The design of curved optical waveguides : analytical and numerical analysis

A model for understanding the formation and propagation of modes in curved optical waveguides is developed. A numerical method for the calculation of curved waveguide mode profiles and propagation constants in two dimensional waveguides is developed, implemented and tested. A numerical method for the analysis of propagation of modes in three dimensional curved optical waveguides is developed, implemented and tested. A technique for the design of curved waveguides with reduced transition loss is presented. A scheme for drawing these new waveguides and ensuring that they have constant width is also provided. Claims about the waveguide design technique are substantiated through numerical simulations.

Investigation of the genotoxic potential of the marine biotoxins okadaic acid and azaspiracids

The present study investigated the genotoxic potential of the marine biotoxins okadaic acid (OA) and azaspiracids (AZAs). Harmful algae blooms (HABs) are an increasing global problem with implications for the ecosystem, economy and human health. Most data available on human intoxication are based on acute toxicity. To date, limited data has been published on possible long term effects, carcinogenicity and genotoxicity. To investigate genotoxicity in the present study, DNA fragmentation was detected using the COMET assay. In contrast to most other available studies, two further endpoints were included. The Trypan Blue Exclusion assay was used to provide information on possible cytotoxicity and assess the right concentration range. Flow cytometer analysis was included to detect the possible involvement of apoptotic processes. In house background data for all endpoints were established using positive controls. Three different cell lines, Jurkat T cells, CaCo-2 cells and HepG-2 cells, representing the main target organs, were exposed to OA and AZA1-3 at different concentrations and exposure times. Data obtained from the COMET assay showed an increase in DNA fragmentation for all phycotoxins, indicating a modest genotoxic effect. However, the data obtained from the Trypan Blue Exclusion assay showed a clear reduction in cell viability and cell number, indicating the involvement of cytotoxic and/or apoptotic processes. This is supported by data obtained by flow cytometer analysis. All phycotoxins investigated showed signs of early/late apoptosis. Therefore, the combined observations made in the present study indicate that OA and AZA1-3 are not genotoxic per se. Apoptotic processes appear to make a major contribution to the observed DNA fragmentation. The information obtained in this study stresses the importance of inclusion of additional endpoints and appropriate positive controls in genotoxicity studies. Furthermore, these data can assist in future considerations on risk assessment, especially regarding repeated exposure and exposure at sub-clinical doses.

The use of different blood sample preparations in the development of biomarkers for the environmental monitoring of domestic farm animals

The application of biological effect monitoring for the detection of environmental chemical exposure in domestic animals is still in its infancy. This study investigated blood sample preparations in vitro for their use in biological effect monitoring. When peripheral blood mononuclear cells (PBMCs), isolated following the collection of multiple blood samples from sheep in the field, were cryopreserved and subsequently cultured for 24 hours a reduction in cell viability (<80%) was attributed to delays in the processing following collection. Alternative blood sample preparations using rat and sheep blood demonstrated that 3 to 5 hour incubations can be undertaken without significant alterations in the viability of the lymphocytes; however, a substantial reduction in viability was observed after 24 hours in frozen blood. Detectable levels of early and late apoptosis as well as increased levels of ROS were detectable in frozen sheep blood samples. The addition of ascorbic acid partly reversed this effect and reduced the loss in cell viability. The response of the rat and sheep blood sample preparations to genotoxic compounds ex vivo showed that EMS caused comparable dose-dependent genotoxic effects in all sample preparations (fresh and frozen) as detected by the Comet assay. In contrast, the effects of CdCl2 were dependent on the duration of exposure as well as the sample preparation. The analysis of leukocyte subsets in frozen sheep blood showed no alterations in the percentages of T and B lymphocytes but led to a major decrease in the percentage of granulocytes compared to those in the fresh samples. The percentages of IFN-γ and IL-4 but not IL-6 positive cells were comparable between fresh and frozen sheep blood after 4 hour stimulation with phorbol 12-myrisate 13-acetate and ionomycin (PMA+I). These results show that frozen blood gives comparable responses to fresh blood samples in the toxicological and immune assays used.

