Immune responses to antigens presented at skin, or other epithelial surfaces such as the cervix, are important for the clearance of viral infections, such as human papillomavirus (HPV) that infect epithelial cells [13]. Elucidation of the components of an effective immune response to antigens presented in this manner will potentially aid in design of immune modulatory techniques or therapeutic vaccine strategies to treat conditions such as cervical cancer. This thesis addresses the role of CD4+ T lymphocytes in immune responses to antigens presented in skin. CD4+ T cells have a well established role in the priming of CD8+ T cells, such that priming without help results in defective CD8+ T cell memory response [15]. The role of CD4+ T cells in the immune response subsequent to priming is less well delineated [15, 16]. Murine skin grafting is a model of antigen presented at an epithelial surface. The model used in this thesis utilises grafts transgenically expressing neo-antigens (human growth hormone=hGH, ovalbumin=OVA) under the control of a keratin promoter (K14 or K5) in the graft. The corresponding mice are termed K14hGH and K5mOVA. With hGH as the antigen, rejection of such skin grafts were shown to require CD4+ T cells [1]. The most surprising finding was that this requirement for CD4+ T cells was maintained even in an antigen-experienced host (in the recall immune response to hGH). CD4+ T cells are required by graft-primed recipients to reject hGH-expressing grafts, but are not required to reject grafts expressing alternative antigens such as OVA. In an adoptive transfer model into lymphopaenic hosts, when high numbers of CD8+ T cells were transferred, any addition of CD4+ T cells was superfluous. However, with low numbers of OVA-specific CD8+ T cells, the addition of CD4+ T cells resulted in a significantly faster rate of K5mOVA skin graft rejection. This helper enhancement of K5mOVA skin graft rejection is maintained, even 7 when CD8+ T cells were previously activated to a memory phenotype prior to transfer, indicating that CD4+ T cells do have effects after CTL priming in vivo. The requirement for CD4+ T cells in the rejection of C57.K14hGH grafts is abrogated by the addition of a local inflammatory stimulus (TLR7 agonist, imiquimod). This is a local rather than systemic effect, suggesting an influence on trafficking or local effector function. Administration of agonist anti-CD40 antibody also partially abrogates the need for CD4+ T cells in rejection of C57.K14hGH grafts by primed hosts. Although CD40 has a well established role in priming of naïve CTL responses, our findings indicate that CD40 can alter events after priming, and suggests a possible mechanism for the role of CD4+ T cells in this system. With these data, we speculate that CD4+ T cells may provide help by altering the state of APC cross-presenting antigen to experienced CD8+ T cells, and that this can be substituted by TLR or CD40 mediated activation of APC. The result may be an increased number of effector CD8+ T cells, as we demonstrate that high numbers of antigen-specific CD8+ T cells can abrogate this effect.

The Mater Medical Research Institute proposes to undertake a Phase I clinical trial using CMRF-56 immunoselected blood dendritic cells (BDC) loaded with control and myeloma-associated tumour peptide antigens for the treatment of multiple myeloma (MM) patients with minimal residual disease. This thesis describes some of the fundamental pre-clinical in vitro experiments undertaken in preparation for this trial so as to maximise the potential of this vaccine to induce myeloma-specific immune responses. These experiments involved determining the parameters for optimal activation of the CMRF-56 immunoselected cell preparation and exploring the potential of novel myeloma peptide antigens to induce anti-myeloma cytotoxic T lymphocyte (CTL) responses. CMRF-56 immunoselected cell preparations, containing predominately myeloid BDC, monocytes and B cells, were prepared from both healthy donors and myeloma patients. Activation of this preparation with granulocyte macrophage colony stimulating factor (GM-CSF) was found to increase co-stimulatory molecule expression by and survival of BDC, improve peptide- and lysate-specific CTL induction, and, in combination with prostaglandin E2 (PGE2), improve chemokine-specific migration of BDC. Following optimisation of in vitro CTL generation protocols, GM-CSF activated CMRF-56 immunoselected cells were examined for their ability to induce myeloma-specific immunity. Using lysate from myeloma cell line U266 as an antigen source, a polyclonal T cell pool was generated within which peptide specific CTL recognising myeloma antigens Muc1, HM1.24/BST2, DKK-1 and CT-7/MAGE-C1 could be identified. Furthermore, GM-CSF activated CMRF-56 immunoselected cells pulsed with HLA-A*201 restricted peptides derived from Muc1, HM1.24/BST2 and CT-7/MAGE-C1 could induce CTL capable of lysing both peptide- and myeloma cell line targets in both healthy donors and myeloma patients. These results provide the first evidence of immunogenic HLA-A*201 restricted epitopes of novel myeloma antigen CT-7/MAGE-C1. The data collected in this study supports the application of GM-CSF activated CMRF-56 immunoselected cells loaded with defined myeloma peptide antigens for the therapeutic vaccination of MM patients with minimal residual disease.

