In this dissertation, we discuss half-BPS solutions of gauged supergravity that are holographic realizations of conformal line defects and interfaces. These solutions are constructed by taking a suitable ansatz for the geometry, consisting of a warped product of an AdS spacetime and a sphere, if necessary, over a line, and solving the supersymmetry variations. Quantities such as one-point functions in the presence of the defect and the entanglement entropy are calculated holographically.

In chapter 1, we review the AdS/CFT correspondence and holography. In chapter 2, we relate two different formulations of AdS6 solutions in type IIB supergravity. In chapter 3, we construct solutions in six-dimensional F(4) gauged supergravity that are dual to line defects. In chapter 4, we construct solutions in four-dimensional N = 2 gauged supergravity that are dual to line defects, obtained by a double-analytic continuation of BPS black hole solutions. In chapter 5, we construct Janus solutions in three-dimensional N = 8 gauged supergravity that are dual to interface CFTs.

With the rise of the Internet of Things (IOT), demand for novel devices and sensors for a variety of applications has exploded, and as a result, there is a need for the development of new processing schemes and materials systems to accommodate the expanding needs of these applications. In particular,

Chapter 2 explores the growth of III-V semiconductors with quality approaching that of epitaxial thin films directly onto amorphous substrates using a new growth mode known as template liquid phase (TLP) crystal growth. The fundamental theory and limitations of TLP growth are explored and the toolboxes necessary for enabling this method to be widely used such as in-situ doping and growth of ternary III-V compounds are demonstrated. Proof of concept demonstrations of multilayer growth for 3D integration, transistors and phototransistors for electronic and optoelectronic integration, and transfer onto plastic for flexible applications are shown.

Chapter 3 extends the concept of using liquid metals to the field of flexible and deformable electronics. As an analogy to solid state electronics, where materials with varying electronic properties (metallic, semiconducting, insulating, etc) are connected together to form functional devices, the concept of “liquid state electronics” is introduced. Liquids, being able to conform to any shape, can enable electronic devices which can sustain extremely large amounts of deformation. By using microchannels to prevent intermixing, liquid-liquid heterojunctions composed of liquid metal (InGaSn) as the interconnect and ionic liquids as sensors are demonstrated.

Chapter 4 focuses on the usage of solution processed carbon nanotubes for enabling high-performing flexible electronic devices. First, a method for n-type doping of carbon nanotubes for CMOS applications is introduce using fixed charge in silicon nitride films. An extension of this doping method to other materials systems, in particular 2D WSe2 is demonstrated as well. The usage of carbon nanotubes in printed electronics for enabling large scale, high throughput, flexible electronics manufacturing is explored, with >97% pixel yield in a 20×20 active matrix backplane array being achieved. A proof of concept demonstration of tactile pressure mapping using the printed nanotube active matrix backplane is shown as a potential application of such devices.

A major component of cancer’s complexity lies in its heterogeneity. Because cancer heterogeneity can manifest across multiple spatiotemporal and biological scales1–4, comprehensive characterization is challenging. Assays that allow controlled experimentation to determine the mechanisms behind cancer heterogeneity remain underdeveloped. Many existing technologies rely on exploitation of predetermined characteristics5–7, which precludes exploration of phenotypes that are ill-defined. Other platforms begin with blind genomics, using post-sequencing experiments for validation8,9. These approaches inherently require significant differences in the genomics underlying heterogeneity to elucidate potential mechanisms, since unsupervised clustering relies on deploying mathematics to obtain clear separations10–12. While successful when involving multiple cell types, since their biological profiles lie in separable state spaces6,8,13,14, unsupervised analysis has limitations when evaluating more similar cells, such as within-cell-type heterogeneity, as it becomes difficult to separate profiles that are highly alike. A study on this specialized scope has not yet been done, probably due to the challenges of parsing a more subtly heterogeneous sample.This dissertation describes the development and application of a platform that enables detailed interrogation of within-cell-type heterogeneous, 3D collective cancer cell migration phenotypes. Collective migration is a process where multiple cells coordinate their movement15,16. Recent studies point to the importance of collective cell migration in cancer metastasis17–20. Although various phenotypes have been identified, factors that regulate collective behavior are not fully understood15,16,21. Using a flexible, microscopy-based platform, I identified and isolated cells that exhibit invasive and non-invasive collective migration. By first defining functional subpopulations, I deployed a supervised approach to determine the mechanisms behind this aspect of heterogeneity. I found that the collectively invasive phenotype is associated with upregulated proliferation, increased stress responses, and the ductal carcinoma subtype, while the collectively non-invasive phenotype was associated with immune-related processes and the luminal carcinoma subtype. Functional perturbation of differentially expressed genes resulted in shifts in migration phenotypes. These results validate the platform I developed for identifying mechanisms of within-cell-type heterogeneity. Furthermore, the results demonstrate a link between migration regulation, stress response, proliferation, and immune response and indicate potential value in exploring how collective invasion may be controlled through these associated modules.

