymeric Delivery Vehicles for Camptothesin and siRNA Via Boronic Acid-Diol Complexation", "author": [ { "family_name": "Han", "given_name": "Han", "clpid": "Han-Han" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Our research lab has developed polymer-based nanoparticle delivery systems for the anticancer drug, camptothecin (CPT), CRLX101; and for the small interfering RNA (siRNA), CALAA-01. CRLX101 has shown great success in both animal studies and clinical trials. However, it is incapable of achieving targeted delivery. CALAA-01 has demonstrated effectiveness in a phase I clinical trial. However, it suffers from its rapid in vivo clearance. To address the issues of targeting in the anticancer drug delivery system and the short circulation time in the siRNA delivery system, we have created a new delivery platform involving the use of boronic acid-diol complexation. This thesis is divided into two parts to discuss CPT delivery and siRNA delivery separately.
\r\n\r\nIn Part I, the targeted delivery of CPT via boronic acid-diol complexation is described. CPT was conjugated to a copolymer of mucic acid and PEG (MAP) and self-assembled into MAP-CPT nanoparticles. The targeting agent, Herceptin antibody was attached to boronic acid (BA), this was then complexed with the diol-containing MAP to form a targeted nanoparticle carrying ca. 60 CPT, with a 40 nm diameter and a slightly negative surface charge. The attachment of a single Herceptin per nanoparticle was sufficient to enhance cellular uptake of nanoparticles into BT-474, a HER2 overexpressing cell line by 70% compared to the non-targeted version. Nude mice bearing BT-474 xenograft tumors treated with targeted MAP-CPT nanoparticles resulted in all mice revealing complete tumor regression.
\r\n\r\nIn Part II, the boronic acid-diol complexation delivery platform is applied for the delivery of siRNA. First, the CALAA-01 delivery system for siRNA was further characterized and optimized. Then, a copolymer of mucic acid and dimethylsuberimidate (MAD) was synthesized and used in condensing the anionic siRNA into nanoparticles. Nanoparticles were stabilized by placing a surface PEG layer through boronic acid-diol complexation. Targeting was achieved by conjugating the distal end of the BA-PEG with a targeting agent, Herceptin antibody. MAD/siRNA nanoparticles effectively entered cells and demonstrated low cellular toxicity. MAD/siRNA nanoparticles stabilized with nitroPBA-PEG resulted in a diameter of 130 nm with a slightly negative surface charge. Pharmacokinetic studies in mice demonstrated improved circulation compared to CALAA-01.
\r\n\r\n", "doi": "10.7907/NWSP-0Y35", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7193", "collection": "thesis", "collection_id": "7193", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:08282012-110955629", "type": "thesis", "title": "A Novel Method for Studying Nucleated Pathways in Membranes: Development and Applications for Gene Delivery", "author": [ { "family_name": "Ting", "given_name": "Christina Lei", "clpid": "Ting-Christina-Lei" } ], "thesis_advisor": [ { "family_name": "Wang", "given_name": "Zhen-Gang", "orcid": "0000-0002-3361-6114", "clpid": "Wang-Zhen-Gang" } ], "thesis_committee": [ { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" }, { "family_name": "Clemons", "given_name": "William M.", "orcid": "0000-0002-0021-889X", "clpid": "Clemons-W-M" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "orcid": "0000-0002-3361-6114", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The development of a safe, selective, and efficient gene delivery system is key to the success of human gene therapy. In polymer-based gene delivery systems, biocompatible polymers electrostatically bind and condense the genetic material into protective nanoparticles. These nanoparticles must subsequently overcome several challenges, which remain poorly understood. In particular, once internalized by the cell, the nanoparticles are trapped inside a membrane-bound compartment called the endosome. In the proton sponge hypothesis, the buffering capacity of the polymers leads to an increase in osmotic pressure that eventually ruptures the endosomal membrane and releases the trapped nanoparticles.
\r\n\r\nTo obtain a mechanistic understanding of the endosomal escape, we first develop a coarse-grained model to study the equilibrium interaction between a positively charged nanoparticle and a lipid membrane. Results indicate the existence of a pore with an inserted particle, whose metastability depends on the membrane tension and particle properties (size and charge). These pores are subsequently shown to lower the critical tension necessary for membrane rupture, thus possibly enhancing the release of the trapped genetic material from the endosome.
\r\n\r\nNext, we address the actual escape pathway, which is likely a thermally nucleated process and cannot be simulated directly or studied by equilibrium methods. Hence, we develop a novel method for studying minimum free energy paths in membranes. Our results indicate that thermally nucleated rupture may be an important factor for the low rupture strains observed in lipid membranes. Under the moderate tensions found in this regime, there are multiple pathways for crossing the membrane: (1) particle-assisted membrane rupture, (2) particle insertion into a metastable pore followed by translocation and membrane resealing, and (3) particle insertion into a metastable pore followed by membrane rupture. This suggests a direct role of the nanoparticle in the endosomal escape not previously envisioned in the proton sponge hypothesis, and illustrates the importance of having an induced tension on the membrane.
\r\n\r\nFinally, the methodology developed in this work represents the most advanced theoretical technique for describing nucleation pathways in soft condensed matter systems that also include hard-particle degrees of freedom. We expect the method to be useful for studying a wide range of nucleation phenomena beyond membrane systems, for example, in nanoparticle polymer composites.
\r\n", "doi": "10.7907/8FTH-8H35", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7198", "collection": "thesis", "collection_id": "7198", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09092012-010239493", "primary_object_url": { "basename": "Stadie_N_2013_Thesis.pdf", "content": "updated", "filesize": 7810642, "license": "other", "mime_type": "application/pdf", "url": "/7198/83/Stadie_N_2013_Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Synthesis and Thermodynamic Studies of Physisorptive Energy Storage Materials", "author": [ { "family_name": "Stadie", "given_name": "Nicholas P.", "clpid": "Stadie-Nicholas-P" } ], "thesis_advisor": [ { "family_name": "Fultz", "given_name": "Brent T.", "clpid": "Fultz-B-T" }, { "family_name": "Ahn", "given_name": "Channing C.", "clpid": "Ahn-C-C" } ], "thesis_committee": [ { "family_name": "Fultz", "given_name": "Brent T.", "clpid": "Fultz-B-T" }, { "family_name": "Ahn", "given_name": "Channing C.", "clpid": "Ahn-C-C" }, { "family_name": "Haile", "given_name": "Sossina M.", "clpid": "Haile-S-M" }, { "family_name": "Johnson", "given_name": "William Lewis", "clpid": "Johnson-W-L" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_eng" } ], "abstract": "Physical adsorption of hydrogen or other chemical fuels on the surface of carbonaceous materials offers a promising avenue for energy storage applications. The addition of a well-chosen sorbent material to a compressed gas tank increases the volumetric energy density of the system while still permitting fast refueling, simplicity of design, complete reversibility, high cyclability, and low overall cost of materials. While physical adsorption is most effective at temperatures below ambient, effective storage technologies are possible at room temperature and modestly high pressure. A volumetric Sieverts apparatus was designed, constructed, and commissioned to accurately measure adsorption uptake at high pressures and an appropriate thermodynamic treatment of the experimental data is presented.
\r\n\r\nIn Chapter 1, the problem of energy storage is introduced in the context of hydrogen as an ideal alternative fuel for future mobile vehicle applications, and with methane in mind as a near-term solution. The theory of physical adsorption that is relevant to this work is covered in Chapter 2. In-depth studies of two classes of materials are presented in the final chapters. Chapter 3 presents a study of the dissociative \u201chydrogen spillover\u201d effect in the context of its viability as a practical hydrogen storage solution at room temperature. Chapters 4-5 deal with zeolite-templated carbon, an extremely high surface-area material which shows promise for hydrogen and methane storage applications. Studies of hydrogen adsorption at high pressure (Chapter 4) and anomalous thermodynamic properties of methane adsorption (Chapter 5) on ZTCs are presented. The concluding chapter discusses the impact of and possible future directions for this work.
", "doi": "10.7907/ZK3P-CV60", "publication_date": "2013", "thesis_type": "phd", "thesis_year": "2013" }, { "id": "thesis:7084", "collection": "thesis", "collection_id": "7084", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05282012-135618123", "primary_object_url": { "basename": "NG_SHEUNGCHEETHOMAS_2012_THESIS.pdf", "content": "final", "filesize": 39932434, "license": "other", "mime_type": "application/pdf", "url": "/7084/1/NG_SHEUNGCHEETHOMAS_2012_THESIS.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Non-Invasive in vivo Molecular Imaging of Cancer Nanotherapy Uptake and Response with PET/MRI", "author": [ { "family_name": "Ng", "given_name": "Thomas Sheung Chee", "clpid": "Ng-Thomas-Sheung-Chee" } ], "thesis_advisor": [ { "family_name": "Jacobs", "given_name": "Russell E.", "clpid": "Jacobs-R-E" }, { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" } ], "thesis_committee": [ { "family_name": "Patterson", "given_name": "Paul H.", "clpid": "Patterson-P-H" }, { "family_name": "Jacobs", "given_name": "Russell E.", "clpid": "Jacobs-R-E" }, { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Jensen", "given_name": "Grant J.", "clpid": "Jensen-G-J" } ], "local_group": [ { "literal": "div_biol" } ], "abstract": "Although researchers have made great strides toward understanding the biological processes underlying cancer pathology, this has not led to major improvements in the management of the disease. Development of new treatments to combat cancer remains imperative. Nanosized therapies show promise to improve tumor treatment response by localizing therapy while reducing treatment-related toxicity. Understanding how nanotherapies are taken up and cause their effects at the intact tumor level in vivo will complement ex vivo histological and in vitro biochemical studies and facilitate the translation of nanotherapy treatments to the clinic. Currently, few in vivo methods exist to study nanotherapy uptake and response at the intact tumor scale. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are imaging methods that provide different but complementary information about the tumor microenvironment and nanotherapy uptake/response. Direct spatiotemporal correlation of PET and MRI data via their simultaneous acquisition has the potential to be powerfully synergistic, especially for the study of physiological processes that are time sensitive or where good spatial coregistration of the multimodal data is important. As the field of hybrid PET/MRI is still in its infancy, with only a handful of active systems worldwide, it is vital that continued PET/MRI technology development be pursued to realize its full potential.
\r\n\r\nThe objective of this thesis is to develop noninvasive, multimodal PET/MRI methods to study the uptake and response of cancer nanotherapies. Three studies were pursued toward this goal. First, we describe the development of a quantitative, small animal simultaneous PET/MRI system that is capable of dynamic, intratumoral imaging. The results show that the system provides quantitative images that are highly correlated with ex vivo autoradiography. The system was able to follow the uptake of a radiolabelled antibody inside the tumor over time, visualizing antibody movement from the vascular space to the tumor mass. Second, we adapted a functional MRI technique, diffusion MRI, to monitor treatment response of the cancer nanotherapy CRLX101. CRLX101-treated animals showed a significant diffusion MRI response within 2 days of treatment, before significant size changes were observed. Modeling of the diffusion MRI data was able to predict the potent antiproliferative effect of CRLX101, commensurate with histological data. Finally, we developed MRI and PET/MRI methods to study the tumor response to the tumor-penetrating peptide iRGD, which has shown good potential to improve cancer nanotherapy uptake. The results show that iRGD can have a variable tumor response, which may be dependent on the tumor microenvironment.
\r\n\r\nThe primary contributions of this thesis work is the development of small animal hybrid PET/MRI technology to enable multimodal intratumoral studies and the development of clinically-applicable imaging methods to monitor the uptake and response of cancer nanotherapies.
", "doi": "10.7907/53JJ-MG42", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:7083", "collection": "thesis", "collection_id": "7083", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05282012-134754737", "primary_object_url": { "basename": "Culic-Viskota_Jelena_2012_thesis.pdf", "content": "final", "filesize": 31966432, "license": "other", "mime_type": "application/pdf", "url": "/7083/1/Culic-Viskota_Jelena_2012_thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Synthesis and Functionalization of Second Harmonic Generation Nanocrystals and Their Application in Biological Imaging", "author": [ { "family_name": "Culic-Viskota", "given_name": "Jelena", "clpid": "Culic-Viskota-Jelena" } ], "thesis_advisor": [ { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Pantazis", "given_name": "Periklis", "clpid": "Pantazis-P" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The discovery and use of fluorescent proteins has been of extreme importance in biological imaging of cells, tissues, and organs. In order to address some of the limitations of fluorescent tags, second harmonic generation can be used. Second harmonic generating nanoprobes allow nontoxic, long-term imaging that, with proper functionalization, can be utilized for biological imaging applications. As a proof of principle, commercial tetragonal barium titanate nanoparticles were functionalized to expose surface amine groups, which could be further modified for a plethora of biological applications. Barium titanate nanoparticles were functionalized for selective targeting of tissue sections, biorthogonal linkages and for nonspecific long-term imaging using biocompatible polymers enabling the study of cells as they differentiate during zebrafish development. Since the commercial barium titanate nanoparticles do not have a narrow size distribution, which limits the application of such nanoprobes, synthesis of monodisperse nanocrystals was attempted.
\r\n\r\nZinc oxide nanocrystals were synthesized by solvothermal methods involving the base hydrolysis of zinc salts in the presence of capping ligands. Different synthesis procedures were investigated based on the properties of the prepared nanoparticles. To prevent nanoparticle aggregation and to achieve good dispersion, a capping agent was chosen that provides a tightly bound shell around the nanoparticles. It was observed that the polymerization of PEG molecules with the organic ligands bound to the surface of zinc oxide provided the most adequate coating for the desired size control and dispersion of the nanocrystals. Exploration of the experimental conditions enabled production of variable size hexagonal zinc oxide nanocrystals, which can be used both as SHG probes and as quantum dots.
", "doi": "10.7907/XFXJ-7987", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:7052", "collection": "thesis", "collection_id": "7052", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05182012-134600511", "primary_object_url": { "basename": "Thesis_Final.pdf", "content": "final", "filesize": 10246787, "license": "other", "mime_type": "application/pdf", "url": "/7052/1/Thesis_Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Targeting Tumors and the Kidney with siRNA Nanoparticles and Evaluation of Extracellular MicroRNA-based Methodologies to Track Their Activity", "author": [ { "family_name": "Zuckerman", "given_name": "Jonathan Eric", "clpid": "Zuckerman-Jonathan-Eric" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Baltimore", "given_name": "David L.", "clpid": "Baltimore-D-L" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The goal of my thesis work is to discover new ways to enable the use of nanoparticle therapeutics to treat human disease. The work presented here touches on several areas in medicine and is united by a common theme: engineering ways to make, use, and evaluate therapeutics that maximize the benefit to the patient and minimize the harm. I have explored three interrelated strategies to achieve my objectives: (1) the use of targeted-nanoparticle-based therapeutics to deliver therapeutic entities to specific sites in the body, (2) the use of a highly specific type of therapeutic, siRNA, and (3) the evaluation of strategies for using extracellular microRNAs to non invasively monitor therapeutic activity and disease response to that activity.
\r\n\r\nIn Chapter 2, I present the first evidence of targeted-nanoparticle delivery of siRNA to solid tumors following systemic administration to patients. My coworkers and I demonstrate both dose-dependent accumulation of the siRNA nanoparticles and evidence of gene knockdown via the canonical RNAi mechanism.
\r\n\r\nChapters 3 \u2013 5 describe the therapeutic potential of targeted nanoparticles (one version used in the clinic and described in Chapter 2) for: (i) targeting ribonucleotide reductase subunit M2 in human melanoma cell lines (Chapter 3), (ii) Herceptin-targeted nanoparticles containing siRNA against Her2 in Her2(+) breast cancer (Chapter 4), and (iii) siRNA targeting the \u201cundruggable\u201d protein N-Ras for N-Ras mutant melanomas (Chapter 5).
\r\n\r\nChapters 6 \u2013 8 focus on the interaction of nanoparticles with the kidney. Chapter 6 explores a previously unknown phenomenon of size-dependent glomerular accumulation of nanoparticles. In Chapter 7, a new mechanism of clearance for polycation-polymer-based nucleic acid delivery systems is demonstrated, based on interactions between polymer components in the nanoparticle and the anionic surface of the renal filtration barrier, explaining the rapid clearance of these siRNA nanoparticle systems. Chapter 8 illustrates targeted-nanoparticle delivery of siRNA to the kidney.
\r\n\r\nIn Chapter 9, I test the hypothesis that analysis of tumor-secreted microRNAs within patient blood samples can be used as real-time markers of drug pharmacodynamics. Specifically, I focus on efforts to characterize microRNA expression patterns following pharmacologic inhibition of the oncogene BRAF in melanoma cells and their secreted exosomes.
", "doi": "10.7907/P4FF-NQ42", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6857", "collection": "thesis", "collection_id": "6857", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03202012-131523365", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 22323051, "license": "other", "mime_type": "application/pdf", "url": "/6857/37/Thesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "The Role of Transport Phenomena in Whispering Gallery Mode Optical Biosensor Performance", "author": [ { "family_name": "Gamba", "given_name": "Jason M.", "clpid": "Gamba-Jason-M" } ], "thesis_advisor": [ { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "thesis_committee": [ { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Armani", "given_name": "Andrea", "clpid": "Armani-A-M" }, { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Whispering gallery mode (WGM) optical resonator sensors have emerged as promising tools for label-free detection of biomolecules in solution. These devices have even demonstrated single-molecule limits of detection in complex biological uids. This extraordinary sensitivity makes them ideal for low-concentration analytical and diagnostic measurements, but a great deal of work must be done toward understanding and optimizing their performance before they are capable of reliable quantitative measurents. The present work explores the physical processes behind this extreme sensitivity and how to best take advantage of them for practical applications of this technology.
\r\n\r\nI begin by examining the nature of the interaction between the intense electromagnetic elds that build up in the optical biosensor and the biomolecules that bind to its surface. This work addresses the need for a coherent and thorough physical model that can be used to predict sensor behavior for a range of experimental parameters. While this knowledge will prove critical for the development of this technology, it has also shone a light on nonlinear thermo-optical and optical phenomena that these devices are uniquely suited to probing. The surprisingly rapid transient response of toroidal WGM biosensors despite sub-femtomolar analyte concentrations is also addressed. The development of asymmetric boundary layers around these devices under ow is revealed to enhance the capture rate of proteins from solution compared to the spherical sensors used previously. These lessons will guide the design of ow systems to minimize measurement time and consumption of precious sample, a key factor in any medically relevant assay.
\r\n\r\nFinally, experimental results suggesting that WGM biosensors could be used to improve the quantitative detection of small-molecule biomarkers in exhaled breath condensate demonstrate how their exceptional sensitivity and transient response can enable the use of this noninvasive method to probe respiratory distress. WGM bioensors are unlike any other analytical tool, and the work presented here focuses on answering engineering questions surrounding their performance and potential.
", "doi": "10.7907/DQP0-RY11", "publication_date": "2012", "thesis_type": "phd", "thesis_year": "2012" }, { "id": "thesis:6215", "collection": "thesis", "collection_id": "6215", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:12172010-180148854", "primary_object_url": { "basename": "Y._Chen_Ph.D._Thesis--Final.pdf", "content": "final", "filesize": 20616999, "license": "other", "mime_type": "", "url": "/6215/11/Y._Chen_Ph.D._Thesis--Final.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Genetic Control of T-Cell Proliferation with Synthetic RNA Regulatory Systems", "author": [ { "family_name": "Chen", "given_name": "Yvonne Yu-Hsuan", "clpid": "Chen-Yvonne-Yu-Hsuan" } ], "thesis_advisor": [ { "family_name": "Smolke", "given_name": "Christina D.", "clpid": "Smolke-C-D" } ], "thesis_committee": [ { "family_name": "Smolke", "given_name": "Christina D.", "clpid": "Smolke-C-D" }, { "family_name": "Jensen", "given_name": "Michael C.", "clpid": "Jensen-M-C" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Adoptive T-cell therapy, or the use of autologous T cells to seek and destroy diseased cells, is a promising treatment option for opportunistic diseases, virus-associated malignancies, and cancers. However, the safety and efficacy of adoptive T-cell therapy depend, in part, on the ability to sustain and tightly regulate the proliferation of transferred T cells in vivo. The emerging field of synthetic biology provides powerful conceptual and technological tools for the construction of regulatory systems that can interface with and reprogram complex biological processes such as cell growth. Here, we present the development of RNA-based regulatory systems that can control T-cell proliferation in a ligand-dependent manner, and examine the construction of integrated control systems capable of fine-tuned programming of cellular behavior.
\r\n\r\nWe systematically investigate the translation of ribozyme-based regulatory devices from yeast to mammalian cells and identify design parameters critical to the portability of regulatory devices across host organisms. We report the construction of ligand-responsive ribozyme switch systems capable of modulating the transgenic expression of growth-stimulatory cytokines in mammalian lymphocytes. We demonstrate the ability of ribozyme switch systems to regulate T-cell proliferation in primary human central memory T cells and in animal models. We further develop ligand-responsive, miRNA-based devices to regulate the endogenous expression of cytokine receptor chains and the functional output of cytokine signaling pathways, highlighting the ability to construct integrated T-cell proliferation control systems employing various regulatory mechanisms to modulate multiple components in relevant signaling pathways. Finally, we describe efforts in the generation of novel RNA aptamers to clinically suitable molecules, which can serve as the molecular inputs for ligand-responsive, RNA-based control systems in therapeutic applications.
\r\n\r\nThe regulatory systems developed in this work are designed to be modular and transportable across host organisms and application contexts, thus providing a template for future designs in RNA-based genetic regulation. This work demonstrates the capability of RNA-based regulatory systems to advance next-generation treatment options for critical diseases, and highlights the potential of synthetic biological systems to achieve novel and practical functions in diverse applications.
\r\n", "doi": "10.7907/AP1T-QM29", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6362", "collection": "thesis", "collection_id": "6362", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:04272011-162341841", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 28111716, "license": "other", "mime_type": "application/pdf", "url": "/6362/6/Thesis.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Biophysics and Protein Engineering with Noncanonical Amino Acids", "author": [ { "family_name": "Van Deventer", "given_name": "James A.", "clpid": "Van-Deventer-James-A" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" }, { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Clemons", "given_name": "William M.", "orcid": "0000-0002-0021-889X", "clpid": "Clemons-W-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Noncanonical amino acids are tools for expanding and altering the chemical functionalities available within proteins. Much recent work has focused on developing biosynthetic means for incorporating noncanonical amino acids into proteins, and applications of noncanonical amino acids to many problems in science and engineering are emerging. The first portion of this thesis describes established methods to incorporate noncanonical amino acids into proteins and efforts to exploit the properties of noncanonical amino acids in areas such as protein structure determination, protein and organism evolution, modulation of the immune system, and proteomics. Researchers\u2019 creative and successful use of this growing toolkit suggests that noncanonical amino acids will continue to be a valuable asset for dissecting biological problems and imparting proteins with new chemical and physical properties.
\r\n\r\nBiophysical studies with noncanonical amino acids provide a platform for studying the effects of atom-by-atom manipulations of amino acid side chains on protein properties. The middle portions of this thesis describe work to better understand how protein properties are affected by subtle amino acid side chain manipulations. This work was aided greatly by the establishment of homoisoleucine as a translationally active analog of leucine in bacterial cells. The small side chain differences between leucine, homoisoleucine, and the fluorinated amino acid trifluoroleucine allow for detailed studies on how amino acid side chain size and fluorination affect protein stability and hydration dynamics. Replacement of leucine by homoisoleucine in coiled-coil peptides stabilizes these proteins, as shown by elevation of the coiled coil thermal denaturation temperature. The stabilization observed when homoisoleucine replaces leucine in the peptides is greater than when trifluoroleucine replaces leucine, suggesting that expansion of side chain volume may play a role in protein stabilization irrespective of hydrocarbon or fluorocarbon character.
\r\n\r\nStudies of water-protein interactions using designed coiled coils containing surface-exposed leucine, homoisoleucine, or trifluoroleucine residues enabled systematic examination of the roles that side chain size and fluorination play in dictating solvation dynamics. Fluorinated side chains appear to exert a large electrostatic drag on nearby water molecules. These results have important implications for the design and engineering of fluorinated proteins due to the critical role water-protein interactions play in many protein properties and functions.
\r\n\r\nThe final portion of this thesis details efforts to engineer the binding properties and chemical reactivity of antibody fragments with noncanonical amino acids. The properties of the single chain variable fragment form of a model anti-digoxin antibody have been studied after replacement of the protein\u2019s methionine residues with methionine analogs containing alkyne, azide, and aliphatic side chains. Experiments with antibody fragments displayed on the surface of Escherichia coli cells revealed that replacement of the methionine residues of the fragment with an analog containing an alkyne side chain reduced the fluorescence levels of cells treated with a fluorescently labeled antigen to background levels, indicating loss of binding function. Replacement of methionine with analogs containing aliphatic and azide side chains left the fluorescence of cells unchanged and reduced by a factor of 0.6, respectively. Fluorescence-activated cell sorting of libraries of cell surface-displayed antibody fragments enabled the isolation of clones functional in multiple amino acid contexts. Cells displaying variants containing alkyne, azide, and aliphatic analogs and treated with fluorescently labeled antigen were more fluorescent than cells displaying the methionine form of the parent antibody fragment by factors of roughly 1.7, 3.5, and 1.3, respectively. Furthermore, the amino acid context used during high-throughput screening experiments appears to affect the frequencies of mutations occurring at various positions within the antibody fragment construct. High-throughput sequencing revealed that populations isolated in different amino acid contexts exhibit mutational rates differing by greater than twenty percent at some residues in the protein.
\r\n\r\nCharacterization of soluble fragments indicated that each noncanonical amino acid used in this study modulates the binding kinetics of antibody fragments in a distinct fashion. Perhaps most interestingly, fragments containing the azide-containing analog azidohomoalanine exhibit improved binding kinetics relative to their methionine-containing counterparts. Replacement of methionine by azidohomoalanine in several variants lowers the dissociation constant of the fragment by up to a factor of two. Chemical conjugation of azide-containing fragments to fluorescent dyes and biotin proved facile with strain-promoted cycloaddition reactions. Quantifications of the extent of reaction using fluorescent dyes revealed that approximately 0.4 dyes had been conjugated per protein, and the resulting conjugates were found to retain their binding function in kinetic and Western blotting assays. Experiments in which azide-containing fragments were displayed on the surface of Escherichia coli cells and subjected to strain-promoted cycloadditions demonstrated that the extent of chemical modification and antigen binding can be monitored simultaneously and used to isolate cells displaying functional, modified proteins. These experiments demonstrate how noncanonical amino acids can be used to modulate multiple properties of antibody fragments and illustrate the feasibility of developing and screening libraries of chemically modified proteins. Evolved, functional bioconjugates may be applicable to a variety of outstanding diagnostic and therapeutic problems.
", "doi": "10.7907/VT2B-8B33", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6373", "collection": "thesis", "collection_id": "6373", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05042011-114651954", "primary_object_url": { "basename": "MMYC_thesis_050411.pdf", "content": "final", "filesize": 4722666, "license": "other", "mime_type": "application/pdf", "url": "/6373/12/MMYC_thesis_050411.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Directed Evolution of Cytochrome P450 for Small Alkane Hydroxylation", "author": [ { "family_name": "Chen", "given_name": "Mike Ming Yu", "clpid": "Chen-Mike-Ming-Yu" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "orcid": "0000-0002-1942-9232", "clpid": "Labinger-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Methane is an ideal alternative to petroleum refining as a chemical feedstock source since it is highly abundant an inexpensive. However, the lack of selective methane oxidation catalysts has limited such utilization. Starting from cytochrome P450 CYP102A1 (BM3) from Bacillus megaterium, which prefers C12-C20 fatty acids as its substrates, I investigated several protein engineering approaches to shift the enzyme\u2019s substrate specificity toward small gaseous alkanes, with the ultimate goal of methane. By continuing previous directed evolution efforts in our group, a variant with wild-type-like affinity and catalytic efficiency for propane, P450PMO, was isolated. To alleviate the loss of protein thermostability (~10 \u00b0C) as a result of this approach, mutations were targeted to the BM3 active site with site saturation mutagenesis, targeted mutagenesis with a reduced set of amino acids, and computationally guided library designs. From these enzyme libraries, variants were identified that replicated much of the P450PMO activities with a minimal number of mutations while maintaining wild-type thermostability.
\r\n\r\nContinuing the protein engineering with a high throughput ethane hydroxylation screen, variants with improved in vitro ethane hydroxylation activity were obtained. However, in whole-cell ethane bioconversions, BM3-derived variants could not match the activity of a natural P450 alkane hydroxylase, CYP153A6. To investigate the oxidation capability of the P450 oxo-ferryl porphyrin radical intermediate directly, I employed a variety of terminal oxidants to support P450 alkane hydroxylation reactions abridging the P450 catalytic cycle. In this study, the CYP153A6 oxo-ferryl intermediate was able to oxidize methane in reactions using iodosylbenzene, which demonstrated that direct methane-to-methanol conversion by a P450 heme porphyrin catalyst at ambient conditions is possible and does not necessarily require the use of additional effectors to alter the active site geometry.
\r\n", "doi": "10.7907/T154-RW89", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6373", "collection": "thesis", "collection_id": "6373", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05042011-114651954", "primary_object_url": { "basename": "MMYC_thesis_050411.pdf", "content": "final", "filesize": 4722666, "license": "other", "mime_type": "application/pdf", "url": "/6373/12/MMYC_thesis_050411.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Directed Evolution of Cytochrome P450 for Small Alkane Hydroxylation", "author": [ { "family_name": "Chen", "given_name": "Mike Ming Yu", "clpid": "Chen-Mike-Ming-Yu" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "orcid": "0000-0002-1942-9232", "clpid": "Labinger-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Methane is an ideal alternative to petroleum refining as a chemical feedstock source since it is highly abundant an inexpensive. However, the lack of selective methane oxidation catalysts has limited such utilization. Starting from cytochrome P450 CYP102A1 (BM3) from Bacillus megaterium, which prefers C12-C20 fatty acids as its substrates, I investigated several protein engineering approaches to shift the enzyme\u2019s substrate specificity toward small gaseous alkanes, with the ultimate goal of methane. By continuing previous directed evolution efforts in our group, a variant with wild-type-like affinity and catalytic efficiency for propane, P450PMO, was isolated. To alleviate the loss of protein thermostability (~10 \u00b0C) as a result of this approach, mutations were targeted to the BM3 active site with site saturation mutagenesis, targeted mutagenesis with a reduced set of amino acids, and computationally guided library designs. From these enzyme libraries, variants were identified that replicated much of the P450PMO activities with a minimal number of mutations while maintaining wild-type thermostability.
\r\n\r\nContinuing the protein engineering with a high throughput ethane hydroxylation screen, variants with improved in vitro ethane hydroxylation activity were obtained. However, in whole-cell ethane bioconversions, BM3-derived variants could not match the activity of a natural P450 alkane hydroxylase, CYP153A6. To investigate the oxidation capability of the P450 oxo-ferryl porphyrin radical intermediate directly, I employed a variety of terminal oxidants to support P450 alkane hydroxylation reactions abridging the P450 catalytic cycle. In this study, the CYP153A6 oxo-ferryl intermediate was able to oxidize methane in reactions using iodosylbenzene, which demonstrated that direct methane-to-methanol conversion by a P450 heme porphyrin catalyst at ambient conditions is possible and does not necessarily require the use of additional effectors to alter the active site geometry.
\r\n", "doi": "10.7907/T154-RW89", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6412", "collection": "thesis", "collection_id": "6412", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05202011-143758537", "type": "thesis", "title": "Factors Governing Photodynamic Cross-Linking of Ocular Coat", "author": [ { "family_name": "Huynh", "given_name": "Joyce", "clpid": "Huynh-Joyce" } ], "thesis_advisor": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" } ], "thesis_committee": [ { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Schwartz", "given_name": "Daniel S.", "clpid": "Schwartz-Daniel-S" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis addresses the challenge of minimizing toxicity of therapeutic protein-protein cross-linking of the cornea and sclera. Protein-protein cross-links include disulfide bonds, enzymatic cross-links and non-enzymatic cross-links. Disulfide bonds and enzymatic cross-links are closely regulated in the body. Non-enzymatic cross-links accumulate in an uncontrolled manner, often leading to deleterious effects. Clinically, non-enzymatic cross-links can be inserted in a controlled manner, both temporally and spatially, using photo-activation to achieve effects ranging from killing tumors to stabilizing ocular shape.
\r\n\r\nThe shape of the eye is maintained by the ocular coat\u2014the cornea and sclera. Diseases that result in progressive shape changes can lead to blindness (degenerative myopia) or necessitate a corneal transplant (keratoconus and post-LASIK ectasia). Photodynamic corneal cross-linking, pioneered by Wollensak et al. using riboflavin activated by near-ultraviolet light (riboflavin/UVA), halts the progression of keratoconus; if applied to the sclera, it might halt the progression of degenerative myopia, as well. However, this treatment suffers from severe cytotoxicity. The literature to date implicitly assumes that photodynamic cross-linking is inherently toxic. The present research demonstrates that protein-protein cross-linking can be achieved with minimal toxicity using eosin Y activated by visible light (eosin Y/visible).