Photonic integrated circuits for the generation of coherent optical signals

The demand for optical bandwidth continues to increase year on year and is being driven primarily by entertainment services and video streaming to the home. Current photonic systems are coping with this demand by increasing data rates through faster modulation techniques, spectrally efficient transmission systems and by increasing the number of modulated optical channels per fibre strand. Such photonic systems are large and power hungry due to the high number of discrete components required in their operation. Photonic integration offers excellent potential for combining otherwise discrete system components together on a single device to provide robust, power efficient and cost effective solutions. In particular, the design of optical modulators has been an area of immense interest in recent times. Not only has research been aimed at developing modulators with faster data rates, but there has also a push towards making modulators as compact as possible. Mach-Zehnder modulators (MZM) have proven to be highly successful in many optical communication applications. However, due to the relatively weak electro-optic effect on which they are based, they remain large with typical device lengths of 4 to 7 mm while requiring a travelling wave structure for high-speed operation. Nested MZMs have been extensively used in the generation of advanced modulation formats, where multi-symbol transmission can be used to increase data rates at a given modulation frequency. Such nested structures have high losses and require both complex fabrication and packaging. In recent times, it has been shown that Electro-absorption modulators (EAMs) can be used in a specific arrangement to generate Quadrature Phase Shift Keying (QPSK) modulation. EAM based QPSK modulators have increased potential for integration and can be made significantly more compact than MZM based modulators. Such modulator designs suffer from losses in excess of 40 dB, which limits their use in practical applications. The work in this thesis has focused on how these losses can be reduced by using photonic integration. In particular, the integration of multiple lasers with the modulator structure was considered as an excellent means of reducing fibre coupling losses while maximising the optical power on chip. A significant difficultly when using multiple integrated lasers in such an arrangement was to ensure coherence between the integrated lasers. The work investigated in this thesis demonstrates for the first time how optical injection locking between discrete lasers on a single photonic integrated circuit (PIC) can be used in the generation of coherent optical signals. This was done by first considering the monolithic integration of lasers and optical couplers to form an on chip optical power splitter, before then examining the behaviour of a mutually coupled system of integrated lasers. By operating the system in a highly asymmetric coupling regime, a stable phase locking region was found between the integrated lasers. It was then shown that in this stable phase locked region the optical outputs of each laser were coherent with each other and phase locked to a common master laser.

Photonic integrated circuit for the manipulation of coherent optical combs

Photonic integration has become an important research topic in research for applications in the telecommunications industry. Current optical internet infrastructure has reached capacity with current generation dense wavelength division multiplexing (DWDM) systems fully occupying the low absorption region of optical fibre from 1530 nm to 1625 nm (the C and L bands). This is both due to an increase in the number of users worldwide and existing users demanding more bandwidth. Therefore, current research is focussed on using the available telecommunication spectrum more efficiently. To this end, coherent communication systems are being developed. Advanced coherent modulation schemes can be quite complex in terms of the number and array of devices required for implementation. In order to make these systems viable both logistically and commercially, photonic integration is required. In traditional DWDM systems, arrayed waveguide gratings (AWG) are used to both multiplex and demultiplex the multi-wavelength signal involved. AWGs are used widely as they allow filtering of the many DWDM wavelengths simultaneously. However, when moving to coherent telecommunication systems such as coherent optical frequency division multiplexing (OFDM) smaller FSR ranges are required from the AWG. This increases the size of the device which is counter to the miniaturisation which integration is trying to achieve. Much work was done with active filters during the 1980s. This involved using a laser device (usually below threshold) to allow selective wavelength filtering of input signals. By using more complicated cavity geometry devices such as distributed feedback (DFB) and sampled grating distributed Bragg gratings (SG-DBR) narrowband filtering is achievable with high suppression (>30 dB) of spurious wavelengths. The active nature of the devices also means that, through carrier injection, the index can be altered resulting in tunability of the filter. Used above threshold, active filters become useful in filtering coherent combs. Through injection locking, the coherence of the filtered wavelengths with the original comb source is retained. This gives active filters potential application in coherent communication system as demultiplexers. This work will focus on the use of slotted Fabry-Pérot (SFP) semiconductor lasers as active filters. Experiments were carried out to ensure that SFP lasers were useful as tunable active filters. In all experiments in this work the SFP lasers were operated above threshold and so injection locking was the mechanic by which the filters operated. Performance of the lasers under injection locking was examined using both single wavelength and coherent comb injection. In another experiment two discrete SFP lasers were used simultaneously to demultiplex a two-line coherent comb. The relative coherence of the comb lines was retained after demultiplexing. After showing that SFP lasers could be used to successfully demultiplex coherent combs a photonic integrated circuit was designed and fabricated. This involved monolithic integration of a MMI power splitter with an array of single facet SFP lasers. This device was tested much in the same way as the discrete devices. The integrated device was used to successfully demultiplex a two line coherent comb signal whilst retaining the relative coherence between the filtered comb lines. A series of modelling systems were then employed in order to understand the resonance characteristics of the fabricated devices, and to understand their performance under injection locking. Using this information, alterations to the SFP laser designs were made which were theoretically shown to provide improved performance and suitability for use in filtering coherent comb signals.