Currently, cancer is the second leading cause of death in the United States, only behind heart disease. Current treatments of cancer include radiation therapy and chemotherapy, and they are often nonspecific, leading to undesired short and long term side effects. In order to improve current treatments and to reduce side effects, researchers have been investigating alternative methods that can increase the specificity of treatments towards tumor cells to reduce the damage to normal cells. This thesis presents two alternative therapeutic formulations that have increased specificity towards tumor cells. These two therapeutic formulations show potential as alternative methods for cancer therapy in the future.

Human glycoprotein transferrin (Tf), which is responsible for transporting iron into cells, has been extensively studied as a tumor-selective targeting ligand since the tumor cells overexpress the transferrin receptor (TfR) in order to support its rapid proliferation rate. However, the short duration of the Tf-TfR trafficking pathway limits the window of opportunity for Tf to function as a drug carrier. In order to increase the cellular association of Tf, our laboratory previously demonstrated that two Tf mutants (K206E/R632A Tf and K206E/R534A Tf) exhibit significant increases in cellular association compared to wild-type Tf. Subsequently, our laboratory showed that these Tf mutants conjugated with diphtheria toxin (DT) have improved drug carrier efficacy relative to the wild-type Tf-DT conjugate in HeLa and glioma cells. However, due to DT’s nonspecific toxicity at off-target sites, DT is not suitable for clinical applications. In Chapter 2 of this thesis, DT was substituted with cross-reacting material 107 (CRM107), a DT mutant with significantly decreased nonspecific toxicity. In vitro cytotoxicity experiments were conducted where the Tf-CRM107 conjugates were incubated with HeLa and glioma cells. These experiments demonstrated that the improvement in efficacy was greater between the mutant Tf-CRM107 conjugates and the wild-type Tf-CRM107 conjugate when compared to similar experiments performed with their DT counterparts. Moreover, in vitro cytotoxicity experiments with non-neoplastic cells demonstrated that cancer selectivity can be achieved with these new mutant and wild-type Tf-CRM107 conjugates due to the IC50 values being significantly higher for the normal cells. These results suggest that CRM107 appears to be a more suitable therapeutic agent in combination with the K206E/R632A and K206E/R534A mutant Tf ligands for future in vivo and clinical studies.

In addition to using molecular conjugates to kill cancer cells, laser-induced photothermal therapy has shown promise as an alternative method for cancer therapy. Photothermal therapy requires the use of a photosensitizer, i.e., a material that has the ability to convert electromagnetic energy into thermal energy, and a molecular targeting ligand for cancer therapy. In Chapter 3 of this thesis, we describe how we combined an engineered prostate cancer-specific targeting ligand, the A11 minibody, with a novel photothermal therapy agent, polypeptide-based gold nanoshells that generate heat in response to near infrared light. Our work demonstrated that the A11 minibody binds strongly to the prostate stem cell antigen (PSCA) that is overexpressed on the surfaces of metastatic prostate cancer cells. Compared to non-conjugated gold nanoshells, the A11 minibody-conjugated gold nanoshell exhibited significant laser-induced, localized killing of prostate cancer cells in vitro. In addition, we improved upon a comprehensive heat transfer mathematical model that was previously developed by our laboratory. By relaxing some of the assumptions of our earlier model, we were able to generate more accurate predictions. In the future, this model can be used to predict the effects of varying parameters in order to design the next generation of gold nanoshells for photothermal therapy. Our experimental and theoretical results demonstrate the potential of our novel minibody-conjugated gold nanoshells for metastatic prostate cancer therapy.