Increased participation rates and significant performances of girls and women in sport over the last three decades would have many believing that the barriers and discrimination experienced in the past have been overcome and that continued participation and success into the future is unproblematic. Feminist research has problematized what now seems like acceptance of women’s participation in sport in this postmodern era by considering the location of the female athlete at the intersecting of discourses of femininity, masculinist sport, heterosexuality and homophobia. Situated among these powerful regulating forces, female athletes become subjects attached to often contradictory identities. For instance, the paradox of femininity and athleticism can result in a troubling experience that requires complex negotiation and time-consuming management of gender boundaries and behaviour expectations. Although sport has been considered a liberatory space for women, that view fails to consider that sport continues to maintain the status quo through workings of power politics that sustain oppressive social structures and relations. In this study, the review of literature in Chapter Two illuminates that sport, as it currently exists, perpetuates gender inequality and builds and maintains socio-cultural boundaries of normative femininity and heterosexuality. Unpacking women’s sport experience, therefore, involves exploring the discursive force fields that structure their everyday lives. Immersed in the dynamics of power and resistance, women performing so-called “masculine” activities such as skilled sport performance create a contradictory and precarious location for themselves. This location could be perceived as transgressive and liberating or as one that must negotiate, and possibly resolve, the tension between discursive expectancies and non-normative performances. My study examined the sport experiences of eight female athletes. Each was interviewed three times using a semi-structured interview process. During the initial interview, the participants were asked to provide the history and priority of sport in their lives and speak about the repetitive act of “becoming” an athlete as they make the transitions from other subjectivities. Chapter Four summarizes this conversation with each of the participants. Through a photo-elicitation process, one of the interviews was dedicated to revealing each of the participants’ movements through the social spaces of their daily lives. Another of the interviews was supported by video footage of the athlete as she trained and/or competed in her sport(s). This data collection process allowed for the participants’ multiple subject positions or locations to be spoken by them throughout the conversations. The interviews were transcribed and analyzed using discourse analysis. In order to critique the various discourses that dis/advantage female athletes, the theoretical framework provided by feminist poststructuralism was chosen for this project. Through this perspective, detailed in Chapter Three, an understanding of how social power is exercised over and experienced by women is helpful in knowledge production that supports women’s on-going efforts of contestation and change. For example, continued improvement and achievement in sport performance vi could be the result of new versions of femininity fostered by my critique of the privileged female identity that allows for less docile and more athletic female bodies. Discourse analysis, as described in Chapter Three, allowed for surveying the discursive terrain of the lives of the participants. This method also illuminated the ways of speaking, descriptions and specific images that the athletes used to speak about their sport experiences. The women spoke sport into their lives and created a positive space that featured personal achievement, escape or freedom from the “rest of life”; an activity that supported a healthy body and a positive body image; a place of family support; and a social, fun and accepting environment. In contrast to this, the participants’ sport space was troubled by the management and negotiation that was required by them to continue participation. Even though, as described in Chapter Five, they could speak sport into their lives in a positive way, they also spoke sport out of their lives (or at least further down the priority list) because of the effort that was required to juggle it or balance it within their multiple subjectivities. The sometimes simultaneous and always sequential contradictory gendered discursive force fields of motherhood, the ideal feminine body image, intimate relationships, compulsory heterosexuality, and physical activity required constant strategies of negotiation and management that are described in Chapter Six. A brief concluding chapter summarizes how the participants in this study found themselves frustrated by their “in-between-ness”. They are not athletes in the dominant heteronormative discursive space of male sport (they are “othered”), and they do not fit in the dominant discursive space of privileged femininity. The results of this study reveal that while sport presents itself as a site of empowerment for women, it also perpetuates and maintains traditional patriarchal values. The participants, however, creatively negotiated and renovated that patriarchal space to create a location in which they could evade the strength of dominant discourses and experience the benefits of sport engagement.

