No description available.

Thesis (M.S.)--University of Wisconsin--Madison, 1969. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for 15-20% of all pediatric brain tumors. In patients with MB, prognosis depends heavily on the molecular makeup of the tumor. New genomic approaches over the last decade have enabled researchers to sub-classify MB based on differences in the transcriptome: WNT, Sonic hedgehog (SHH), Group 3 (MYC-amplified), and Group 4 (heterogeneous). SHH tumors represent a third of all MB cases, and small-molecule inhibitors have already been developed that target SHH signaling. Most notably, vismodegib has shown great promise in the treatment of MB and other SHH-driven cancers by targeting Smoothened (SMO), an upstream regulator of GLI activity. However, most patients who had initially responded to the drug quickly acquired point mutations in SMO that led to treatment resistance. In addition, patients who harbored mutations downstream of SMO had no response to treatment and were found to be intrinsically resistant. Although most patients with SHH-MB can be cured, current treatments often require broad base therapies, such as radiation and chemotherapy, which can have harmful and long-lasting side effects. These observations underscore the need for less toxic, more targeted therapies that act at the level of the GLI family of transcription factors themselves. However, as transcription factors are generally considered undruggable, Dr. Robbins’ group at the University of Miami Miller School of Medicine sought to address this need by using focused screens of siRNAs or small molecules that target epigenetic GLI regulators. They identified several candidates that act as readers, writers, and/or erasers of protein acetylation and methylation and showed that a subset of these candidates act downstream of SMO to attenuate GLI signaling (data not yet published). Bromodomain- and Plant Homeodomain-linked Zinc Finger-containing Protein 1 (BRPF1) was one of these candidates and further analysis revealed that its knockdown reduced Gli1 expression by more than 50%. Recent studies link BRPF1 to cerebellar development and tumor formation in SHH-MB and may be suggestive of its role as a negative regulator. OBJECTIVES: We sought to compare basal levels of Brpf1 expression in normal versus MB in mice; to characterize Brpf1 knockdown versus overexpression in SHH cell lines; and to determine if BRPF1 merits further investigation as a candidate for future drug targeting therapies in MB and other SHH-driven cancers. METHODS: We used RT-qPCR and immunoblotting analysis to look at Brpf1 expression in Ptch+/- and adult wild-type mice. cDNA and protein samples were donated by colleagues in the lab. We also grew and maintained SHH Light2 cells in culture and then used these cells to carry out siRNA and plasmid DNA transfections. RNA extraction, RT-PCR, and RT-qPCR were used to examine transfection efficiency and its effect on Gli1 expression. RESULTS: Brpf1 levels were higher in SHH-MB compared to normal cerebellum. However, BRPF1 proteins were not detected in either normal or tumor samples. Brpf1 knockdown in Light2 cells correlated with an overall decrease in Gli1 expression while overexpression had no obvious affect on Gli1 expression. CONCLUSIONS: Our findings suggest that BRPF1 may function as a positive regulator of GLI activity. Recent studies verify this claim at least partially stating that BRPF1 acts as both a positive and negative regulator of gene expression depending on the context. Thus, before we can draw any final conclusions, more research is needed to look at BRPF1 in the specific context of the SHH pathway and developing cerebellum.

During embryonic development, the Hedgehog (Hh) signaling pathway plays an important role in the growth and patterning of numerous tissues and organs. In the developing retina, Hh signaling regulates the proliferation and differentiation of retinal progenitor cells (RPC) through mechanisms that are not completely understood. The principal downstream mediators of the Hh pathway are the Gli transcription factors (Gli1-3), which regulate the expression of target genes responsible for the effects of the Hh pathway on RPC. The network of genes targeted by this pathway in neural progenitor cells however, remains unknown. The objective of this thesis was to identify and characterize novel targets of Hh/Gli during retinal development. Using a computation approach, 390 genes were identified as having at least one conserved Gli binding motif within the vicinity of the coding sequence between humans and mice. During validation, I demonstrate that 30 of 46 selected targets were modulated in response to Hh pathway activation in either E14.5 and/or P0.5 retinal explants and that the induction of 25 of these were significantly different between the two developmental stages. Included in this list of Hh-modulated genes were Sox8 and Ndp, two highly inducible genes that are direct targets of Gli2. Functionally, I was unable to determine a role for Sox8 during retinal development which could reflect compensation by the closely related Sox9 and Sox10 genes. Ndp on the other hand was found to be sufficient and required for Hh mediated induction in progenitor cell proliferation and cell fate determination. Therefore, in this thesis Hh target genes have been identified which could provide some insight into the mechanisms that are responsible for the cellular outcome of a response to the pathway.

No description available.

ABSTRACT In this dissertation I offer a critical review of ‘sound art’ in Johannesburg between 2005 and 2009. The term ‘sound art’ was coined by Dan Lander in 1989. According to Christoph Cox, Dan Lander’s lament that sound art lacked “any substantial discourse” in 1989 still applied in 2007. My intention in this research is to start such a critical discourse for sound art in Johannesburg. I argue that sound art is a distinctive practice in the city, involving the body politic and underground, surface and edge as characterised by Achille Mbembe and Sarah Nuttall in their recent major work on Johannesburg. First I briefly consider the history of sound art, referring to Brandon Labelle’s view that this history parallels that of site-specific art. I then suggest that the popularity of sound art under review became popular for a number of reasons; what Walter Ong’s termed “a shift in the sensorium”, the immediacy and inexpensiveness of working with sound, and the rise of the home computer. I also locate the sonic practices constituting sound art in audio culture as a whole, focussing on the structure, materiality, recording, playback and transmission of the sonic event in the sonic landscape. Sound, silence, noise and music are all part of this focus. I finally examine sound in terms of space, time, body and network in the work of Frances Goodman, Siobhan McCusker, The Trinity Session, Teamuncool, Gerhard Marx and my own sound work involving sampling, Happy Station (2008) and Slice Me Nice (2009).

journal's webpage is available at http://www.karger.com/bbe .