Voltage properties of optically injected long wavelength VCSELs: Theory and experiment

Future high speed communications networks will transmit data predominantly over optical fibres. As consumer and enterprise computing will remain the domain of electronics, the electro-optical conversion will get pushed further downstream towards the end user. Consequently, efficient tools are needed for this conversion and due to many potential advantages, including low cost and high output powers, long wavelength Vertical Cavity Surface Emitting Lasers (VCSELs) are a viable option. Drawbacks, such as broader linewidths than competing options, can be mitigated through the use of additional techniques such as Optical Injection Locking (OIL) which can require significant expertise and expensive equipment. This thesis addresses these issues by removing some of the experimental barriers to achieving performance increases via remote OIL. Firstly, numerical simulations of the phase and the photon and carrier numbers of an OIL semiconductor laser allowed the classification of the stable locking phase limits into three distinct groups. The frequency detuning of constant phase values (ø) was considered, in particular ø = 0 where the modulation response parameters were shown to be independent of the linewidth enhancement factor, α. A new method to estimate α and the coupling rate in a single experiment was formulated. Secondly, a novel technique to remotely determine the locked state of a VCSEL based on voltage variations of 2mV−30mV during detuned injection has been developed which can identify oscillatory and locked states. 2D & 3D maps of voltage, optical and electrical spectra illustrate corresponding behaviours. Finally, the use of directly modulated VCSELs as light sources for passive optical networks was investigated by successful transmission of data at 10 Gbit/s over 40km of single mode fibre (SMF) using cost effective electronic dispersion compensation to mitigate errors due to wavelength chirp. A widely tuneable MEMS-VCSEL was established as a good candidate for an externally modulated colourless source after a record error free transmission at 10 Gbit/s over 50km of SMF across a 30nm single mode tuning range. The ability to remotely set the emission wavelength using the novel methods developed in this thesis was demonstrated.

Indication of electron neutrino appearance from an accelerator-produced off-axis muon neutrino beam.

The T2K experiment observes indications of ν(μ) → ν(e) appearance in data accumulated with 1.43×10(20) protons on target. Six events pass all selection criteria at the far detector. In a three-flavor neutrino oscillation scenario with |Δm(23)(2)| = 2.4×10(-3)  eV(2), sin(2)2θ(23) = 1 and sin(2)2θ(13) = 0, the expected number of such events is 1.5±0.3(syst). Under this hypothesis, the probability to observe six or more candidate events is 7×10(-3), equivalent to 2.5σ significance. At 90% C.L., the data are consistent with 0.03(0.04) < sin(2)2θ(13) < 0.28(0.34) for δ(CP) = 0 and a normal (inverted) hierarchy.