\r\n\r\nAt a molecular level, both eosin Y/visible and riboflavin/UVA are shown to act through a singlet oxygen mechanism; therefore, they are expected to produce similar covalent modifications of collagenous tissues. Real-time measurements of the increase in elastic modulus during irradiation show that the eosin Y/visible and riboflavin/UVA produce similar rates of cross-linking. The transport coefficients of both eosin Y and riboflavin were measured for both sclera and de-epithelialized cornea. The diffusivity and partition coefficient values, together with the cross-linking kinetics, were used in a predictive model of the cross-linking profile as a function of treatment parameters. The predictive model also serves as an optimization tool for guiding the selection of treatment parameters in pre-clinical studies. In contrast to the dramatic toxicity of the riboflavin/UVA treatment (which kills all of the keratocytes and the endothelium in the rabbit model), the eosin Y/visible treatment achieves comparable cross-linking with negligible phototoxicity.
\r\n", "doi": "10.7907/GQ57-4J30", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:6245", "collection": "thesis", "collection_id": "6245", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:02162011-153857988", "primary_object_url": { "basename": "thesis.pdf", "content": "final", "filesize": 14305814, "license": "other", "mime_type": "application/pdf", "url": "/6245/1/thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Pharmacological Behavior of Systemically Administered Nanoparticles of Defined Properties: Mechanistic Investigations at the Organ, Tissue, and Cellular Levels", "author": [ { "family_name": "Choi", "given_name": "Chung Hang Jonathan", "clpid": "Choi-Chung-Hang-Jonathan" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Brady", "given_name": "John F.", "clpid": "Brady-J-F" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" }, { "family_name": "Webster", "given_name": "Paul", "clpid": "Webster-P" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The objective of this thesis is to establish design rules for nanoparticle properties that enable their in vivo transport to target destinations. Gold nanoparticles containing surface-engrafted polyethylene glycol (PEG) chains are prepared with controlled physicochemical properties (hydrodynamic size, surface charge, targeting ligand density). Upon systemic injection into mice, the transport of nanoparticles is monitored by blood pharmacokinetics as well as distribution at the organ, tissue, and subcellular levels from the same injection in an individual animal.
\r\n\r\nAt a constant, slightly negative surface charge (ca. -10 mV), most PEGylated gold nanoparticles (PEG-AuNPs) deposit in the liver, spleen, and kidney of normal mice 24 hours after injection. Increasing retention in the liver (Kupffer cells) and spleen correlate positively with increasing nanoparticle diameter over the range of 25-165 nm, largely due to phagocytic uptake. Accumulation in the kidney is size-dependent, but shows a maximum uptake at ca. 75 \u00b1 25 nm that also gives the highest deposition in the mesangium (uptake by mesangial cells).
\r\n\r\nTumor-bearing mice received injections of PEG-AuNPs of near-constant size (ca. 75 nm) and surface charge (ca. -10 mV) but with variable amounts of ligands that target cancer cells (0-144 ligands per nanoparticle). Independent of ligand content, nanoparticles accumulate in the tumor by the enhanced permeation and retention effect to the same magnitude, and adjacent to leukocytes. Nanoparticles only enter cancer cells in significant amounts when they contain targeting ligands above a threshold amount (between 18 and 144 ligands per nanoparticle).
\r\n\r\nMechanistic studies from model nanoparticles provide insights for the delivery of therapeutic nanoparticles. Systemic administrations of targeted, cyclodextrin-based, siRNA-containing nanoparticles are investigated in animals and humans (Phase I clinical trial). A fluorescent chemical stain with exposed adamantane molecules for binding into the cyclodextrin cups of the targeted nanoparticles is created, allowing for the examination of tumor tissue sections from animals and patient biopsies. Results from both animal and human tissues reveal intracellular, dose-dependent accumulation of targeted nanoparticles in cancer cells of the tumor.
", "doi": "10.7907/33C2-FY20", "publication_date": "2011", "thesis_type": "phd", "thesis_year": "2011" }, { "id": "thesis:3416", "collection": "thesis", "collection_id": "3416", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-09092009-091741", "primary_object_url": { "basename": "Full_Thesis_final_version.pdf", "content": "final", "filesize": 8068557, "license": "other", "mime_type": "application/pdf", "url": "/3416/1/Full_Thesis_final_version.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Applications and Extensions of Living Ring-Opening Metathesis Polymerization", "author": [ { "family_name": "Matson", "given_name": "John B.", "orcid": "0000-0001-7984-5396", "clpid": "Matson-John-B" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Living ring-opening metathesis polymerization (ROMP) is a polymerization method that has recently become popular in the synthesis of complex polymers due to advances in olefin metathesis catalyst design. The unrivaled degree of functional group tolerance of the method, coupled with a high level of control and synthetic ease, make living ROMP a valuable tool in the assembly of complex nanostructures and functional polymers. Work in this thesis details methods for applying living ROMP in the assembly of complex nanostructures and extending the uses of living ROMP to end-functionalized polymers and to polymers synthesized in a catalyst economical manner.
\r\n\r\nChapter 2 describes the synthesis and radiofluorination of fluorine-18 functionalized nanoparticles assembled from polynorbornene block copolymers synthesized via living ROMP. The block copolymers include a hydrophobic photo-crosslinkable block made from a novel cinnamate-containing norbornene, as well as a hydrophilic block made from a PEGylated norbornene. Chapter 3 illustrates another application of ROMP-based nanoparticles in which polynorbornene block copolymers are assembled into Janus (hemispherical) nanoparticles.
\r\n\r\nA method for end-capping ROMP polymers using a symmetrical alpha\u2013bromoester-containing cis-olefin terminating agent is described in Chapter 4. Subsequent atom transfer radical polymerization (ATRP) from the functionalized chain end confirms complete end-functionalization and was used to synthesize mechanistically incompatible block copolymers. Chapter 5 extends this polymer end-functionalization approach to additional functional groups, including alcohols, bromides, thioacetates, fluorescent compounds, biotin, and others.
\r\n\r\nA thorough study of pulsed-addition ROMP (PA-ROMP) performed using a Symyx robotic system is presented in Chapter 6. Extending the end-capping methodology described in Chapters 4 and 5 to the synthesis of additional polymer chains led to a homo- and block copolymerization strategy that can produce more than one polymer chain per molecule of metal initiatior. The PA-ROMP strategy reduces catalyst consumption as much as sevenfold in the synthesis of polynorbornenes.
\r\n\r\nAppendix 1 describes the synthesis and ROMP of several norbornene monomers, including a copper-64 chelating norbornene, that were not addressed in the previous chapters but that may be useful for future studies on functional ROMP polymers and nanostructures. Appendix 2 contains additional mathematical details on PA-ROMP.
\r\n", "doi": "10.7907/4QZ8-CS23", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5250", "collection": "thesis", "collection_id": "5250", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-09042009-115118", "primary_object_url": { "basename": "BMackThesis.pdf", "content": "final", "filesize": 2034398, "license": "other", "mime_type": "application/pdf", "url": "/5250/1/BMackThesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Biodegradable Filaments for Controlled Ophthalmic Drug Delivery", "author": [ { "family_name": "Mack", "given_name": "Brendan Cahill", "clpid": "Mack-Brendan-Cahill" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Wright", "given_name": "Kenneth", "clpid": "Wright-K" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The focus of this thesis is the wet-spinning, in-vitro characterization, and in-vivo implantation of drug loaded filaments for ophthalmic, controlled-release applications. Filaments of ca. 200-300 micrometers in diameter are comprised of the copolymer poly(d,l-lactide-co-glycolide), with various lactide to glycolide ratios, and either the antibiotic levofloxacin or the steroid dexamethasone. The objective of this work is to develop implantable filaments that can provide long release of drugs in the eye and then dissolve in order to replace eye drops, since poor patient compliance can limit the utility of drops.
\r\n\r\nFilament formation by wet-spinning is examined in Chapter 2. Mass transfer during filament coagulation is experimentally probed. The experimental plan explores the effect of drug on the mass flux of solvent and antisolvent. Drug retention during extrusion is examined in the context of mass transport, as well as solid-state and solution-state thermodynamics. Chapter 3 presents data that show how the composition of the filaments affects the thermal, mechanical, and release properties. By manipulating various aspects of filament formulation (drug content, polymer type, etc.), release rate and mechanical properties can be greatly changed. The development of an in-vivo model (rabbit) to verify in-vitro results is described in Chapter 4. Drug release into the tear film and mechanical stability are determined for one filament using three different implantation techniques. Large exposed sections of filament are necessary for drug release into the tear fluid and filament ends must be secured for in-vivo mechanical stability. In-vivo results correlate well to in-vitro results for both drug release and mechanical life span. A method of combining the properties of different single component filaments through side-by-side multicomponent wet-spinning is described in Chapter 5. Single component properties are maintained by this method, so mechanical and release properties of various monocomponent filaments described in Chapter 3 can be combined into a single filament. This thesis shows that wet-spinning is a versatile method of producing drug loaded filaments with various drug encapsulation and release properties, and that these filaments are well suited for ophthalmic controlled release applications.
\r\n", "doi": "10.7907/NFRZ-BY29", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5271", "collection": "thesis", "collection_id": "5271", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-07142009-090835", "primary_object_url": { "basename": "Kuhn_Thesis_Final2.pdf", "content": "final", "filesize": 4361681, "license": "other", "mime_type": "application/pdf", "url": "/5271/1/Kuhn_Thesis_Final2.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Understanding and Improving Efficiency in Ruthenium Olefin Metathesis", "author": [ { "family_name": "Kuhn", "given_name": "Kevin Michael", "clpid": "Kuhn-Kevin-Michael" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "thesis_committee": [ { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Olefin metathesis has become an increasingly important and powerful reaction. The development of the well-defined ruthenium alkylidene complexes, in particular, has broadened the scope and utility of the olefin metathesis reaction in both organic synthesis and polymer science. Despite these advances, complete control of the parameters (activity, stability, and selectivity) that affect efficiency in olefin metathesis remains a major challenge, and the development of more efficient catalysts for a variety of applications remains a very important goal. With that in mind, this thesis primarily focuses on understanding the requirements for and improving the efficiency of ruthenium-based olefin metathesis.
\r\n\r\nIn chapter two, a series of ruthenium olefin metathesis catalysts bearing N-heterocyclic carbene (NHC) ligands with varying degrees of backbone and N-aryl substitution were prepared. These complexes show greater resistance to decomposition through C-H activation of the N-aryl group, resulting in increased catalyst lifetimes. This work utilized robotic technology to examine the activity and stability of each catalyst in metathesis, providing insights into the relationship between ligand architecture and catalyst efficiency.
\r\n\r\nIn chapter three, the high-throughput assay developed in the previous chapter was utilized to screen a series of ruthenium catalysts for the ring-closing metathesis (RCM) of acyclic carbamates to form the corresponding di-, tri-, and tetrasubstituted five-, six-, and seven-membered cyclic carbamates. While disubstituted cyclic olefins were easily formed by a variety of catalysts, NHC-bearing catalysts were required to produce trisubstituted cylic olefin products at low catalyst loadings. Furthermore, only catalysts bearing small N-aryl bulk on the NHC ligands were found to effectively accomplish the RCM reaction for sterically challenging substrates, providing a reminder that more-efficient catalysts still need to be developed.
\r\n\r\nA process for the preparation of symmetric and unsymmetric imidazolinium chlorides that involves reaction of a formamidine with dichloroethane and a base is described in chapter four. This method makes it possible to obtain numerous imidazolinium chlorides under solvent-free reaction conditions and in excellent yields with purification by simple filtration.
\r\n\r\nIn chapter five, both chiral triazolylidenes and cyclic alkyl amino carbenes (CAACs) were chosen as ligands for the preparation of chiral ruthenium olefin metathesis catalysts. These C1 symmetric ligands were chosen to create non-conformationally flexible environments in proximity to the ruthenium center, potentially bringing chirality extremely close to the site of catalysis. These new motifs for ligand architecture show great promise. The moderate enantioselectivies obtained for AROCM and ARCM indicate potential utility toward both synthetic methodology and mechanistic insight.
\r\n\r\nFinally, appendix A describes the preparation of a series of ruthenium olefin metathesis catalysts bearing acenapthylene-annulated NHC ligands with varying degrees of N-aryl substitution. Initial evaluation of their performance in olefin metathesis demonstrated that these complexes show greater resistance to decomposition, resulting in increased catalyst lifetimes. While this work has significant potential, the results are preliminary.
\r\n", "doi": "10.7907/XT5J-TA64", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5287", "collection": "thesis", "collection_id": "5287", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:09292009-141737581", "primary_object_url": { "basename": "JRC_Thesis_Full.pdf", "content": "final", "filesize": 1815815, "license": "other", "mime_type": "application/pdf", "url": "/5287/1/JRC_Thesis_Full.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "I. Synthesis and Testing of a Supported Shilov Oxidation Catalyst and II. Influence of Structural Features on Zeolite Characterization by Constraint Index Testing", "author": [ { "family_name": "Carpenter", "given_name": "John Reeves, III", "clpid": "Carpenter-John-Reeves" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis is composed of two separate projects invoking the use of heterogeneous catalyst, one focused on catalyst development and another on characterization.
\r\n\r\nThe first project concentrates on the development of a heterogeneous catalyst for alkane oxidation utilizing Shilov chemistry. Three techniques for creating heterogeneous catalyst are compared using Wacker oxidation: supported molten salts, supported aqueous phases (SAP), and ion-exchanged zeolites. From the Wacker oxidation study the supported aqueous phase catalyst was identified as the best potential method for developing a Shilov oxidation catalyst.
\r\n\r\nInitial work focused on oxidation of ethanesulfonate loaded onto the SAP catalyst. Similar turnovers were achieved on the SAP catalyst as have been seen in the homogeneous system. The reaction parameters of liquid loading, oxygen pressure, reactant concentration, copper (II) chloride concentration, and acid addition were investigated. While the SAP catalyst was successful in the oxidation of ethanesulfonate, attempts to perform ethane oxidation in a flow system were not. The loss of chloride ions is believed to lead to the deactivation.
\r\n\r\nThe second project investigates anomalous Constraint Index (CI) results for zeolites containing cages that are relatively larger than their pore opening. The CI test utilizes the competitive cracking of 3-methylpentane and n-hexane to classify structures as having small, medium, or large pores. However, structures like SSZ-23, SSZ-25, SSZ-28 and SSZ-35 with these large cages have CI results consistent with a larger pore classification than the pores in them.
\r\n\r\nIncomplete hemi-cages on the external surface may provide a nonselective active site that would result in lower CI results. This work looks at this possibility by comparing SSZ-25 and SSZ-35 with ZSM-5 and BEA* that are normally behaving medium- and large-pore structures respectively. The surface is passivated by a dealumination treatment and the CI test is compared on the parent and treated samples. No evidence of activity on the external surface having an influence on the CI test is observed. Several techniques are also used to further investigate accessibility. Finally we observed that for structures with multiple distinct features, different fouling rates in each feature may result in observable changes in the CI value over time.
\r\n", "doi": "10.7907/WGZA-R541", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5294", "collection": "thesis", "collection_id": "5294", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10082009-183206738", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 4068185, "license": "other", "mime_type": "application/pdf", "url": "/5294/12/Thesis.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "I. Development of Facile Route to Fluoride-Mediated, Pure-Silica Zeolite Thin Films. II. Removal of Structure-Directing Agents from Molecular Sieves via the Use of Photolabile Structure-Directing Agents", "author": [ { "family_name": "Hunt", "given_name": "Heather Kristine", "orcid": "0000-0001-8412-2774", "clpid": "Hunt-Heather-Kristine" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Greer", "given_name": "Julia R.", "clpid": "Greer-J-R" }, { "family_name": "Yan", "given_name": "Yushan", "clpid": "Yan-Yushan" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis consists of two projects related to the development of new routes to zeolite films. In an effort to expand the known library of pure-silica zeolites accessible in planar conformation, Part I details the development of a new synthetic technique, the vapor phase transport of fluoride, to produce pure-silica zeolite films with the LTA, CHA, STT, ITW and \u2013SVR topologies. The films are characterized by X-ray diffraction, field emission scanning electron microscopy, X-ray energy dispersive analyses, and mechanical testing. Such pure-silica zeolite films could be useful in a variety of applications, due to their porosity, crystallinity, and general stability. For example, these materials could be employed as low dielectric constant materials, which are needed for microprocessors as the feature size is continually reduced. Upon investigation of the aforementioned zeolite powders and films, we find that the materials with the LTA topology have the lowest dielectric constant of all the pure-silica zeolites. Additionally, all the zeolites investigated, except STT, give k-values lower than predicted from their structures using the Bruggeman effective medium model, which has been commonly employed and found able to predict dielectric constants of amorphous silicas.
\r\n\r\nThe second part of this thesis presents the development of an alternative method to thermal combustion to remove organics from zeolite pores, which can degrade zeolite films, using a photolabile structure-directing agent that can be removed from the zeolite pore space using UV photolysis. Here, the synthesis, photocleavage, and structure-directing ability of two different photolabile molecules (8,8-dimethyl-2-(2-nitrophenyl)-1,4-dioxa-8-azoniaspiro[4.5]decane hydroxide (P-SDA 1) and 1-(2-nitrobenzyl)-1H-imidazole (P-SDA 2)), are presented and discussed. Cleavage of the photolytic P-SDA 1 is demonstrated in a homogeneous solution, and intercalated into a dealuminated zeolite FAU. The structure-directing ability of P-SDA 1 is evaluated via attempts to synthesize silicate and aluminosilicate zeolites, resulting in the formation of amorphous and layered materials. The structure-directing ability of P-SDA 2 is evaluated via attempts to produce aluminophosphate zeolites, resulting in several unknown crystalline phases, in addition to dense and hydrated phases. Lastly, complete photocleavage of P-SDA 2 within the crystalline, aluminophosphate materials is also demonstrated. \r\n
", "doi": "10.7907/P09Y-2K69", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5583", "collection": "thesis", "collection_id": "5583", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03092010-121643566", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 5771024, "license": "other", "mime_type": "application/pdf", "url": "/5583/11/Thesis.pdf", "version": "v8.0.0" }, "type": "thesis", "title": "Rapid Construction of Protein Capture Agents with Chemically Designed Stability and Antibody-Like Recognition Properties", "author": [ { "family_name": "Agnew", "given_name": "Heather Dawn", "clpid": "Agnew-Heather-Dawn" } ], "thesis_advisor": [ { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" } ], "thesis_committee": [ { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis describes technologies for the rapid and scalable production of high-affinity, high-specificity protein capture agents which possess the affinities and specificities of antibodies, but also exhibit improved chemical, biochemical, and physical stability. I will discuss how the chemical flexibility of comprehensive, one-bead-one-compound (OBOC) libraries of oligopeptides may be combined with iterative in situ click chemistry to select multi-ligand capture agents. Large OBOC libraries form the basis of individual peptide ligands, and also permit chemically designed stability through the incorporation of artificial (azide or acetylene) and non-natural amino acid building blocks. The in situ click chemistry method then utilizes the target protein as the catalyst, or template, for assembling its own biligand via formation of a 1,2,3-triazole linkage between two individual ligands (azide and acetylene). This process can be repeated to produce triligands, tetraligands, and other higher-order multi-ligands with an accompanying increase in affinity and specificity through cooperative interactions. Once found, multi-ligand capture agents can be produced in gram amounts via conventional synthetic methods such as the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). This is a general and robust strategy for the inexpensive, high-throughput construction of protein capture agents that can be exploited to detect protein biomarkers in multi-parameter clinical diagnostic assays.
\r\n\r\nWhile high-affinity protein capture agents represent a significant technology advance, they are just one component of what is necessary for highly multiplexed measurements of protein biomarkers. It is also important to develop or optimize the actual assay platforms that can enable sensitive multi-parameter protein measurements using these capture agents. Silicon nanowire (SiNW) nanoelectronic sensors can provide quantitative, label-free multi-parameter measurements of protein biomarkers in real time. However, SiNW sensors can be challenging to deploy because unprotected Si forms a native oxide layer that can significantly reduce the detection sensitivity of the nanowire sensors via dielectric shielding. Another technical challenge is the development of chemistries which allow for the selective encoding of nanowire surfaces with the capture agents. To overcome these challenges, the final part of this thesis presents a general method to functionalize organic and biological molecules on highly passivated Si(111) surfaces with minimal surface oxidation.
", "doi": "10.7907/1HJG-AQ59", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5620", "collection": "thesis", "collection_id": "5620", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03252010-121803765", "primary_object_url": { "basename": "Jina_Choi_Thesis_(Entire).pdf", "content": "final", "filesize": 3475763, "license": "other", "mime_type": "application/pdf", "url": "/5620/9/Jina_Choi_Thesis_(Entire).pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Development of Visible-Light-Active Photocatalyst for Hydrogen Production and Environmental Application", "author": [ { "family_name": "Choi", "given_name": "Jina", "clpid": "Choi-Jina" } ], "thesis_advisor": [ { "family_name": "Hoffmann", "given_name": "Michael R.", "clpid": "Hoffmann-M-R" } ], "thesis_committee": [ { "family_name": "Wennberg", "given_name": "Paul O.", "clpid": "Wennberg-P-O" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Hoffmann", "given_name": "Michael R.", "clpid": "Hoffmann-M-R" } ], "local_group": [ { "literal": "div_eng" } ], "abstract": "Semiconductor photocatalysis has been intensively studied in recent decades for a wide variety of application such as hydrogen production from water splitting and water and air treatment. The majority of photocatalysts are, however, wide band-gap semiconductors which are active only under UV irradiation. In order to effectively utilize visible solar radiation, this thesis investigates various types of visible-light active photocatalysts including metal ion-doped TiO\u2082, nanocomposites of potassium niobate (KNbO\u2083) and CdS with Ni co-catalyst, and a mixed-phase CdS matrix interlinked with elemental Pt deposits.
\r\n\r\nThirteen different metal ion-doped TiO\u2082 nanoparticles are synthesized. I compare the effects of individual dopants on the resulting physicochemical properties and corresponding photocatalytic activities with respect to the catalysis of several reactions under visible-light irradiation. I found several metal ion-doped Ti\u2082 nanoparticles such as Pt, Cr, and V had visible-light photocatalytic activities and the presence of rutile phase in these metal ion-doped TiO\u2082 may affect their photoreactivities. In addition, visible-light photocatalytic activities of TiO\u2082 are enhanced by co-doping with two metal ions.
\r\n \r\nHybrid nanocomposite photocatalysts based on CdS nanoparticles (e.g., Ni(0)/NiO/ KNbO\u2083/CdS, Zeolite/CdS, and nanocomposites of Q-sized cubic phase CdS and bulk-phase hexagonal CdS interlinked with elemental Pt deposits) are also studied. Different types of CdS nanocomposite photocatalysts are synthesized, optimized, and characterized using various analytical techniques. It is shown that these nanocomposites can enhance inherent photocatalytic activity of bulk-phase CdS for hydrogen production via effective charge separation of photogenerated electrons and holes in CdS under visible-light irradiation.
\r\n \r\nAdditionally, a sub-pilot size hybrid electrochemical system with Bi-doped TiO\u2082 anodes and SS cathodes for the degradation of organic pollutants and simultaneous hydrogen production has been developed to make the electrochemical system more economically viable. This system degrades a variety of organic pollutants and real wastewater with simultaneous production of hydrogen at the current efficiencies of 50~70%. Furthermore, it is demonstrated that this electrochemical system can be driven by a photovoltaic (PV) cell.
\r\n", "doi": "10.7907/90AX-KS12", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5818", "collection": "thesis", "collection_id": "5818", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05192010-182707354", "primary_object_url": { "basename": "YanXia_complete_thesis.pdf", "content": "final", "filesize": 4398856, "license": "other", "mime_type": "application/pdf", "url": "/5818/9/YanXia_complete_thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Syntheses of Polymers with Diverse Architectures via Metathesis Polymerization and Investigation of Their Structure-Property Relationships", "author": [ { "family_name": "Xia", "given_name": "Yan", "clpid": "Xia-Yan" } ], "thesis_advisor": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Metathesis polymerization using highly active, functional-group-tolerant catalysts is a powerful and versatile method for polymer synthesis. This thesis focuses on the preparation of a variety of advanced polymer architectures using well-defined ruthenium-based metathesis catalysts and the study of materials properties dictated by those unique macromolecular structures.
\r\n\r\nChapter 1 introduces olefin metathesis, metathesis polymerization, and recent developments in living/controlled polymerization and polymer functionalization. The goal is to provide a summary of the current toolbox of polymer chemists. The second part of Chapter 1 describes using these tools to synthesize different macromolecular architectures.
\r\n\r\nChapters 2 and 3 describe ring-expansion metathesis polymerization (REMP) using cyclic catalysts. Chapter 2 focuses on catalyst development, while Chapter 3 focuses on the REMP mechanism and cyclic polymer characterization.
\r\n\r\nChapters 4 and 5 focus on brush polymers. Chapter 4 describes the syntheses of linear and cyclic brush polymers using ring-opening metathesis polymerization (ROMP) and REMP of macromonomers (MMs), respectively. Chapter 5 describes the efficient synthesis of brush copolymers and the study of their melt state self-assembly into highly ordered nanostructures.
\r\n\r\nChapter 6 describes the synthesis and electro-optic response of well-defined liquid crystalline (LC) gels that were made from controlled end-linking of telechelic LC polymers. These gels possessed very fast, reversible electro-optic switching; the degree of response was closely related to network structure.
", "doi": "10.7907/WTBS-F528", "publication_date": "2010-06-11", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5929", "collection": "thesis", "collection_id": "5929", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06072010-151443763", "primary_object_url": { "basename": "FONG_thesis.pdf", "content": "final", "filesize": 3908813, "license": "other", "mime_type": "application/pdf", "url": "/5929/21/FONG_thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Wound Healing on Artificial Extracellular Matrix Proteins", "author": [ { "family_name": "Fong", "given_name": "Eileen", "clpid": "Fong-Eileen" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Bronner", "given_name": "Marianne E.", "clpid": "Bronner-M-E" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_eng" } ], "abstract": "Collective cell migration is a key process in tissue repair, and in drawing parallels from complex multi-cellular events such as tumor morphogenesis and embryogenesis. Mechanisms of wound healing have been studied extensively in vitro. Extracellular matrix (ECM) is required to support cell migration and ensure rapid coverage of the wound area. The main challenge in designing biomaterials for tissue repair is to provide cells with the appropriate biological and mechanical cues. Hence, understanding key cell-ECM interactions during wound healing is necessary for effective biomaterial design.
\r\n\r\nGenetic engineering provides a convenient avenue to customize materials for any given application. The artificial protein-based biomaterials discussed in this work were derived from fibronectin and elastin. These proteins have a modular design, and have material properties that can be fine-tuned according to specific applications. The artificial extracellular matrix (aECM) proteins prepared by previous members of our laboratory have been shown to promote attachment of endothelial cells. In this work, we studied extensively epithelial and fibroblast wound healing behavior on these aECM biomaterials.
\r\n\r\nCrosslinked aECM protein films of varying RGD densities have been prepared by mixing aECM proteins with the RGD cell binding domain with aECM proteins containing the scrambled RDG sequence. Corneal epithelial wound healing was observed on aECM films with 100% RGD but not on aECM films with 2.5% RGD. Surprisingly, we found a five fold difference between the wound closure rates between these surfaces, but individual cell speeds did not increase significantly. We proposed that the five fold increase in wound closure rate was determined by the rate of crossing the boundary between the wound area and the area underneath the cell sheet. Both simulation and experimental data verified that the rate of boundary-crossing was sufficient to account for five-fold difference in wound closure rates between 100% RGD and 2.5% RGD surfaces.
\r\n\r\nFull-length fibronectin domains have also been incorporated to improve the overall cell binding properties of the aECM proteins. The aECM proteins containing full-length fibronectin domains were shown to facilitate rapid spreading of Rat-1 fibroblasts. The aECM protein containing both fibronectin domains 9 and 10 exhibited an increased binding affinity to the \u03b15\u03b21 integrin. More importantly, these aECM proteins also promoted rapid wound closure, which was comparable to that on fibronectin. We showed that aECM proteins containing full-length fibronectin domains also promoted higher phosphorylated levels of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), consistent with the faster cell migration and proliferation observed.
\r\n\r\nTo try to understand how cells select wound healing mechanisms, wound healing of Madin-Darby Canine Kidney (MDCK) epithelial cells were examined in vitro. On surfaces containing the aECM protein bearing the fibronectin domain 10, characteristic healing patterns were observed in MDCK wound healing. These patterns are defined by the formation of leader cells at regular intervals of actomyosin purse strings. The spacing between consecutive leader cell groups was also found to be independent of the wound diameter. This spacing however, was found to decrease with increasing myosin II inhibition. These observations could be explained using a simple force transmission mechanical model. Consistent with the model predictions, we demonstrated that wounds with a zigzag geometry biased the selection of the wound healing mechanism along the wound edge. These zigzag wounds also healed nearly eight fold faster than wounds with straight edges.
\r\n", "doi": "10.7907/8VQJ-DS58", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5933", "collection": "thesis", "collection_id": "5933", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:06072010-170215356", "primary_object_url": { "basename": "MorganCharlesPutnamThesis2010.pdf", "content": "final", "filesize": 93941366, "license": "other", "mime_type": "application/pdf", "url": "/5933/1/MorganCharlesPutnamThesis2010.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "Si Microwire-Array Solar Cells", "author": [ { "family_name": "Putnam", "given_name": "Morgan Charles", "clpid": "Putnam-Morgan-Charles" } ], "thesis_advisor": [ { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" } ], "thesis_committee": [ { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "By allowing for the fabrication of flexible crystalline-Si (c-Si) solar cells that employ ~1/100th) the Si of a traditional wafer-based c-Si solar cell, while maintaining high photovoltaic efficiencies, vertically aligned arrays of c-Si microwires provide a novel photovoltaic geometry that has the potential to dramatically reduce the cost of solar electricity. In this thesis we report on 1) the growth of Si microwire arrays, 2) the chemical and electrical characterization of Si microwire arrays, and 3) the fabrication of Si microwire-array solar cells.
\r\n\r\nUsing the vapor-liquid-solid (VLS) growth mechanism in combination with photolithographic patterning, vertically aligned arrays of Si microwires, with nominally identical heights and diameters, were fabricated over areas > 1 cm2. Chemical characterization of the Si wires was then performed using secondary ion mass spectrometry to measure the incorporation of the Au VLS-catalyst into the Si wire. The incorporation of the VLS-catalyst into the Si wires at its thermodynamic equilibrium concentration suggested that the use of Cu as a VLS-catalyst was less likely to limit the photovoltaic performance of Si microwire-array solar cells. Switching to the Cu-catalyzed growth of Si wires, in-situ doping with BCl3 was used to demonstrate control of the electrically active dopant concentration from 8 x 1015 to 4 x 1019 dopants cm-3. Scanning photocurrent measurements were then made to measure the minority-carrier diffusion length. The observation of 10 \u03bcm minority-carrier diffusion lengths indicated that solar cells with efficiencies of 17.5% should be possible. With the knowledge that highly efficient solar cells were possible, methods for the fabrication of a p-n junction and a transparent top contact in a solid-state solar cell were developed. This culminated in the demonstration of Si microwire-array solar cells with Air Mass 1.5 Global photovoltaic conversion efficiencies of up to \u03b7 = 7.9%. Through improved device processing and the use of an amorphous Si passivation layer at the top contact, ~15% efficient solar cells should be possible.
\r\n", "doi": "10.7907/JSVM-J029", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5834", "collection": "thesis", "collection_id": "5834", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05252010-102954788", "primary_object_url": { "basename": "abf_thesis-double.pdf", "content": "final", "filesize": 3760541, "license": "other", "mime_type": "application/pdf", "url": "/5834/1/abf_thesis-double.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Investigating Molecular Size Variations in Thin Film Chemical Vapor Sensors", "author": [ { "family_name": "Folinsky", "given_name": "Anna Barr", "clpid": "Folinsky-Anna-Barr" } ], "thesis_advisor": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" } ], "thesis_committee": [ { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Stoltz", "given_name": "Brian M.", "clpid": "Stoltz-B-M" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Vapor sensing arrays composed of broadly responsive, chemically sensitive detectors have been explored for many years. They have been used in fields ranging from good quality control, to environmental monitoring and explosives detection, to disease diagnostics. All of these tasks require high sensitivity and fine discrimination ability. As new challenges arise, the ability to understand the performance and improve the availability of array components becomes paramount.