Ophidiidae are major benthopelagic fishes with wide distribution and depth range. Three types of sonic structural patterns have been described in some studied ophidiid fishes, however, the significance of the different types of the sonic apparatus, and the distribution in the subfamilies remain unclear. In addition, although the sonic apparatus and the sonic mechanisms of the high frequency sounds produced by cusk-eels has been explained, the characteristics of extrinsic swimbladder sonic muscle is still unknown. In this study, I investigated three ophidiid subfamilies from Taiwan and reviewed the published data to study the morphological traits of their sonic apparatus. Inaddition, Hoplobrotula armata were related to study the proteomic characterization of the extrinsic swimbladder sonic muscle. Results indicate that the 13 ophidiid species in this study could be grouped into five sonic structural patterns, and three subfamilies could be separated accordingly. Furthermore, because the sister group of the family Ophidiidae-carapidae is soniferous, I suggest that the common ancestor of the three ophidiid subfamilies should also be soniferous. Comparisons made in regarded to environmental factors indicate that diversity of sonic apparatus in three ophidiids subfamiliesis depth dependent. The extrinsic swimbladder sonic muscles could be separated into ventral sonic muscle and intermediate sonic muscle. The histological cross-sections of the ventral sonic muscle fibers show peripheral ring myofibrillar region and central core and they are similar with the sonic muscle. Ventral muscle weights were higher in males than females, but the muscle fibers are smaller in males. Protein values of ventral sonic muscles showed high expression in fast and long duration constructional proteins, and males were higher in protein expression than females. Intermediate sonic muscles, on the other hand, were larger in females than males. The cross-sections of muscle fibers were similar to the white muscle. Expression in the fast constructional related protein in the intermediate sonic muscle was higher than ventral sonic muscles, and the metabolically related protein was lower than ventral sonic muscles. The phylogeny of ophidiiform fishes is not clear at present; the sonic-apparatus diversity in ophidiid fishes observed in this study becomes useful to reveal the relationship phylogenetic of ophidiids fishes. Regard the physiology of sound production, I suggest that the larger ventral sonic muscle in males are be provides a better constructional ability, and their smaller fibers are adaptative for energy metabolism regarded for continuous fast constraction and fatigue resistance. The longer intermediate sonic muscle in females is a better constructional ability than male. In intermediate sonic muscle were be fast constructional related protein, higher in expression than the ventral sonic muscles, the metabolic related protein was lower than the ventral sonic muscles. These results suggest that the intermediate sonic muscle has a hight constructional ability but has a disventage of being easily fatigue.

No description available.

This thesis describes a number of compositions in which the objective was to investigate whether, and how far, the organisation of light can function as an extension of musical expression in the non-figurative visual realm. I explore the extent to which sound and light are compatible as media, in the sense of both being able to communicate a common set of ideas. The thesis begins by placing the discussion in a historical context, with an overview of the history of analogies between sound and light from Antiquity to the 19th century, as well as the history of Light Art. The second part of the thesis describes synaesthesia as a historically developed aesthetic concept and as a field of research that reveals interesting facts about the neuronal processing of stimulations from the senses. The third part forms the core of the research. It leads from a general historic discussion to more specific problems that emerged in my own work with sound and light. Light is a medium strongly characterised by purity; at first, light therefore seemed an inappropriate medium in which to offer plausible translations of different degrees of sonic noise. However, because of the importance that the inclusion of noise has taken in music since the 20th century, this would have meant a severe handicap in looking for a homological relationship between sound and light in artistic contexts. From a discussion of the broad implications the idea of dirt has in social and cultural contexts, the focus is eventually reduced to the aesthetic problem at hand. By means of a classification of three different sorts of noise, a more differentiated understanding becomes possible of the various functions that noise can have. Corresponding forms of ‘dirty light’ eventually become conceivable and artistically applicable. In the fourth part, six compositions and one audiovisual installation are discussed. Each of these works explores different relationships between the visual and sonic component. When appropriate, the various concepts of ‘dirty light’ that have been derived in the third part are reflected in the form of concrete examples. After discussing each work individually, certain practical problems are addressed that surfaced repeatedly under different performance circumstances. In the fifth part I pose the question of how far events that are conceived to be musical have to be based on sonic events. Common definitions of music that describe sonic events as its exclusive concern are questioned and a number of examples of music are discussed where the sonic outcome is hardly audible or even completely silent. I propose a notion that conceives music as a larger field of activity in which visual manifestations form an integral part. The seven audiovisual works form the practical component of this dissertation. As a result of this research a more differentiated understanding of the nature of the coupling of sound and light has emerged, alongside a comprehension of the at times strongly differing views on the general nature of cross-disciplinary works.