Increased participation rates and significant performances of girls and women in sport over the last three decades would have many believing that the barriers and discrimination experienced in the past have been overcome and that continued participation and success into the future is unproblematic. Feminist research has problematized what now seems like acceptance of women’s participation in sport in this postmodern era by considering the location of the female athlete at the intersecting of discourses of femininity, masculinist sport, heterosexuality and homophobia. Situated among these powerful regulating forces, female athletes become subjects attached to often contradictory identities. For instance, the paradox of femininity and athleticism can result in a troubling experience that requires complex negotiation and time-consuming management of gender boundaries and behaviour expectations. Although sport has been considered a liberatory space for women, that view fails to consider that sport continues to maintain the status quo through workings of power politics that sustain oppressive social structures and relations. In this study, the review of literature in Chapter Two illuminates that sport, as it currently exists, perpetuates gender inequality and builds and maintains socio-cultural boundaries of normative femininity and heterosexuality. Unpacking women’s sport experience, therefore, involves exploring the discursive force fields that structure their everyday lives. Immersed in the dynamics of power and resistance, women performing so-called “masculine” activities such as skilled sport performance create a contradictory and precarious location for themselves. This location could be perceived as transgressive and liberating or as one that must negotiate, and possibly resolve, the tension between discursive expectancies and non-normative performances. My study examined the sport experiences of eight female athletes. Each was interviewed three times using a semi-structured interview process. During the initial interview, the participants were asked to provide the history and priority of sport in their lives and speak about the repetitive act of “becoming” an athlete as they make the transitions from other subjectivities. Chapter Four summarizes this conversation with each of the participants. Through a photo-elicitation process, one of the interviews was dedicated to revealing each of the participants’ movements through the social spaces of their daily lives. Another of the interviews was supported by video footage of the athlete as she trained and/or competed in her sport(s). This data collection process allowed for the participants’ multiple subject positions or locations to be spoken by them throughout the conversations. The interviews were transcribed and analyzed using discourse analysis. In order to critique the various discourses that dis/advantage female athletes, the theoretical framework provided by feminist poststructuralism was chosen for this project. Through this perspective, detailed in Chapter Three, an understanding of how social power is exercised over and experienced by women is helpful in knowledge production that supports women’s on-going efforts of contestation and change. For example, continued improvement and achievement in sport performance vi could be the result of new versions of femininity fostered by my critique of the privileged female identity that allows for less docile and more athletic female bodies. Discourse analysis, as described in Chapter Three, allowed for surveying the discursive terrain of the lives of the participants. This method also illuminated the ways of speaking, descriptions and specific images that the athletes used to speak about their sport experiences. The women spoke sport into their lives and created a positive space that featured personal achievement, escape or freedom from the “rest of life”; an activity that supported a healthy body and a positive body image; a place of family support; and a social, fun and accepting environment. In contrast to this, the participants’ sport space was troubled by the management and negotiation that was required by them to continue participation. Even though, as described in Chapter Five, they could speak sport into their lives in a positive way, they also spoke sport out of their lives (or at least further down the priority list) because of the effort that was required to juggle it or balance it within their multiple subjectivities. The sometimes simultaneous and always sequential contradictory gendered discursive force fields of motherhood, the ideal feminine body image, intimate relationships, compulsory heterosexuality, and physical activity required constant strategies of negotiation and management that are described in Chapter Six. A brief concluding chapter summarizes how the participants in this study found themselves frustrated by their “in-between-ness”. They are not athletes in the dominant heteronormative discursive space of male sport (they are “othered”), and they do not fit in the dominant discursive space of privileged femininity. The results of this study reveal that while sport presents itself as a site of empowerment for women, it also perpetuates and maintains traditional patriarchal values. The participants, however, creatively negotiated and renovated that patriarchal space to create a location in which they could evade the strength of dominant discourses and experience the benefits of sport engagement.

