Theses and Dissertations from UMD
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Item British Viola Repertoire of the First Half of the Twentieth Century(2015) Luce, Gregory; Murdock, Katherine; Music; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The aim of this dissertation performance project has been to obtain a familiarity with the sound and emotional palette of the British viola repertoire of 1900-1950. The music of this time and place has a uniquely soulful, pensive, and internally wrought emotional quality which translates perfectly into the character of the viola. The first recital consisted of music written for the world’s then-preeminent viola virtuoso, Lionel Tertis (1876-1975). This program included Vaughan Williams’ Romance for Viola and Piano, Frank Bridge’s Two Pieces for Viola and Piano (Pensiero and Allegro Appassionato), Arnold Bax’s Sonata for Viola and Piano, and finally York Bowen’s thrilling Sonata No. 1 in C Minor. The second recital contained the chronologically ordered complete works for viola and piano of Rebecca Clarke (1886-1979). Thanks to the monumental sonata of 1919, Rebecca Clarke is thought of by many as a composer, but she was most certainly a remarkable violist as well, making her one of the last performer-composers to continue the legacy of the great composer-virtuosi of the late nineteenth and early twentieth centuries. Clarke was at the very forefront of a time when female composers were beginning to be accepted socially. She is removed by only fifty or so years from the time of Clara Schumann, another great female artist, but is perhaps more remarkable in that her instrument of choice was not as widely accepted as a solo instrument at that time. The final recital consisted of several works chosen to showcase the viola’s unique relationship with British composers over time. The first half of the recital featured three under-celebrated works by Arnold Bax: Concert Piece, Trio in One Movement, and Legend. The second half of this program reached back into the late Renaissance with a pair of pieces by John Dowland arranged for violin and viola, then finishing with Benjamin Britten’s Lachrymae of 1950, which was inspired by these two works.Item Ceramide Channels and the Induction of Apoptosis: Structural Insights on Channel Formation and Regulation by Bcl-2 Family Proteins(2012) Perera, Meenu Nadisha; Colombini, Marco; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)A critical event in apoptosis is the release of intermembrane space proteins from mitochondria following mitochondrial outer membrane (MOM) permeabilization (MOMP). The Bcl-2 family of proteins regulates MOM integrity and includes pro- and anti-apoptotic members, like Bax and Bcl-xL respectively. Preceding MOMP, the MOM becomes enriched with the sphingolipid, ceramide, which can self-assemble to form ceramide channels, contributing to MOMP. Bax and ceramide channels were found to act synergistically in the generation of MOMP and a direct interaction between these was observed in phospholipid membranes. The apparent affinity of activated Bax for ceramide channels increases with ceramide channel size, consistent with an induced fit mechanism; Bax drives the enlargement of ceramide channels to an optimum fit for the Bax binding site. A ceramide channel specific inhibitor prevented the enhanced MOMP in the presence of Bax and ceramide indicating ceramide channels were the primary permeabilizing entity. Analogs with changes to all the major structural features of ceramide were used to assess the molecular basis of stability of ceramide channels. Methylation of the C1- hydroxy group abrogated channel formation in mitochondria. Methylation of the amide nitrogen or a change in chirality at C2, which influences the C1-hydroxy group orientation, greatly reduced channel-forming ability whereas other changes were well tolerated. Competition experiments between ceramide and analogs resulted in synergism or antagonism, depending on compatibility of the analog structure with the ceramide channel model. The results provide evidence for ceramide channels being highly organized structures, stabilized by specific inter-molecular interactions. Analogs that retained channel-forming ability were used to assess the structural features of ceramide channels required for regulation by Bcl-2 family proteins. The stereochemistry of the ceramide head group and access to the amide nitrogen is indispensible for regulation by Bax, implicating the polar portion of the channel as the Bax binding site. Bcl-xL's ability to disassemble ceramide channels depends on the length of the hydrophobic chains of ceramide. Specific Bcl-xL inhibitors reveal that BclxL binds ceramide channels through its hydrophobic groove and this is supported by simulated docking. The opposite effects of pro-and anti-apoptotic proteins are achieved at different sites on the ceramide channel.Item Protein permeability pathways in the mitochondrial outer membrane during apoptosis(2012) Vidyaramanan, Ganesan; Colombini, Marco; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Apoptosis, a form of programmed cell death is a physiological, homeostatic process that guides the systematic removal of unwanted, dying or damaged cells from the body. A key step in apoptosis is the irreversible release of mitochondrial intermembrane space (IMS) proteins into the cytosol by a process called Mitochondrial Outer Membrane Permeabilization (MOMP). MOMP is regulated by a special class of proteins called Bcl-2 family proteins and a sphingolipid called ceramide. The pro-apoptotic Bcl-2 proteins, especially Bax and Bak can cooperate with ceramide to form channels in mitochondria that cause protein efflux during MOMP. The ability of ceramide to form protein-permeable channels in MOM is established. Bax and ceramide enhanced MOMP synergistically. The ability of Bax to stimulate ceramide channels was investigated. It was found that the apparent affinity of Bax for a ceramide channel increases with the ceramide channel size. The results indicate that Bax binds a small ceramide channel and drives its growth until the Bax molecule finds the best fit to the channel. This interaction between Bax and a ceramide channel does not require of the presence of other Bcl-2 proteins or mitochondrion-specific factors. The critical structural features of ceramide were investigated for their role in ceramide channel formation. Analogs of ceramide bearing modifications in the functional groups were analyzed for their ability to form channels to assess stability and also to interact with native ceramide to form channels to assess compatibility between interacting groups. The C1-hydroxyl was found to be indispensable for channel formation while the C3-hydroxyl was inconsequential to channel formation. The amide nitrogen with its ability to donate hydrogen was important for stability as methylating the nitrogen diminished the channel forming ability. Similarly, converting the carbonyl oxygen to a urea group, now more polar and a stronger hydrogen bond former resulted in more stable permeabilization. Changes to the hydrocarbon tails did not affect the ability to form channels. Phytoceramide, which has a C4 hydroxyl instead of the C4-C5 trans double bond formed stable channels but phytoceramide inhibited channel formation by ceramide suggesting incompatibility in structure. Bax activation involves translocation of Bax from the cytosol to the MOM, conformational changes and subsequent channel formation. All steps involved in Bax activation are not well-understood. We have used ionic strength as a modulating tool to dissect the different steps in Bax mediated MOMP. Increasing the ionic strength was found to delay formation of real-time permeability by Bax. Increasing the ionic strength resulted in smaller channels that grew in size slowly. The high permeability induced by low ionic strength was not reversed by raising the ionic strength suggesting that Bax channels are not in dynamic equilibrium with Bax monomers. Ionic strength also altered the sensitivity of Bax mediated MOMP to inhibition by Bcl-xL. Ionic strength, however did not affect Bax insertion into membranes. Thus, ionic strength presents a good diagnostic tool to modulate Bax mediated channel formation downstream of Bax insertion into membranes.