Nonlinear optics is a rapidly growing field of research, in which the light-matter interaction between intense light field from lasers and strong optical nonlinearity of the materials is investigated. The capability to create a material system with high nonlinearity and furthermore control it for tailor-made properties is captivating and unlocks the potential for more interesting applications.In Chapter 1, an electrically tunable nonlinear optical device working at near-infrared wavelength is theoretically and experimentally demonstrated. Ultrahigh optical second-order nonlinearity from TiN-based coupled metallic quantum wells can be electrically tuned by external electric field. Tunability of second-order susceptibility χ(2) reaches a 63% modulation depth with an average tunability of 10.5% per volt. In addition, electro-optic modulation of second-harmonic signal is presented by continuous tuning of χ(2) over a long period of time with high stability. These results provide a new material platform with actively controllable strong nonlinearity for future nonlinear photonic systems. In Chapter 2, a material system with strong and broadband optical second-order nonlinearity in the near-infrared is theoretically and experimentally demonstrated. Multiple units of TiN-based coupled metallic quantum wells with slightly shifted nonlinear response peaks are uniquely designed and epitaxially grown to form a multilayered stack. By measuring near-infrared to visible second-harmonic generation, second-order susceptibility χ(2) reaches 740 pm/V at 900 nm and spreads 200 nm, covering wavelength range from 800 nm to 1000 nm. Our discoveries open up the possibility to create materials with tailored broadband optical nonlinearity. In Chapter 3, a material platform excels in both optical second- and third- order nonlinearity at telecom wavelength is theoretically and experimentally demonstrated. In this TiN-based coupled metallic quantum wells structure, electronic sub-bands are engineered to support doubly resonant inter-sub-band transitions for exceptionally high second-order nonlinearity and provide single-photon transitions for remarkable third-order nonlinearity within the 1400–1600 nm bandwidth. Second-order susceptibility χ(2) reaches 2840 pm/V at 1440 nm, while Kerr coefficient n2 arrives at 2.8×10-10 cm2/W at 1460 nm. The achievement of simultaneous strong second- and third- order nonlinearity in one material at telecom wavelength creates opportunities for multi-functional advanced applications in the field of nonlinear optics.

Kidney cancer or renal cell carcinoma (RCC) is the 6th most common type of cancer in men and the 9th common cancer in women in the United States and claims nearly 15,000 lives annually. 75% of total RCC cases are clear-cell renal cell carcinoma (ccRCC) which is refractory to the conventional chemotherapy and there is currently no effective cure against ccRCC except for surgical removal. While Fuhrman nuclear grading has been widely used as a prognostic tool for ccRCC, its subjective nature hinders precise and reliable patient-specific prognosis. The overarching aim of this dissertation is to characterize the molecular components of Fuhrman nuclear grades to understand the molecular underpinning of ccRCC chemoresistance and to identify proteomic and metabolomic signatures of ccRCC that can be harnessed to establish novel diagnostic tools complimentary to the Fuhrman nuclear grading and to identify potential novel grade-defined pharmacological targets. This dissertation first aims to characterize the molecular mechanisms behind the ccRCC chemoresistance using Roscovitine (Seliciclib) as an example of conventional chemotherapy via cyclin dependent kinase (CDK) inhibition. Second, Fuhrman nuclear grade-defined proteomes are characterised to identify a set of proteins that can be used as diagnostic biomarkers and grade-specific pharmacological ccRCC targets. Third, the potential role of Argininosuccinate Synthetase (ASS1), whose expression was suppressed across all Fuhrman grades, in ccRCC pathogenesis is investigated. Additionally, in order to establish novel diagnostic criteria, this study aims to characterize the grade-dependent subcellular localization of novel ccRCC biomarker proteins that are found to behave as moonlighting proteins.

This dissertation focuses on discussing how metabolic reprogramming shapes pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease with an unfavorable outcome. Although the etiology remains unknown, cigarette smoking has been considered as a risk factor for IPF. Previous findings have found that smoking can alter metabolic regulation in inflammatory lung diseases, including COPD, asthma and IPF. Metabolomics has been a powerful tool to identify putative biomarkers and novel signaling mechanisms in disease research. Untargeted metabolomics approach was used in our study to profile cellular metabolic changes in primary lung fibroblasts derived from normal and IPF patients. IPF lung fibroblasts displayed a different metabolic landscape as compared to normal lung fibroblasts, in which arginine-related metabolic pathways were significantly altered due to the absence of argininosuccinate synthase (ASS1) expression in IPF lung fibroblasts. Removing arginine from cell culture and media was specific to IPF lung fibroblast and pulmonary fibrosis. Because of the critical function of arginine metabolism in lung fibroblasts, ASS1 expression was knocked down in normal lung fibroblasts to examine the changes in metabolic pathways. Myo-inositol metabolism was found to be significantly disturbed in ASS1-deficient lung fibroblasts. Myo-inositol treatment demonstrated in vivo and in vitro antifibrotic effects. Overall, our studies have demonstrated the pivotal role of amino acid metabolism in IPF lung fibroblasts.