NEGLECTED CELLO REPERTOIRE OF TWENTIETH CENTURY ENGLISH COMPOSERS

In the Twentieth Century, the proliferation of cellists and the exceptional development of cello techniques, combined with composers' acceptance of the challenges by these developments, led many British composers to contribute to the enrichment of the cello concert repertoire. A great number of compositions written for the cello in the Twentieth Century England have been long neglected. In comparison with their other works in the genres of concerto, symphony, and opera, works for cello by prominent Twentieth Century English composers Elgar, Walton, and Britten are relatively unknown, except for Elgar's cello concerto. There are also many lesser-known composers like Delius, Bax, Bridge, and Clarke, who flourished in the fmt half of the century, but eventually became disregarded. Some reasons for this neglect may be as follows: the reluctant attitude toward new trends in the English musical establishment around the turn of the century; a lack of readily available editions of these composers' compositions; an over-abundance of fine composers at one time; and lastly, an overly individualistic approach to the music restricting a general public appreciation and recognition. Encountering a recording of the Walton cello concerto prompted me to further study the neglected Twentieth Century English cello repertoire. Many works of the above-mentioned composers still have not been fully valued in the cello repertoire. For this reason, the purpose of this project was to inspire cellists to learn and broaden as well as to appreciate the beauty of the Twentieth Century cello literature. As part of the doctoral performance project, three recitals featuring the works by six English composers were performed. My collaborator in all three recitals was pianist Eunae KO. The fmt recital included the Sonata for cello and piano by Frank Bridge and the Concerto by William Walton. The second recital was comprised of relatively unknown cello works: Sonatina in D major by Arnold Bax, Romance by Frederick Delius, and the Sonata Op. 40 by Rebecca Clarke. The third recital consisted of Folk-Tale by Arnold Bax and the Symphony for Cello and Orchestra Op. 68 by Benjamin Britten.

LIONEL TERTIS AND THE FLOWERING OF EARLY TWENTIETH CENTURY ENGLISH VIOLA REPERTOIRE

This performance project focused on English viola literature written in the first half of the twentieth century. During this time, numerous English composers were influenced by Lionel Tertis' unprecedented approach to the viola as a virtuosic and solo instrument. In addition to being an inspiration to composers of whom he was not in direct contact, Tertis' innovative vision for the viola led to numerous collaborations with prominent English composers of his generation. Ralph Vaughan Williams, Arnold Bax, York Bowen, Frank Bridge, Benjamin Britten, and Rebecca Clarke -his own protégé - composed some of the most important works for viola thus directly shaping the impression of the instrument as we know it today. Tertis' artistry as a performing violist was unmatched at the beginning of the twentieth century. He had a unique approach to the instrument which focused on concept of sound, tone color, concentrated listening, continuous vibrato, discreet portamento, and expressive interpretation. His convincing musical and technical ideas led him to write a treatise about how to achieve a beautiful tone. His passion for teaching and concern for the viola's posterity greatly enhanced the development of the viola. Tertis transcribed, edited, and premiered many works during his career. The music that Lionel Tertis influenced can be seen as a microcosm for a musical resurgence in England during the first half of the twentieth-century. The catalyst for this was artistic influences in the form of nationalism, folk music, romanticism, modernism, and impressionism, among others. Before this, England was widely referred to as ''the land without music" but in a very real sense, .Lionel Tertis was one of the pioneers who, through his artistry of the viola, led the way to the renaissance of music in England in the twentieth century.

OPERA IN AMERICA: MUSIC OF, BY, AND FOR THE PEOPLE­: A PERFORMANCE DISSERTATION

Opera in America: Music of, by, and for the people is a study of the relationship between American popular culture and opera in the United States. Four performance projects demonstrate the on-going exchange between the operatic community-including its composer, singers, and patrons-and the country's popular entertainment industry with its broad audience base. Numerous examples of artistic cross pollination between lowbrow and highbrow music will illustrate the artistic and social consequences created by this artistic amalgamation. Program #1, By George! By Ira! By Gershwin!, is a retrospective of Gershwin's vocal music representing a blending of popular and serious music in both style and form. The concert includes selections from Porgy and Bess, a work considered by many musicologists as the first American opera. Program #2, Shadowboxer, is a premiere performance of an opera by Frank Proto and John Chenault. For this newly commissioned work, I serve as Assistant Director to Leon Major. Shadowboxer provides a clear example of opera utilizing popular culture both musically and dramatically to tell the true story of American hero and legendary boxer, Joe Louis. Program #3, Just a Song at Twilight, is an original theatrical music piece featuring music, letters, diaries, and journals of the Gilded Age, an era when opera was synonymous with popular entertainment. Special attention is focused on tum-of­ the-century singers who performed in both opera and vaudeville. Program #4 is a presentation of Dominick Argento's Miss Manners on Music and illustrates the strong relationship that can exist between opera and American popular entertainment. Originally conceived as a song cycle, I have staged the work as a one-act opera sung and acted by soprano Carmen Balthrop. This piece is based on the writings of pop icon and newspaper columnist Judith Martin, otherwise known as Miss Manners. All four performances are recorded in audio and video formats.