\r\n\r\nThis work details progress in gaining greater understanding of certain chemical substrates used in sensor arrays. Specifically, arrays using insulator/carbon black composite sensors have been prepared using either polymer or non-volatile small organic molecules as the insulating, chemically sensitive component. The crystallinity of the small molecules as compared to the polymers was determined to cause the differing formulation requirements between the polymers and the small molecules.
\r\n\r\nAdditionally, arrays of sensors composed of varying molecular weights of a given polymer were examined. Very low molecular weights of polystyrene, a high glass transition temperature polymer, exhibited improved behavior and response times compared to higher molecular weights. Finally, arrays composed of varied length carboxylic and dicarboxylic acids were studied. Of these two homologous series, the arrays composed of carboxylic acids provided better discrimination than did those composed of dicarboxylic acids, suggesting the utility of sensor materials containing multiple accessible functional groups.
\r\n\r\nThese studies, taken together, suggest several new ways to increase the number of compounds and chemical functionalities available to use in chemical vapor sensors. Increased sensor choice allows construction of more broadly responsive and finely discriminating sensor arrays, thereby increasing the general utility of composite vapor sensor arrays.
", "doi": "10.7907/EGMC-C788", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5867", "collection": "thesis", "collection_id": "5867", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05272010-170914354", "primary_object_url": { "basename": "CarboneThesis.pdf", "content": "final", "filesize": 11842243, "license": "other", "mime_type": "application/pdf", "url": "/5867/1/CarboneThesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Characterization of the Functional Diversity and Evolvability of Chimeric Enzymes Assembled by Structure-Guided SCHEMA Recombination", "author": [ { "family_name": "Carbone", "given_name": "Martina Nini", "clpid": "Carbone-Martina-Nini" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" }, { "family_name": "Adami", "given_name": "Christoph Carl", "orcid": "0000-0002-2915-9504", "clpid": "Adami-C-C" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "In nature proteins evolve by a combination of point mutagenesis and recombination. This process has generated hundreds of fascinating and structurally complex protein folds capable of performing a myriad of important and diverse biochemical functions. This has inspired protein engineers to mimic natural protein evolution in the library to construct synthetic proteins with new or improved properties. Here I show that homologous protein recombination can be used in the library to engineer novel enzymes with new catalytic activities and altered substrate specificities. I also propose that homologous recombination can be used in the laboratory to overcome the challenge of improving the native activities of wild-type proteins. In nature recombination may have helped proteins escape local maxima of the fitness landscape by introducing many homologous mutations to which proteins are highly tolerant. Protein engineers can possibly use it for the same purpose. I validate this hypothesis computationally with highly simplified protein models, and I attempt an experimental verification of this theory with cellulases. ", "doi": "10.7907/QE98-1921", "publication_date": "2010", "thesis_type": "phd", "thesis_year": "2010" }, { "id": "thesis:5264", "collection": "thesis", "collection_id": "5264", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05212009-144705", "primary_object_url": { "basename": "08-CLB-thesis.pdf", "content": "final", "filesize": 3984809, "license": "other", "mime_type": "", "url": "/5264/8/08-CLB-thesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "Engineering Ligand Control of RNA Interference", "author": [ { "family_name": "Beisel", "given_name": "Chase Lawrence", "orcid": "0000-0003-0650-9943", "clpid": "Beisel-Chase-Lawrence" } ], "thesis_advisor": [ { "family_name": "Smolke", "given_name": "Christina D.", "clpid": "Smolke-C-D" } ], "thesis_committee": [ { "family_name": "Smolke", "given_name": "Christina D.", "clpid": "Smolke-C-D" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Pierce", "given_name": "Niles A.", "clpid": "Pierce-N-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "RNA is a rich and versatile substrate for the construction of information processing devices. These devices detect the levels of specified intracellular biomolecules and control cellular behavior accordingly. With few superficial constraints on the identity of the recognized biomolecule or the targeted gene, RNA-based information processing devices can be rapidly implemented toward various applications in medicine and biotechnology. To advance the design and implementation of RNA-based information processing devices, we delineated general design principles and applied these principles to the construction of devices that operate through RNA interference (RNAi).
\r\n\r\nRNAi represents an endogenous enzymatic pathway present in humans and other eukaryotes that mediates targeted gene silencing. The pathway has garnered recent interest as a revolutionary biological research tool and as a targeted therapeutic strategy. While RNAi has left an indelible mark on the scientific community, exerting greater control would advance the applicability and safety of this already impressive gene silencing mechanism. Toward this goal, we engineered ligand control of three types of RNAi effectors in mammalian cells: small interfering (si)RNAs, small hairpin (sh)RNAs, and microRNAs (miRNAs). Engineering frameworks enabled facile replacement of the biomolecule sensory and gene targeting domains, thus lending to rapid implementation as biosensors or autonomous control devices. Experimental and computational characterization studies provided a comprehensive understanding of device behavior, thereby facilitating forward design.
\r\n\r\nNaturally-occurring analogs of RNA-based information processing devices are riboswitches. Riboswitches predominantly mediate dynamic feedback in metabolism and share many traits with current examples of engineered information processing devices. Various experimental characterization studies of riboswitches showed that kinetics underlying events such as conformational switching and ligand binding have a substantial impact on device performance, although these factors remain to be comprehensively evaluated or considered when formulating design principles for synthetic riboswitch construction. We explored the contribution of kinetic factors to riboswitch performance in silico, where model predictions matched experimental observations, including results from our ligand-responsive RNAi effectors. From our modeling results, we developed a general set of design principles that guide riboswitch assembly and performance tuning.
", "doi": "10.7907/CBRX-PG36", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:689", "collection": "thesis", "collection_id": "689", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-02202009-142419", "primary_object_url": { "basename": "CompleteDocument.pdf", "content": "final", "filesize": 6742559, "license": "other", "mime_type": "application/pdf", "url": "/689/6/CompleteDocument.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Quantitative Performance and Tradeoffs in the MAP Kinase Signaling Module", "author": [ { "family_name": "Chapman", "given_name": "Stephen Allen", "clpid": "Chapman-Stephen-Allen" } ], "thesis_advisor": [ { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" } ], "thesis_committee": [ { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Smolke", "given_name": "Christina D.", "clpid": "Smolke-C-D" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Sternberg", "given_name": "Paul W.", "clpid": "Sternberg-P-W" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Intracellular signal transduction networks propagate and integrate the information that cells sense from environmental stimuli. The quantitative performance of signaling networks regulates cell decisions, and aberrations in network performance lead to pathologies such as cancer. The mitogen-activated protein (MAP) kinase cascade is a highly-conserved signaling module that regulates diverse cellular processes, such as proliferation, differentiation, and apoptosis in eukaryotic species ranging from yeast to human. While the principal components and mechanisms that define the MAP kinase module are well established, our understanding of and ability to tune its quantitative performance is limited. Here, we probe more deeply how the quantitative properties of the MAP kinase module may be affected by variations in the expression levels of the key constituents of the cascade\u2014kinases, phosphatases and scaffolds.
\r\n\r\nUsing a computational approach, we delineate how four quantitative properties\u2014responsiveness to input, dynamic range of output, signal amplification, and signal lifetime\u2014depend on the relative abundances of the two core components of the MAPK module, kinases and phosphatases. We identify a reduced metric termed the \u2018resistance to activation\u2019 that predicts the quantitative properties of the module across a wide range of parameter values. Its predictive utility extends to dynamic properties such as signal lifetime, which often dictates the MAP kinase\u2019s effect on cell function. Our analysis highlights tradeoffs in design, as not all quantitative attributes of the module can be simultaneously optimized. Thus, the resistance to activation captures the fundamental principles that determine cascade behavior and can be exploited to guide quantitative redesign of the MAP kinase module.
\r\n\r\nIn addition to the expression levels of kinases and phosphatases, scaffolds play a key role in signal propagation through the MAP kinase module. Protein scaffolds bring together multiple components of a signaling pathway, thereby promoting signal flux along a common physical \u201cbackbone.\u201d Scaffolds figure prominently in natural signaling pathways and are emerging as a promising platform for synthetic circuits. To better understand how scaffolding quantitatively affects signal transmission, we conducted an in vivo experimental sensitivity analysis of MAP kinase response to broad perturbations in the expression level of Ste5, an exemplar scaffold of the yeast mating pathway. Our results demonstrate that the expression level of Ste5 significantly affects several quantitative aspects of signal propagation, including signal throughput, pathway ultrasensitivity, and baseline leakage. These new insights into the quantitative role of scaffolding in MAP kinase signaling suggest advantages and limitations in designing synthetic scaffold-based regulatory networks.
\r\n", "doi": "10.7907/YVHW-Z764", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:2412", "collection": "thesis", "collection_id": "2412", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06022009-100039", "primary_object_url": { "basename": "RHA_Thesis_Complete.pdf", "content": "final", "filesize": 4095228, "license": "other", "mime_type": "application/pdf", "url": "/2412/7/RHA_Thesis_Complete.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Molecular Sieve Synthesis Using Imidazolium Structure Directing Agents", "author": [ { "family_name": "Archer", "given_name": "Raymond Humphrey", "clpid": "Archer-Raymond-Humphrey" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The synthesis of high-silica molecular sieve SSZ-70 is investigated through a guest/host study of imidazolium structure directing agents (SDAs). The original borosilicate synthesis is extended to pure-silica and aluminosilicate compositions using six imidazolium SDAs. Physical characterization using powder X-ray diffraction (XRD), 29Si solid-state NMR, electron microscopy, thermogravimetric analysis, and nitrogen adsorption shows SSZ-70 to be layered with similarity to MCM-22 (MWW). Aluminum-containing SSZ-70 is evaluated for catalytic activity using the constraint index (CI) test and shows a similar cracking rate to SSZ-25 (MWW structure). Distinct differences in CI as a function of time on stream are observed between MWW and SSZ-70 materials. Additional molecular sieve phases observed in this guest/host study included Theta-1 (TON), ZSM-5 (MFI), ZSM-23 (MTT), ZSM-12 (MTW), Beta, Mordenite (MOR), CIT-5 (CFI), SSZ-16 (AFX), and SSZ-35 (STF).
\r\n\r\nAttempts to synthesize Beta enriched in chiral polymorph A are investigated in a second guest/host study using five chiral imidazolium SDAs. Two SDAs successfully gave Beta, but no enrichment in polymorph A is observed. The remaining SDAs do not direct the formation of any molecular sieve phases. Molecular modeling indicates both SDAs occupy the straight [100]/[010] 12 membered ring (MR) pores of Beta. In this configuration, no chirality could be projected across the [001] fault planes and this offers an explanation for not observing enrichment. Modeling shows careful consideration must be given to efficiently filling the entire void volume when large SDAs are used. Additional molecular sieve phases observed in the guest/host study are EU-1 (EUO) and MOR.
\r\n\r\nFinally, attempts to synthesize novel materials using supramolecular SDAs are described. Supramolecular SDAs are created through adamantyl/beta-cyclodextrin inclusion complex formation. Both 2:1 and 1:1 inclusion complex stoichiometries are attempted. Significant cyclodextrin degradation occurs at temperatures above 90\u00b0C and no structure-directing effect can be attributed to the cyclodextrin. Molecular sieve phases observed in the study are SSZ-16 (AFX), MOR, B-SSZ-13 (CHA), VPI-8 (VET), and SSZ-24 (AFI).
\r\n", "doi": "10.7907/GJT6-1C73", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:3822", "collection": "thesis", "collection_id": "3822", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-09292008-153208", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 6880746, "license": "other", "mime_type": "application/pdf", "url": "/3822/1/Thesis.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Increased Classification Rates of Chemical Vapor Detectors Using Novel Sensor Types and Optimized Sensing Geometries", "author": [ { "family_name": "Woodka", "given_name": "Marc Dominic", "clpid": "Woodka-Marc-Dominic" } ], "thesis_advisor": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" } ], "thesis_committee": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Perona", "given_name": "Pietro", "clpid": "Perona-P" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Broadly responsive vapor sensor arrays, or so-called \"electronic noses,\" have been explored and/or used for many years as a means to detect the vapors present in the headspace of a variety of targets, such as coffees, wines, vinegars, oils, explosives, and nerve agents, and for disease diagnosis. Electronic nose sensing modalities often exhibit a response that is linear with concentration, and additive with respect to multiple vapors. Ideally, one could simply train an array towards the pure vapors of interest, and use that pure vapor training to identify either pure vapors or vapor mixtures during field-testing. This, however, has proven difficult, and has limited the utility of this vapor detection approach for a number of applications.
\r\n\r\nThis thesis utilized a low-cost, low-power sensing modality, insulator \u2013 carbon black composite chemiresistors, and exploited their linear response properties to enhance the classification rates of both pure vapors and vapor mixtures, based on pure vapor training. Sensors utilizing non-polymeric, small organic molecules as the insulating component were demonstrated to offer enhanced separation between pure vapor response clusters, and lower detection limits, relative to the traditional use of polymers as the insulating phase. These sensors were then used in a sensing geometry that induced a space- and time, or spatiotemporal (ST) dependence, to the sensor response, which increased the amount of chemical information extracted from the sensor response. This ST response information allowed for the correct classification of vapor mixtures consisting of up to 5 components, with training on only pure vapors.
\r\n\r\nA mass uptake model for the ST response of the sensors was developed, and vapor detection and mixture analysis was simulated for chamber geometries and vapor delivery flow rates spanning several orders of magnitude. The data were first used to define an optimized ST sensing regime for mixture analysis, based on two dimensionless Peclet number analogs. The data were then used to identify the inherent properties of the pure vapor training data that allowed for mixture analysis to be performed at high levels, specifically that the minimum resolution factor between all binary vapor combinations in the training library was sufficiently high.
\r\n\r\nFinally, the utility of the ST response was demonstrated to offer enhanced pure-vapor classification rates, relative to the traditional steady state approach typically employed with broadly responsive array-based sensing. These enhanced classification rates were demonstrated using a number of classification algorithms, including a bioinspired algorithm based on Fisher\u2019s Linear Discriminant. In summary, the results demonstrated herein quantify, in different ways, what is required for classification optimization, and in doing so increase the utility of this approach to vapor detection for a number of applications.
\r\n", "doi": "10.7907/ZMTF-DV91", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:2179", "collection": "thesis", "collection_id": "2179", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05272009-144416", "primary_object_url": { "basename": "Thesis_V3.pdf", "content": "final", "filesize": 3615450, "license": "other", "mime_type": "application/pdf", "url": "/2179/1/Thesis_V3.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Proton and Ion Conductivity in Microporous Materials", "author": [ { "family_name": "McKeen", "given_name": "John Charles", "clpid": "McKeen-John-Charles" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Giapis", "given_name": "Konstantinos P.", "clpid": "Giapis-K-P" }, { "family_name": "Yazami", "given_name": "Rachid", "clpid": "Yazami-R" }, { "family_name": "Yan", "given_name": "Yushan", "clpid": "Yan-Yushan" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Two separate but related investigations on proton and ion conductivity in microporous materials are presented. In the first study, the effect of hydroxyl group density on the proton conductivity in a family of sulfonic-acid functionalized microporous materials with the *BEA framework topology is investigated. Pure silica, aryl sulfonic acid-functionalized microporous materials are synthesized with high concentration of hydroxyl groups from tetraethylammonium hydroxide and aluminum-containing gels and by post synthetic modification of zinc containing CIT-6, and they exhibit proton conductivities of ~5*10\u207b\u00b3 S/cm. Pure-silica materials with nearly defect free structures (low hydroxyl group density) are synthesized from tetraethylammonium fluoride containing gels and by post synthetic modification of CIT-6, and exhibit proton conductivities an order of magnitude lower, ~5 x 10\u207b\u2074 S/cm, than the samples with a high \u2013OH density. Propyl sulfonic acid, ethyl phosphoric acid, and carboxylic acid containing pure-silica zeolite beta, MCM-41, and MCM-48 are also prepared and investigated for use as solid proton conductors. Strong acids are necessary for fast proton transport in hydrated systems. The proton conductivities of the functionalized solids decrease accordingly with the strength of the organic acids in solutions, and little difference is observed between microporous and mesoporous solids when functionalized to the same level.
\r\n\r\nIn the second study, the ion conducting properties of the microporous, zincosilicate VPI-9 (Si/Zn = 4.0) containing the alkali cations Li\u207a, Na\u207a, K\u207a, Rb\u207a, and Cs\u207a, and the alkaline earth cations Mg\u00b2\u207a, Ca\u00b2\u207a, and Sr\u00b2\u207a are studied using impedance spectroscopy. Monovalent cation exchanged samples Li- and Na-VPI-9 lose X-ray crystallinity upon vacuum dehydration at 450 \u00b0C, while K-, Rb-, and Cs-VPI-9 remain crystalline and exhibit conductivities of 1.7 x 10\u207b\u2074, 3.5 x 10\u207b\u2074, and 4.9 x 10\u2074 S/cm, respectively, at 450 \u00b0C in vacuum. While K-VPI-9 is less conductive than K-X, Rb- and Cs-VPI-9 are more conductive than corresponding zeolite X samples. Divalent cation exchanged sample Mg-VPI-9 also loses X-ray crystallinity, while Ca-, and Sr-VPI-9 remain crystalline and exhibit conductivities of 2.3 x 10\u207b\u2076 S/cm and 7.7 x 10\u2077 S/cm, respectively, at 450 \u00b0C, greatly exceeding the conductivity of correspondingly divalent exchanged zeolite X materials. Dense, crystalline zincosilicate samples with the compositions K\u2082ZnSixO\u2082(x=1) (x = 2 - 5), Rb\u2082ZnSi\u2085O\u2081\u2082, and Cs\u2082ZnSi\u2085O\u2081\u2082 are also prepared and exhibit much lower conductivities than their microporous counterparts.
\r\n", "doi": "10.7907/N0GH-3B50", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:2120", "collection": "thesis", "collection_id": "2120", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05262009-145437", "primary_object_url": { "basename": "FinalThesisDocumentIII.pdf", "content": "final", "filesize": 9966032, "license": "other", "mime_type": "application/pdf", "url": "/2120/1/FinalThesisDocumentIII.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "I. Synthesis and Proton Conductivity Studies of Mesostructured Organosilicates and Bitriazole-Polymer Composites. II. Targeted Nanoparticles for siRNA Delivery", "author": [ { "family_name": "Alabi", "given_name": "Christopher Akinleye", "orcid": "0000-0003-2654-018X", "clpid": "Alabi-Christopher-Akinleye" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The underlying theme of the research outlined in both parts of this report is centered on the ability to use synthetic design as a probe to investigate and answer fundamental mechanistic questions in an effort to improve the function of materials employed in energy and biological research. Specifically in the field of energy research, we have designed a new strategy aimed at improving the proton conductivity of organically modified silica-based polymer electrolyte membranes for use in direct methanol fuel cells. Our design involves the incorporation of the desired organic functional group into a siloxane-modified polymerizable surfactant that can be used in mesoporous silicate synthesis. This approach takes advantage of the silicate assembly mechanism, which places surfactants exclusively within the pores of the silicate at high loadings. The desired functional group is revealed upon selective cleavage after hydrothermal silicate synthesis. We have used this approach to synthesize organosilicates with different sized organic groups displaying high organic acid densities and have studied their proton conductivity under fully hydrated conditions. Under these conditions, structural diffusion via a percolated water network is the dominant mechanism of proton transport.
\r\n\r\nWith regards to membranes for use in hydrogen fuel cells that operate best at temperatures above the dew point of water, the need for an alternative to water as the proton conducting medium is desired. Towards this end, we designed a new nitrogen-containing heterocycle (NCH), 4,4-1H-1H-bi-1,2,3-triazole (bitriazole) capable of mimicking water in the solid state and have investigated its ability to conduct protons in the presence of polyethylene oxides under anhydrous conditions. With numerous chemical tools at our disposal, we probed the mechanism of proton conduction and confirmed the bitriazole proton to be the source of anhydrous proton conductivity. Our data suggests structural diffusion as the dominant transport mechanism via synergistic interactions between bitriazole and polyethylene oxides in the polymer-rich region of the composite material that is encapsulated by a crystalline nonconductive bitriazole framework.
\r\n\r\nIn the second part of this report, we shift our focus to the investigation of antibody-mediated targeting, using our well-established cyclodextrin polycation (CDP) nanoparticles containing therapeutic oligonuleotides, to epitopes expressed at the surface of cancer cells as a means of increasing site-specific therapeutic delivery. To do this, we synthesized fragments of anti-CD20 (rituximab) and conjugated them to flexible poly(ethylene glycol) (PEG) linkers with terminal adamantane groups that can interact with the cyclodextrins on the surface of the CDP nanoparticle via the formation of an inclusion complex. With the PEGylated antibody fragments in hand, we investigate, via a B-cell lymphoma model, the binding characteristics of the targeting ligands as well as their effect on the binding, internalization, and efficacy of the targeted CDP-nucleic acid therapeutic nanoparticles.
\r\n", "doi": "10.7907/9SNH-2A91", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:1930", "collection": "thesis", "collection_id": "1930", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05212009-221851", "primary_object_url": { "basename": "FinalThesis.pdf", "content": "final", "filesize": 20402703, "license": "other", "mime_type": "application/pdf", "url": "/1930/1/FinalThesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Multiscale and Multiphysics Computational Frameworks for Nano- and Bio-Systems", "author": [ { "family_name": "Kim", "given_name": "Hyungjun", "orcid": "0000-0001-8261-9381", "clpid": "Kim-Hyungjun" } ], "thesis_advisor": [ { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "thesis_committee": [ { "family_name": "McKoy", "given_name": "Basil Vincent", "clpid": "McKoy-B-V" }, { "family_name": "Heath", "given_name": "James R.", "clpid": "Heath-J-R" }, { "family_name": "Beauchamp", "given_name": "Jesse L.", "clpid": "Beauchamp-J-L" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Goddard", "given_name": "William A., III", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Multiscale and multiphysics simulation strategy is important to investigate complex problems in nature because it provides a systematic method to understand underpinning physics of the systems depending on the size. In this thesis, we discuss how such multiscale and multiphysics simulation framework can explain and rationalize the experimental observations in several nano- and biosystems. Furthermore, we exhibit the computational simulation methods that play major roles to rationally design novel materials with desired properties in next generation nano electronic devices, alternative energy materials, life science, and so on.
\r\n\r\nChapter 1 reviews the significance of multiscale and multiphysics simulation strategy. In this chapter, we briefly discuss the multiscale and multiphysics natures in nano- and bio-systems, and detailed examples are contained in the next chapters. Chapter 2 introduces an electric field induced conformational change mechanism, which is responsible for the unique current-voltage (I-V) behavior of nano device, negative differential resistance (NDR). In Chapter 3, the on/off kinetics of the Stoddart-Heath rotaxane-based programmable molecular electronic switch is discussed in terms of the free energy quantities. Chapter 4 explores sodium diffusion through the aluminum-doped zeolite BEA system, and the effect of water uptake amount is thoroughly discussed. This has importance for the application of zeolite to proton exchange membranes for fuel cells (PEMFC). In Chapters 5 and 6, the ion mobilities of tertiary and quaternary ammonium cations (precursors for lipids), and phosphatidylcholine (PC) lipid cations are investigated, respectively. In order to compute the ion mobilities of the precursors and entire lipids, we develop a modified trajectory (TJ) method dealing with the complicated integrals of interaction terms. QM and MD simulations are performed to determine the structures and charge distributions. In Chapter 7, we study how the model lung system of lipid monolayer with surfactant protein B (SP-B) responds to ozone introduction. In parallel with the field induced droplet ionization (FIDI) mass spectrometry study, MD simulations identify the distinct ozone reaction mechanism at the interface, and the role of SP-B at the pulmonary surfactant (PS) system on the oxidative stresses.
\r\n\r\nFrom these studies, we suggest various multiscale and multiphysics modeling approaches depending on the characteristics of systems and objectives. These efforts allow us to overcome the limited time- and length-scales of the monoscale simulations. In addition, we expect that an establishment of such multiscale modeling procedures will invoke interdisciplinary studies by tightly combining the developments occurring independently across fields.
\r\n", "doi": "10.7907/0PFF-R531", "publication_date": "2009", "thesis_type": "phd", "thesis_year": "2009" }, { "id": "thesis:5244", "collection": "thesis", "collection_id": "5244", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08022007-141737", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 4139235, "license": "other", "mime_type": "application/pdf", "url": "/5244/1/Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Quantitative Insights into Developmental Signals and Phenotypes in C. elegans", "author": [ { "family_name": "Giurumescu", "given_name": "Claudiu Adrian", "clpid": "Giurumescu-Claudiu-Adrian" } ], "thesis_advisor": [ { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" } ], "thesis_committee": [ { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Sternberg", "given_name": "Paul W.", "clpid": "Sternberg-P-W" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Design of biomaterials and cellular scaffolds for tissue-engineering applications and regenerative medicine requires a precise understanding of the principles underlying multicellular patterning. Adhesion, migration, division, differentiation, and apoptosis are characteristic cellular behaviors, the engineering of which has the potential to allow creation of custom, multicellular structures. These cellular events occur naturally during embryonic and postembryonic development of multicellular organisms. Development thus offers the opportunity to learn about the design principles and molecular mechanisms that guide cellular patterning.
\r\n\r\nA key finding in developmental biology is that a limited set of conserved molecular signaling pathways act at multiple times and locations throughout the embryo to introduce cell-fate asymmetries in homogenous populations of cells. In turn, these asymmetries serve as starting points for the patterning of new organs. These signaling pathways interact quantitatively at multiple levels, including signaling cues, post-translational regulation, and gene-regulatory networks, to guide multicellular patterning.
\r\n\r\nHow does the quantitative performance of these signaling networks ensure the intended phenotype pattern? How do changes in the quantitative performance of these networks, possibly over the course of evolution, give rise to new phenotypes? These are the central questions pursued in this thesis.
\r\n\r\nIn order to answer such questions, we used vulva formation in the nematode Caenorhabditis elegans as a model system of cellular patterning. We formulated a mathematical model of the molecular network underlying cellular-fate specification in this system. Computational analysis of this molecular network reveals that cell\u2013cell coupling through lateral LIN-12/Notch signaling amplifies the perception of the gradient in the epidermal-growth-factor-like soluble cue, LIN-3. Thus, the gradient in LIN-3 concentration produces an even steeper difference in LIN-3-mediated intracellular signals between adjoining cells. Such gradient amplification may be particularly important in converting a shallow, graded-specification signal into a spatial pattern of distinct fate choices.
\r\n\r\nThrough quantitative perturbations of interaction strengths between components of the vulval patterning network, we further show that our modeling approach can correctly predict phenotype patterns observed in C. elegans mutation studies. This study generated a framework for quantitative analysis of molecular networks that links quantitative molecular perturbations to patterning outcomes. This framework will prove useful in the analysis of other systems involving cellular fate decisions and in tissue engineering applications where the generation of precise cell patterns is needed. We demonstrate the generality of our approach through an application to evolutionary developmental biology. Since molecular connectivity of the vulva patterning network of several closely related Caenorhabditis species is preserved, we correctly predict the quantitative diversification that must have occurred in this network during species evolution.
", "doi": "10.7907/FVD0-R331", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:1503", "collection": "thesis", "collection_id": "1503", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04252008-104916", "primary_object_url": { "basename": "Eric_Margelefsky-thesis-2008.pdf", "content": "final", "filesize": 970511, "license": "other", "mime_type": "application/pdf", "url": "/1503/24/Eric_Margelefsky-thesis-2008.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Cooperative Catalysis by Bifunctionalized Mesoporous Silica", "author": [ { "family_name": "Margelefsky", "given_name": "Eric Louis", "clpid": "Margelefsky-Eric-Louis" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The objective of my work was to prepare heterogeneous catalysts that can perform cooperative catalysis. Cooperative catalysis occurs when the presence of two or more functional groups provide an acceleration of a chemical reaction beyond what is possible when either of the two species is used independently. New catalytic materials were synthesized by functionalizing mesoporous silica (SBA-15) with two different functional groups with the groups distributed either randomly or arranged into heterodimeric pairs. The dependence of catalytic activity and selectivity on the surface arrangement (random vs. paired, distance between paired species) was investigated for several different condensation reactions.
\r\n\r\nCatalysts featuring both sulfonic acid and thiol groups were investigated for the synthesis of various bisphenols. Paired alkylsulfonic acid/thiol catalysts outperformed randomly-distributed catalysts in the synthesis of bisphenol A and bisphenol Z. The distance between the two groups in the acid/thiol pair was varied and the activity and selectivity were found to diminish rapidly as the acid/thiol distance grows. Paired arylsulfonic acid/thiol catalysts outperformed randomly-distributed catalysts in the synthesis of bisphenol Z, whereas the synthesis of bisphenol A was insensitive to spatial arrangement.
\r\n\r\nThe second reaction investigated was the aldol reaction in order to investigate the possibility of acid/base cooperativity. A catalyst containing alkylsulfonic acid and primary amines grouped into pairs were generated by opening surface sultone rings with ammonia. This material was catalytically inactive in the aldol reaction due to acid/base neutralization, whereas randomly-distributed acid-base materials exhibit good catalytic activity. Primary amine/carboxylic acid cooperativity was also investigated, both with homogeneous amino acids and bifunctional heterogeneous silicas. While amine/acid cooperativity was conclusively demonstrated with the homogeneous catalysts, in the heterogeneous case the cooperativity due to surface silanol groups actually overshadowed the effect of the carboxylic acids.
\r\n\r\nThe results obtained provide evidence that the spatial arrangement of disparate functional groups on the surface of a heterogeneous catalyst can have profound effects on the activity and selectivity of the catalyst.
\r\n", "doi": "10.7907/9FET-BR51", "publication_date": "2008", "thesis_type": "phd", "thesis_year": "2008" }, { "id": "thesis:1477", "collection": "thesis", "collection_id": "1477", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04232007-111928", "primary_object_url": { "basename": "N_Graham_Complete_Thesis.pdf", "content": "final", "filesize": 12852475, "license": "other", "mime_type": "application/pdf", "url": "/1477/8/N_Graham_Complete_Thesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Crosstalk Between Soluble Factors and Cell-Cell Interactions: Implications for Cell Cycle Control and Tumor Development", "author": [ { "family_name": "Graham", "given_name": "Nicholas Alexander", "orcid": "0000-0002-6811-1941", "clpid": "Graham-Nicholas-Alexander" } ], "thesis_advisor": [ { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" } ], "thesis_committee": [ { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Smolke", "given_name": "Christina D.", "clpid": "Smolke-C-D" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Precise and dynamic control of cell behaviors, including proliferation, adhesion, and migration, is required for proper tissue organization and homeostasis. A key element to understanding how these cellular functions are controlled lies in uncovering the topology of the molecular signaling networks that couple environmental signals to cellular responses. In this study, we have parsed the signaling networks involved in cell cycle regulation and tumor development and uncovered novel mechanisms of crosstalk between soluble factors and cell-cell interactions.
\r\n\r\nOur findings demonstrate that extracellular cues, including the epidermal growth factor (EGF), stimulate proliferative signaling through beta-catenin, an intracellular protein that participates in both cell adhesion at the plasma membrane and transcription of cell cycle genes in the nucleus. In fact, EGF-mediated beta-catenin transcriptional activity is an essential signal for proliferation of normal epithelial cells. Additionally, in a cancer cell system, we discover that EGF cooperates with Wnt 3a, a classical agonist of beta-catenin transcriptional activity, to induce greater signaling than either ligand alone. Notably, EGF and Wnt 3a activate transcription using different sub-cellular pools of beta-catenin. Because hyperactive beta-catenin signaling drives proliferation in cancer, this suggests that attenuation beta-catenin signaling may require different therapeutic strategies for EGF- and Wnt-driven tumors.
\r\n\r\nSince beta-catenin signaling can be antagonized by binding to the cell-cell contact protein E-cadherin at the plasma membrane, proliferative signals mediated by beta-catenin may regulate growth suppression at high density, a property of normal cells that is often lost during tumorigenesis. Indeed, in non-tumorigenic epithelial cells, we demonstrate that E-cadherin is upregulated in contexts where beta-catenin signaling and DNA synthesis are suppressed. Additionally, exogenous E-cadherin suppresses proliferation with a strict requirement for beta-catenin binding. Future studies to test the hypothesis that E-cadherin regulates the growth of normal cells will benefit from a quantitative assay developed to measure E-cadherin:beta-catenin complexes. Such quantitative measurements are likely to be important because contact-mediated growth suppression by E-cadherin is coupled with a density-dependent, ligand-depletion mechanism that concomitantly regulates proliferation.
\r\n\r\nFinally, we demonstrate that EGF and other soluble factors synergistically control cell-cell interactions governing organization of normal epithelial cells into multicellular structures. Notably, this behavior resembles the program initiated during metastatic cancer, thus illustrating the flexibility of the epithelial phenotype even in non-cancerous cells. Together, these studies illustrate how the topology of molecular signaling networks can couple environmental cues including soluble extracellular factors and cell-cell interactions to regulate fundamental cellular functions.
