http://www.dspace.cam.ac.uk:80/handle/1810/221812 Sun, 19 May 2013 18:09:57 GMT 2013-05-19T18:09:57Z http://www.dspace.cam.ac.uk:80/handle/1810/244396 Title: Transcriptional functions of the corepressor Sin3A in skin Authors: Cox, Claire Abstract: Upon activation in epidermal stem cells, the proto-oncogene c-Myc triggers their exit from the stem cell compartment resulting in an increase in progenitor cell proliferation and an induction in terminal differentiation. Whether c-Myc plays a direct transcriptional role in epidermal stem cell differentiation was unknown. The exploration of c-Myc's transcriptional roles at the epidermal differentiation complex (EDC), a locus essential for skin maturation demonstrated that binding of c-Myc to the EDC can simultaneously recruit and displace specific sets of differentiation-specific transcriptional regulators to EDC genes. Among these factors, Sin3A acts as a transcriptional co-repressor and was initially discovered via its direct interaction with Mxi1 and Mxd1, which are antagonists of the Myc family network. As such, I concentrated on the role of Sin3A as a potential opposing factor to c-Myc activity in the epidermis. To analyse the role of Sin3A in regulating epidermal stem cell fate in vivo, I generated a number of transgenic mouse models. To determine whether Sin3A functions in hair follicle stem cells, I inducibly deleted Sin3A in the hair follicle bulge, where quiescent stem cells reside. However, lack of Sin3A in the hair bulge did not cause any aberrant phenotype and I concluded that Sin3A is dispensable for hair follicle homeostasis. I next analysed a mouse model in which Sin3A is inducibly deleted in the basal layer of the epidermis. Deletion of Sin3A resulted in a severe disruption of epidermal homeostasis-namely due to increases in proliferation and differentiation. Further investigation demonstrated that this phenotype is driven by enhanced genomic recruitment of c-Myc to the epidermal differentiation complex and reactivation of c-Myc target genes involved in cellular proliferation. I found that Sin3A causes de-acetylation of the c-Myc protein to directly repress c-Myc’s transcriptional activity and is antagonistic to c-Myc in the interfollicular epidermis. I hypothesised that simultaneous deletion of Sin3A and c-Myc might return the skin to normality. Indeed, when Sin3A and Myc are concurrently deleted, proliferation and differentiation levels returned to normal. These results demonstrate how levels of Sin3A and c-Myc must be carefully balanced for epidermal homeostasis to be maintained. Decreased expression of Sin3A has been linked to tumour susceptibility in other tissues for example in non-small cell lung carcinoma making Sin3A a candidate tumour suppressor gene. I therefore considered that loss of Sin3A may lead to increased susceptibility to skin cancer. To investigate this I performed pilot experiments using UVB irradiation of skin that has one copy of Sin3A deleted in the basal layer of the epidermis. Under normal conditions, these mice have no identifiable phenotype, but pilot experiments demonstrated that after short term and long term UVB irradiation, they exhibit increased epidermal thickness and proliferation relative to controls. This recapitulated the phenotype observed when Sin3A is inducibly deleted in the interfollicular epidermis and further demonstrates the role of SinA as an inhibitor of proliferation in this tissue. Overall, these results demonstrate that an interplay between the opposing functions of Sin3A and c-Myc are necessary to ensure that there is balanced homeostasis in the interfollicular epidermis. Tue, 12 Mar 2013 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244396 2013-03-12T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/240577 Title: Auditory-based processing of communication sounds Authors: Walters, Thomas C. Abstract: This thesis examines the possible benefits of adapting a biologically-inspired model of human auditory processing as part of a machine-hearing system. Features were generated by an auditory model, and used as input to machine learning systems to determine the content of the sound. Features were generated using the auditory image model (AIM) and were used for speech recognition and audio search. AIM comprises processing to simulate the human cochlea, and a ‘strobed temporal integration’ process which generates a stabilised auditory image (SAI) from the input sound. The communication sounds which are produced by humans, other animals, and many musical instruments take the form of a pulse-resonance signal: pulses excite resonances in the body, and the resonance following each pulse contains information both about the type of object producing the sound and its size. In the case of humans, vocal tract length (VTL) determines the size properties of the resonance. In the speech recognition experiments, an auditory filterbank was combined with a Gaussian fitting procedure to produce features which are invariant to changes in speaker VTL. These features were compared against standard mel-frequency cepstral coefficients (MFCCs) in a size-invariant syllable recognition task. The VTL-invariant representation was found to produce better results than MFCCs when the system was trained on syllables from simulated talkers of one range of VTLs and tested on those from simulated talkers with a different range of VTLs. The image stabilisation process of strobed temporal integration was analysed. Based on the properties of the auditory filterbank being used, theoretical constraints were placed on the properties of the dynamic thresholding function used to perform strobe detection. These constraints were used to specify a simple, yet robust, strobe detection algorithm. The syllable recognition system described above was then extended to produce features from