RUSSIAN THREADS: THE PRESENCE OF RUSSIAN INFLUENCES IN TWENTIETH­ CENTURY ENGLISH CELLO MUSIC

A cursory glance at cello works by English composers during the twentieth- century yields an unexpected relationship to Russian musicians, history, culture, and religion. One must wonder how this connection or "Russian thread" came to be. When considering the working relationship of Benjamin Britten and Mstislav Rostropovich, the likelihood of such a connection is tangible, since their deeply personal friendship influenced Britten's music for cello. However, what is perhaps more interesting is the emergence of connections to Russia in the works of other English composers of the twentieth-century, featuring works from 1913-1996. This project was conceived after close study and analysis of Benjamin Britten's Third Suite for Solo Cello, Op. 87 (1971). Britten's inclusion of Russian folk tunes and an Orthodox Church hymn signaled the penetrating presence of Russian elements in his works. Britten's First Suite for Solo Cello, Op. 72, Third Suite for Cello, Op. 87, and Sonata for Piano and Cello in C, Op. 65 are presented in this project. Further exploration of works for cello by English composers unveiled similar connections to Russia. The Sonata for Cello and Piano of Frank Bridge is likened to Russian romanticism and the Cello Sonata of Sergei Rachmaninoff. William Walton's Cello Concerto was written for the Russian-American cellist Gregor Piatigorsky. Wake Up ...and die is John Tavener's deeply spiritual work, which is rooted in his Russian Orthodoxy. John Ireland, influenced by models of French and Russian Impressionism, contributed works colored with Russian folk influences, of which his Piano Trio No. 2 is an example. Finally, Arnold Bax traveled to Russia as a young man and his Folk Tale and Legend Sonata are imbued with the spirit of Russian folk music and architecture. This dissertation project is comprised of three recitals featuring English works for cello connected by a "Russian Thread." All events took place on the campus of University of Maryland, College Park: Recital #1 on December 4, 2011 in the Gildenhorn Recital Hall of the Clarice Smith Performing Arts Center, Recital #2 on February 11,2012, and Recital #3 on April 15, 2012, both in the Ulrich Recital Hall.

Explicit DNase sequence bias modeling enables high-resolution transcription factor footprint detection.

DNaseI footprinting is an established assay for identifying transcription factor (TF)-DNA interactions with single base pair resolution. High-throughput DNase-seq assays have recently been used to detect in vivo DNase footprints across the genome. Multiple computational approaches have been developed to identify DNase-seq footprints as predictors of TF binding. However, recent studies have pointed to a substantial cleavage bias of DNase and its negative impact on predictive performance of footprinting. To assess the potential for using DNase-seq to identify individual binding sites, we performed DNase-seq on deproteinized genomic DNA and determined sequence cleavage bias. This allowed us to build bias corrected and TF-specific footprint models. The predictive performance of these models demonstrated that predicted footprints corresponded to high-confidence TF-DNA interactions. DNase-seq footprints were absent under a fraction of ChIP-seq peaks, which we show to be indicative of weaker binding, indirect TF-DNA interactions or possible ChIP artifacts. The modeling approach was also able to detect variation in the consensus motifs that TFs bind to. Finally, cell type specific footprints were detected within DNase hypersensitive sites that are present in multiple cell types, further supporting that footprints can identify changes in TF binding that are not detectable using other strategies.