", "doi": "10.7907/DJ7K-MW95", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:695", "collection": "thesis", "collection_id": "695", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-02212007-101608", "primary_object_url": { "basename": "zeidanthesis-PDF.pdf", "content": "final", "filesize": 5631864, "license": "other", "mime_type": "application/pdf", "url": "/695/1/zeidanthesis-PDF.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Design of New Multifunctional Materials", "author": [ { "family_name": "Zeidan", "given_name": "Ryan K.", "clpid": "Zeidan-Ryan-K" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Peters", "given_name": "Jonas C.", "clpid": "Peters-J-C" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Research in areas of science and technology critical to society, such as energy, medicine, electronics, protective equipment, and consumer goods relies on the ability to create new materials with desirable properties. The diversity in the properties of these materials is enormous. An important factor in the quest for developing exciting new materials is the ability to use synthetic chemistry to prepare new materials starting from a molecular point of view. It is this approach that I use in this work.
\r\n\r\nI have used principles of synthetic organic chemistry to guide the molecular design of materials that contain a variety of functionalities. This thesis describes three types of designed functional materials. First, new heterogeneous catalysts have been prepared that incorporate two organic functional groups in a manner that allows for cooperativity between them in catalyzing organic reactions, giving increases in reaction rates and selectivities. In particular, thiol/sulfonic acid bi-functional mesoporous materials have been prepared that give significant enhancements in reactivity and selectivity towards bisphenol A synthesis. These enhancements arise from interactions between thiol and sulfonic acid sites due to their proximity on the surface of the catalyst. Acid-base bi-functional materials have also been synthesized that exhibit excellent reactivity in the aldol condensation between acetone and 4-nitrobenzaldehyde. These catalysts are particularly important as the acid and base groups are mutually incompatible in solution and provide reactivity not achievable without immobilization on the surface of solids. Second, a method for incorporating traceable and quantifiable labels onto cyclodextrins and cyclodextrin containing polymers has been designed that utilizes the reactivity between the primary alcohols on cyclodextrins and ethylene oxide gas, and allows the cyclodextrins to be labeled for use in animal biodistribution studies. Third, polymers bearing aromatic disulfide groups have been prepared that can be degraded through a dual-trigger mechanism requiring simultaneous photochemical and hydrogen peroxide activation.
", "doi": "10.7907/CK8E-7H82", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:1923", "collection": "thesis", "collection_id": "1923", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05212007-230239", "primary_object_url": { "basename": "Balcerski2007-thesis-Intro pages.pdf", "content": "final", "filesize": 37902, "license": "other", "mime_type": "application/pdf", "url": "/1923/19/Balcerski2007-thesis-Intro pages.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Applications of Semiconductor Photocatalysis for Both Degradation of Organics and Hydrogen Production", "author": [ { "family_name": "Balcerski", "given_name": "William Clifford", "clpid": "Balcerski-William-Clifford" } ], "thesis_advisor": [ { "family_name": "Hoffmann", "given_name": "Michael R.", "clpid": "Hoffmann-M-R" } ], "thesis_committee": [ { "family_name": "Beauchamp", "given_name": "Jesse L.", "clpid": "Beauchamp-J-L" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Hoffmann", "given_name": "Michael R.", "clpid": "Hoffmann-M-R" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "clpid": "Lewis-N-S" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) was used to study illuminated TiO2 surfaces under both vacuum conditions and in the presence of organic molecules (decane and methanol). In the presence of a hole scavenger, electrons are trapped at Ti(III)-OH sites, and a free electrons are generated. These free electrons are seen to decay by either exposure to oxygen or to heat; in the case of heating, reinjection of holes into the lattice by loss of sorbed hole scavenger leads to a decrease in Ti(III)-OH centers. Decane adsorption experiments lend support to the theory that removal of hydrocarbon contaminants is responsible for superhydrophilic TiO2 surfaces. Oxidiation of methanol led to formation of surface bound formic acid.
\r\n\r\nTitanium dioxide was then doped with nitrogen atoms via high temperature treatment with ammonia, toward the goal of developing a catalyst capable of using visible light to degrade organic substrates. Catalyst efficiency was tested by monitoring formate degradation to CO\u2082 and H\u2082O under visible light using ion chromatography. However, reduced photocatalytic activity in the UV region, as well as a strong synthesis temperature dependence on catalytic efficiency, was observed. The N-doped TiO\u2082 surface was probed with diffuse infrared Fourier transform spectroscopy (DRIFTS), leading us to conclude that Ti-N triple bond defect sites control visible light activity and lead to an apparent reduction in overall crystallinity.
\r\n\r\nVisible light photocatalytic H\u2082 production was then studied. Microporous and mesoporous silicas (Zeolite-Y, Zeolite-L, SBA-15) and niobium oxides (KNbO\u2083, K\u2084Nb\u2086O\u2081\u2087) were combined with nanoparticulate CdS particles and Ni to form hybrid photocatalysts that produced H2 from water/ethanol solutions under visible light irradiation. Silica cavity size, which determines CdS particle size, and photocatalytic activity were found to be correlated. Photocatalytic activity was seen to decrease under acidic or basic conditions with an associated negative ionic strength effect. In the niobate catalysts, Ni doping was shown to lead to higher-energy Nb-O bonding states and to compete with Cd for ion exchange sites. XPS analysis indicated loss of Cd\u00b2\u207a ion from the metal oxide supports occured during the course of the photochemical reaction, with apparent retention of bound CdS for most catalysts.
", "doi": "10.7907/23VK-VS37", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:1848", "collection": "thesis", "collection_id": "1848", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05172007-150701", "primary_object_url": { "basename": "Bartlett_Thesis.pdf", "content": "final", "filesize": 14914066, "license": "other", "mime_type": "application/pdf", "url": "/1848/13/Bartlett_Thesis.pdf", "version": "v6.0.0" }, "type": "thesis", "title": "An Engineering Approach to Cancer Therapy Using Systemically Delivered siRNA", "author": [ { "family_name": "Bartlett", "given_name": "Derek William", "clpid": "Bartlett-Derek-William" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Smolke", "given_name": "Christina D.", "clpid": "Smolke-C-D" }, { "family_name": "Rossi", "given_name": "John J.", "clpid": "Rossi-J-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The next generation of cancer therapeutics will specifically target processes responsible for the growth and survival of cancer cells. Among the most promising of these molecularly targeted therapeutics are small interfering RNAs (siRNAs). These siRNAs serve as the effectors of RNA interference, a naturally occurring and highly specific mechanism for regulating gene expression through sequence-specific degradation of messenger RNA. While these siRNAs have shown potential in vitro and in preclinical animal models, safe and effective systemic delivery remains one of the greatest challenges hindering their clinical application. This thesis describes an engineering approach to address the challenge of systemic delivery of siRNAs for cancer therapy.
\r\n\r\nAnalysis of the kinetics of siRNA-mediated gene silencing reveals that gene inhibition by unmodified siRNAs can last for one week in rapidly dividing cells and up to one month in cells with minimal division. Additionally, chemical modifications to enhance siRNA nuclease stability do not prolong intracellular siRNA activity. These data, when used in combination with results from a mathematical model of siRNA function, demonstrate that dilution from cell division, and not intracellular nuclease stability, is the dominant factor governing the duration of gene inhibition by siRNAs.
\r\n\r\nCyclodextrin-containing polycations (CDP) can self-assemble with siRNAs to form nanoparticles with desirable properties for systemic application. Characterization of these nanoparticles demonstrates that they can contain several thousand siRNAs, protect the siRNA payload from nuclease degradation, and be modified with transferrin targeting ligands that show multivalent binding to cell surface receptors.
\r\n\r\nMultimodality in vivo imaging with positron emission tomography (PET) and bioluminescent imaging (BLI) is used to monitor the biodistribution and function of the siRNA nanoparticles after intravenous administration in live mice. Attachment of targeting ligands to the surface of the nanoparticles enhances gene inhibition within the tumor, although the biodistribution and tumor localization are not dependent on the amount of targeting ligand. The targeting ligand likely serves to augment nanoparticle uptake by the tumor cells. When the siRNA nanoparticles are used to deliver therapeutic siRNAs to achieve tumor growth inhibition in disseminated and subcutaneous murine cancer models, schedule-dependent anti-tumor effects are observed.
", "doi": "10.7907/TS5S-FD74", "publication_date": "2007", "thesis_type": "phd", "thesis_year": "2007" }, { "id": "thesis:3692", "collection": "thesis", "collection_id": "3692", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-09222005-123557", "primary_object_url": { "basename": "thesis.pdf", "content": "final", "filesize": 11991748, "license": "other", "mime_type": "application/pdf", "url": "/3692/1/thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Intracellular Considerations in the Development of Non-Viral Nucleic Acid Delivery Systems for Systemic Administration", "author": [ { "family_name": "Mishra", "given_name": "Swaroop", "clpid": "Mishra-Swaroop" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Webster", "given_name": "Paul", "clpid": "Webster-P" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Non-viral nucleic acid delivery systems must condense nucleic acids into small particles, confer protection from degrading factors in serum and in cells, achieve uptake to targeted cells, direct nucleic acids to appropriate intracellular destinations, release this cargo to permit its action, and exhibit minimal toxicity. The nature of synthetic vectors allows for facile addition of new features, but these modifications can affect performance in unanticipated ways. The effective combination of functional components necessitates a systems approach, where the materials design simultaneously considers the functional environment of and the various barriers to delivery. This thesis facilitates and promotes a systems approach by undertaking development of an improved mechanistic understanding of non-viral gene transfer in vitro, emphasizing elucidation of delivery vehicles\u2019 interactions with and behavior within cells. Special attention is given to the gene delivery behavior of cyclodextrin-containing polycations.
\r\n\r\nSimple modifications to delivery systems can have unanticipated consequences. In Chapter 2, it is shown that greater distance between toxicity-reducing cyclodextrin moieties and amidine charge centers increases both the transfection efficiency and toxicity of a polycationic vector. Chapter 3 shows data demonstrating that modification with poly(ethylene glycol) for extracellular salt-stabilization alters non-viral gene delivery particles\u2019 intracellular trafficking and resulting gene expression. Taken together, the results reveal that non-viral gene delivery vehicles behave as assembled, multifunctional systems.
\r\n\r\npH-buffering components exhibit complex behavior in non-viral gene delivery. In Chapter 4, the intracellular activity of such components is quantified using confocal microscopy. Analysis of chloroquine and its chemical analogues demonstrates in Chapter 5 that chloroquine improves non-viral gene transfer through pH-buffering as well as through enhanced nucleic acid unpackaging and its own interactions with nucleic acids. Chapter 6 gives results that characterize delivery behavior of analogous vectors with and without pH-buffering capacity and show that factors beyond buffering activity contribute to improved transfection efficiency. Collectively, these results emphasize consideration of new system components\u2019 effects on all functions of a non-viral gene delivery system.
\r\n\r\nA systems approach requires comprehensive consideration of the gene delivery process. Chapter 7 reviews current understanding of intracellular barriers to non-viral gene delivery, and Chapter 8 offers recommendations for future work.
\r\n", "doi": "10.7907/7MP8-JJ24", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:923", "collection": "thesis", "collection_id": "923", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-03112006-214258", "primary_object_url": { "basename": "Rajan_Kulkarni_Thesis.pdf", "content": "final", "filesize": 1931379, "license": "other", "mime_type": "application/pdf", "url": "/923/1/Rajan_Kulkarni_Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Mechanics of the Cytoskeleton: Examining the Dynamics of Cytoplasmic Transport through Fluorescence Microscopy", "author": [ { "family_name": "Kulkarni", "given_name": "Rajan P.", "clpid": "Kulkarni-Rajan-P" } ], "thesis_advisor": [ { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Elowitz", "given_name": "Michael B.", "clpid": "Elowitz-M-B" }, { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" } ], "local_group": [ { "literal": "div_biol" } ], "abstract": "The cellular cytoplasmic space contains many different molecules and complexes confined within a small volume. Understanding how objects are transported in this crowded space is important for many potential applications. In this work, we examined various aspects of cytoskeletal mechanics, including microtubule-mediated and diffusive transport using advanced fluorescence microscopy techniques. Spatio-temporal image correlation spectroscopy (ICS) was employed to first examine microtubule-mediated transport of non-viral polyplexes within endosomes through the cytoplasm. ICS analysis of these polyplex-loaded endosomes revealed that they utilized microtubule motors for intracellular trafficking and exhibited different transport behaviors for short (<10 seconds) versus long (~60 seconds) correlation times. These results indicated that, while motor biases may be present for short periods of time, resulting in a net directional velocity, the overall long term motion of the polyplexes is best described as a random walk-like process.
\r\n\r\nMultiple particle tracking (MPT) was next used to independently confirm these results. The labeled endosomes demonstrated enhanced diffusion at short times (t < 7 seconds), with their mean square displacement (MSD) scaling as t1.25. For longer time intervals, their MSD scaled as t0.7. This crossover from an enhanced diffusion to a subdiffusive regime is explained by considering the action of motor proteins and the thermal bending modes of the microtubule network.
\r\n\r\nWe then developed an assay to examine the pH characteristics of the polyplex-loaded endosomes as a function of time and distance from entry. Certain nonviral vectors, including poly-L-lysine (PLL) and cyclodextrin-containing polymers (CDP), cannot buffer the endocytic vesicles, while polyethyleneimine (PEI), CD-PEI, and CDP-imidazole can. When combined with cell uptake and luciferase expression data, we found that there was no correlation between buffering capacity and gene expression.
\r\n\r\nFinally, we developed multi-photon fluorescence recovery after photobleaching (FRAP) to determine diffusion rates in developing zebrafish growth cones in vivo. Leader growth cones had consistently longer recovery times compared to followers. This difference was abolished by perturbing the actin cytoskeleton, thus indicating that diffusion is important during axon navigation. Collectively, these findings reveal important biophysical aspects of intracellular transport that impact diverse physiological processes.
", "doi": "10.7907/85ea-ed40", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:1268", "collection": "thesis", "collection_id": "1268", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-04042006-205243", "primary_object_url": { "basename": "Nowatzki-Full_Text.pdf", "content": "final", "filesize": 2117273, "license": "other", "mime_type": "application/pdf", "url": "/1268/9/Nowatzki-Full_Text.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Characterization of Crosslinked Artificial Protein Films", "author": [ { "family_name": "Nowatzki", "given_name": "Paul John", "clpid": "Nowatzki-Paul-John" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Ravichandran", "given_name": "Guruswami", "clpid": "Ravichandran-G" }, { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Genetically engineered artificial proteins are promising candidates for new biomaterials because their amino acid sequences can be precisely controlled. This work describes the characterization of crosslinked films of biomimetic artificial extracellular matrix (aECM) proteins with hybrid functions designed to meet materials needs in applications such as small diameter vascular grafts and corneal tissue implants. Elastin-derived polypeptides give the proteins flexibility, while RGD and CS5 peptide domains from fibronectin serve to adhere cells.
\r\n\r\nTechniques were sought to crosslink aECM proteins in ways that resulted in tunable mechanical properties. Hexamethylene diisocyanate was used to crosslink aECM proteins into uniform, transparent, highly-extensible hydrogel films with low water contents characteristic of native elastin. Their elastic moduli, 0.1 \u2013 1.1 MPa, depended on crosslinker concentration and aECM protein length, and spanned the observed range of elastin fibers.
\r\n\r\nThe suitability of biomaterials implants depends strongly on their susceptibility to proteolytic degradation in vivo. It was shown that small sequence changes in the elastin-like portion of aECM proteins were sufficient to decrease their rate of degradation by elastase sevenfold, illustrating a simple method to tune the protease sensitivity of designed proteins. The effects were seen in both soluble proteins and crosslinked films analyzed by measuring their decrease in elastic modulus during degradation.
\r\n\r\nAn aECM protein was examined for its effectiveness as a corneal onlay, or permanent contact lens. The protein was crosslinked into transparent, elastic, water-rich lenses and was implanted into rabbit corneas. The onlays were stable and well-tolerated, and full re-epithelialization occurred within 4-7 days. Histological examination revealed normal regenerating epithelial cell morphology on the anterior surface, good interfaces between the onlay and surrounding tissue, and only minimal inflammation.
\r\n\r\nTo create substrates for studying the coordinating effects of mechanical and biological signals on cell behavior, thin films were made from a photoreactive aECM protein containing the non-canonical amino acid para-azidophenylalanine. Atomic force microscopy (AFM) nanoindentation was used to calculate elastic modulus, and the technique was confirmed by bulk tensile measurements and finite element simulations. Film modulus could be tuned either by differential irradiation or variable incorporation of para-azidophenylalanine.
", "doi": "10.7907/AAWE-NV35", "publication_date": "2006", "thesis_type": "phd", "thesis_year": "2006" }, { "id": "thesis:1753", "collection": "thesis", "collection_id": "1753", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05122005-144223", "primary_object_url": { "basename": "Thesisfinal2.pdf", "content": "final", "filesize": 3190119, "license": "other", "mime_type": "application/pdf", "url": "/1753/1/Thesisfinal2.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "A New Strategy for Synthesizing Zeolites and Zeolite-Like Materials", "author": [ { "family_name": "Lee", "given_name": "Hyunjoo", "orcid": "0000-0002-4538-9086", "clpid": "Lee-Hyunjoo" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Zeolite and molecular sieve materials are broadly used as ion-exchangers, adsorbents and catalysts in the chemical industry. Zeolites are typically synthesized by using organic molecules as structure-directing agents (SDA). The SDA should be removed from the pore cavity of the zeolite framework to create microporous void space before the zeolite can be used for further purposes. Porous zeolites have been prepared by calcination, or extraction in very limited cases. However, calcination has several undesired aspects mainly resulted from a high temperature. A combustion-free methodology is developed in this work by using a new concept for the SDAs. An organic molecule that can be easily cleaved into smaller fragments and subsequently recombined into the original molecule by simple treatments can be used as a 'recyclable SDA'. That is, after synthesizing a zeolite using this type of organic molecule as the SDA, the molecule can be fragmented in the pore cavity, and its fragments removed due to their smaller size. The recovered fragments are then recombined into the original SDAs, which can be used for further zeolite syntheses. The cyclic ketal molecule, 8,8-dimethyl-1,4-dioxa-8-azaspiro[4,5]decane, is used here to prove this new methodology. The ketal is fragmented into its corresponding ketone and diol molecules after structure-directing the synthesis of the zeolite, ZSM-5. The fragments are successfully removed by ion-exchange, and the prepared porous ZSM-5 shows equivalent porosity, catalytic activity and shape selectivity as conventional ZSM-5. In some cases, the SDA can be so tightly packed inside the pore cavity that the small reagent molecules required for fragmentation by acid hydrolysis have no access to the pore cavity. Therefore, the original methodology was expanded to provide a solution for this problem by utilizing two different kinds of organic molecules, a SDA and a pore-filling agent (PFA), during the zeolite syntheses. The removal of the PFA by simple extraction generates the necessary space inside the pore cavity for agents necessary for the hydrolysis to transport into the zeolite. Using this methodology, ZSM-5, ZSM-12, VPI-8 and MOR are successfully synthesized with various ketal SDAs whose hydrolysis depends on the hydrophilicity and pore connectivity of the synthesized zeolites.", "doi": "10.7907/N5NX-2T83", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:1202", "collection": "thesis", "collection_id": "1202", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-03302005-120327", "primary_object_url": { "basename": "Popielarski_Final_Submitted_Thesis.pdf", "content": "final", "filesize": 7067218, "license": "other", "mime_type": "application/pdf", "url": "/1202/1/Popielarski_Final_Submitted_Thesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "I. Structural Effects of Carbohydrate-Containing Polycations on Gene Delivery. II. Development of a Nanoparticle-Based Model Delivery System to Guide the Rational Design of Gene Delivery to the Liver\r ", "author": [ { "family_name": "Popielarski", "given_name": "Stephen R.", "clpid": "Popielarski-Stephen-R" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Linear cationic beta-cyclodextrin (b-CD)-based polymers can bind with plasmid DNA to form colloid-sized composite particles that transfect cultured cells. In the first part of this thesis, synthetic variations of the b-CD structure are used to probe structure-function gene delivery properties. The type of cyclodextrin and its functionalization are investigated by synthesizing numerous 3A,3B-dideoxy-3A,3B-diamino-b- and g-CD monomers, which are polymerized with dimethyl suberimidate to yield amidine-based polycations. The nature of the spacer between the CD-ring and the primary amines of each monomer is found to influence both molecular weight and polydispersity of the polycations. When complexed with plasmid DNA, polycations with longer alkyl regions between the CD and the charge centers show increased transfection efficiency and toxicity in BHK-21 cells. More hydrophilic spacers resulted in lower toxicity, and g-CD-based polycations were less toxic than otherwise identical b-CD-based polycations.
\r\n\r\nIn the second part of this thesis, a model delivery system is developed that can mimic the size and surface properties of the cyclodextrin-based gene-delivery particles, and this system is used to define design constraints that should be applied to next generation gene delivery particles targeted to the liver. Gal-50 and Gal-140 are galactosylated 50 nm and 140 nm nanoparticles that have the same surface galactose density, while MeO-50 and MeO-140 are methoxy-terminated 50 nm and 140 nm nanoparticles. All four particles have the same surface charge and resist aggregation in serum.
\r\n\r\nIn freshly isolated hepatocytes, Gal-50 nanoparticles are taken up to a greater extent than are MeO-50, but both 50 nm beads are taken up to a much greater extent than are either of the 140 nm nanoparticles. TEM and immunohistochemistry confirm that Gal-140 nanoparticles are primarily internalized by Kupffer cells, though isolated examples of a few Gal-140 in hepatocytes can also be found. On the other hand, Gal-50 nanoparticles are overwhelmingly found in vesicles throughout the cytoplasm of hepatocytes, with only isolated examples of Kupffer cell uptake. As such, it is clear that slightly anionic, galactose-PEGylated nanoparticles should be about 50 nm in diameter to preferentially target hepatocytes while they should be about 140 nm in diameter to selectively target Kupffer cells.
", "doi": "10.7907/rskv-rf12", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2006", "collection": "thesis", "collection_id": "2006", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05242005-230657", "primary_object_url": { "basename": "FrontMatter.pdf", "content": "final", "filesize": 391273, "license": "other", "mime_type": "application/pdf", "url": "/2006/2/FrontMatter.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "I. Synthesis, Characterization, and Base Catalysis of Novel Zeolite Supported Super-Basic Materials. II. Oxidative Dehydrogenation of Ethane Over Reduced Heteropolyanion Catalysts", "author": [ { "family_name": "Galownia", "given_name": "Jonathan Michael", "clpid": "Galownia-Jonathan-Michael" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis is composed of two separate and unrelated projects. The first part of this thesis outlines an investigation into the synthesis and characterization of a novel zeolite supported super-base capable of carbon-carbon olefin addition to alkyl aromatics. A zeolite supported basic material capable of such reactions would benefit many fine chemical syntheses, as well as vastly improve the economics associated with production of the high performance thermoplastic polyester polyethylene naphthalate.
\r\n\r\nThe thermal decomposition of alkali\u2014metal azides impregnated in zeolite X is investigated as a novel route to the synthesis of a zeolite supported super-base. Impregnation of the alkali\u2014metal azide precursor is shown to result in azide species occluded within the pores of the zeolite support by using high speed, solid-state 23Na MAS and 2D MQMAS NMR, FTIR, and TGA characterization methods. Addition of alkali\u2014metal azides to the zeolite results in redistribution of the extra-lattice cations in the zeolite framework. Thermal decomposition of impregnated azide species produces further cation redistribution, but no neutral metallic clusters are detected by high speed, solid-state 23Na MAS NMR following thermal activation of the materials. Instead, it is possible that inactive ionic clusters are formed. The thermally activated materials do not promote base catalysis for the isomerization of 1-butene, the ethylation of toluene and o-xylene, and the alkenylation of o-xylene with 1,3-butadiene to produce 5-ortho-tolyl-pent-2-ene (5-OTP). The lack of catalytic activity in the materials is attributed to failure of the materials to form neutral metallic clusters during thermal treatment, possibly due to preferential formation of NMR silent ionic clusters. The formation of neutral metallic clusters is found to be insensitive to synthesis technique and activation procedure. It is concluded that the impregnation of alkali\u2014metal azides in zeolite X does not provide a reliable precursor for the formation of zeolite supported super-basic materials.
\r\n\r\nThe second part of this thesis describes the oxidative dehydrogenation of ethane over partially reduced heteropolyanions. Niobium and pyridine exchanged salts of phosphomolybdic (NbPMo12Pyr) and phosphovanadomolybdic (NbPMo11VPyr) acids are investigated as catalyst precursors to prepare materials for catalyzing the oxidative dehydrogenation of ethane to ethylene and acetic acid at atmospheric pressure. The effects of feed composition, steam flow, temperature, and precursor composition on catalytic activity and selectivity are presented for both ethane and ethylene oxidation. Production of ethylene and acetic acid from ethane using the catalytic materials exceeds that reported in the literature for Mo-V-Nb-Ox systems under atmospheric or elevated pressure. Production of acetic acid from ethylene is also greater than that observed for Mo-V-Nb-Ox systems. Addition of vanadium reduces catalytic activity and selectivity to both ethylene and acetic acid while niobium is essential for the formation of acetic acid from ethane. Other metals such as antimony, iron, and gallium do not provide the same beneficial effect as niobium. Molybdenum in close proximity to niobium is the active site for ethane activation while niobium is directly involved in the transformation of ethylene to acetic acid. A balance of niobium and protonated pyridine is required to produce an active catalyst. Water is found to aid in desorption of acetic acid, thereby limiting deep oxidation to carbon oxides. A reaction scheme is proposed for the production of acetic acid from ethane over the catalytic materials.
", "doi": "10.7907/QZ7V-5W65", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2052", "collection": "thesis", "collection_id": "2052", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05252005-114817", "primary_object_url": { "basename": "heidel_thesis.pdf", "content": "final", "filesize": 4815091, "license": "other", "mime_type": "application/pdf", "url": "/2052/1/heidel_thesis.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Targeted, Systemic Non-Viral Delivery of Small Interfering RNA in vivo", "author": [ { "family_name": "Heidel", "given_name": "Jeremy David", "clpid": "Heidel-Jeremy-David" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Rossi", "given_name": "John J.", "clpid": "Rossi-J-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Armed with the complete sequence of the human genome and an ever-increasing array of biological techniques, researchers continue to learn more about the genetic basis of diseases. For two decades, scientists and physicians have been developing therapeutic strategies for treating many diseases at the genetic level, creating the field of \"gene therapy.\" For those diseases caused by loss-of-function mutations in a specific gene, delivery of a wild-type copy of that gene to affected cells can reduce or eliminate the disease phenotype. Viruses, having evolved to be extremely effective at delivering nucleic acids (i.e., their own genes for viral production) to cells, have been modified to include therapeutic genes of interest. While such viral gene therapy vectors are the most efficient vectors developed, concerns about their safety and immunogenicity have prompted many to investigate non-viral vector alternatives. Cationic polymers and lipids have emerged as leading non-viral vector materials. Our laboratory has developed a class of cyclodextrin-containing polycations (CDPs) that condense DNA into complexes that can be endocytosed by cells, achieve expression of their genetic payload in those cells, and may be modified to target particular cell types within an animal.
\r\n\r\nIn the past five years, scientists have discovered a new mechanism for the reduction of gene expression in mammalian cells via sequence-specific cleavage of a particular messenger RNA (mRNA); this phenomenon is known as RNA interference (RNAi). Since RNAi is triggered by nucleic acids (small interfering RNA (siRNA) duplexes), I hypothesized that CDPs may be suitable vectors for the delivery of siRNA. In my thesis work, the safety of synthetic siRNA duplexes is examined both in cultured cells and in vivo. Using a number of different siRNA sequences, two different strains of mice, and three different methods of administration, I fail to observe any cytokine (IL-12 or IFN-a) responses, morphological changes, or alterations in complete blood counts (CBCs) or liver enzyme levels.
\r\n\r\nThe ability of CDP to serve as a delivery vehicle for siRNA is also explored. I demonstrate that CDP/siRNA complexes can be formed that are small enough to be endocytosed, can be modified to ensure stability in physiological fluid, and protect the siRNA payload from serum nuclease degradation. Finally, down-regulation of specific target genes, including genes implicated in disease, is shown in vitro and in mice. An endogenous reporter gene (luciferase) in the livers of transgenic mice is down-regulated by galactosylated CDP/siRNA formulations that target hepatocytes. The level of a chimeric oncogene, EWS-Fli1, is reduced by polyplex formulations in cultured Ewing\u2019s sarcoma cells and by transferrin-targeted formulations in tumor-bearing mice; this in vivo down-regulation corresponds to an inhibition of tumor growth. These results suggest that CDP-containing siRNA formulations have the potential for development into therapeutics.
", "doi": "10.7907/F5AX-3Y24", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:2723", "collection": "thesis", "collection_id": "2723", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06252004-101813", "primary_object_url": { "basename": "JFM_Thesis_Complete.pdf", "content": "final", "filesize": 2117681, "license": "other", "mime_type": "application/pdf", "url": "/2723/1/JFM_Thesis_Complete.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Methods for Collection and Processing of Gene Expression Data", "author": [ { "family_name": "Murphy", "given_name": "John Frank", "clpid": "Murphy-John-Frank" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "orcid": "0000-0002-4925-7523", "clpid": "Asthagiri-A-R" }, { "family_name": "Wold", "given_name": "Barbara J.", "orcid": "0000-0003-3235-8130", "clpid": "Wold-B-J" }, { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Examination of the transcriptional messages encoded in the manifold of mRNA molecules within a cell is a central task of molecular biology and functional genomics. This examination can be broken down into two parts: collection of gene expression data, and analyses of those data. Here, a new method for collecting gene expression data, and two new methods for analyzing those data are presented.
\r\n\r\nA new method for quantifying gene expression denoted as the Mass-spectrometric Analysis of Gene Expression (MAGE) is developed. MAGE relies on novel conjugates of DNA oligonucleotide 30-mers; each unique sequence is conjugated via photolabile linker to an N-substituted glycine oligomer (peptoid) of unique mass. Deuterated bromoacetic acid is incorporated into some peptoids yielding two chemically identical probe conjugates of different molecular weights for each nucleic acid sequence of interest. Mixtures of these probes, along with 3' adjacent biotin-labeled oligonucleotides, are used to interrogate a target mixture of cDNA. Following hybridization, the two adjacent probes are ligated to enhance the specificity of the identification, and to enable the use of a biotin-affinity column for removal of confounding peptoid tags. The resulting mixture is exposed to longwave ultraviolet light to release the peptoid tags, that are quantified using MALDI-TOF mass spectrometry using the isotopically labeled peptoids as internal standards. These individual components of MAGE are demonstrated.
\r\n\r\nA strategy for simplification and visualizing of high-dimensional gene expression data, as well as a strategy for inferring the presence of clusters within those data, is formulated and implemented. In order to visualize high-dimensional gene expression data, principle components analysis is used with subsequent mapping of the data onto an orthogonal set of basis functions known as Andrews curves. This analysis method is demonstrated by visualizing of breast cancer tumor data and yeast sporulation data. In order to cluster gene expression data, the expectation-maximization algorithm is employed to optimize the parameters of a mixture model of Lorentzian distributions. The difference between Lorentzian and Gaussian mixture models is first demonstrated with artificial data, and then applied to yeast sporulation data. The results indicate that mixtures of Lorentzian distributions may have significant utility for gene expression analysis.
\r\n\r\nThe tools demonstrated here offer unique advantages when compared to the current suite of experimental and analytical tools employed by investigators of functional genomics.
\r\n", "doi": "10.7907/8p8e-2147", "publication_date": "2005", "thesis_type": "phd", "thesis_year": "2005" }, { "id": "thesis:5029", "collection": "thesis", "collection_id": "5029", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-12172003-140435", "primary_object_url": { "basename": "toc.pdf", "content": "final", "filesize": 627204, "license": "other", "mime_type": "application/pdf", "url": "/5029/9/toc.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Expanding the Biosynthetic Capacity of the Aminoacyl-tRNA Synthetases", "author": [ { "family_name": "Wang", "given_name": "Pin", "clpid": "Wang-Pin" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Mayo", "given_name": "Stephen L.", "orcid": "0000-0002-9785-5018", "clpid": "Mayo-S-L" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Incorporation of non-natural amino acids into proteins in vivo can provide biological materials with new chemical functions and improved physical properties. Examples include new posttranslational modification chemistry by introducing azide and ketone moieties into recombinant proteins, and novel strategies for engineering hyper-stable proteins by incorporating fluorinated side chains. Implementing such methods requires manipulation of protein biosynthesis to specifically alter the genetic code. The rules of the genetic code are established by the aminoacylation reaction, where the aminoacyl-tRNA synthetases (aaRS) catalyze the attachment of the amino acids to their cognate tRNAs. Thus manipulation of cellular aminoacylation reactions could potentially expand the available set of amino acid building blocks for protein engineering and biomaterials engineering.