Program music has been a subject of controversy for over two centuries. When we consider the concept of programmatic elements in music, we often associate it with works from the Romantic Period. Yet in the historical account, there are numerous examples of compositions that were composed before the Romantic period, especially keyboard compositions, that have already attempted to express extra-musical concepts without resorting to lyrics. These keyboard compositions have been overlooked and undervalued for their contribution to the development of programme music. Therefore, this study examines five Baroque composers' keyboard compositions composed during the early Baroque period, in order to analyze the relationship between the given titles and musical representation, and to decipher and interpret the composer's intentions behind the musical notes in terms of modulation, melodic figure, rhythm, texture, form, symbolism (numerical, pictorial, chorale, figure, form), and musical-rhetorical figures (Figurenlehre).This paper examines the following keyboard works by German composers: Johann Jacob Froberger’s Lamentation, faite sur la tres douloreuse Mort de Sa Majeste Imperiale, Ferdinand le Troisieme, et se joüe lentement avec discretion (Lamentation, composed on the very painful Death of His Imperial Majesty, Ferdinand the Third, and played slowly with discretion), FbWV 633, Allemande faite en passant le Rhin dans une barque en grand peril, la quelle se joüe lentement â la discretion Allemande, while crossing the Rhine in a boat in great danger), Suite XXVII, FbWV 627, the first movement; Johann Kuhnau’s First Biblical Sonata, Il Combattimento trà David e Goliath (The Combat between David and Goliath) from Musicalische Vorstellung einiger biblischer Historien in Six Sonaten (Musical presentation of some biblical histories in Six Sonatas, known popularly as the six Biblical Sonatas); and Johann Sebastian Bach’s Capriccio sopra la lontananza de il fratro dilettissimo (Capriccio on the Departure of a Beloved Brother), BWV 992. Moreover, I explore two other French keyboard composers and their keyboard works: François Couperin’s five acts of Les Fastes de la grande Mxnxstrxndxsx (The Splendors of the Grand and Ancient Ménéstrandise) from the Onziême Ordre; Jean-Philippe Rameau’s La Poule (The Hen) from the Troisième Livres de Pièces de Clavecin (1728).

The human sensorimotor cortex contains topologically organized maps of the body and movements, usually referred to as Penfield’s homunculus. The initial homun-cular map was depicted using electrical stimulation in patients undergoing brain surgery. For the last 25 years, noninvasive functional magnetic resonance imaging (fMRI) has allowed researchers to map brain organization and function with high spatial resolution (on the order of millimeters). However, less research has been conducted to model the temporal dynamics of fMRI for its low temporal resolution (on the order of seconds). To map topological organization in visual, auditory, and sensorimotor cortices, the phase-encoded paradigm uses time delays in periodic fMRI signals to encode and decode the representations of different brain regions. Phase-encoded fMRI data are typically ana-lyzed by Fourier transform, and an overall signal-to-noise ratio and a single phase of periodic signals are estimated from the entire time series. However, this method cannot fully characterize the temporal dynamics and stability of periodic signals and phases.

This dissertation includes three fMRI studies that aim to map the cortical repre-sentations of body parts (face and hand) and unravel the spatiotemporal brain dynamics during a reach-to-eat task. I proposed a data processing pipeline that uses independent component analysis to separate periodic noise from periodic signals, and use time-frequency analysis and circular statistics to model the spread of phase angle of fMRI time series and determine the stability of periodic signals. These analyses provide additional statistical measures, not obtainable using conventional linear methods, to validate the observed periodic fMRI signals. These methods are fundamental steps to construct a more accurate and comprehensive functional brain atlas of the human sensorimotor cortex.

Overall, this review aims to outline IPF regarding macrophage and fibroblast interactions, in addition to the therapeutic roles that macrophages may play in becoming an inhibitory target for IPF. Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disease in which the tissue surrounding the alveoli within the lungs undergoes fibrosis or permanent scarring. IPF and the consequent disruption to lung blood flow, in addition to the change in immune landscape, will cause severe impact to lung function to the point of fatalities. The estimated number of patients in the United States affected by IPF is between 35,000 and 55,000 cases, with cases expected to rise as older generations continue to grow proportional to the total size of the population.2,53,141,142 Due to a lack of effective therapies, this disease exhibits a median survival time of 3 to 5 years from the time of diagnosis53,140, much worse than many cancer types. In recent years, there has been a renewed appreciation for the role of immune cells in mediating the fibrotic process with an increased interest in the role of macrophages, a type of innate immune cell which responds to environmental stimuli by secreting a wide range of biochemical signaling compounds. Macrophages help to break down the ECM using matrix metalloproteinases (MMPs). Macrophages also produce tissue inhibitors of metalloproteinases (TIMPs) to inhibit the process of ECM breakdown. Macrophages have been shown to be increased in IPF lung tissue and have a significant and poorly appreciated role in mediating fibrosis. In general, fibrotic diseases are characterized by excessive M2-associated and Th2-driven responses. Therefore, macrophages are an attractive target for inhibiting progressive pulmonary fibrosis. Recent literature has further shown that macrophages and fibroblasts directly interact with each other to influence the tissue microenvironment to affect disease outcomes26,28. In other words, both cell types interact to maintain tissue homeostasis. Together, these cells may interact during IPF and the overall fibrotic lung process to affect pulmonary homeostasis and IPF disease progression.