Soluble oligomers of amyloid-β (Aβ) have been implicated as the culprit for neurodegeneration in Alzheimer's disease. Familial mutations of Aβ can lead to early-onset Alzheimer's disease. Structures of fibrils formed by wild-type Aβ and Aβ familial mutants differ. Structural elucidation of Aβ oligomers containing Aβ familial mutations may further our understanding of the disease. High resolution structures of Aβ oligomers can provide useful information for medicinal chemists to design therapeutics to treat Alzheimer's disease. The first chapter of this dissertation describes the X-ray crystallographic structures of two macrocyclic β-sheets containing Aβ familial mutations. The oligomeric structures of these two macrocyclic β-sheets are slightly different than the structure from the macrocyclic β-sheet containing the wild-type Aβ sequence. Preliminary results of cytotoxicity studies showed that some Aβ familial mutants are more toxic toward neuronal cells than the wild-type Aβ. The findings of this chapter are significant, because the newly elucidated chemical models of Aβ oligomers containing Aβ familial mutations can potentially provide insights to early-onset Alzheimer's disease.

Supramolecular assemblies of Aβ are interesting to investigate, because they are central in Alzheimer's disease. They also act as a good starting point to study molecular recognition of peptides and fabrication of nanostructures. The second chapter of this dissertation describes the X-ray crystallographic structure of an Aβ-inspired macrocyclic β-sheet that forms a giant double-walled nanotube. Monomers of the macrocyclic β-sheet adopt two different conformations. The size of the nanotube rivals the size and complexity of the largest tubular biomolecular assemblies, such as microtubules. The findings of this chapter are significant, because a peptide nanotube of this size cannot currently be predicted from the Aβ16–22 sequence.

Structural chemists are interested in understanding the rules that govern molecular recognition and self-assembly of peptides. Currently, it is difficult to predict self-assembly of peptides, and the resulting oligomeric structures. The third chapter of this dissertation describes a different X-ray crystallographic structure formed from an analogue of the macrocyclic β-sheet that yielded the peptide nanotube. The new macrocyclic β-sheet has the same peptide sequence with a different β-turn stabilizer. Changing the β-turn stabilizer eliminates some existing molecular interactions. As a result, the new structure is very different than the peptide nanotube. The structural difference is yet another example that self-assembly of peptides cannot be reliably predicted. The findings of this chapter are significant, because they demonstrate that simple peptide modifications can induce an alternative supramolecular assembly from the same Aβ peptide sequence.

Teixobactin is a promising recently discovered antibiotic. The undecapeptide contains a 13-membered macrolactone ring and a non-proteinogenic amino acid allo-enduracididine. Teixobactin can kill drug-resistant Gram-positive bacteria without acquiring antibiotic resistance. Teixobactin binds to bacterial cell wall precursors such as lipid II and inhibits bacterial cell wall biosynthesis, which leads to cell lysis. The fourth and last part of this dissertation describes an alanine scan of Lys10-teixobactin. This traditional structure-activity-relationship study revealed that the cationic allo-enduracididine is not necessary for activity. The solubility, cytotoxicity, and hemolytic activities of these alanine scan analogues were evaluated. Reduced aqueous solubility correlates with better antibiotic activity. The alanine scan analogues are non-cytotoxic and non-hemolytic. The findings of this chapter are significant, because the results from the alanine scan of a teixobactin analogue provides a solid foundation to guide future teixobactin analogue design.