SELECTED TWENTIETH-CENTURY BRITISH & AMERICAN ENGLISH SONG REPERTOIRE WRITTEN FOR SOPRANO

English language song (both British and American) is influenced by a variety of cultures, races, and musical forms and has produced a broad range of song repertoire. Like songs in all countries and throughout history, these songs can be classified into three categories: imitative songs, experimental songs, and songs of individuality. Music experimentation, necessary and welcome as it is, can hardly command broad international attention. Thus, the songs of this dissertation performance project are chosen from the first and third categories: imitative songs and individual songs in the composer's own unique style. This project concentrates its exploration on twentieth-century solo songs written in English. Although twentieth-century British & American composers also produced solos and chamber music in other languages, this dissertation focuses upon their English repertoire. This performance project consists of three programs: one British repertoire and two American. The first program titled An Evening of British Song examines twentieth-century British song written by Roger Quilter, Peter Warlock, William Walton, Benjamin Britten, Thomas F. Dunhill, Ivor Gurney, and Frank Bridge. It was presented on December 12, 2001, in Homer Ulrich Recital Hall with the collaborative pianist Meriel Owen. The second program titled An Evening of American Song I comprises music written by Dominick Argento, Samuel Barber, Ned Rorem, Leonard Bernstein, and Lee Hoiby. It was presented on October 23, 2002, in Joseph & Alma Gildenhorn Recital Hall with the collaborative pianist R. Timothy McReynolds. The third program titled An Evening of American Song II written by John Duke, John Corigliano, Charles Ives, Richard Hundley, Lori Laitman, Frederick Loewe, George Gershwin, and Jerome Kern was presented on December 18, 2003, again in Joseph & Alma Gildenhorn Recital Hall with the collaborative pianist R. Timothy McReynolds and the flutist Jessica Dunnavant. Each of these three dissertation recitals occurred at the University of Maryland in College Park and was recorded. These CD recordings are held by the Michelle Smith Performing Arts Library at the University of Maryland.

HDAC inhibitors cause site-specific chromatin remodeling at PU.1-bound enhancers in K562 cells

BACKGROUND: Small molecule inhibitors of histone deacetylases (HDACi) hold promise as anticancer agents for particular malignancies. However, clinical use is often confounded by toxicity, perhaps due to indiscriminate hyperacetylation of cellular proteins. Therefore, elucidating the mechanisms by which HDACi trigger differentiation, cell cycle arrest, or apoptosis of cancer cells could inform development of more targeted therapies. We used the myelogenous leukemia line K562 as a model of HDACi-induced differentiation to investigate chromatin accessibility (DNase-seq) and expression (RNA-seq) changes associated with this process. RESULTS: We identified several thousand specific regulatory elements [~10 % of total DNase I-hypersensitive (DHS) sites] that become significantly more or less accessible with sodium butyrate or suberanilohydroxamic acid treatment. Most of the differential DHS sites display hallmarks of enhancers, including being enriched for non-promoter regions, associating with nearby gene expression changes, and increasing luciferase reporter expression in K562 cells. Differential DHS sites were enriched for key hematopoietic lineage transcription factor motifs, including SPI1 (PU.1), a known pioneer factor. We found PU.1 increases binding at opened DHS sites with HDACi treatment by ChIP-seq, but PU.1 knockdown by shRNA fails to block the chromatin accessibility and expression changes. A machine-learning approach indicates H3K27me3 initially marks PU.1-bound sites that open with HDACi treatment, suggesting these sites are epigenetically poised. CONCLUSIONS: We find HDACi treatment of K562 cells results in site-specific chromatin remodeling at epigenetically poised regulatory elements. PU.1 shows evidence of a pioneer role in this process by marking poised enhancers but is not required for transcriptional activation.

Salvianolic Acid B Inhibits Growth of Cervical Cancer Cells in vitro via Induction of Apoptosis through the Extrinsic Pathway

In 2014 alone, over 12,000 women are expected to be diagnosed with cervical cancer. Of these women who are diagnosed, about 3,909 will result in death. Despite developments in prevention methods, cervical cancer remains a major health concern for women. Growing evidence suggests that Salvianolic acid B (Sal B), a major component of the Chinese herb Danshen, may inhibit cancer cell growth and help fight against cervical cancer. This study characterizes the potential of Sal B as a cervical cancer drug through in vitro testing on HeLa cells. We hypothesized that application of Sal B to HeLa cells will result in decreased cell viability and increased apoptosis in a dose dependent manner. HeLa cells were treated with varying concentrations of Sal B: 25µM, 50µM, 100µM, and 200µM. Cell viability was determined through colony formation assay, cell death ELISA, and nuclear morphology. An inhibitor study was also conducted for further apoptosis pathway analysis. Colony formation assay demonstrated a significant decrease in cell viability with increasing concentrations of Sal B with 75% viability at 50µM down to 0% viability at 200µM. Cell death ELISA and the analysis of nuclear morphology via Hoechst staining reported significant levels of apoptosis at concentrations equal to 50µM and greater. Furthermore, experiments using caspase inhibitors indicated that Sal B’s apoptotic effects are caspase-8 dependent. In conclusion, our results demonstrate that Sal B inhibits cancer cell growth by a mechanism that involves apoptosis induction through the extrinsic pathway.