\r\n\r\nBy simple depletion of the cellular pool of isoleucine and utilization of isoleucine auxotrophic hosts, we were able to force the endogenous isoleucyl-tRNA synthetase to join 5,5,5-trifluoroisoleucine (5TFI) to tRNAIle and assign it to isoleucine codons in vivo. Murine interleukin 2 containing 5TFI retains its biological activity. We showed that engineering of bacterial expression hosts can allow a single RNA message to be read in different ways, depending on the relative rates of competing aminoacylation reactions. Specifically, we showed that the 2S,3R-form of 4,4,4-trifluorovaline can be assigned either to isoleucine or to valine codons, depending on whether the bacterial host overexpresses the isoleucyl- or the valyl-tRNA synthetase. When an amino acid analog of interest is not recognized by the corresponding wild-type aaRS, we can either identify the appropriate modification of the amino acid as a promising ligand or design new synthetase activity. We describe an attempt to develop a virtual ligand screening method to find non-natural amino acids that can serve as ligands for the phenylalanyl-tRNA synthetase and our computational results correlate well with experimental results in vitro and in vivo. We also present a computational method for identifying the sites of mutations to relax the substrate specificity of the E. coli phenylalanyl-tRNA synthetase (ePheRS). One designed variant of ePheRS allows the efficient in vivo incorporation of aryl ketone functionality into proteins in vivo. Proteins outfitted with ketone functionality can be chemoselectively ligated with hydrazide reagents under mild conditions. Three designed mutants of ePheRS were subjected to extensive examination, and a broad activation profile toward many non-natural aromatic amino acids was observed. E. coli host strains were established to over-express these mutant ePheRSs, enabling the re-assignment of the Phe codons to many non-natural amino acids. By rational attenuation of the editing function of a leucyl-tRNA synthetase, oxonorvaline was incorporated into a recombinant protein in Escherichia coli.
\r\n\r\nThe work described above addresses the multi-site incorporation of new amino acids into proteins in vivo, which can be utilized to engineer the overall properties of biomacromolecules such as protein stability. The second component of this thesis focused on the site-specific incorporation of novel amino acids into proteins in vivo, which can be applied to problems that require local change of protein behavior. We have refined a previously described system, where we introduce a mutant form of yeast PheRS co-transformed with a cognate suppressor tRNA, allowing incorporation of several aromatic amino acids into proteins in response to an amber codon. The results firmly demonstrate the general strategy of importing an exogenous synthetase/tRNA pair to achieve site-specific incorporation of non-natural amino acids into proteins in vivo.
", "doi": "10.7907/99W6-8F08", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:2469", "collection": "thesis", "collection_id": "2469", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06062003-164310", "primary_object_url": { "basename": "cirinothesis.pdf", "content": "final", "filesize": 4182705, "license": "other", "mime_type": "application/pdf", "url": "/2469/2/cirinothesis.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Laboratory Evolution of Cytochrome P450 Peroxygenase Activity", "author": [ { "family_name": "Cirino", "given_name": "Patrick Carmen", "orcid": "0000-0002-7245-6205", "clpid": "Cirino-Patrick-Carmen" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" }, { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The ability of the cytochrome P450 heme monooxygenases to catalyze difficult oxidation reactions, often with high specificity and selectivity, makes them attractive for numerous biotechnological applications. However they are generally limited by low turnover rates and low stability, and their minimum requirements for catalysis include a cofactor as source of electrons (NAD(P)H), partner proteins for electron transfer, and dioxygen. Some P450s are capable of supporting low levels of peroxygenase activity, in which a peroxide is utilized to drive catalysis via a \"shunt\" pathway. This mechanism for substrate oxidation, although inefficient and not generally utilized in nature, simplifies P450 catalysis by eliminating the need for NAD(P)H.
\r\n\r\nOur goal was to engineer an efficient P450 peroxygenase which utilizes hydrogen peroxide (H\u2082O\u2082). Directed evolution is a powerful enzyme engineering methodology which mimics nature's algorithm for evolution. Enzyme libraries are generated via DNA mutagenesis or recombination techniques, and variants with improved function are isolated using an appropriate screen or selection. Using this strategy, in combination with site-directed mutagenesis, we have created P450 BM-3 heme domain variants with more than 100-fold improved H\u2082O\u2082-driven hydroxylation activity compared to wild-type, showing both an improved kcat as well as a lower Km for H\u2082O\u2082. Thermostability was also improved by directed evolution.
\r\n\r\nWe have engineered a cell-free, biomimetic hydroxylase that requires only H\u2082O\u2082 to exploit the hydroxylating power of P450 BM-3. Peroxide-mediated inactivation as a result of heme destruction remains a major obstacle and presents an important enzyme engineering challenge. This research has broadened the potential applications of P450 biocatalysis by exploiting the versatility of heme-containing proteins.
", "doi": "10.7907/KWGR-DF47", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:1", "collection": "thesis", "collection_id": "1", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-01022004-085659", "primary_object_url": { "basename": "totalthesis.pdf", "content": "final", "filesize": 15737774, "license": "other", "mime_type": "application/pdf", "url": "/1/2/totalthesis.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Low-Energy Ion Beamline-Scattering Apparatus with Application to Charge Exchange Collisions at Surfaces", "author": [ { "family_name": "Gordon", "given_name": "Michael Joseph", "orcid": "0000-0003-0123-9649", "clpid": "Gordon-Michael-Joseph" } ], "thesis_advisor": [ { "family_name": "Giapis", "given_name": "Konstantinos P.", "clpid": "Giapis-K-P" } ], "thesis_committee": [ { "family_name": "Giapis", "given_name": "Konstantinos P.", "clpid": "Giapis-K-P" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Okumura", "given_name": "Mitchio", "clpid": "Okumura-M" }, { "family_name": "Corngold", "given_name": "Noel Robert", "clpid": "Corngold-N-R" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Ion-surface interactions are important in a variety of fields such as plasma physics, surface analysis, and semiconductor manufacturing. However, the low-energy regime (50 eV - 1 keV) has been generally avoided by the research community because of the experimental challenges associated with providing sufficient ion beam current at low impact energy to conduct surface scattering studies. This energy regime is a useful range to study because threshold physical and chemical processes occur at low energies. We have set out to probe this neglected energy range by developing an ion scattering system to investigate a wide variety of ion-surface interaction phenomena below 1 keV. This thesis describes the design and construction of our system and its application to charge exchange collisions at surfaces.
\r\n\r\nOur design philosophy has been to take an inductively coupled plasma (ICP) source and couple it to a high-voltage ion beam transport line with magnetic mass- filtering to provide a clean ion beam surface probe with high current (>100 uA/cm\u00b2) and tunable energy (~50 eV - 1 keV). Space charge repulsion between the ions, which usually precludes high current at low energy, is circumvented using the accel-decel scheme for transport. In this arrangement, ions are created at the desired collision energy in the plasma source, extracted and accelerated to high transport energy (to fight space charge forces), and then decelerated back down to their original creation potential right before impacting the grounded target. In this way, the beam current is high, the collision energy is easily tunable (just by floating the whole plasma source above ground), and the target is always kept grounded. The ICP-based beamline is a generic and robust system because any ion created in the plasma can be individually singled out and delivered to the target as a clean surface probe composed of only one species and one charge state.
\r\n\r\nThe particle flux leaving the target surface is analyzed with a hybrid scattered product detector which allows simultaneous mass and energy filtering. The detector combines an electron-impact ionizer, hemispherical electrostatic sector, and quadrupole mass filter in series with single ion detection capabilities so that small signals of both ions and neutrals can be analyzed. Energy dispersion, followed by mass dispersion, is an effective combination because overlapping signals can be separated easily (i.e., multiple charge states or a mix of ion species leaving the target).
\r\n\r\nThe performance of the entire scattering system has been evaluated in an investigation of Ne+ scattering off lighter target materials (Mg, Al, Si , and Ti), where the scattered particle flux can contain inelastic Ne\u207a and Ne\u207a\u207a exit channels as a result of charge exchange between the projectile and target nuclei. Specifically, we have seen a sudden \"turn-on\" in Ne\u207a\u207a generation as the collision energy is raised above a threshold value. This turn-on seems indicative of inelastic loss channels that open up as the distance-of-closest-approach gets smaller during the hard collision. Values for the inelastic loss in the center-of-mass frame for Ne\u207a and Ne\u207a\u207a have been evaluated with our system for collision energies up to 1.3 keV and compared with literature data at higher energies. The inelasticity values we see in the threshold region are too small to be readily explained by the mechanisms proposed for higher collision energies in the literature for both Ne\u207a and Ne\u207a\u207a. Finally, a simple orbital overlap model is presented which suggests that Ne\u207a\u207a generation is coincident with a required atomic orbital overlap between the projectile and target atom L-electron shells, which signify that the Ne 2p orbital is promoted through the 4f\u03c3 molecular orbital at some threshold internuclear distance.
", "doi": "10.7907/w315-sr88", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:1991", "collection": "thesis", "collection_id": "1991", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05242004-103633", "primary_object_url": { "basename": "01_title.pdf", "content": "final", "filesize": 267594, "license": "other", "mime_type": "application/pdf", "url": "/1991/1/01_title.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Design and Characterization of Artificial Extracellular Matrix Proteins for Use as Small-Diameter Vascular Grafts", "author": [ { "family_name": "Heilshorn", "given_name": "Sarah Christine", "orcid": "0000-0002-9801-6304", "clpid": "Heilshorn-Sarah-Christine" } ], "thesis_advisor": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" } ], "thesis_committee": [ { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Asthagiri", "given_name": "Anand R.", "clpid": "Asthagiri-A-R" }, { "family_name": "Wold", "given_name": "Barbara J.", "clpid": "Wold-B-J" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Synthetic small-diameter vascular grafts often fail within three years of implantation. The underlying causes of graft failure are thought to be i) a mismatch in the mechanical properties between the graft and host material and ii) an inability of the graft to support the adhesion of endothelial cells. To address these two issues, artificial extracellular matrix (aECM) proteins contain elastin-like regions to provide physical integrity and cell-binding domains derived from fibronectin to promote endothelial cell attachment. Using recombinant protein technology, a family of artificial proteins was created with differing ratios of elastin-like regions to cell-binding domains, with variable placement of amino acid crosslinking residues, and with differing identity of cell-binding domain.
\r\n\r\nHuman umbilical vein endothelial cells (HUVEC) adhere in a sequence-specific manner to aECM proteins, secrete basal levels of key fibrinolytic regulators, and are capable of resisting a physiologically relevant detachment force. HUVEC spread more quickly and adhere more firmly to aECM proteins that contain the RGD versus the CS5 cell-binding domain. Decreasing the density of RGD cell-binding domains results in decreased HUVEC adhesion. Furthermore, amino acid selection even at sites up to 16 residues away from the cell-binding domain impacts HUVEC spreading and adhesion. HUVEC also adhere more strongly to stiffer aECM films. Therefore, the identity, density, and context of the cell-binding domain as well as the elastic modulus of the substrate are all important variables in influencing cell-substrate interactions.
\r\n\r\nProper amino acid sequence choice also influences the susceptibility of aECM proteins to elastase proteolysis; modifying 3% of the amino acid side chains results in a 7-fold reduction in degradation rate. An alternative strategy to decrease degradation involves incorporation of the noncanonical amino acid, 5,5,5-trifluoroisoleucine, into the favored proteolytic cut site, isoleucine. Replacing 82% of the isoleucines results in a twofold reduction in degradation rate without compromising sequence-specific HUVEC adhesion. Incorporation of another noncanonical amino acid, para-azidophenylalanine, allows synthesis of photoreactive proteins that can be patterned using photolithography. These protein patterns retain their ability to adhere HUVEC and produce stable cell patterns after 48 hours in medium supplemented with serum.
\r\n", "doi": "10.7907/BX95-3X10", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:2039", "collection": "thesis", "collection_id": "2039", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-05252004-102344", "primary_object_url": { "basename": "aw_master.pdf", "content": "final", "filesize": 3377734, "license": "other", "mime_type": "application/pdf", "url": "/2039/1/aw_master.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "I. Synthesis, Characterization, and Base Catalysis of Organic-Functionalized Molecular Sieves. II. Selective Oxidation of Ethane via Heteropolyanion-Containing Solid Catalysts", "author": [ { "family_name": "Wight", "given_name": "Andrea Palmisano", "clpid": "Wight-Andrea-Palmisano" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis is composed of two separate and unrelated projects. The first project examines the preparation of functional groups that can serve as immobilized bases in molecular sieves. Many heterogeneous, base catalysts are not able to promote diverse reaction types that require strong bases as catalysts. Additionally, some of the stronger solid base catalysts are sensitive to carbon dioxide and moisture in air and therefore are not easily suitable for recycling. Organic-functionalized molecular sieves possess an organic moiety within the pore space of a molecular sieve by incorporation of an organosilane directly into the synthesis gel of the molecular sieve. Previous work reported by Davis and co-workers demonstrated the incorporation of an acid site in zeolite Beta (*BEA type) and its use in shape-selective acid catalysis.
\r\n\r\nHere, a phosphonium functionality is prepared from halogen-containing alkyl groups in *BEA to allow the incorporation of a strong base (OH-) within the molecular sieve for base catalysis. Characterization of the phosphonium-containing material prepared is accomplished. Shape-selective chemical reactions and ion-exchanges are presented, and the results of these experiments suggest that the functional groups are located within the molecular sieve pore space, although the exact structure of these moieties is not conclusively obtained.
\r\n\r\nThe second part of this thesis examines the use of niobium- and pyridine-exchanged heteropolyanions as catalyst precursors for the selective oxidation of light alkanes with dioxygen. The versatility of many oxidation catalysts is limited, thereby restricting potential usefulness. Alkenes, typically used as feedstock, are becoming costly as their demand for use in many other industrial processes increases. The use of light alkanes as reactants for selective oxidation would allow one to take advantage of an under-utilized and relatively inexpensive feedstock for selective oxidation.
\r\n\r\nNiobium- and pyridine-exchanged heteropolyanions (HPAs) have been shown to produce highly active and selective catalysts for the oxidation of propane and n-butane to acrylic acid and maleic acid, respectively, by Davis and co-workers. Specifically, molybdophosphoric acid and molybdovanadophosphoric acid were exchanged with niobium oxalate and pyridine to produce the exchanged HPAs (denoted NbPMo12pyr and NbPMo11Vpyr, respectively). Preliminary work in these studies indicates that the exchanged HPAs may also be effective for the oxidation of ethane to acetic acid. The application of this catalyst system to the selective oxidation of ethane to acetic acid and ethylene is explored here.
\r\n\r\nThe exchanged heteropolyanions give higher ethane conversion at elevated pressures (230 psig and 280oC) but better yields at atmospheric pressure and 380oC. Variations of steam flow rates or reaction temperatures are not observed to improve acetic acid space-time-yield (STY). Lower gas-hourly-space-velocity (GHSV) causes the ethylene and acetic acid to over-oxidize to COx. The maximum STY of acetic acid using NbPMo12pyr is 0.021 mmol/min/g catalyst at 380oC, 0 psig, and flows of 16: 8: 16: 20 mL/min of ethane: oxygen: helium: steam.
\r\n\r\nAt elevated pressure (230 psig) the addition of vanadium into the Keggin ion precursor is shown to decrease conversion (from 6.0% to 2.2%) but improve selectivity to ethylene (from 23.2% to 46.8%). The formation of acetic acid is not affected (0.002 mmol/min/g catalyst). At atmospheric pressure the addition of vanadium into the Keggin precursor does have a favorable affect on the acetic acid formation. NbPMo11Vpyr is shown to have a maximum acetic acid production of 0.062 mmol/min/g catalyst at 380oC, 0 psig, and flows of 16: 8: 16: 20 mL/min of ethane: oxygen: helium: steam.
\r\n\r\nThe addition of both Nb and pyridine to the HPA is crucial for active catalyst formation, for reactions both at atmospheric pressure and 230 psig. Substitution of other metals for Nb does not yield materials that give significant ethane conversion.
\r\n\r\nHigher ethane/oxygen ratios increase the selectivity to acetic acid over NbPMo12pyr at atmospheric pressure. The oxidation of ethylene over NbPMo12pyr is accomplished, and the results indicate that acetic acid is formed from ethylene during the oxidation of ethane. D2O is substituted as the source of steam, and the observation that acetic acid contains deuterium shows that the steam in the feed is involved in its formation.
\r\n\r\nThe data obtained from NbPMo11Vpyr suggest that this precursor can give a catalyst that is active and selective for producing ethylene and acetic acid from ethane and dioxygen. Further experimentation is necessary to optimize performance.
", "doi": "10.7907/DCKV-0007", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:3160", "collection": "thesis", "collection_id": "3160", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08182003-150957", "primary_object_url": { "basename": "ThesisFinalDefended.pdf", "content": "final", "filesize": 10179172, "license": "other", "mime_type": "application/pdf", "url": "/3160/1/ThesisFinalDefended.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Quantitative Biaxial Texture Analysis with Reflection High-Energy Electron Diffraction for Ion Beam-Assisted Deposition of MgO and Heteroepitaxy of Perovskite Ferroelectrics", "author": [ { "family_name": "Brewer", "given_name": "Rhett Ty", "clpid": "Brewer-Rhett-Ty" } ], "thesis_advisor": [ { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" } ], "thesis_committee": [ { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" }, { "family_name": "Bhattacharya", "given_name": "Kaushik", "clpid": "Bhattacharya-K" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Haile", "given_name": "Sossina M.", "clpid": "Haile-S-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "To facilitate ferroelectric-based actuator integration with silicon electronics fabrication technology, we have developed a route to produce biaxially textured ferroelectrics on amorphous layers by using biaxially textured MgO templates.
\r\n\r\nUsing a kinematical electron scattering model, we show that the RHEED pattern from a biaxially textured polycrystalline film can be calculated from an analytic solution to the electron scattering probability. We found that diffraction spot shapes are sensitive to out-of-plane orientation distributions and in-plane RHEED rocking curves are sensitive to the in-plane orientation distribution. Using information from the simulation, a RHEED-based experimental technique was developed for in situ measurement of MgO biaxial texture. The accuracy of this technique was confirmed by comparing RHEED measurements of in-plane and out-of-plane orientation distribution with synchrotron x-ray rocking curve measurements.
\r\n\r\nBiaxially textured MgO was grown on amorphous Si3N4 by ion beam-assisted deposition (IBAD). MgO was e-beam evaporated onto the amorphous substrate with a simultaneous 750-1200 eV Ar\u207a ion bombardment at 45\u00b0 from normal incidence. We observed a previously unseen, dramatic texture evolution in IBAD MgO using transmission electron microscopy (TEM) and RHEED-based quantitative texture measurements of MgO. The first layers of IBAD MgO are diffraction amorphous until the film is about 3.5 nm thick. During the next 1 nm of additional growth, we observed rapid biaxial texture evolution. RHEED and TEM studies indicate that biaxially textured MgO film results from a solid phase crystallization of biaxially textured MgO crystals in an amorphous matrix.
\r\n\r\nBiaxially textured perovskite ferroelectrics were grown on biaxially textured MgO templates using sol-gel, metallorganic chemical vapor deposition (MOCVD), and molecular beam epitaxy (MBE). Through RHEED-based biaxial texture analysis we observed that the heteroepitaxial ferroelectric in-plane orientation distribution, deposited using ex situ techniques (not performed in the same high vacuum growth environment where the MgO was deposited), narrowed significantly with respect to the in-plane orientation distribution of its MgO template (from 11\u00b0 to 6\u00b0 FWHM). Evidence from cross section TEM and RHEED suggest that atmospheric moisture degrades the crystallinity of highly defective, misaligned MgO grains and that heteroepitaxially grown ferroelectrics preferentially nucleate on well-aligned grains and over grow misaligned regions of MgO.
", "doi": "10.7907/J5PY-RS79", "publication_date": "2004", "thesis_type": "phd", "thesis_year": "2004" }, { "id": "thesis:4669", "collection": "thesis", "collection_id": "4669", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11262002-143938", "primary_object_url": { "basename": "JKHthesis.pdf", "content": "final", "filesize": 3181526, "license": "other", "mime_type": "application/pdf", "url": "/4669/1/JKHthesis.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Hot-Wire Chemical Vapor Deposition of Silicon and Silicon Nitride for Photovoltaics: Experiments, Simulations, and Applications", "author": [ { "family_name": "Holt", "given_name": "Jason Knowles", "clpid": "Holt-Jason-Knowles" } ], "thesis_advisor": [ { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" }, { "family_name": "Goodwin", "given_name": "David G.", "clpid": "Goodwin-D-G" } ], "thesis_committee": [ { "family_name": "Atwater", "given_name": "Harry Albert", "clpid": "Atwater-H-A" }, { "family_name": "Goodwin", "given_name": "David G.", "clpid": "Goodwin-D-G" }, { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Hot-wire chemical vapor deposition is a promising technique for deposition of thin amorphous, polycrystalline, and epitaxial silicon films for photovoltaic applications. Fundamental questions remain, however, about the gas-phase and surface-kinetic processes involved. To this end, the nature of the wire decomposition process has been studied in detail by use of mass spectrometry. Atomic silicon was the predominant radical formed for wire temperatures above 1500 K, and catalysis was evident for SiH3 production with the use of a new wire. Aged wires appear to produce radicals by a non-catalyzed route and chemical analysis of these wires reveal large quantities of silicon at the surface, consistent with the presence of a silicide layer. This study is the first of its kind to correlate radical desorption kinetics with filament aging for the hot-wire chemical vapor deposition technique.
\r\n\r\nThreshold ionization mass spectrometry revealed large quantities of the SiH2 radical, attributed to heterogeneous pyrolysis on the walls of the reactor. At dilute (1%) silane pressures of up to 2 Torr, a negligible amount of ions and silicon agglomerates (Si2, Si2H, Si2H6) were detected. Density functional theory calculations reveal an energetically favorable route for the reaction of Si and SiH4, producing Si2H2 and H2. The trace amounts of Si2H2 observed experimentally, however, may suggest that an intermediate spin state transition involved in this reaction is slow under the hot-wire conditions used. Monte Carlo simulations of the hot-wire reactor suggest SiH3 is the predominant growth species under conditions leading to amorphous and polycrystalline growth. The flux of atomic hydrogen, rather than the identity of the precursor, appears to be the more important factor in governing the amorphous-to-microcrystalline transition that occurs upon hydrogen-dilution. Two-dimensional Monte Carlo simulations were used to model a hot-wire reactor for the first time, showing that filament arrays can be used to improve film growth uniformity. Under conditions where agglomerate formation does not occur, continuum simulations predict a maximum growth rate of 10 nm/s for dilute (1%) silane conditions and a rate of 50 nm/s for pure silane.
\r\n\r\nHot-wire chemical vapor deposition was used to deposit silicon nitride films with indices of refraction from 1.8-2.5 and hydrogen content from 9-18 atomic %. By tuning the SiH4/NH3 flow ratio, films in which the hydrogen was predominantly bound to N or Si could be produced, each of which reveal different hydrogen release kinetics. Platinum-diffused silicon samples, capped by a hydrogenated silicon nitride layer revealed, upon annealing at 700oC, platinum-hydrogen complexes with a bulk concentration of 1014 cm-3. This constitutes the first direct evidence for bulk silicon passivation by hydrogen release from a silicon nitride layer and hydrogen complex formation. Photovoltaic cells employing a hot-wire nitride layer were found to have comparable electrical properties to those using plasma nitride layers.
\r\n\r\nFinally, a method for in situ generation of SiH4 by atomic hydrogen etching was evaluated. Using a cooled crystalline silicon target in an H/H2 ambient produced negligible etching, while a cooled amorphous silicon film target was etched at a rate of up to 14 nm/min. In the latter case, net deposition at 0.6 nm/min onto a heated Ge(100) substrate resulted. A method for more efficient etching of crystalline silicon materials was proposed.
", "doi": "10.7907/Z9S6-8J66", "publication_date": "2003", "thesis_type": "phd", "thesis_year": "2003" }, { "id": "thesis:4188", "collection": "thesis", "collection_id": "4188", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-10202002-002307", "primary_object_url": { "basename": "Thesis.pdf", "content": "final", "filesize": 13085158, "license": "other", "mime_type": "application/pdf", "url": "/4188/11/Thesis.pdf", "version": "v7.0.0" }, "type": "thesis", "title": "I. Structure-Function Analysis of the Mechanosensitive Channel of Large Conductance. II. Design of Novel Magnetic Materials using Crystal Engineering", "author": [ { "family_name": "Maurer", "given_name": "Joshua Ahab", "orcid": "0000-0002-6663-0721", "clpid": "Maurer-Joshua-Ahab" } ], "thesis_advisor": [ { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" } ], "thesis_committee": [ { "family_name": "Grubbs", "given_name": "Robert H.", "clpid": "Grubbs-R-H" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "clpid": "Dougherty-D-A" }, { "family_name": "Lester", "given_name": "Henry A.", "clpid": "Lester-H-A" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "clpid": "Barton-J-K" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The work presented here encompasses two distinct areas, with the first section addressing structure-function relationships in the mechanosensitive channel of large conductance (MscL) from bacteria. A high-throughput fluorescent screening technique has been developed for the E. coli homologue of MscL. This technique has been applied to a large library of random E. coli MscL mutations to provide insights into channel function. Additionally, attempts have been made to characterize the functionally important regions of MscL and comparisons have been made between the E. coli and M. tuberculosis homologues of MscL.
\r\n\r\nThe second section addresses the design of novel magnetic materials. The guanidinium sulfonate \"Ward lattice\" from crystal engineering has been used to develop a new family of frustrated magnetic materials.
", "doi": "10.7907/DNFY-8G73", "publication_date": "2003", "thesis_type": "phd", "thesis_year": "2003" }, { "id": "thesis:5495", "collection": "thesis", "collection_id": "5495", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:01062010-084034470", "primary_object_url": { "basename": "Piccione_pm_2002.pdf", "content": "final", "filesize": 8240658, "license": "other", "mime_type": "application/pdf", "url": "/5495/1/Piccione_pm_2002.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Thermodynamics of Formation of Molecular Sieves", "author": [ { "family_name": "Piccione", "given_name": "Patrick Manuel", "clpid": "Piccione-Patrick-Manuel" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Navrotsky", "given_name": "Alexandra", "orcid": "0000-0002-3260-0364", "clpid": "Navrotsky-Alexandra" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Molecular sieves, porous, crystalline frameworks with pore sizes of molecular dimensions, are of great industrial importance as detergents, catalysts and absorbants. Despite their technological importance, the syntheses of these materials are still not well understood and typically rely on extensive series of trials to produce new framework structures.
\r\n\r\nThermodynamic investigations are undertaken to better understand the energetic differences amongst molecular sieve frameworks and the mechanisms and interactions important in molecular sieve self-assembly. The enthalpies relative to quartz at 298.15 K are determined by high-temperature solution calorimetry for a collection of calcined pure-silica molecular sieves with diverse structural features. Si0_2 molecular sieves are shown to be only modestly (6.8-14.4 kJ/mol) metastable with respect to quartz. A strong linear correlation between enthalpy and molar volume is observed, implying that the overall packing quality determines the relative enthalpies of Si0_2 molecular sieves. Silanol (Si-O-H) defect sites lead to an additional destabilization of no more than 2.4 kJ/mol. The entropies of four pure-silica molecular sieves spanning the entire range of molar volumes available to Si0_2 frameworks are determined by the integration of heat capacity measurements from 5 to 400 K. The entropies of these structures are almost identical (3.2-4.2 J\u2219K^(-1)\u2219mol^(-1) above quartz), hence the empty pore volume and cages do not contribute appreciably to the vibrational density of states. The enthalpy and entropy data are combined to calculate the Gibbs free energies of transition from quartz to eight other silica polymorphs, including four molecular sieves as well as silica glass. At typical synthesis conditions, the available thermal energy is RT = 3.5 kJ/mol. The molecular sieve Gibbs free energies are only slightly larger than RT at 5.5-12.6 kJ/mol above quartz and lie in the same energetic region as the amorphous precursors used for molecular sieve preparation. There are therefore no significant thermodynamic barriers to transformations among silica polymorphs. Thus the role of SDA in molecular sieve syntheses is not the stabilization of otherwise very unstable phases.
\r\n\r\nInteraction enthalpies between inorganic frameworks and organic SDAs are measured by HF solution calorimetry for six molecular sieve/SDA pairs. The enthalpies are only moderately exothermic (-1.1 to -5.9 kJ/mol SiO_2), as expected if the predominant interactions are van der Waals contacts between the hydrophobic silica frameworks and the hydrocarbon portions of the SDAs. Interaction entropies can be estimated for three framework/SDA pairs, and, when used in combination with the interaction enthalpies, allow the calculation of the Gibbs free energies of interaction between these three inorganic/organic pairs. The latter values range from -2.0 to -5.4 kJ/mol SiO_2, smaller in magnitude than twice the available thermal energy at molecular sieve synthesis temperatures. This energy range is comparable to the range observed for the molecular sieve frameworks alone, showing that energetics of both the frameworks and of the molecular sieve/SDA interactions must be considered in order to adequately describe molecular sieve synthesis. The energetics of the synthesis of molecular sieves (considering all components present in the synthesis mixture) are examined here and also reveal small differences between various molecular sieve/SDA combinations. The energetic contribution of the effective dilution experienced by the SDA upon occlusion is similar in magnitude to the other energetic effects. The strong selectivity of organic SDAs experimentally observed in the face of the comparatively small energetic differences suggests that kinetic factors dominate in molecular sieve preparation.
", "doi": "10.7907/TQVE-FW28", "publication_date": "2002", "thesis_type": "phd", "thesis_year": "2002" }, { "id": "thesis:6376", "collection": "thesis", "collection_id": "6376", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05052011-134334164", "primary_object_url": { "basename": "Sundaresan_v_2002.pdf", "content": "final", "filesize": 78961721, "license": "other", "mime_type": "application/pdf", "url": "/6376/1/Sundaresan_v_2002.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Selective Molecular Recognition in Imprinted Polymeric Adsorbents and in Biological Macromolecules", "author": [ { "family_name": "Sundaresan", "given_name": "Vidyasankar", "clpid": "Sundaresan-Vidyasankar" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Kornfield", "given_name": "Julia A.", "orcid": "0000-0001-6746-8634", "clpid": "Kornfield-J-A" }, { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" }, { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This thesis describes the synthesis and use of molecularly imprinted polymeric adsorbents for use in ligand-exchange chromatographic separations of structurally similar substrates. A general model of stereo selectivity is also described, which can be applied both to chromatographic adsorbents and to biological receptors.
\r\n\r\nCrosslinking polymerization of trimethylolpropane trimethacrylate (TRIM), under controlled conditions yields macroporous polymers bearing surface-accessible unpolymerized methacrylate residues. These residues have been utilized for copolymerization with different functional monomers to obtain composite polymer matrices with surface coatings of functional polymer chains. Surface modification has been carried out by molecular imprinting, using ternary Cu^(2+) complexes of [N-(4-vinylbenzyl)imino]diacetate and bisimidazole templates, with ethylene glycol dimethacrylate as comonomer. Selectivity characteristics similar to bulk-copolymerized polymers have been observed. The physicochemical characteristics of these functional polymer matrices have been evaluated by ^(13)C NMR, X-ray photoelectron spectroscopy, IR spectroscopy, and scanning electron microscopy.
\r\n\r\nThe ability of molecular imprinting to impart enantioselectivity to polymeric adsorbents has been studied using Cu^(2+) complexes of the achiral monomer [N-(4-vinylbenzyl)imino]diacetate and \u03b1-amino acids. Crosslinking polymerization with ethylene glycol dimethacrylate as the comonomer yields polymeric adsorbents capable of enantioresolutions of underivatized \u03b1-amino acids. Chromatographic adsorbents have been prepared by grafting the imprinted polymer on to silica particles. The observed enantioselectivity increases corresponding to the size of the side chain of the amino acid used as template, with the best enantioresolutions being obtained for materials imprinted against phenylalanine (~1.65 for D,L-phenylalanine enantioresolution). Adsorbents imprinted for alanine show negligible enantioselectivity. Cross-selectivity patterns towards non-template amino acids have been investigated, and the ability of an amino acid imprinted material to resolve analogous chiral amines has been demonstrated.
\r\n\r\nThe mechanisms underlying enantioselectivity in imprinted polymers are discussed in terms of the three-point interaction model. This model has been extended to a stereocenter-recognition (SR) model for substrates with multiple stereocenters. For N stereocenters in a linear chain, it has been demonstrated that a minimum of N + 2 interactions need to be distributed over all stereocenters, such that three effective interactions exist per stereocenter. The general applicability of the SR model is demonstrated for biological ligand-receptor interactions, by reinterpreting several previous experimental observations.