Survival of patients with poor prognosis or relapsed haematopoietic malignancies can be markedly improved by allogeneic haematopoietic stem cell transplantation (HSCT). HSCT reconstitutes the immune and haematopoietic systems after myeloablative conditioning and inhibits the recurrence of the malignancy by a graft-versus-leukaemia (GVL) response mediated by donor T cells. However, significant post-transplant complications such as graft-versus-host disease (GVHD) continue to plague the event-free survival of this curative procedure. GVHD is facilitated by donor T cells that recognise histocompatibility antigens on host antigen presenting cells (APC), such as dendritic cells (DC). Current treatment options for GVHD are focused on these T cells. However, these treatments result in an increased incidence of infection, graft rejection and relapse. A novel means of immunosuppression in GVHD is the use of multi-potent, mesenchymal stromal cells (MSC). MSC are non-immunogenic cells that actively suppress T cell function in vitro, and can resolve steroid-refractory GVHD in the clinic. Despite their use in the clinic, there is a paucity of pre-clinical data. Our aim was to investigate the in vivo efficacy of MSC to control GVHD while maintaining the beneficial GVL effect, and to begin to understand the mechanism by which MSC exert their immunosuppressive effects. We isolated and characterised MSC from murine bone/bone marrow and demonstrated that they suppressed T cell proliferation in vitro, even at low ratios of 1 MSC per 100 T cells. This was true of both donor-derived MSC, and MSC derived from unrelated donors (third party). Importantly, we observed that MSC significantly reduced T cell production of the pro-inflammatory cytokines TNFα and IFNγ in culture supernatants and that IFNγ plays a key role in the ability of MSC to suppress T cell proliferation. In vivo, we examined the effects of donor-derived MSC on GVHD severity and onset in two myeloablative murine models of HSCT. A major histocompatibility complex (MHC)-mismatched donor-recipient pair combination was used as a proof–of-principle model [UBI-GFP/BL6 (H-2b)àBALB/c (H-2d)], and an MHC-matched, minor histocompatibility antigen (miHA) mismatched donor-recipient pair combination was used to mimic MHC-matched sibling transplantation [UBI-GFP/BL6 (H-2b)àBALB.B (H-2b)]. We examined a number of variables related to MSC infusion including timing, dose and route of injection. We found that early post transplant infusion of MSC by the intraperitoneal injection was most effective at delaying death from GVHD, compared to pre-transplant infusion or intravenous injection. Furthermore, we found that the dose of MSC was critical, as infusion of too few MSC was ineffective and infusion of too many MSC exacerbated the development of GVHD. Taken together, these results suggest that timing, dose and route of injection are all important factors to be considered to ensure successful therapeutic outcome. To investigate the in vivo mechanism of action, we conducted timed sacrifice experiments in the MHC-mismatched model to determine if MSC altered cytokine secretion and cellular effectors, such as DC, known to play a key role in GVHD. Despite the fact that MSC given post-HSCT enter an environment full of activated DC and IFNγ levels, by day 3 and 6 post infusion, these activated DC and IFNγ levels are decreased compared to controls or mice infused with MSC pre-transplant (p<0.05). This confirmed our in vitro data that IFNγ played an important role in MSC-mediated immunosuppression. In addition, when we removed a major source of IFNγ production in vivo by administering the T cell depleting antibody KT3 to mice with or without MSC, we found that although T cell depletion prolonged survival, MSC were unable to further enhance this effect. This was also true when MSC were used in combination with the conventional immunosuppressant cyclosporine. Finally, we examined whether the infusion of MSC would compromise the GVL effect. We found that whilst MSC could delay the onset of GVHD, in our model they did not alter the anti-tumour effects of the donor T cells. Overall, we have shown that MSC can delay but not prevent death from GVHD when administered at an appropriate time and dose and that IFNγ is required for MSC-mediated immunosuppression in our model. These data suggest that patients undergoing HSCT should be monitored for IFNγ, and administered MSC when high levels are reached. Whilst MSC may be a promising therapy for patients with severe GVHD, we highlight that further investigation is warranted before MSC are accepted for widespread use in the clinic. The risks and benefits for transplant recipients should be carefully considered before utilising MSC to treat or prevent GVHD.

Most signal processing methods were developed for continuous signals. Digital devices, such as the computer, process only discrete signals. This dissertation proposes new techniques to accurately define and efficiently implement an important signal processing method---the time--frequency distribution (TFD)---using discrete signals. The TFD represents a signal in the joint time--frequency domain. Because these distributions are a function of both time and frequency they, unlike traditional signal processing methods, can display frequency content that changes over time. TFDs have been used successfully in many signal processing applications as almost all real-world signals have time-varying frequency content. Although TFDs are well defined for continuous signals, defining and computing a TFD for discrete signals is problematic. This work overcomes these problems by making contributions to the definition, computation, and application of discrete TFDs. The first contribution is a new discrete definition of TFDs. A discrete TFD (DTFD) should be free from the sampling-related distortion known as aliasing and satisfy all the important mathematical properties that the continuous TFD satisfies. Many different DTFD definitions exist but none come close to attaining this ideal. I propose three new components which make up the DTFD: 1) a new discrete Wigner--Ville distribution (DWVD) definition which satisfies all properties, 2) a new discrete analytic signal which minimises aliasing in the DWVD, and 3) a new method to define and convolve the discrete kernel with the DWVD to produce the DTFD. The result: a DTFD definition that, relative to the existing definitions, better approximates the ideal DTFD. The second contribution is two sets of computationally efficient algorithms to compute the proposed DTFD. The first set of algorithms computes the DTFD exactly; the second set requires less memory than the first set by computing time- and, or frequency-decimated versions of the DTFD. Both sets of algorithms reduce the computational load by exploiting symmetries in the DTFD and by constructing kernel-specific algorithms for four different kernel types. The third, and final, contribution is a biomedical application for the proposed DTFD and algorithms. This application is to accurately detect seizure events in newborn electroencephalogram (EEG) signals. Existing detection methods do not perform well enough for use in a clinical setting. I propose a new method which is more robust than existing methods and show how using the proposed DTFD, comparative to an existing DTFD, improves detection performance for this method. In summary, this dissertation makes practical contributions to the area of time--frequency signal processing by proposing an improved DTFD definition, efficient DTFD algorithms, and an improved newborn EEG seizure detection method using DTFDs.