profiles of the SAI and tested with the same syllable database as before. For clean speech, performance of the features was comparable to that of those generated from the filterbank output. However when pink noise was added to the stimuli, performance dropped more slowly as a function of signal-to-noise ratio when using the SAI-based AIM features, than when using either the filterbank-based features or the MFCCs, demonstrating the noise-robustness properties of the SAI representation. The properties of the auditory filterbank in AIM were also analysed. Three models of the cochlea were considered: the static gammatone filterbank, dynamic compressive gammachirp (dcGC) and the pole-zero filter cascade (PZFC). The dcGC and gammatone are standard filterbank models, whereas the PZFC is a filter cascade, which more accurately models signal propagation in the cochlea. However, while the architecture of the filterbanks is different, they have all been successfully fitted to psychophysical masking data from humans. The abilities of the filterbanks to measure pitch strength were assessed, using stimuli which evoke a weak pitch percept in humans, in order to ascertain whether there is any benefit in the use of the more computationally efficient PZFC. Finally, a complete sound effects search system using auditory features was constructed in collaboration with Google research. Features were computed from the SAI by sampling the SAI space with boxes of different scales. Vector quantization (VQ) was used to convert this multi-scale representation to a sparse code. The ‘passive-aggressive model for image retrieval’ (PAMIR) was used to learn the relationships between dictionary words and these auditory codewords. These auditory sparse codes were compared against sparse codes generated from MFCCs, and the best performance was found when using the auditory features. Mon, 06 Jun 2011 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/240577 2011-06-06T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/237472 Title: Orang-utan feeding behaviour in Sabangau, Central Kalimantan Authors: Harrison, Mark Edward Abstract: Detailed studies of energy/nutrient acquisition and food selection have been completed for both African apes and orang-utans in mast-fruiting dipterocarp forests, but, to date, no studies of this type have been completed on orang-utans in non-masting forests, which experience more muted fluctuations in fruit availability. Such studies may be instructive in understanding whether the observations on orang-utans in masting habitats are specific to orang-utans, or specific only to orang-utans in masting habitats. To investigate this, orang-utan diet composition, energy intake, food selection and behaviour were studied in relation to orang-utan fruit/flower availability, and chemical and non-chemical food properties, in the Sabangau peat-swamp forest, Central Kalimantan from July 2005-June 2007. All data were collected using standard methods, and comparisons made with published data on orang-utans in mast-fruiting habitats and on African apes. Orang-utan fruit availability in Sabangau was lower and less variable than in the masting forests of Gunung Palung National Park, West Kalimantan. Daily energy intake was below requirements in most months, and similar to periods of very low food availability between mast-fruiting events in Gunung Palung. Mechanisms through which orang-utans may have survived this prolonged energetic shortfall are suggested. In addition, unlike in Gunung Palung, where energy intake and fruit availability are tightly linked in both sexes, the only age-sex class in which energy intake in Sabangau was related to fruit availability was flanged males. Although selection of preferred vs. fall-back food types in Sabangau appears to be governed at least partially by the expected rate of energy returns, fruit and flower selectivity rank appears better explained by food quality: the best multiiii variate model of adult female fruit selectivity rank contained only protein/fibre ratio, and bivariate correlations between fruit-pulp selectivity rank and protein/fibre ratio were also significant for flanged males. Furthermore, adult female and flanged male fruit selectivity rank was negatively affected by fibre, weight or energy intake in at least one bivariate analysis. This is suggested to represent selection against ingestion of large amounts of relatively indigestible fibre, and implies that maximising dietary quality, rather than energy intake, as has been suggested in masting forests in Borneo, may be the optimal feeding strategy for orang-utans in habitats where fruit quality is relatively poor and/or fruit availability is relatively consistent. Finally, compared to orang-utans in Bornean masting forests, Sabangau orang-utans exhibit a relative lack of modifications in nonfeeding behaviours in response to reductions in preferred food availability. These results suggest that, compared to masting forests in Borneo, lower mean quality and quantity of fruit, and lower variability in these parameters, in the Sabangau peat swamps leads to important differences in feeding behaviour between these habitat types. When compared to data on orang-utans in other sites and African great apes, these observations are compatible with a graded-response hypothesis, in which the less predictable the availability of high-energy fruit in a site: (1) the stronger the relationship between fruit availability, fruit consumption and energy intake, (2) the more food is selected based on energy content, and (3) the stronger the influence of fluctuations in fruit availability on behaviour and, ultimately, probably also female reproduction. The implications of these findings are discussed. Mon, 13 Apr 2009 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/237472 2009-04-13T23:00:00Z