", "doi": "10.7907/jvev-x884", "publication_date": "2002", "thesis_type": "phd", "thesis_year": "2002" }, { "id": "thesis:6268", "collection": "thesis", "collection_id": "6268", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03072011-155440857", "primary_object_url": { "basename": "Noelte_j_2002.pdf", "content": "final", "filesize": 48859581, "license": "other", "mime_type": "application/pdf", "url": "/6268/1/Noelte_j_2002.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Effects of Surface Chemistry on Deposition Kinetics of Colloidal Hematite (\u03b1-Fe2O3) in Packed Beds of Silica Sand", "author": [ { "family_name": "Noelte", "given_name": "Jeff Lee", "clpid": "Noelte-Jeff-Lee" } ], "thesis_advisor": [ { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" }, { "family_name": "Morgan", "given_name": "James J.", "clpid": "Morgan-J-J" } ], "thesis_committee": [ { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" }, { "family_name": "Morgan", "given_name": "James J.", "clpid": "Morgan-J-J" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" } ], "local_group": [ { "literal": "div_eng" } ], "abstract": "The removal of colloidal (sub-micrometer) particles from flowing suspensions by deposition on surfaces is important in many natural and industrial processes (e.g., the fate\r\nof colloids and associated pollutants in groundwater systems and water treatment involving separation processes). In deposition, colloidal particles are transported to the vicinity of the collector surface by advection and diffusion. Colloidal interactions at\r\nshort distances determine whether a particle will attach to a collector. Deposition rates are reduced by the presence of repuls4e colloidal interactions. Van der Waals attraction\r\nand electric double layer repulsion are combined in DLVO theory to describe the total interaction energy between two surfaces. The total interaction energy depends on the\r\nsolution chemistry and the electric charge and potential of the interacting surfaces. To understand the attachment step of particle deposition, an understanding of the role of\r\nsimple chemical changes in the water altering the electrostatic interaction is critical.\r\n\r\nDeposition experiments using hematite particles and a silica sand were conducted to investigate the influence of specific adsorption to hematite on deposition kinetics. A\r\nvariety of electrolytes, both inorganic and organic, were studied (e.g., phosphate, small organic acids, and polymeric organic compounds including fulvic and humic acid). Electrokinetic measurements were carried out, under chemical conditions similar to those in the deposition experiments, to provide information about the sign and magnitude of the surface charge on hematite particles.\r\n\r\nExperimental results show that the deposition rate is influenced primarily by electrostatic interactions, which are determined by the adsorption of potential\r\ndetennining ions. In the absence of specifically adsorbed species, hematite deposition is transport limited (favorable deposition) at pH 6.5 and 1 millimolar NaCl. The addition of 100 micromolar total phosphate results in unfavorable deposition in which the deposition\r\nrate is reduced by approximately two orders of magnitude. Polymeric organic compounds produce unfavorable deposition at total concentrations around 10^(-5) g/L. It was observed that electrokinetic measurements in the presence of polymeric organic compounds are influenced by the particle concentration when hematite mobility is measured as a function of the total solute concentration. Experimental results indicated that adjusting the total polyelectrolyte concentration by the same factor relating the particle concentrations in the mobility measurements and deposition experiments resulted in matching the hematite surface properties in the mobility measurements to the\r\ndeposition experiments.\r\n\r\nThe experimental collision efficiency for hematite deposition was consistent with deposition under conditions of surface heterogeneity (i.e., the collision efficiency\r\ndecreased gradually as electrostatic repulsion increased). The natural silica sand used (Ottawa 30) has a high degree of surface roughness and is expected to be chemically\r\nheterogeneous.\r\n", "doi": "10.7907/KSZB-2238", "publication_date": "2002", "thesis_type": "phd", "thesis_year": "2002" }, { "id": "thesis:2934", "collection": "thesis", "collection_id": "2934", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-07192007-103729", "primary_object_url": { "basename": "Tae_g_2002.pdf", "content": "final", "filesize": 5606627, "license": "other", "mime_type": "application/pdf", "url": "/2934/1/Tae_g_2002.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "In situ Forming Hydrogels Using Self-Assembly of Fluoroalkyl-Ended Poly(ethylene Glycol)s", "author": [ { "family_name": "Tae", "given_name": "Giyoong", "clpid": "Tae-Giyoong" } ], "thesis_advisor": [ { "family_name": "Kornfield", "given_name": "Julia A.", "orcid": "0000-0001-6746-8634", "clpid": "Kornfield-J-A" }, { "family_name": "Hubbell", "given_name": "Jeffrey A.", "clpid": "Hubbell-J-A" } ], "thesis_committee": [ { "family_name": "Kornfield", "given_name": "Julia A.", "orcid": "0000-0001-6746-8634", "clpid": "Kornfield-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Hubbell", "given_name": "Jeffrey A.", "clpid": "Hubbell-J-A" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "orcid": "0000-0002-3361-6114", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Telechelic polymers with hydrophilic midblocks (poly(ethylene glycol), PEG) and hydrophobic end groups (fluoroalkyl, Rf) are synthesized and explored as candidates for in situ forming hydrogels for biomedical applications. Relevant physical properties, including phase behavior, rheology and erosion kinetics, are characterized to guide rational design of polymers for specific applications, including controlled release of therapeutic proteins and deposition of biocompatible surface layers. Disruption of the aggregation of the end groups using biocompatible complexing agents or solvents produces a low viscosity liquid that is injectable; self-assembly of the gel once inside the body can be achieved gently by diffusion of the complexing agent or solvent out into the surrounding tissue. By modulating molecular structure, the mechanical and erosion properties of these hydrogels can be systematically varied over a wide range for desired applications.
\r\n\r\nWith increasing fluoroalkyl length relative to PEG length, the phase behavior of these fluoroalkyl-ended PEGs (Rf-PEGs) polymers in aqueous solution changes from singlephase behavior (continuous transition in properties from solution-like to gel-like with increasing concentration), to sol-gel coexistence, to an insoluble precipitate (Chapter 2). For sol-gel coexisting polymers, the equilibrium gel concentration and the modulus of the gel phase are governed by the length of the PEG midblock, whereas the relaxation time is determined by the hydrophobe length. The erosion characteristics of these hydrogels correlate with their phase behavior: the gels of sol-gel coexisting species exhibit surface erosion in an open system with slow dissolution rate controlled by the end-group length, whereas gels showing single-phase behavior exhibit bulk erosion that is relatively fast.
\r\n\r\nAqueous solutions of Rf-PEGs exhibit ordering transitions, with increasing concentration (Chapter 3). The hydrophobic cores of the micelle-like aggregates order into a body-centered-cubic (BCC) structure. The aggregated state of the hydrophobic core is determined by the length of the hydrophobic end group, and is insensitive to the concentration of the polymer solution or the temperature. A shorter PEG length for a given end group produces a much enhanced ordering compared to a longer one. This micelle packing effect is manifested in changes in the viscoelastic properties: the single-relaxation behavior evolves to the appearance of a new low frequency elastic plateau in the dynamic moduli, and a linear response changes to a yielding behavior in creep.
\r\n\t\r\nThe gel phase of sol-gel coexisting polymers can be transformed into an injectable state by the addition of a bio-tolerable organic solvent, such as N-methyl pyrrolidone (NMP), and this solution can be restored to a hydrogel state quickly after injection by removal of the organic solvent by diffusion. Release of Human growth hormone (hGH) using this injectable formulation (Chapter 4) reveals that hGH remains stable inside the hydrogel formed, and more than 2 weeks of prolonged release of hGH pretreated with zinc is obtained using the injectable formulation without irreversible aggregation. For the Rf-PEGs examined here, the release rate of hGH is determined by the rate of diffusion through the hydrogel.
\r\n\r\nThe telechelic Rf-PEGs that exhibit sol-gel equilibrium or precipitated gel phase behavior provide a facile route to hydrophilic modification of poly(tetrafluoroethylene) (PTFE) surfaces that are frequently encountered in biomedical devices (Chapter 5). Dip coating of PTFE into 1 wt % Rf-PEGs in ethanol, followed by immersing into water, converts the surface of PTFE from hydrophobic to hydrophilic. The lifetime of this modification is correlated to the phase behavior of the bulk gel state, and stable in the various ranges of shear rates. An Rf-PEG that is insoluble in water gave a stable modification over a period of weeks in the absence of shear, and persisted for days when subjected to the highest shear stresses encountered in arteries (3-4Pa). Telechelic Rf-PEGs are effective, while monofunctional PEGs with a single fluoroalkyl group are not.
\r\n\r\nThe swelling and drying behaviors of thin films of RfPEGs (~0.1 [mu]m) show abnormalities relative to glassy and semi-crystalline films (Chapter 6). In a humidity ramp test starting from a dry state, thin films of Rf-PEGs show a distinctive hysteresis behavior; as humidity increases, little swelling occurs until ~ 85% humidity, then the film swells rapidly; as the humidity decreases, a rapid deswelling occurs near ~75% humidity. In a humidity step test, following a step-up the mass increase shows an overshoot, followed by a gradual approach to the equilibrium value, whereas the film tracks the equilibrium state very rapidly and monotonically following a step down from high to low humidity.
", "doi": "10.7907/xrnv-yh71", "publication_date": "2002", "thesis_type": "phd", "thesis_year": "2002" }, { "id": "thesis:6268", "collection": "thesis", "collection_id": "6268", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03072011-155440857", "primary_object_url": { "basename": "Noelte_j_2002.pdf", "content": "final", "filesize": 48859581, "license": "other", "mime_type": "application/pdf", "url": "/6268/1/Noelte_j_2002.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Effects of Surface Chemistry on Deposition Kinetics of Colloidal Hematite (\u03b1-Fe2O3) in Packed Beds of Silica Sand", "author": [ { "family_name": "Noelte", "given_name": "Jeff Lee", "clpid": "Noelte-Jeff-Lee" } ], "thesis_advisor": [ { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" }, { "family_name": "Morgan", "given_name": "James J.", "clpid": "Morgan-J-J" } ], "thesis_committee": [ { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" }, { "family_name": "Morgan", "given_name": "James J.", "clpid": "Morgan-J-J" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Blake", "given_name": "Geoffrey A.", "orcid": "0000-0003-0787-1610", "clpid": "Blake-G-A" } ], "local_group": [ { "literal": "div_eng" } ], "abstract": "The removal of colloidal (sub-micrometer) particles from flowing suspensions by deposition on surfaces is important in many natural and industrial processes (e.g., the fate\r\nof colloids and associated pollutants in groundwater systems and water treatment involving separation processes). In deposition, colloidal particles are transported to the vicinity of the collector surface by advection and diffusion. Colloidal interactions at\r\nshort distances determine whether a particle will attach to a collector. Deposition rates are reduced by the presence of repuls4e colloidal interactions. Van der Waals attraction\r\nand electric double layer repulsion are combined in DLVO theory to describe the total interaction energy between two surfaces. The total interaction energy depends on the\r\nsolution chemistry and the electric charge and potential of the interacting surfaces. To understand the attachment step of particle deposition, an understanding of the role of\r\nsimple chemical changes in the water altering the electrostatic interaction is critical.\r\n\r\nDeposition experiments using hematite particles and a silica sand were conducted to investigate the influence of specific adsorption to hematite on deposition kinetics. A\r\nvariety of electrolytes, both inorganic and organic, were studied (e.g., phosphate, small organic acids, and polymeric organic compounds including fulvic and humic acid). Electrokinetic measurements were carried out, under chemical conditions similar to those in the deposition experiments, to provide information about the sign and magnitude of the surface charge on hematite particles.\r\n\r\nExperimental results show that the deposition rate is influenced primarily by electrostatic interactions, which are determined by the adsorption of potential\r\ndetennining ions. In the absence of specifically adsorbed species, hematite deposition is transport limited (favorable deposition) at pH 6.5 and 1 millimolar NaCl. The addition of 100 micromolar total phosphate results in unfavorable deposition in which the deposition\r\nrate is reduced by approximately two orders of magnitude. Polymeric organic compounds produce unfavorable deposition at total concentrations around 10^(-5) g/L. It was observed that electrokinetic measurements in the presence of polymeric organic compounds are influenced by the particle concentration when hematite mobility is measured as a function of the total solute concentration. Experimental results indicated that adjusting the total polyelectrolyte concentration by the same factor relating the particle concentrations in the mobility measurements and deposition experiments resulted in matching the hematite surface properties in the mobility measurements to the\r\ndeposition experiments.\r\n\r\nThe experimental collision efficiency for hematite deposition was consistent with deposition under conditions of surface heterogeneity (i.e., the collision efficiency\r\ndecreased gradually as electrostatic repulsion increased). The natural silica sand used (Ottawa 30) has a high degree of surface roughness and is expected to be chemically\r\nheterogeneous.\r\n", "doi": "10.7907/KSZB-2238", "publication_date": "2002", "thesis_type": "phd", "thesis_year": "2002" }, { "id": "thesis:4490", "collection": "thesis", "collection_id": "4490", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11102005-103556", "primary_object_url": { "basename": "Lai_r_2001.pdf", "content": "final", "filesize": 4700896, "license": "other", "mime_type": "application/pdf", "url": "/4490/1/Lai_r_2001.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Synthesis and Characterization of ZSM-5 Zeolite Membranes", "author": [ { "family_name": "Lai", "given_name": "Re", "clpid": "Lai-Re" } ], "thesis_advisor": [ { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Anson", "given_name": "Fred C.", "clpid": "Anson-F-C" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Synthesis of ZSM-5 zeolite membranes supported on porous alumina substrates was conducted in autoclave reactors. The film morphologies and structures were characterized by scanning electron microscopy, energy dispersive spectroscopy and X-ray diffraction. Gas adsorption was used to estimate the crystalline fraction of the products. The gas permeation properties of the membranes were evaluated for H\u2082, CH\u2084, O\u2082, N\u2082, and n-butane and other gases singly or in mixtures.
\r\n\r\nZSM-5 film formation on alumina and other surfaces in certain clear, tetrapropylammonium(TPA\u207a)-containing synthesis solutions was found to be preceded by a gel layer. The presence of alumina and other substrates of a high Hamaker constant facilitated formation of the surface gel layer and accelerated zeolite crystallization. Aluminum added to the solution or leached from alumina substrates had dual effects, to induce surface gelation and to retard crystallization of that layer as well as crystallization in the bulk solution.
\r\n\r\nGrowth of ZSM-5 membranes was facilitated by using alumina tubes pre-coated with silicalite seeds. Accompanied with gradual growth of an external polycrystalline layer, siliceous deposits accumulated as deep as 100 \u00b5m inside the pores of the support, converting gradually from amorphous to crystalline. Pure gas permeation results are presented for membranes prepared in a solution of composition SiO\u2082: 0.15TPAB4: 0.7NaOH: 98H\u2082O using 0.4 and 2 \u00b5m seeds.
\r\n\r\nOrganic-free hydrogel reaction mixtures were further used to grow ZSM-5 membranes on seeded porous alumina substrates, eliminating the crack-prone calcination step for removing organic TPA\u207a templates from as-synthesized ZSM-5. The optimum composition SiO\u2082: 0.0125Al\u2082O\u2083: 0.2675Na\u2082O: 46H\u2082O was identified to produce membranes with permeation selectivities for H\u2082 over n-butane above 10\u2074 and for O\u2082 over N\u2082 9-10. The permeation was strongly activated with the activation energies increasing sharply with molecular size.
\r\n\r\nParallel synthesis of zeolite films was developed to expedite composition screening. The films prepared in an array reactor of multiple wells each containing 35 micro-liter synthesis solution displayed morphology similar to that produced by the conventional synthesis. The method was applied to explore the composition space of clear, organic-free synthesis solutions for ZSM-5 films growth: SiO\u2082: (700-300)Al\u2082O\u2083: (0.5-0.7)NaOH: 80H\u2082O.
", "doi": "10.7907/m5xs-mq20", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:244", "collection": "thesis", "collection_id": "244", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-01202002-221541", "primary_object_url": { "basename": "Winblade_nd_2001.pdf", "content": "final", "filesize": 9533440, "license": "other", "mime_type": "application/pdf", "url": "/244/1/Winblade_nd_2001.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Blocking Adhesion to Cell and Tissue Surfaces via Steric Stabilization with Graft Copolymers Containing Poly(Ethylene Glycol) and Phenylboronic Acid", "author": [ { "family_name": "Winblade", "given_name": "Natalie Dawn", "orcid": "0000-0003-1293-345X", "clpid": "Winblade-Natalie-Dawn" } ], "thesis_advisor": [ { "family_name": "Hubbell", "given_name": "Jeffrey A.", "orcid": "0000-0003-0276-5456", "clpid": "Hubbell-J-A" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" } ], "thesis_committee": [ { "family_name": "Hubbell", "given_name": "Jeffrey A.", "orcid": "0000-0003-0276-5456", "clpid": "Hubbell-J-A" }, { "family_name": "Hoffman", "given_name": "Allan S.", "clpid": "Hoffman-A-S" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Bjorkman", "given_name": "Pamela J.", "orcid": "0000-0002-2277-3990", "clpid": "Bjorkman-P-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Graft copolymers were designed to coat biological surfaces and thereby block subsequent adhesion and recognition events with other proteins, cells, and tissues. Inspired by polymeric steric stabilization of colloidal dispersions, the copolymers contain a backbone with affinity for biological surfaces and grafted side-chains that are resistant to adhesion of biological elements. Phenylboronic acid (PBA) moieties in the polymer backbone provided for binding, by forming reversible covalent complexes with cis-diols in oligosaccharides that are ubiquitous on cell surfaces and secreted macromolecules. The PBA moieties were conjugated to a poly-L-lysine (PLL) backbone via a secondary amine linker. Grafted poly(ethylene glycol) (PEG) side-chains provided for resistance of adhesion of proteins and cells. It was hypothesized that these PLL-g-(PEG;PBA) copolymers would spontaneously assemble on biological (e.g., cell or tissue) surfaces, where the PBA-containing backbone would bind to the surfaces and thereby anchor a dense PEG brush on the surface.
\r\n\r\nPLL-g-(PEG;PBA) copolymers were synthesized with varying degrees of PEG and PBA grafting. The pKa of the PBA groups was found to be circa 6, allowing for stronger binding at physiological pH than most PBA groups, which have pKas circa 8.8. The PLL-g-(PEG;PBA) copolymers were found to bind specifically to a mannan resin, where the PEG grafting ratio sterically controlled the binding. The copolymers coated red blood cells and blocked their agglutination by lectins and by blood group antibodies. The copolymers were also found to coat tissue culture polystyrene, adsorbed serum proteins, and extracellular matrix and to prevent the adhesion, spreading, and/or migration of rabbit lens epithelial cells on those surfaces. The copolymers displayed evidence of toxicity in vitro but no toxicity was seen when administered in vivo in models of posterior capsule opacification or peritoneal adhesion formation. PLL-g-(PEG;PBA) was found to interfere with the worsening of peritoneal adhesions following adhesiolysis. The efficacy of the copolymers was a function of the degree of PEG and PBA grafting, and PLL-g-(PEG;PBA) copolymers were found to be more effective than electrostatically-binding PLL-g-PEG copolymers. PLL-g-(PEG;PBA) copolymers have many possible clinical applications where blocking protein or cell interactions with cell, tissue, or biomaterial surfaces via a simple aqueous lavage is desired.
", "doi": "10.7907/B47A-E319", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:6184", "collection": "thesis", "collection_id": "6184", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11192010-081828575", "primary_object_url": { "basename": "Hwang_sj_2001.pdf", "content": "final", "filesize": 7869336, "license": "other", "mime_type": "application/pdf", "url": "/6184/1/Hwang_sj_2001.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Rational Design of a New Class of Cyclodextrin-Containing Polymers for Gene Delivery", "author": [ { "family_name": "Hwang", "given_name": "Suzie Jean", "orcid": "0000-0003-1443-4996", "clpid": "Hwang-Suzie-Jean" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Farbstein", "given_name": "Mark", "clpid": "Farbstein-M" }, { "family_name": "Fraser", "given_name": "Scott E.", "orcid": "0000-0002-5377-0223", "clpid": "Fraser-S-E" }, { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" }, { "family_name": "Triche", "given_name": "Timothy", "clpid": "Triche-T" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The transfer of gene therapy from an academic exercise to a clinical setting demands the development of an efficient, biocompatible gene delivery vector. Current non-viral systems suffer from toxicity, low transfection efficiency, and in vivo instability. In this work, a new class of polymers was designed to address these issues. Linear, polyamidine, \u03b2-cyclodextrin (\u03b2CD)-containing polymers (\u03b2CDPs) are synthesized by polymerizing difunctionalized cyclodextrins with other difunctionalized comonomers. The inclusion of \u03b2CD in the backbone of the polyamidine polymers decreases the IC\u2085\u2080s by three orders of magnitude, resulting in a polymer with very low in vitro and in vivo toxicity. The cationic \u03b2CDPs are able to self-assemble with and condense DNA into small particles (100-150 nm in diameter). When formulated at a positive charge, the complexes are readily internalized by nearly all exposed cultured cells.
\r\n\r\nThe transgene expression from the delivered complexes was increased by fine-tuning the \u03b2CDP structure for optimum reporter gene activity and by modifying the polymer to enhance endosomal release. The function of the \u03b2CDPs was found to be highly dependent on the polymer structure; changes in position of the amidine charge centers by a few angstroms resulted in transfection and toxicity differences of one order of magnitude. The highest transfection is achieved with the \u03b2CDP6 polymer, that contains a 2 methylene spacer between the cyclodextrin and amidine group and a 6 methylene spacer between adjacent amidine functionalities. The conjugation of a pH-sensitive moiety, histidine, to \u03b2CDP6 endgroups also increases transgene expression by 20-fold without a change in polymer toxicity. Flow cytometry and confocal microscopy experiments with fluorescently-Iabeled DNA suggest that histidylation of \u03b2CDP6 enhances transfection by buffering the endosomal pH, thereby delaying lysosomal degradation and allowing for more endosome release.
\r\n\r\nThe \u03b2CDP-based particles (\u03b2CD-polyplexes) were modified for in vivo stability by using the ability of cyclodextrins to form inclusion complexes with hydrophobic guest molecules. Various compounds were conjugated to adamantane, a molecule that has a high cyclodextrin association constant. The adamantane conjugates, when added to preformed \u03b2CD-polyplexes, are able to self-assemble with the \u03b2CD-polyplexes without disrupting the polymer/DNA binding interactions. Using this method, \u03b2CD-polyplexes were modified with adamantane-polyethylene glycol (PEG) conjugates. The PEGylated particles were salt stabilized in a PEG length-dependent manner. In a second example, modification of \u03b2CD-polyplexes with anionic peptide-adamantane conjugates prevented non-specific cellular uptake in cultured cells. The assembly of the three components, DNA, \u03b2CDP, and adamantane-based modifer, results in a particle with the potential for achieving systemic, in vivo gene delivery. Finally, a small molecule, fluorescein, was conjugated to adamantane and co-delivered with \u03b2CD-polyplexes to cultured cells, thus demonstrating the possibility for therapeutic pouches of small molecule and gene-drugs.
", "doi": "10.7907/jvc2-6q78", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:6109", "collection": "thesis", "collection_id": "6109", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:10062010-111511765", "primary_object_url": { "basename": "Pantu_p_2001.pdf", "content": "final", "filesize": 32331729, "license": "other", "mime_type": "application/pdf", "url": "/6109/1/Pantu_p_2001.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Methane Conversion to Synthesis Gas over Platinum Supported on Rare Earth Oxides", "author": [ { "family_name": "Pantu", "given_name": "Piboon", "clpid": "Pantu-Piboon" } ], "thesis_advisor": [ { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" } ], "thesis_committee": [ { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "orcid": "0000-0002-1942-9232", "clpid": "Labinger-J-A" }, { "family_name": "Seinfeld", "given_name": "John H.", "orcid": "0000-0003-1344-4068", "clpid": "Seinfeld-J-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The central theme of this research is to study methane conversion to synthesis gas focusing on the redox capabilities of cerium oxide. Reaction of methane with platinum or ruthenium supported on Ce_(1-x)Zr_xO_2 (x=0, 0.2, 0.5) in the absence of gaseous oxygen was studied in a packed-bed reactor at 550-700\u00b0C. The oxidation of methane utilized lattice oxygen of the support, which was subsequently restored by reacting with oxygen in a separate step. Thus, by using theredox property of cerium oxide, methane oxidation can be carried out by air without diluting the product with nitrogen. Addition of ZrO_2 into CeO_2 increased the reducibility of the oxide as well as the rate of methane oxidation but decreased the selectivity to CO and H_2. The rate of oxidation was initially very fast but slowed down as the oxide support became progressively reduced. On the other hand, the selectivity increased with the reduction of the support and sharply rose to over 90% as the support attained 10%,40%, and 65% degree of reduction for the oxide compositions x=0, 0.2, and 0.5, respectively.
\r\n\r\nPartial oxidation of methane to synthesis gas over 0.5wt% Pt/Al_2O_3 and 0.5wt% PtfCeO_2 catalysts was studied in a packed-bed reactor. At temperatures up to 650\u00b0C, the PtfCeO_2 catalyst gave higher conversion and higher selectivity but the activity and selectivity became comparable to those of Pt/Al_2O_3 above 700\u00b0C. The Pt/CeO_2 catalyst also maintained high conversion and high selectivity when the CH_4:O_2 feed ratio varied from 1.7 to 2.3 while the Pt/Al_2O_3 catalyst had considerably lower selectivity under methane-rich conditions. The effect of reducibility of support on the catalytic activity was discussed. A multiple microreactor system for parallel testing of heterogeneous catalysts was developed. The reactor system was composed of nine tubular microreactors housed in a single wider tube and used a multiposition valve to conduct the reaction products sequentially from each microreactor to a mass spectrometer for analysis. The catalyst samples were prepared in the form of thin films coated on quartz rods for convenience of preparation and loading samples in the reactors. The system was tested with the reaction of methane reforming with carbon dioxide over Pt/Ce_(1-x)Gd_xO_(2-0.5x) and Pt/Ce_(1-x)Sm_xO_(2-0.5x) at 650\u00b0C and 700\u00b0C. The measurements showed that Pt/CeO_2 had the highest activity and, generally, the activity increased with cerium oxide content. After exposure to the feed stream for 2-3 hours at 700\u00b0C, most catalysts suffered significant deactivation with the exception of the mixed oxides with 25-85% samarium oxide that maintained relatively stable activity.
", "doi": "10.7907/rksa-xc11", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:5387", "collection": "thesis", "collection_id": "5387", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:11192009-085252318", "primary_object_url": { "basename": "Kua_j_2001.pdf", "content": "final", "filesize": 7674564, "license": "other", "mime_type": "application/pdf", "url": "/5387/1/Kua_j_2001.pdf", "version": "v5.0.0" }, "type": "thesis", "title": "Computational Studies of Heterogeneous and Homogeneous Catalysis by Late Transition Metals", "author": [ { "family_name": "Kua", "given_name": "Jeremy Soo Pin", "orcid": "https://orcid.org/0000-0002-2472-1887", "clpid": "Kua-Jeremy-Soo-Pin" } ], "thesis_advisor": [ { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" }, { "family_name": "Myers", "given_name": "Andrew G.", "clpid": "Myers-A-G" } ], "thesis_committee": [ { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Dougherty", "given_name": "Dennis A.", "orcid": "0000-0003-1464-2461", "clpid": "Dougherty-D-A" }, { "family_name": "Goddard", "given_name": "William A., III", "orcid": "0000-0003-0097-5716", "clpid": "Goddard-W-A-III" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "To design new catalysts that meet the environmental, materials and energy concerns of modern society, it is vital to understand the fundamental mechanisms involved in catalytic reactions. This thesis focuses on using quantum mechanical methods to determine the mechanisms for several critical catalytic processes in chemical industry.
\r\n\r\nLate transition metals are widely used as heterogeneous catalysts involving organic substrates. To lay a foundation for developing an orbital view useful for reasoning about surface reactions, we have developed the interstitial electron model (IEM) for bonding in platinum described in Chapter 1. To test the validity of the model cluster chosen to represent the surface, we studied the chemistry of C\u2081 and C\u2082 hydrocarbons, for which the most single-crystal experimental data is available, as described in Chapter 2.
\r\n\r\nIn Chapter 3, we extend this model to the second and third row Group VIII transition metals (Ir, Os, Pd, Rh, Ru) and develop a thermochemical group additivity framework for hydrocarbons on metal surfaces similar to the Benson scheme so useful for gas phase hydrocarbons. This provides a potentially powerful technique for deriving a mechanistic understanding on complex hydrocarbon reactions on catalytic surfaces, applicable to hydrocarbon reforming processes.
\r\n\r\nAn advantage of direct methanol fuel cells (DMFCs) over the internal combustion engines is to avoid the environmental damage caused by the latter. Chapter 4 describes our studies on electrocatalysis of methanol oxidation in direct methanol fuel cells. In particular, we focus on the role of different metals at the anode as alloys and as promoters for various aspects of the reaction converting methanol and water to CO\u2082 and energy.
\r\n\r\nOne of the most important challenges is to find ways to utilize the enormous resources in methane around the world as the fundamental feedstock for the chemical and energy industries. Perhaps the most promising progress in developing low-temperature highly selective homogeneous catalysts have been the Hg and PtCl\u2082 catalysts from Catalytica. Chapter 5 reports our studies on the stability, thermodynamics, and reaction mechanism of the PtCl\u2082 catalysts, with suggestions of possible modifications necessary to make this process economic.
", "doi": "10.7907/M9WN-7M53", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:4492", "collection": "thesis", "collection_id": "4492", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11102005-135122", "primary_object_url": { "basename": "Luo_l_2001.pdf", "content": "final", "filesize": 12298676, "license": "other", "mime_type": "application/pdf", "url": "/4492/1/Luo_l_2001.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Partial Oxidation of Propane Over Vanadium-Containing Zeolite Catalysts", "author": [ { "family_name": "Luo", "given_name": "Lin", "clpid": "Luo-Lin" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Labinger", "given_name": "Jay A.", "orcid": "0000-0002-1942-9232", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Over the past few decades, significant efforts have been devoted to the development of new catalysts and processes for the partial oxidation of cheap and abundant light alkanes directly into oxygenates and olefins. One of the main challenges in the partial oxidation of light alkanes is that they are usually less reactive than the desired products, and further oxidation to total oxidation products, COx, is thermodynamically favored. With a few exceptions, e.g., partial oxidation of n-butane to malefic anhydride by V-P-O and a oxidation of propane to acrylonitrile by V-Al-Sb, catalysts investigated for the partial oxidation of light alkanes consist of complicated elemental compositions of metal oxides that have less than desirable catalytic behavior.
\r\n\r\nCompared to the traditional bulk metal oxides where the active sites selective for partial oxidation of hydrocarbons are usually lattice oxygens, small metal oxide clusters that do not have lattice energies are anticipated to offer oxygen with a lower energetic barrier. Thus, by using metal oxide clusters, the reaction temperature for oxidation of hydrocarbons may possibly be lowered and total oxidation reduced. Zeolites have been shown to be able to provide an excellent matrix for stabilizing metal oxide clusters. Here, a new approach is investigated for the partial oxidation of propane that combines the tunable advantages of zeolites with possibility of high reactivity of metal oxide clusters by using zeolite supported metal oxide clusters as catalysts.
\r\n\r\nVarious methods are employed to synthesize zeolite supported small metal oxide clusters, including ion-exchange-hydrolysis, liquid phase impregnation, vapor phase impregnation, and post-synthesis modification methods. Vanadium is used as the transition metal of interest and is combined with zeolite L, beta and SSZ-33. Vanadium oxide clusters are successfully incorporated inside zeolites and they have remarkably lower reduction temperatures than the bulk metal oxide. These zeolite based catalysts are studied for propane oxidation. The influence of the locations of the vanadium, the acidity of the zeolite matrix, the hydrophobicity of the zeolite framework and the addition of a second metal(Mo and Sb) are discussed. It is found that vanadium oxide cluster catalysts (VxOy/zeolite L, VxOy/zeolite beta, V-Sb/zeolite beta, V-Mo/zeolite beta) are not particularly selective for the partial oxidation of propane at the reaction conditions investigated (contact time 2 s, reaction temperature 350-450\u00b0C, feed gas molar ratio C3H8:O2:H2O:He=4:2:4:5), and most of the vanadium-containing zeolite beta catalysts are as active as V2O5 (as suggested by the turnover frequency).
\r\n\r\nA considerable amount of acetic acid is produced with vanadyl ion-exchanged zeolite beta (VO-H-beta), with a selectivity to acetic acid of 21.1% at propane conversion 1.62% (350\u00b0C). It appears that more valuable oxygenates, e.g., acrylic acid, may have been produced in the reaction and overoxidized to COx, since feeding acrylic acid into this VO-H-beta reaction system at 350\u00b0C results in complete oxidation of the acid to CO\u2093. Motivated by these data, the reaction pathways for propane and propylene oxidation are investigated on this catalyst. For comparison, reaction pathways are also studied with a \"Mitsubishi\" type catalyst, Mo1V0.3Te0.23Nb0.120x, one of the best catalysts for propane partial oxidation to acrylic acid. With VO-H-beta, propylene is the primary product of propane oxidation and acetic acid is a sequential oxidation product of the formed propylene possibly through an acetone intermediate. Mo1V0.3Te0.23Nb0.120x also gives propylene as the primary product of propane oxidation and the propylene thus formed further oxidizes to acrylic acid and acetone. Reactions of individual oxygenate compounds, e.g., propanal, acrolein, etc., suggest a need to further suppress the total oxidation and to improve allylic oxidation feature for the zeolite based catalysts.
", "doi": "10.7907/ce5g-3606", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:244", "collection": "thesis", "collection_id": "244", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-01202002-221541", "primary_object_url": { "basename": "Winblade_nd_2001.pdf", "content": "final", "filesize": 9533440, "license": "other", "mime_type": "application/pdf", "url": "/244/1/Winblade_nd_2001.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Blocking Adhesion to Cell and Tissue Surfaces via Steric Stabilization with Graft Copolymers Containing Poly(Ethylene Glycol) and Phenylboronic Acid", "author": [ { "family_name": "Winblade", "given_name": "Natalie Dawn", "orcid": "0000-0003-1293-345X", "clpid": "Winblade-Natalie-Dawn" } ], "thesis_advisor": [ { "family_name": "Hubbell", "given_name": "Jeffrey A.", "orcid": "0000-0003-0276-5456", "clpid": "Hubbell-J-A" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" } ], "thesis_committee": [ { "family_name": "Hubbell", "given_name": "Jeffrey A.", "orcid": "0000-0003-0276-5456", "clpid": "Hubbell-J-A" }, { "family_name": "Hoffman", "given_name": "Allan S.", "clpid": "Hoffman-A-S" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Bjorkman", "given_name": "Pamela J.", "orcid": "0000-0002-2277-3990", "clpid": "Bjorkman-P-J" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Graft copolymers were designed to coat biological surfaces and thereby block subsequent adhesion and recognition events with other proteins, cells, and tissues. Inspired by polymeric steric stabilization of colloidal dispersions, the copolymers contain a backbone with affinity for biological surfaces and grafted side-chains that are resistant to adhesion of biological elements. Phenylboronic acid (PBA) moieties in the polymer backbone provided for binding, by forming reversible covalent complexes with cis-diols in oligosaccharides that are ubiquitous on cell surfaces and secreted macromolecules. The PBA moieties were conjugated to a poly-L-lysine (PLL) backbone via a secondary amine linker. Grafted poly(ethylene glycol) (PEG) side-chains provided for resistance of adhesion of proteins and cells. It was hypothesized that these PLL-g-(PEG;PBA) copolymers would spontaneously assemble on biological (e.g., cell or tissue) surfaces, where the PBA-containing backbone would bind to the surfaces and thereby anchor a dense PEG brush on the surface.
\r\n\r\nPLL-g-(PEG;PBA) copolymers were synthesized with varying degrees of PEG and PBA grafting. The pKa of the PBA groups was found to be circa 6, allowing for stronger binding at physiological pH than most PBA groups, which have pKas circa 8.8. The PLL-g-(PEG;PBA) copolymers were found to bind specifically to a mannan resin, where the PEG grafting ratio sterically controlled the binding. The copolymers coated red blood cells and blocked their agglutination by lectins and by blood group antibodies. The copolymers were also found to coat tissue culture polystyrene, adsorbed serum proteins, and extracellular matrix and to prevent the adhesion, spreading, and/or migration of rabbit lens epithelial cells on those surfaces. The copolymers displayed evidence of toxicity in vitro but no toxicity was seen when administered in vivo in models of posterior capsule opacification or peritoneal adhesion formation. PLL-g-(PEG;PBA) was found to interfere with the worsening of peritoneal adhesions following adhesiolysis. The efficacy of the copolymers was a function of the degree of PEG and PBA grafting, and PLL-g-(PEG;PBA) copolymers were found to be more effective than electrostatically-binding PLL-g-PEG copolymers. PLL-g-(PEG;PBA) copolymers have many possible clinical applications where blocking protein or cell interactions with cell, tissue, or biomaterial surfaces via a simple aqueous lavage is desired.
", "doi": "10.7907/B47A-E319", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:4490", "collection": "thesis", "collection_id": "4490", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11102005-103556", "primary_object_url": { "basename": "Lai_r_2001.pdf", "content": "final", "filesize": 4700896, "license": "other", "mime_type": "application/pdf", "url": "/4490/1/Lai_r_2001.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Synthesis and Characterization of ZSM-5 Zeolite Membranes", "author": [ { "family_name": "Lai", "given_name": "Re", "clpid": "Lai-Re" } ], "thesis_advisor": [ { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" } ], "thesis_committee": [ { "family_name": "Anson", "given_name": "Fred C.", "clpid": "Anson-F-C" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Synthesis of ZSM-5 zeolite membranes supported on porous alumina substrates was conducted in autoclave reactors. The film morphologies and structures were characterized by scanning electron microscopy, energy dispersive spectroscopy and X-ray diffraction. Gas adsorption was used to estimate the crystalline fraction of the products. The gas permeation properties of the membranes were evaluated for H\u2082, CH\u2084, O\u2082, N\u2082, and n-butane and other gases singly or in mixtures.
\r\n\r\nZSM-5 film formation on alumina and other surfaces in certain clear, tetrapropylammonium(TPA\u207a)-containing synthesis solutions was found to be preceded by a gel layer. The presence of alumina and other substrates of a high Hamaker constant facilitated formation of the surface gel layer and accelerated zeolite crystallization. Aluminum added to the solution or leached from alumina substrates had dual effects, to induce surface gelation and to retard crystallization of that layer as well as crystallization in the bulk solution.
\r\n\r\nGrowth of ZSM-5 membranes was facilitated by using alumina tubes pre-coated with silicalite seeds. Accompanied with gradual growth of an external polycrystalline layer, siliceous deposits accumulated as deep as 100 \u00b5m inside the pores of the support, converting gradually from amorphous to crystalline. Pure gas permeation results are presented for membranes prepared in a solution of composition SiO\u2082: 0.15TPAB4: 0.7NaOH: 98H\u2082O using 0.4 and 2 \u00b5m seeds.
\r\n\r\nOrganic-free hydrogel reaction mixtures were further used to grow ZSM-5 membranes on seeded porous alumina substrates, eliminating the crack-prone calcination step for removing organic TPA\u207a templates from as-synthesized ZSM-5. The optimum composition SiO\u2082: 0.0125Al\u2082O\u2083: 0.2675Na\u2082O: 46H\u2082O was identified to produce membranes with permeation selectivities for H\u2082 over n-butane above 10\u2074 and for O\u2082 over N\u2082 9-10. The permeation was strongly activated with the activation energies increasing sharply with molecular size.
\r\n\r\nParallel synthesis of zeolite films was developed to expedite composition screening. The films prepared in an array reactor of multiple wells each containing 35 micro-liter synthesis solution displayed morphology similar to that produced by the conventional synthesis. The method was applied to explore the composition space of clear, organic-free synthesis solutions for ZSM-5 films growth: SiO\u2082: (700-300)Al\u2082O\u2083: (0.5-0.7)NaOH: 80H\u2082O.
", "doi": "10.7907/m5xs-mq20", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:3115", "collection": "thesis", "collection_id": "3115", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08132007-143014", "primary_object_url": { "basename": "Pratt_a_2001.pdf", "content": "final", "filesize": 9666316, "license": "other", "mime_type": "application/pdf", "url": "/3115/1/Pratt_a_2001.pdf", "version": "v4.0.0" }, "type": "thesis", "title": "Cell-Responsive Synthetic Biomaterials Formed in situ", "author": [ { "family_name": "Pratt", "given_name": "Alison Beth", "clpid": "Pratt-Alison-Beth" } ], "thesis_advisor": [ { "family_name": "Hubbell", "given_name": "Jeffrey A.", "orcid": "0000-0003-0276-5456", "clpid": "Hubbell-J-A" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" } ], "thesis_committee": [ { "family_name": "Kornfield", "given_name": "Julia A.", "orcid": "0000-0001-6746-8634", "clpid": "Kornfield-J-A" }, { "family_name": "Tirrell", "given_name": "David A.", "orcid": "0000-0003-3175-4596", "clpid": "Tirrell-D-A" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Hubbell", "given_name": "Jeffrey A.", "orcid": "0000-0003-0276-5456", "clpid": "Hubbell-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Two-way communication between cells and their extracellular matrices plays an important role in establishing and maintaining cell and tissue morphology. Synthetic materials for tissue engineering have so far not been able to mimic these interactions. This work describes a new class of synthetic biomaterials that display the essential characteristics of naturally occurring matrices. The materials can be formed in contact with cells and tissues to create covalently cross-linked hydrogels which are effectively nonporous on the length scale of a cell process. The otherwise nonadhesive gels can be rendered specifically cell-adhesive by incorporation of ligands for cell surface adhesion molecules, such as integrins. The materials are degradable by plasmin, a proteolytic enzyme used by cells during proliferation and migration in natural matrices. Furthermore, the materials can be designed to sequester heparin-binding growth factors.
\r\n\r\nThe materials consist primarily of poly(ethylene glycol) which is cross-linked in situ by selective conjugate addition reactions of its termini, activated with conjugate acceptors such as vinylsulfones, with peptides containing three or more cysteine residues in the form of reduced thiols. The cross-linking peptides are designed such that they are hydrolyzed by plasmin. A simple cell migration assay was developed to evaluate the material design parameters. Human fibroblasts were observed to migrate out of microliter fibrin clots into the synthetic materials in a manner dependent on the type of material and the culture conditions. Inhibiting fibrinolysis with a plasmin-insensitive substrate or with a plasmin inhibitor, [epsilon]-amino-n-caproic acid, inhibited migration. Adding growth factors, FGF-2 or PDGF-BB, that upregulate plasminogen activation increased the rate of cell migration. Decreasing the amount of RGD within the materials decreased the rate and extent of cell migration in a concentration-dependent manner. Replacing the RGD peptide with an RDG peptide decreased the amount of outgrowth.
\r\n\r\nIn a critical size calvarial defect in the rat, the synthetic materials were formed in the presence of an osteoinductive protein, rhBMP-2, and supported de novo bone formation. Materials containing a heparin-based growth factor delivery system promoted significantly more bone than materials without the delivery system. After three weeks, 94% of the defect area was covered with new bone, and the opacity of the new bone was 84% of that of neighboring, uninjured bone.
", "doi": "10.7907/HFEF-7F61", "publication_date": "2001", "thesis_type": "phd", "thesis_year": "2001" }, { "id": "thesis:3098", "collection": "thesis", "collection_id": "3098", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-08112006-152417", "primary_object_url": { "basename": "Sakiyama-Elbert_se_2000.pdf", "content": "final", "filesize": 10397827, "license": "other", "mime_type": "application/pdf", "url": "/3098/1/Sakiyama-Elbert_se_2000.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Biofunctional polymers for the controlled release of growth factors in the peripheral nervous system", "author": [ { "family_name": "Sakiyama-Elbert", "given_name": "Shelly Elese", "clpid": "Sakiyama-Elbert-S-E" } ], "thesis_advisor": [ { "family_name": "Hubbell", "given_name": "Jeffrey A.", "clpid": "Hubbell-J-A" } ], "thesis_committee": [ { "family_name": "Hubbell", "given_name": "Jeffrey A.", "clpid": "Hubbell-J-A" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Kornfield", "given_name": "Julia A.", "clpid": "Kornfield-J-A" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Fraser", "given_name": "Scott E.", "clpid": "Fraser-S-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Fibrin is the natural biomaterial of nerve regeneration. Fibrin possesses the ability to promote cell adhesion and can be degraded locally by cell-regulated proteases. However, fibrin lacks sufficient neuroinductive character to promote nerve regeneration across large gaps. A previously developed method for the incorporation of peptides via the transglutaminase activity of factor XIIIa was used to immobilize cell adhesion sites and growth factors within fibrin matrices that could serve as potential therapeutics for peripheral nerve regeneration.\n\nHeparin-binding domains from several proteins have been shown to promote neurite extension on surfaces. Four different heparin-binding domains were immobilized within fibrin matrices using factor XIIIa and all four domains were found to enhance three-dimensional neurite extension through fibrin. The ability of these domains to enhance neurite extension was found to correlate positively with their relative heparin-binding affinity.\n\nProlonged release of exogenous growth factors over the duration of nerve regeneration could potentially enhance regeneration. Two delivery systems were developed to provide controlled release of exogenous growth factors, where the rate of release could be regulated by cellular activity rather than by diffusion. The first system developed was designed to mimic the ability of the extracellular matrix to sequester heparin-binding growth factors based on interactions with heparin sulfate proteoglycans. It was hypothesized that by immobilizing a high excess of heparin sites within fibrin, diffusion of growth factors from the matrix could be slowed, and this would allow release to be dominated by cell-regulated matrix degradation. The ability of such systems to immobilize growth factors and release them in an active form was assayed using neurite extension from dorsal root ganglia (DRGs).\n\nA second method of delivery was developed consisting of recombinantly expressed nerve growth factor (NGF) fusion proteins containing an exogenous crosslinking substrate. A plasmin-degradable linker was placed between the crosslinking substrate and the NGF domain. These fusion proteins could be immobilized in fibrin using factor XIIIa and released in a native form by plasmin cleavage. Immobilized NGF fusion proteins were found to enhance neurite extension from DRGs within fibrin matrices versus similar concentrations of native NGF in the medium.\n", "doi": "10.7907/0k5s-vf32", "publication_date": "2000", "thesis_type": "phd", "thesis_year": "2000" }, { "id": "thesis:17072", "collection": "thesis", "collection_id": "17072", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03192025-175557925", "primary_object_url": { "basename": "Wagner_PA_1999.pdf", "content": "final", "filesize": 70820925, "license": "other", "mime_type": "application/pdf", "url": "/17072/1/Wagner_PA_1999.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Structural Investigation of Zeolites", "author": [ { "family_name": "Wagner", "given_name": "Paul A.", "clpid": "Wagner-Paul-A" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Rees", "given_name": "Douglas C.", "orcid": "0000-0003-4073-1185", "clpid": "Rees-D-C" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Grubbs", "given_name": "Robert H.", "orcid": "0000-0002-0057-7817", "clpid": "Grubbs-R-H" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Microporous materials (including zeolites) that contain molecular-sized pores and\r\ncavities have found wide-spread use in industry as molecular sieves for chemical separations,\r\nas ion-exchangers for detergents and as heterogeneous, shape-selective catalysts. The number\r\nof unique molecular sieve structures discovered over the past few decades has burgeoned and\r\ncurrently is over 121.
\r\n\r\nKnowledge of the crystal structure of these microporous solids can provide important\r\ninsights into their properties that can ultimately lead to the design of desirable materials.\r\nHowever, the structure solution of microporous materials can be challenging because they tend\r\nto form as micron or submicron sized crystals that are too small for single crystal X-ray\r\nanalysis. Thus, the objective of this work is to develop and apply new techniques for solving\r\nthe structures of microporous materials that tend to form micro- and nanocrystals and to utilize\r\nthese structural investigations to gain a more thorough understanding of the zeolite/ organic\r\nstructure directing agent (SDA) interactions that lead to the observed zeolite phase selectivity in\r\ntheir synthesis.
\r\n\r\nIn the absence of single crystal data, structure solution and refinement have typically\r\nrequired the use of powder X-ray data. The difficulty in solving crystal structures from\r\npowder X-ray data is that the three dimensions of information available in a single crystal data\r\nset are collapsed into one dimension (d-spacing) in a powder X-ray data set. If the reflections\r\nin the powder X-ray data are significantly overlapping then solving the crystal structure from\r\nthis data can be extremely difficult. Several techniques are applied here for solving\r\nmicroporous crystal structures from powder X-ray data.
\r\n\r\nThe structure solution of CIT-5 (California Institute of Technology Number 5), a new\r\nhigh-silica molecular sieve synthesized under hydrothermal conditions in the presence of\r\nN(16) methylsparteinium and lithium cations, is obtained though an iterative process of model\r\nbuilding and comparison of the simulated powder X-ray data with the experimental powder X-ray\r\ndata. Rietveld refinement of the synchrotron powder X-ray data supports the symmetry and\r\nspace group assignment for the structure as Pmn21(No.31) with refined unit cell parameters of\r\na=l3.6738(8) \u00c5, b=S.0216(3) \u00c5 and c=25.4883(7) \u00c5 (V=1750.1 \u00c53) and confirms that CIT-5\r\nis the first ordered zeolite to contain one-dimensional extra-large pores circumscribed by\r\n14 tetrahedral-atoms (14 MR).
\r\n\r\nComputational techniques for solving the structures of microcrystals from powder Xray\r\ndata are continuing to increase in sophistication and capability. The crystal structures of\r\ntwo high-silica molecular sieves, SSZ-44 and SSZ-35, are solved using Fourier recycling and\r\nrepresents the first application of this new computational technique for solving novel high-silica\r\nzeolite structures from powder X-ray data. Both materials contain unusual 1-dimensional\r\npores circumscribed by 10 and 18 membered-rings, and are the first high-silica zeolites found\r\nthat possess pores containing greater than 14 membered-rings.
\r\n\r\nElectron diffraction data, obtained from a transmission electron microscope (TEM),\r\nhas inherent advantages over X-ray data for analyzing small crystals due to the stronger\r\ninteraction between the electron beam and matter compared to X-rays. This stronger\r\ninteraction allows a single crystal diffraction data set to be obtained from much smaller\r\ncrystals. Provided that the interaction of the incident electron beam with the crystal is\r\nnearly kinematical direct methods can be used as a powerful tool for obtaining the phase\r\ninformation required to solve the crystal structure.
\r\n\r\nThe development of electron diffraction methods for solving the structure of\r\nnanocrystals is described and the application of this technique to solve the structure of a\r\nlarge-pore, high-silica zeolite, SSZ-48, that contains an occluded organic structure directing\r\nagent is presented. The structure is confirmed by electron diffraction refinement and by\r\nhigh resolution transmission electron microscopy and is found to contain a one-dimensional\r\npore system circumscribed by 12 tetrahedral atoms (12 MR). SSZ-48 is the most complex\r\nthree-dimensional material to be solved at atomic resolution using electron diffraction\r\nmethods and illustrates the power of electron diffraction data for resolving the structures of\r\nmaterials that form crystals too small for standard single crystal X-ray analysis.
\r\n\r\nThese investigations into the structural details of micro- and nanocrystalline\r\nmicroporous materials can be utilized to gain a more thorough understanding of the zeolite/\r\norganic structure directing agent (SDA) interactions that lead to the observed zeolite\r\nsynthesis phase selectivity. Two studies are conducted to probe the relationship between\r\nthe organic structure directing agent and the zeolite framework that is formed from its use.
\r\n\r\nThe first study probes the interaction between the CIT-5 framework and the N(l)-\r\nmethyl-\u03b1-isosparteine SDA I that is found to be a more effective structure directing agent\r\nfor CIT-5 than the diastereomer N(l6)-methylsparteinium II originally used to direct this\r\nnew high-silica zeolite. Molecular modeling calculations reveal that I is capable of forming\r\na greater number of van der Waals interactions with the framework than II thereby\r\nproviding a greater degree of stabilization for the CIT-5 structure as compared to II.
\r\n\r\nFinally, a study into the guest/host interactions between three new zeolite\r\nstructures, SSZ-35, SSZ-36 and SSZ-39 and the 37 organic structure directing agents that\r\nare capable of directing for these zeolites is presented. The size and shape of the organic\r\nSDAs presented in this study are designed in order to obtain novel, open framework\r\nzeolites. The design effort focused on synthesizing large rigid spheroidal SDAs that will\r\npreclude the crystallization of the commonly observed clathrates and straight I-dimensional\r\nchannel system zeolites that result when either small or rigid elongated molecules are\r\nemployed as SDAs. Computational calculations of the organic/inorganic energy of\r\ninteractions provided significant insights into the observed zeolite phase selectivity by the\r\norganic SDAs. The molecular modeling investigations presented here highlight the\r\npotential for developing a rational route to the design of desirable zeolite frameworks.
", "doi": "10.7907/t8qz-qa09", "publication_date": "1999", "thesis_type": "phd", "thesis_year": "1999" }, { "id": "thesis:4576", "collection": "thesis", "collection_id": "4576", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11152005-152437", "primary_object_url": { "basename": "Jones_c_1999.pdf", "content": "final", "filesize": 8608188, "license": "other", "mime_type": "application/pdf", "url": "/4576/1/Jones_c_1999.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Organic-functionalized molecular sieves (OFMS'S): A new class of materials", "author": [ { "family_name": "Jones", "given_name": "Christopher W.", "clpid": "Jones-C-W" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Tirrell", "given_name": "David A.", "clpid": "Tirrell-D-A" }, { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Throughout the last two decades, there has been a tremendous interest and growth in molecular sieve science. In particular, substantial attention has been paid to the development of new molecular sieves for catalytic applications, as molecular sieves have the unique ability to promote reactions in a shape-selective manner. To increase the variety of reactions that can be catalyzed by molecular sieves, recent efforts have focused on generating new types of active sites in molecular sieves by incorporating transition metals into the silicate framework or by supporting metal-based species within the micropores. Despite this, there are still many chemistries that can not be carried out over molecular sieve catalysts where significant benefit could be gained if the reaction were to be accomplished in a shape-selective manner. To address this problem, I have prepared a new class of molecular sieves that contain intracrystalline organic functionalities [denoted organic-functionalized molecular sieves (OFMS's)]. Previous attempts to synthesize silicate-based molecular sieves with organic functionalities within the micropores have focused on grafting organic groups onto preformed zeolites. However, this is not a viable route to the production of OFMS's that can function as shape-selective catalysts, as the organic groups preferentially functionalize the external crystal surface. Here, the problems with this approach are circumvented by preparing OFMS's by direct synthesis.\n\nAttempts to synthesize OFMS's directly both in the presence and absence of organic structure-directing agents (SDA's) are described. Pure-silica beta zeolites containing a variety of intracrystalline organic groups are synthesized using tetraethyl ammonium fluoride (TEAF) as the SDA. Porosity is generated by removing the occluded TEAF by solvent-extraction techniques. Following extraction, the exposed organic functionalities are further altered by chemical techniques, e.g., amines to imines, phenethyl groups to phenethylsulfonic acid groups. The ability to perform shape-selective acid catalysis (phenethylsulfonic acid) and shape-selective formation of imines from amines indicates that the organic moieties reside largely in the micropores of the molecular sieve. Several preparation variables have an impact on the nature of the resulting OFMS's, the most of important of which are the synthetic method, silicon source, and extraction method. The effects of these synthetic factors on the crystal size and morphology, porosity and hydrophobicity of the products are discussed.", "doi": "10.7907/6xz1-hh23", "publication_date": "1999", "thesis_type": "phd", "thesis_year": "1999" }, { "id": "thesis:117", "collection": "thesis", "collection_id": "117", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-01102008-150302", "primary_object_url": { "basename": "Khodabandeh_s_1997.pdf", "content": "final", "filesize": 6345664, "license": "other", "mime_type": "application/pdf", "url": "/117/1/Khodabandeh_s_1997.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Synthesis of Alkaline-earth Zeolites", "author": [ { "family_name": "Khodabandeh", "given_name": "Shervin", "clpid": "Khodabandeh-Shervin" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Giapis", "given_name": "Konstantinos P.", "clpid": "Giapis-K-P" }, { "family_name": "Rossman", "given_name": "George Robert", "clpid": "Rossman-G-R" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "Zeolite molecular sieves have found extensive applications in ion-exchange, separation and catalytic processes, particularly in the chemical and petroleum industries. Currently, the state-of-the-art in synthesis of high-silica zeolites involves the use of complex organic molecules to direct the formation of zeolitic materials with novel pore structures. While efforts towards preparation of new zeolites using organic molecules as structure-directing agents continues, synthesis of calcium and other alkaline-earth zeolites has not received much attention since the inception of the systematic investigation of zeolite synthesis some 35 years ago. Of the approximate 50 natural zeolites discovered to date, over 20% have eluded synthesis and another 10% have proven exceedingly difficult to synthesize at typical hydrothermal conditions. The overwhelming majority of these zeolites are calcium-dominant. The difficulty encountered in the synthesis of these alkaline-earth zeolites is in direct contrast to their natural occurrence as alteration products of volcanic glasses. Thus, the objective of this work is developing practical methodolgies for the synthesis of alkaline-earth zeolites.
\r\n\r\nHydrothermal transformation of perlite (a natural rhyolitic glass) to calcium zeolites is investigated as a first step towards developing synthesis procedures for the preparation of calcium and other alkaline-earth zeolites from pure starting reagents. In particular, synthetic analogues of the calcium zeolites gismondine, heulandite and epistilbite are obtained as alteration products of perlite glass reacting with calcium-containing solutions. The influence of the solution phase species and their concentrations, the pH and the temperature on the distribution of the zeolite products obtained are discussed. It is observed that the crystallization of heulandite from perlite is preceded by the transient formation of a gismondine-type zeolite most similar to the synthetic zeolite P1. This information is exploited to devise methodology for the preparation of zeolite P1 from pure starting reagents and its subsequent conversion to calcium and other alkaline-earth zeolites upon treatment with solutions containing alkaline-earth cations. Thus, a novel approach for the synthesis of alkaline-earth zeolites based on the hydrothermal conversion of zeolite P1 is developed. Details of the synthesis procedures are enumerated for the preparation of alkaline-earth zeolites CIT-3 (HEU), CIT-4 (BRE), epistilbite (EPI), harmotome (PHI), and yugawaralite (YUG). Transformation of zeolite P1 to alkaline-earth zeolites is governed by factors such as the Si/Al ratio of the starting P1 material, the composition of the solution phase and the presence or absence of seed crystals. The effects of these factors on the products obtained, i.e., phase selectivity, are discussed.
", "doi": "10.7907/35dq-qn66", "publication_date": "1997", "thesis_type": "phd", "thesis_year": "1997" }, { "id": "thesis:4493", "collection": "thesis", "collection_id": "4493", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-11102005-141042", "primary_object_url": { "basename": "Yan_y_1997.pdf", "content": "final", "filesize": 17311051, "license": "other", "mime_type": "application/pdf", "url": "/4493/1/Yan_y_1997.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Preparation of zeolite ZSM-5 membranes", "author": [ { "family_name": "Yan", "given_name": "Yushan", "clpid": "Yan-Yushan" } ], "thesis_advisor": [ { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Giapis", "given_name": "Konstantinos P.", "clpid": "Giapis-K-P" }, { "family_name": "Wang", "given_name": "Zhen-Gang", "clpid": "Wang-Zhen-Gang" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.\r\n\r\nZeolite ZSM-5 membranes were prepared on porous [...] disks by in-situ crystallization using a clear solution of optimized composition [...]. During the synthesis, the disk was fixed horizontally at the air-liquid interface and a continuous polycrystalline zeolite film of about 10 \u00b5m thickness formed on the bottom surface of disk. Extensive experimentation was carried out to find the optimal composition. Pure gas permeation measurements of the most successful preparation yielded hydrogen:isobutane and n-butane:isobutane ratios of 151 and 18 at room temperature and 54 and 31 at 185\u00b0C, respectively.\r\n\r\nElectron probe microanalysis of the cross section of a membrane prepared on a bare alumina disk revealed a layer of crystalline or amorphous silica extending 80 \u00b5m inside the pores of the support. It is believed that this internal layer adds resistance to permeation and degrades selectivity. To limit the excessive penetration of siliceous species into the support pores, a diffusion barrier was introduced into the pores of the support prior to zeolite crystallization by impregnating the disk with a 1:1 molar mixture of furfuryl alcohol and tetraethylorthosilicate, polymerizing the mixture retained in the disk, and carbonizing the resulting polymer. Following carbonization, a partial carbon burnoff was carried out to generate a carbon-free region near the surface of the support. Membranes synthesized using barriers have n-butane flux and n-butane:isobutane selectivity 2.7 x [...] and 45 at 185\u00b0C which are, respectively, about 1.6 and 4 times as large as those of membranes prepared without the use of barriers.\r\n\r\nThe n-butane:isobutane selectivity of ZSM-5 membranes was substantially improved (e.g. 322 vs. 45 at 185\u00b0C) by a post-synthetic coking treatment which was accomplished by impregnating the membranes with liquid 1,3,5-triisopropylbenzene (TIPB) for 24 hours at room temperature and then calcining them in air at 500\u00b0C for 2 hours. Calcination at 500\u00b0C for up to 30 hours does not destroy the high n-butane:isobutane selectivity. Thermogravimetric analysis experiments suggest that microdefects in the zeolite membranes were selectively eliminated by the TIPB coking treatment while the intracrystalline pore space of the ZSM-5 was not affected.\r\n\r\nA model of surface-induced nucleation, crystal growth, and crystal adhesion was proposed for the aforementioned heterogeneous hydrothermal synthesis system. During the synthesis, aluminosilicates in the aged solution interact favorably with and travel toward the [...] surface, resulting in concentration and nucleation in the vicinity of the surface. Some of the nuclei become attached to the surface and grow into a zeolite film while others settle and produce loose zeolite crystals at the bottom of the autoclave. The nutrients for crystal growth is supplied by active gel particles and the synthesis solution. Surface -OH groups on the substrate appear important for crystal adhesion via condensation. As for zeolite membrane formation on a surface of certain area, the location and orientation of the surface as well as the amount of synthesis liquid accessible to the surface are critical for the quality of the zeolite membrane.\r\n", "doi": "10.7907/05FZ-JS07", "publication_date": "1997", "thesis_type": "phd", "thesis_year": "1997" }, { "id": "thesis:95", "collection": "thesis", "collection_id": "95", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-01092008-135803", "primary_object_url": { "basename": "Fernandes_ne_1997.pdf", "content": "final", "filesize": 4649283, "license": "other", "mime_type": "application/pdf", "url": "/95/1/Fernandes_ne_1997.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Diffusion in mesoporous glass : simulations and experiments", "author": [ { "family_name": "Fernandes", "given_name": "Neil Edward", "clpid": "Fernandes-N-E" } ], "thesis_advisor": [ { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" } ], "thesis_committee": [ { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Giapis", "given_name": "Konstantinos P.", "clpid": "Giapis-K-P" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.\r\n\r\nThe diffusivities of simple gases in mesoporous glass were studied by experiment and simulation.\r\n\r\nPorous Vycor[...] glass was modified by deposition of silica on the internal pore surface using consecutive cycles of liquid phase silylation with silicon tetrachloride, and hydrolysis. Macroscopically uniform deposition was achieved by exploiting the self limiting nature of the reaction and the extent of deposition was monitored by the weight change of the samples. Weight increases as high as 24% were recorded and the average pore diameter was estimated to decrease from [...]. Permeation measurements were conducted in the Henry's law region at various levels of deposition for hydrogen, methane, isobutane and nitrogen, at temperatures between 60[degrees]C and 180[degrees]C. The measurements were compared to values calculated with a model using the effective medium approximation to treat network effects and Clausing's correction to account for conductances in pores of finite aspect ratio. The calculated values proved to be inaccurate for hydrogen, overestimating the permeance by a factor of two at high levels of deposition possibly because of non-ideal pore shapes accentuated by the deposition. For nitrogen and methane the agreement between calculations and measurements was better due to a fortuitous cancellation of deviations caused by the enhanced potential energy well within the pores and the non ideal pore shape. The intrapore potential energy effect was especially strong for isobutane and as a result the calculated flux was always less than the experimental.\r\n\r\nIn an effort to understand the importance of the intrapore potential and pore surface roughness on diffusion, molecular dynamics simulations of nitrogen and isobutane in a mesoporous glass pore, under free molecular flow conditions, were conducted for pores of diameter [...], and for temperatures between 200K and 800K. To study the effect of the intrapore potential, the gases were treated as simple Lennard-Jones atoms and the pore was simulated as a perfect cylinder exerting a 9-3 potential, but with its surface roughened by the superposition of spherical Lennard-Jones atoms representing silica tetrahedra. The molecular trajectories were calculated by the application of Nose-Hooverian mechanics and no momentum transfer was allowed between the pore walls and the gas molecules. Random walk behavior resulted from the resulting specular collisions. The effect of the intrapore potential was decoupled into two contributions. The effective diffusivity was respectively increased and decreased by a partitioning effect (or Henry's law adsorption) and a path curvature effect (the trapping of molecules near the surface). In pores of radius [...], both effects were present for temperatures as high as 500K, and were enhanced as the temperature decreased. For nitrogen, the combination of effects canceled over the temperature range of 500-200K and resulted in a temperature dependence similar to that of Knudsen diffusion. For isobutane, the partitioning effect overwhelmed the path curvature effect, resulting in significant surface flows at temperatures as high as 500K. At a temperature of 393K, as the pore radius was reduced from [...], the path curvature effect decreased and the partitioning effect increased. Although the intrapore potential becomes more negative as the pore size decreases, the magnitude of the potential energy barrier trapping molecules near the surface also decreases. The effect of surface roughness was studied through a hard sphere dynamics version of the above simulation. Diffusivities were obtained for various surface coverage of the silica tetrahedra. The specular reflection condition resulted in diffusivities at least twice that of the Knudsen value.", "doi": "10.7907/HPPB-TJ55", "publication_date": "1997", "thesis_type": "phd", "thesis_year": "1997" }, { "id": "thesis:17525", "collection": "thesis", "collection_id": "17525", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07142025-223721756", "primary_object_url": { "basename": "Kesselman_JM_1997.pdf", "content": "final", "filesize": 48945859, "license": "other", "mime_type": "application/pdf", "url": "/17525/1/Kesselman_JM_1997.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Fundamental Photoelectrochemical Properties of TIO\u2082/Water Interfaces : Relevance for Hazardous Waste Remediation", "author": [ { "family_name": "Kesselman", "given_name": "Janet M.", "clpid": "Kesselman-Janet-M" } ], "thesis_advisor": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "orcid": "0000-0001-5245-0538", "clpid": "Lewis-N-S" }, { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" } ], "thesis_committee": [ { "family_name": "Anson", "given_name": "Fred C.", "clpid": "Anson-F-C" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "orcid": "0000-0001-5245-0538", "clpid": "Lewis-N-S" }, { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "TiO\u2082 photocatalysis is a promising technology for the treatment of aqueous or\r\ngaseous systems contaminated by low levels of organic pollutants. The research\r\ndescribed in this thesis explores fundamental mechanistic and kinetic questions for both\r\nTiO\u2082 photocatalytic and electrocatalytic degradation of aqueous organic contaminants. A\r\nrecurring theme in this thesis is the use of TiO\u2082 electrodes to investigate kinetic and\r\nmechanistic aspects of the TiO\u2082 photocatalytic process. The use of electrodes provides\r\nadditional experimental control of system parameters that is not possible in conventional\r\nTiO\u2082 slurry reactors.
\r\n\r\nThe first study reports the kinetics of oxygen reduction at single-crystal, rutile\r\nTiO\u2082 electrodes as a function of applied potential. Platinum deposits are found to\r\ncatalyze the reduction of oxygen at this surface. Application of a flux-matching condition\r\nto the independently measured reduction and photooxidation currents predicts significant\r\nrecombination losses for TiO\u2082 particles operating under steady-state photocatalytic\r\nconditions.
\r\n\r\nIn a second project, the contributions of direct and hydroxyl radical mediated\r\noxidation pathways are determined at Nb-doped, polycrystalline TiO\u2082 electrodes. In addition to quantifying the branching ratio of these two mechanisms for a variety of\r\norganic substrates, the results suggest that surface interactions are important in\r\ndetermining the predominant reaction pathway in these systems.
\r\n\r\nFinally, the adsorption of 4-chlorocatechol at the TiO\u2082/H\u2082O interface is\r\ninvestigated as a function of pH and solution concentration. Quantitative measurements\r\nof the extent of adsorption are reported as well as spectroscopic evidence for the structure\r\nof the adsorbed complex. Further work correlates observed photocatalytic degradation\r\nrates with the extent of adsorption under various solution conditions.
", "doi": "10.7907/5dmz-sa21", "publication_date": "1997", "thesis_type": "phd", "thesis_year": "1997" }, { "id": "thesis:17525", "collection": "thesis", "collection_id": "17525", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:07142025-223721756", "primary_object_url": { "basename": "Kesselman_JM_1997.pdf", "content": "final", "filesize": 48945859, "license": "other", "mime_type": "application/pdf", "url": "/17525/1/Kesselman_JM_1997.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Fundamental Photoelectrochemical Properties of TIO\u2082/Water Interfaces : Relevance for Hazardous Waste Remediation", "author": [ { "family_name": "Kesselman", "given_name": "Janet M.", "clpid": "Kesselman-Janet-M" } ], "thesis_advisor": [ { "family_name": "Lewis", "given_name": "Nathan Saul", "orcid": "0000-0001-5245-0538", "clpid": "Lewis-N-S" }, { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" } ], "thesis_committee": [ { "family_name": "Anson", "given_name": "Fred C.", "clpid": "Anson-F-C" }, { "family_name": "Lewis", "given_name": "Nathan Saul", "orcid": "0000-0001-5245-0538", "clpid": "Lewis-N-S" }, { "family_name": "Hoffmann", "given_name": "Michael R.", "orcid": "0000-0001-6495-1946", "clpid": "Hoffmann-M-R" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Okumura", "given_name": "Mitchio", "orcid": "0000-0001-6874-1137", "clpid": "Okumura-M" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "TiO\u2082 photocatalysis is a promising technology for the treatment of aqueous or\r\ngaseous systems contaminated by low levels of organic pollutants. The research\r\ndescribed in this thesis explores fundamental mechanistic and kinetic questions for both\r\nTiO\u2082 photocatalytic and electrocatalytic degradation of aqueous organic contaminants. A\r\nrecurring theme in this thesis is the use of TiO\u2082 electrodes to investigate kinetic and\r\nmechanistic aspects of the TiO\u2082 photocatalytic process. The use of electrodes provides\r\nadditional experimental control of system parameters that is not possible in conventional\r\nTiO\u2082 slurry reactors.
\r\n\r\nThe first study reports the kinetics of oxygen reduction at single-crystal, rutile\r\nTiO\u2082 electrodes as a function of applied potential. Platinum deposits are found to\r\ncatalyze the reduction of oxygen at this surface. Application of a flux-matching condition\r\nto the independently measured reduction and photooxidation currents predicts significant\r\nrecombination losses for TiO\u2082 particles operating under steady-state photocatalytic\r\nconditions.
\r\n\r\nIn a second project, the contributions of direct and hydroxyl radical mediated\r\noxidation pathways are determined at Nb-doped, polycrystalline TiO\u2082 electrodes. In addition to quantifying the branching ratio of these two mechanisms for a variety of\r\norganic substrates, the results suggest that surface interactions are important in\r\ndetermining the predominant reaction pathway in these systems.
\r\n\r\nFinally, the adsorption of 4-chlorocatechol at the TiO\u2082/H\u2082O interface is\r\ninvestigated as a function of pH and solution concentration. Quantitative measurements\r\nof the extent of adsorption are reported as well as spectroscopic evidence for the structure\r\nof the adsorbed complex. Further work correlates observed photocatalytic degradation\r\nrates with the extent of adsorption under various solution conditions.
", "doi": "10.7907/5dmz-sa21", "publication_date": "1997", "thesis_type": "phd", "thesis_year": "1997" }, { "id": "thesis:17086", "collection": "thesis", "collection_id": "17086", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:03212025-215725447", "type": "thesis", "title": "I. The Use of Spherosiloxanes as Molecular Building Blocks for Material and Thin Films. II. A Method of Using SC-Cut Quartz Oscillators for Chemical Sensing", "author": [ { "family_name": "Nagel", "given_name": "John Frederick", "clpid": "Nagel-John-Frederick" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "orcid": "0000-0001-5690-770X", "clpid": "Flagan-R-C" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" }, { "family_name": "Giapis", "given_name": "Konstantinos P.", "orcid": "0000-0002-7393-298X", "clpid": "Giapis-K-P" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The ability to prepare a priori ordered materials of a desired structure is a long\r\nstanding goal in materials research. Recently, there has been great interest in the use of\r\nwell-defined molecular precursors that can, in principle, be combined in a regular way\r\nwithout degradation to produce ordered materials. This process has been dubbed \"lego-chemistry.\"\r\nThis work examines the use of spherosiloxanes, a family of polyhedral silicate\r\ncage molecules, as molecular building blocks for the synthesis of bulk microporous\r\nmaterials and microporous thin films.
\r\n\r\nThe process for synthesizing and functionalizing the spherosiloxanes with a variety\r\nof reactive functional ligands is presented. The reactive molecules are characterized\r\nusing a suite of analytical and spectroscopic techniques. In order to achieve some degree\r\nof control over the condensation process, a binary reaction mechanism utilizing nonhydrolytic\r\nreaction conditions is proposed for the production of bulk materials. Experimental\r\nresults from the non-hydrolytic condensation of spherosiloxanes are presented.\r\nThe effects of adding various catalysts to the reaction mixture are described. A multinuclear\r\nsolution NMR study was performed on monomeric silicate analogues of the\r\nspherosiloxanes in order to elucidate the non-hydrolytic reaction pathways. It is found\r\nthat under the conditions of interest ligand exchange predominates over condensation.
\r\n\r\nA reaction scheme and growth mechanism for the production of a microporous\r\nthin film from spherosiloxane precursors is presented and discussed. It is speculated that\r\nsuch an ordered film could function as a framework for the production of a molecular electronic\r\ndevice. The first important steps in this scheme, namely the condensation behavior\r\nof spherosiloxanes on the Si (100) - (2x1) reconstructed surface, are explored through a\r\nvariety of surface characterization techniques. In particular, low temperature STM is used\r\nto record the nature of the species condensed on the surface. An image of a single isolated\r\n(CH3O)8Si8O12 is recorded and its position and orientation are discussed in the context of the reaction scheme. A HREELS/TPD study of the spherosiloxanes on the same surface is\r\nperformed and the results discussed.
\r\n\r\nA new technique for chemical sensing is proposed and is based on the recently\r\ndeveloped SC-cut quartz oscillator used in conjunction with the analytical technique\r\nknown as thermal programmed desorption (TPD). This technique is developed in order to\r\naddress the need to develop new sensing techniques that are sensitive, selective and cost\r\nefficient, for application to the rising threats of terrorism and pollution present today. The\r\ntechnique utilizes two vibrational modes of the crystal, one very sensitive and one relatively\r\ninsensitive to changes in temperature, that are monitored throughout the experiment.\r\nThe two mode sensing allows in principle for the simultaneous monitoring of the mass and\r\ntemperature of the sensor.
\r\n\r\nA system for evaluating the performance of this sensor is designed and built, and\r\nincludes an automated data acquisition and control system. The sensor is tested using a\r\nvariety of chemically selective coatings and analytes. The structure and morphology of\r\nthe coating used is shown to have a significant effect on the oscillation behavior of the\r\ncrystal used. TPD experiments are performed with the sensor in order to evaluate its characteristics.\r\nIn nearly all cases, it is impossible to discern any desorption signal during the\r\nTPD experiment. A dual mode analysis that is used to deconvolute the temperature and\r\nmass responses of the sensor fails to distinguish any desorption signals except from a very\r\nheavily loaded sample, i.e., water on a polyethyleneimine coated crystal where bulk\r\nabsorption occurs. A TPD experiment is performed on a hydrated, PEI coated crystal\r\nusing a Cahn microbalance, and a relationship between the mass loading and frequency\r\nchange is determined for this system. These values are used to calculate the frequency\r\nresponse for a typical coating where only surface adsorption occurs, and the result is\r\nbelow the minimum detection level of the system. Based on these data, it is determined\r\nthat the SC-cut sensor fails to show the sensitivity necessary for application as a practical\r\nsensor device.
", "doi": "10.7907/wkz6-jt81", "publication_date": "1997", "thesis_type": "phd", "thesis_year": "1997" }, { "id": "thesis:4972", "collection": "thesis", "collection_id": "4972", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-12122007-111327", "primary_object_url": { "basename": "Dartt_cb_1996.pdf", "content": "final", "filesize": 6583349, "license": "other", "mime_type": "application/pdf", "url": "/4972/1/Dartt_cb_1996.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Synthesis and characterization of titanium-containing molecular sieves", "author": [ { "family_name": "Dartt", "given_name": "Christopher Bruce", "clpid": "Dartt-Christopher-Bruce" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Gavalas", "given_name": "George R.", "clpid": "Gavalas-G-R" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" }, { "family_name": "Zones", "given_name": "Stacey I.", "clpid": "Zones-S-I" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The use of zeolites and molecular sieves as catalysts for important organic reactions is reviewed. One emerging area of particular interest is the use of titanium-containing molecular sieves as partial oxidation catalysts and is chosen for further study.\r\n\r\nIn order to elucidate the relationships between the physicochemical properties of titanium-containing molecular sieves and their ability to act as partial oxidation catalysts, titanium-containing pure-silica ZSM-5 (TS-1) materials are synthesized using different methods. The activities of the titanium-containing catalysts for the oxidation of alkanes, alkenes, and phenol at temperatures below 100 [degrees]C using aqueous hydrogen peroxide H2O2 as the oxidant are reported. The relationships between the physicochemical and catalytic properties of these titanium silicates are discussed. The effects of added aluminum and sodium on the catalytic activity of TS-1 are described. The addition of sodium during the synthesis of TS-1 is detrimental to the catalytic activity while sodium incorporation into pre-formed TS-1 is not. The framework substitution of aluminum for silicon appears to decrease the amount of framework titanium.\r\n\r\nThe relationships between catalytic performance and physicochemical properties that are controlled through synthetic methods are further investigated using a series of titanium-containing molecular sieves. Titanium-containing pure-silica ZSM-5 (TS- 1), pure-silica ZSM-48 (Ti-ZSM-48) and zeolite beta (Ti-Al-beta) are synthesized and characterized by X-ray powder diffraction (XRD), elemental analysis, physical adsorption of N2, Fourier transform infrared (FT-IR), FT-Raman, and diffuse reflectance ultraviolet (DR-UV) spectroscopies. TS-1 is synthesized by five different methods. All materials are evaluated for their ability to oxidize 1-hexene and n-octane using aqueous H2O2 as the oxidant. The relationships between the physicochemical and catalytic properties of these titanium-containing zeolites are discussed. TS-1 samples synthesized at high pH are catalytically active and framework titanium is shown to be necessary for olefin epoxidation and alkane hydroxylation to occur. The existence of anatase in active TS-1 samples results in decreased hydrogen peroxide efficiencies in the epoxidation reaction. TS-1 produced at pH=7.4 and Ti-ZSM-48 each contain anatase and are not active. Ti-beta is found to contain framework titanium and be free of anatase. However, at the conditions used in this study these samples are not able to activate 1-hexene or n-octane.\r\n\r\nIn attempts to prepare large pore titanium-containing molecular sieves, postsynthetic incorporation of titanium in the borosilicate SSZ-33 and the direct synthesis of an aluminum-free titanium-containing zeolite Beta (Ti-Beta) are reported. These materials are characterized by XRD, FT-IR, FT-Raman, and DR-UV spectroscopies. The molecular sieves are shown to catalyze the epoxidation of various olefins using aqueous hydrogen peroxide as the oxidant. The physicochemical properties as found by the characterization methods are correlated to the catalytic data and the results compared to a high quality sample of TS-1. The modified SSZ-33 samples contain titanium primarily in the form of isolated tetrahedrally coordinated Ti atoms, although some extra-framework Ti is observed by Raman and DR-UV spectroscopies. Ti-Beta samples show no evidence of extra-framework titanium. For the epoxidation of cis-cyclooctene, the Ti-Beta catalysts give quantitative conversion to epoxide, and both the Ti-Beta and Ti-SSZ-33 catalysts are able to epoxidize substrates too large to be oxidized by TS-1.\r\n", "doi": "10.7907/0pnv-rt94", "publication_date": "1996", "thesis_type": "phd", "thesis_year": "1996" }, { "id": "thesis:2631", "collection": "thesis", "collection_id": "2631", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-06172005-085103", "primary_object_url": { "basename": "Lobo_rf_1995.pdf", "content": "final", "filesize": 7848477, "license": "other", "mime_type": "application/pdf", "url": "/2631/1/Lobo_rf_1995.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "The Synthesis and Characterization of Novel High-Silica Zeolites", "author": [ { "family_name": "Lobo", "given_name": "Raul Francisco", "clpid": "Lobo-Raul-Francisco" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" }, { "family_name": "Myers", "given_name": "Andrew G.", "clpid": "Myers-A-G" }, { "family_name": "Gavalas", "given_name": "George R.", "orcid": "0000-0003-1468-6835", "clpid": "Gavalas-G-R" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "The synthesis and characterization of high-silica molecular sieves is reviewed using molecular recognition phenomena and structure-direction as the unifying themes. A comparative analysis between the synthesis conditions employed and the zeolite structures formed is carried out starting with the synthesis of clathradils or 0-dimensional zeolites, and extending to one-dimensional, multi-dimensional zeosils. The review finishes with the analysis of the combined effects of heteroatoms (Al, B and Zn) and organic structure-directing agents in zeolite product selectivity and thermodynamic stability.\r\n\r\nStructure-direction phenomena is further investigated using the synthesis and characterization of the pure-silica zeolite SSZ-24, prepared using the chiral molecule N(16)methylsparteinium hydroxide as the structure-directing agent. The material is characterized using X-ray powder diffraction (XRD), scanning electron microscopy (SEM), solid-state NMR spectroscopy, fourier transform IR spectroscopy (FTIR) and physical adsorption experiments. The B-substituted SSZ-24 prepared here is the first example where the isomorphous substitution of B for Si in the SSZ-24 framework is accomplished during synthesis using sodium borate as the source of B. The B can be easily substituted by Al. The Al-substituted SSZ-24 is an active catalyst for the cracking of alkanes and may be potentially useful in refinery and chemical processes.\r\n\r\nThe structure solutions and a detailed structural characterizations of the disordered zeolites SSZ-26 and SSZ-33 is presented. These two materials are the first synthetic zeolites with intersecting open 10- and 12-ring pore systems. SSZ-26 and SSZ-33 are expected to show a combination of reaction activity, selectivity and stability unique among known zeolites. SSZ-26 and SSZ-33 may be very useful for catalytic applications in the petrochemical and refining industries. The feasibility of synthesizing a zeolite whose pore structure has been designed a priori is demonstrated with the zeolite SSZ-26 and its structure-directing agent.\r\n\r\nThe synthesis of a new borosilicate, CIT-1, is described. The proposed structure of CIT-1 is confirmed by a Rietveld refinement of the synchrotron XRD pattern. CIT-1 is demonstrated to be an ordered polymorph of the SSZ-33 zeolites. The catalytic properties of CIT-1 are compared to the catalytic properties of known high-silica zeolites (ZSM-5 and zeolite beta) and CIT-1 is shown to be a very active catalyst for the cracking of n-butane. The synthesis of CIT-1 supports the idea that the chiral polymorph A of zeolite beta can be synthesized using the appropriate structure-directing agent.\r\n\r\nA combination of molecular modeling and 1H MAS NMR spectroscopy are used to characterize the interactions of structure-directing agents with the zeolite framework. The results indicate that to simulate correctly the energetic interaction and motional properties of structure-directing agents in zeolites, short-range and long-range forces, water molecules, silanol groups and defects need to be considered simultaneously.\r\n", "doi": "10.7907/01DX-QC48", "publication_date": "1995", "thesis_type": "phd", "thesis_year": "1995" }, { "id": "thesis:4052", "collection": "thesis", "collection_id": "4052", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-10122007-091509", "primary_object_url": { "basename": "Johnson_rd_1995.pdf", "content": "final", "filesize": 10056797, "license": "other", "mime_type": "application/pdf", "url": "/4052/1/Johnson_rd_1995.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Multivalent Protein Binding to Metal-Complexing Materials: Applications to Synthetic Receptors and Affinity Chromatography", "author": [ { "family_name": "Johnson", "given_name": "Robert David", "clpid": "Johnson-Robert-David" } ], "thesis_advisor": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" } ], "thesis_committee": [ { "family_name": "Arnold", "given_name": "Frances Hamilton", "orcid": "0000-0002-4027-364X", "clpid": "Arnold-F-H" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Barton", "given_name": "Jacqueline K.", "orcid": "0000-0001-9883-1600", "clpid": "Barton-J-K" }, { "family_name": "Brady", "given_name": "John F.", "orcid": "0000-0001-5817-9128", "clpid": "Brady-J-F" }, { "family_name": "Davis", "given_name": "Mark E.", "orcid": "0000-0001-8294-1477", "clpid": "Davis-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.\r\n\r\n\r\nThis investigation demonstrates that proteins have the capability to bind \r\nsimultaneously to multiple transition metals of metal-complexing materials. This finding \r\nhas important implications for the design of novel materials for protein recognition. Our \r\napproach to protein recognition, based on intermolecular metal-to-ligand interactions, \r\nmatches a protein's unique pattern of histidines with a complementary arrangement of \r\ntransition metal complexes.\r\n\r\n A model system is used to demonstrate the validity of this approach in the \r\nsimplest case by matching the distance between metal ions of rationally designed bis-metal [...] \"receptors\" to that between imidazoles of bis-imidazole \"targets.\" This \r\nsystem additionally demonstrates how other features of receptor design can influence \r\nbinding selectivity. A 2D NMR procedure is developed to measure directly protein \r\nsurface histidine binding to copper complexes, and subsequently demonstrates that the \r\nlocal environment of the histidine and the structure of the copper complex can modulate \r\nindividual copper-histidine interactions. Thus it may indeed be possible to design metal-containing receptors which are able to form simultaneous metal-ligand bonds with a \r\nspecific arrangement of protein metal-coordinating groups.\r\n\r\n There are two important obstacles preventing a similarly detailed description of \r\nprotein binding to metal-complexing surfaces: protein adsorption may involve binding to \r\none or more metal sites, and a detailed description of the geometry of surface metal sites \r\nwould be hopelessly complex. We can, however, apply the microscopic concept of \r\nsimultaneous metal-ligand interactions to interpret the macroscopic phenomena of \r\nprotein partitioning in immobilized metal affinity chromatography (IMAC). In this \r\ncontext, the ability of commercially available IMAC materials to support multiple \r\nprotein-surface interactions is shown to be dependent on three factors: the number of\r\nhistidines on the protein (as manipulated by site directed mutagenesis), the number of \r\ndeprotonated amino groups on the protein (pH control), and the density of binding sites \r\non the surface (copper loading). These results demonstrate that a realistic description of \r\nprotein binding in IMAC must consider a heterogeneous population of surface binding \r\nsites. In IMAC this is shown to be conveniently expressed by the Temkin isotherm, \r\nmaking it an instructive model to explore heterogeneity displayed by other \r\nchromatographic materials and by biological systems.", "doi": "10.7907/6kdk-t643", "publication_date": "1995", "thesis_type": "phd", "thesis_year": "1995" }, { "id": "thesis:4054", "collection": "thesis", "collection_id": "4054", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-10122007-103304", "primary_object_url": { "basename": "Khouw_cb_1995.pdf", "content": "final", "filesize": 4929571, "license": "other", "mime_type": "application/pdf", "url": "/4054/1/Khouw_cb_1995.pdf", "version": "v3.0.0" }, "type": "thesis", "title": "Partial oxidation of hydrocarbons using titanium containing molecular sieves", "author": [ { "family_name": "Khouw", "given_name": "Charles B.", "clpid": "Khouw-C-B" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" }, { "family_name": "Bercaw", "given_name": "John E.", "clpid": "Bercaw-J-E" }, { "family_name": "Flagan", "given_name": "Richard C.", "clpid": "Flagan-R-C" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.\r\n\r\nThe objective of this work is to investigate the reaction mechanism of alkane activation on titanium containing, aluminum-free ZSM-5 (TS-1) and to elucidate the relationships between the physicochemical properties of the catalyst and its reactivity. Samples of TS-1 have been synthesized using different methods. The activities of these catalysts for the oxidation of alkanes, alkenes and phenol at temperatures below 100 [...] using aqueous [...] as oxidant are reported and compared to those from other titanium containing materials, e.g., anatase and an amorphous [...] coprecipitate.\r\n\r\nComparisons between the activities of TS-1 and [...] coprecipitate for alkane oxidation and alkene epoxidation using non-aqueous [...] indicate that the absence of water is crucial for the catalytic activity of silica-supported titanium oxide. Due to the hydrophobicity of TS-1, the concentration of water surrounding the titanium is maintained at low value so that aqueous [...] can be used as oxidant on this catalyst.\r\n\r\nIssues of mechanism of the alkane oxidation on TS-1 are investigated by analyzing the stereoselectivity pattern of cis- and trans-1,3-dimethylcyclopentane, the \"radical clock\" rearrangement of ethyl- and isopropylcyclopropane and the effect of oxidants on the catalytic activity of TS-1. The stereoselective reaction pattern of cis- and trans-1,3-dimethylcyclopentane indicates that radicals are formed during alkane oxyfunctionalization with TS-1. The presence of stereos crambling without any \"radical clock\"\r\nrearrangement during alkane oxidation on TS-1 reveals that the radicals formed may have a very short life-time or their movements are restricted such that no rearrangement can occur. A proposal for the mechanism of alkane oxidation on TS-1 is given and compared to a mechanism suggested for alkene epoxidation on TS-1 and the [...] coprecipitate. Alkyl hydroperoxides are active as oxidants for alkene epoxidation on the [...] coprecipitate but not for alkane oxidation reactions on both TS-1 and the [...] coprecipitate. A plausible explanation for the above results is provided.\r\n\r\nThe presence of alkali metal ions in the synthesis mixture of TS-1 completely eliminates the catalytic activity of this material. However, the catalytic activity can be restored by washing the solid with acid solution prior to catalytic testing. The washing removes [...] ions from silanol groups adjacent to the framework titanium active centers. Thus, it is postulated that a silanol group in the neighborhood of the titanium atom is a necessary feature for catalytic activity. The acid treatment may be useful in overcoming the problems of synthesizing TS-1 from reagents that contain alkali metal ions, e.g., TPAOH solutions. More importantly, this treatment opens the possibility of synthesizing other titanium containing silicate structures that require the presence of alkali metal ions in the synthesis mixture for their formation.\r\n\r\n", "doi": "10.7907/9dyq-m742", "publication_date": "1995", "thesis_type": "phd", "thesis_year": "1995" }, { "id": "thesis:4283", "collection": "thesis", "collection_id": "4283", "cite_using_url": "https://resolver.caltech.edu/CaltechETD:etd-10282005-134201", "primary_object_url": { "basename": "Chen_r_1994.pdf", "content": "final", "filesize": 5380247, "license": "other", "mime_type": "application/pdf", "url": "/4283/1/Chen_r_1994.pdf", "version": "v2.0.0" }, "type": "thesis", "title": "Metabolic and energetic studies of recombinant Escherichia coli strains : applications of NMR techniques", "author": [ { "family_name": "Chen", "given_name": "Ruizhen", "clpid": "Chen-R" } ], "thesis_advisor": [ { "family_name": "Bailey", "given_name": "James E.", "clpid": "Bailey-J-E" } ], "thesis_committee": [ { "family_name": "Bailey", "given_name": "James E.", "clpid": "Bailey-J-E" }, { "family_name": "Roberts", "given_name": "John D.", "clpid": "Roberts-J-D" }, { "family_name": "Ross", "given_name": "Brian", "clpid": "Ross-Brian" }, { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Lidstrom", "given_name": "Mary E.", "clpid": "Lidstrom-M-E" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.\r\n\r\nThis work concerns applications of NMR techniques in metabolic engineering studies. As demonstrated here, NMR is a valuable tool in analyzing intracellular metabolic and energetic states. When combined with growth and fermentation studies, it greatly enhances the understanding of cellular responses to particular genetic modifications.\r\n\r\nA novel on-line NMR system has been developed in this work which extends the capacities of in vivo NMR to growing cell cultures. This new approach eliminates possible artifacts and time limitations associated with conventional NMR methods. Furthermore, experiments can be conducted under well-defined conditions. New types of physiological states and experimental regimes are accessible with this on-line system.\r\n\r\nSteady-state levels of ATP and [...] have been measured using the on-line NMR system for strains with and without Vitreoscilla hemoglobin (VHb) (GRO21 and MG1655, respectively) during their growth under oxygen-limited conditions. GRO21 has similar levels of ATP and [...] while exhibiting a higher specific growth rate, indicating that the net ATP accumulation rate is enhanced. Studies on ATP synthase (ATPase) kinetics show that the presence of VHb accelerates ATP synthesis rate catalyzed by ATPase by 30%.\r\n\r\nSwitching from the phosphotransferase system (PTS) to the galactose-proton symport system for glucose uptake brings about many changes in cell energetics and metabolism. The extra energy cost in the non-PTS glucose uptake has a greater effect on the specific growth rates in anaerobic conditions than in aerobic conditions. Fermentation patterns are significantly different in the non-PTS strain, compared to the PTS strain. The non-PTS strain has a much lower NTP and [...] and higher NDP; NAD(H) is also considerably reduced. Different levels of glycolytic intermediates have also been observed in these two strains.\r\n\r\nThe non-PTS strain carrying a phenylalanine overproduction plasmid exhibits much lower energy level (NTP and ApH), lower sugar phosphate (S-P) total concentration, NAD(H) and PEP concentrations than its PTS counterpart. The compositions of S-P are significantly different between the two strains. Phenylalanine production is not increased in the non-PTS strain and a larger portion of carbon is oxidized to CO2.", "doi": "10.7907/PEEN-4S74", "publication_date": "1994", "thesis_type": "phd", "thesis_year": "1994" }, { "id": "thesis:7712", "collection": "thesis", "collection_id": "7712", "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05152013-113928711", "type": "thesis", "title": "The Design and Synthesis of a True, Heterogeneous, Asymmetric Catalyst", "author": [ { "family_name": "Wan", "given_name": "Kam To", "clpid": "Wan-Kam-To" } ], "thesis_advisor": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" } ], "thesis_committee": [ { "family_name": "Davis", "given_name": "Mark E.", "clpid": "Davis-M-E" }, { "family_name": "Gray", "given_name": "Harry B.", "clpid": "Gray-H-B" }, { "family_name": "Anson", "given_name": "Fred C.", "clpid": "Anson-F-C" }, { "family_name": "McKoy", "given_name": "Basil Vincent", "clpid": "McKoy-B-V" }, { "family_name": "Labinger", "given_name": "Jay A.", "clpid": "Labinger-J-A" } ], "local_group": [ { "literal": "div_chem" } ], "abstract": "This work describes the design and synthesis of a true, heterogeneous,\r\nasymmetric catalyst. The catalyst consists of a thin film that resides on a high-surface-\r\narea hydrophilic solid and is composed of a chiral, hydrophilic\r\norganometallic complex dissolved in ethylene glycol. Reactions of prochiral\r\norganic reactants take place predominantly at the ethylene glycol-bulk organic\r\ninterface.
\r\n\r\nThe synthesis of this new heterogeneous catalyst is accomplished in a\r\nseries of designed steps. A novel, water-soluble, tetrasulfonated 2,2'-bis\r\n(diphenylphosphino)-1,1'-binaphthyl (BINAP-4S0_3Na) is synthesized by\r\ndirect sulfonation of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP).\r\nThe rhodium (I) complex of BINAP-4SO_3Na is prepared and is shown to be\r\nthe first homogeneous catalyst to perform asymmetric reductions of prochiral\r\n2-acetamidoacrylic acids in neat water with enantioselectivities as high as\r\nthose obtained in non-aqueous solvents. The ruthenium (II) complex,\r\n[Ru(BINAP-4SO_3Na)(benzene)Cl]Cl is also synthesized and exhibits a broader\r\nsubstrate specificity as well as higher enantioselectivities for the homogeneous\r\nasymmetric reduction of prochiral 2-acylamino acid precursors in water.\r\nAquation of the ruthenium-chloro bond in water is found to be detrimental to\r\nthe enantioselectivity with some substrates. Replacement of water by ethylene\r\nglycol results in the same high e.e's as those found in neat methanol. The\r\nruthenium complex is impregnated onto a controlled pore-size glass CPG-240 by the incipient wetness technique. Anhydrous ethylene glycol is used as the\r\nimmobilizing agent in this heterogeneous catalyst, and a non-polar 1:1\r\nmixture of chloroform and cyclohexane is employed as the organic phase.
\r\n\r\nAsymmetric reduction of 2-(6'-methoxy-2'-naphthyl)acrylic acid to the\r\nnon-steroidal anti-inflammatory agent, naproxen, is accomplished with this\r\nheterogeneous catalyst at a third of the rate observed in homogeneous\r\nsolution with an e.e. of 96% at a reaction temperature of 3\u00b0C and 1,400 psig of\r\nhydrogen. No leaching of the ruthenium complex into the bulk organic phase\r\nis found at a detection limit of 32 ppb. Recycling of the catalyst is possible\r\nwithout any loss in enantioselectivity. Long-term stability of this new\r\nheterogeneous catalyst is proven by a self-assembly test. That is, under the\r\nreaction conditions, the individual components of the present catalytic system\r\nself-assemble into the supported-catalyst configuration.
\r\n\r\nThe strategies outlined here for the design and synthesis of this new\r\nheterogeneous catalyst are general, and can hopefully be applied to the\r\ndevelopment of other heterogeneous, asymmetric catalysts.
\r\n", "doi": "10.7907/6m3g-3y70", "publication_date": "1994", "thesis_type": "phd", "thesis_year": "1994" } ]