Most signal processing methods were developed for continuous signals. Digital devices, such as the computer, process only discrete signals. This dissertation proposes new techniques to accurately define and efficiently implement an important signal processing method---the time--frequency distribution (TFD)---using discrete signals. The TFD represents a signal in the joint time--frequency domain. Because these distributions are a function of both time and frequency they, unlike traditional signal processing methods, can display frequency content that changes over time. TFDs have been used successfully in many signal processing applications as almost all real-world signals have time-varying frequency content. Although TFDs are well defined for continuous signals, defining and computing a TFD for discrete signals is problematic. This work overcomes these problems by making contributions to the definition, computation, and application of discrete TFDs. The first contribution is a new discrete definition of TFDs. A discrete TFD (DTFD) should be free from the sampling-related distortion known as aliasing and satisfy all the important mathematical properties that the continuous TFD satisfies. Many different DTFD definitions exist but none come close to attaining this ideal. I propose three new components which make up the DTFD: 1) a new discrete Wigner--Ville distribution (DWVD) definition which satisfies all properties, 2) a new discrete analytic signal which minimises aliasing in the DWVD, and 3) a new method to define and convolve the discrete kernel with the DWVD to produce the DTFD. The result: a DTFD definition that, relative to the existing definitions, better approximates the ideal DTFD. The second contribution is two sets of computationally efficient algorithms to compute the proposed DTFD. The first set of algorithms computes the DTFD exactly; the second set requires less memory than the first set by computing time- and, or frequency-decimated versions of the DTFD. Both sets of algorithms reduce the computational load by exploiting symmetries in the DTFD and by constructing kernel-specific algorithms for four different kernel types. The third, and final, contribution is a biomedical application for the proposed DTFD and algorithms. This application is to accurately detect seizure events in newborn electroencephalogram (EEG) signals. Existing detection methods do not perform well enough for use in a clinical setting. I propose a new method which is more robust than existing methods and show how using the proposed DTFD, comparative to an existing DTFD, improves detection performance for this method. In summary, this dissertation makes practical contributions to the area of time--frequency signal processing by proposing an improved DTFD definition, efficient DTFD algorithms, and an improved newborn EEG seizure detection method using DTFDs.

Most signal processing methods were developed for continuous signals. Digital devices, such as the computer, process only discrete signals. This dissertation proposes new techniques to accurately define and efficiently implement an important signal processing method---the time--frequency distribution (TFD)---using discrete signals. The TFD represents a signal in the joint time--frequency domain. Because these distributions are a function of both time and frequency they, unlike traditional signal processing methods, can display frequency content that changes over time. TFDs have been used successfully in many signal processing applications as almost all real-world signals have time-varying frequency content. Although TFDs are well defined for continuous signals, defining and computing a TFD for discrete signals is problematic. This work overcomes these problems by making contributions to the definition, computation, and application of discrete TFDs. The first contribution is a new discrete definition of TFDs. A discrete TFD (DTFD) should be free from the sampling-related distortion known as aliasing and satisfy all the important mathematical properties that the continuous TFD satisfies. Many different DTFD definitions exist but none come close to attaining this ideal. I propose three new components which make up the DTFD: 1) a new discrete Wigner--Ville distribution (DWVD) definition which satisfies all properties, 2) a new discrete analytic signal which minimises aliasing in the DWVD, and 3) a new method to define and convolve the discrete kernel with the DWVD to produce the DTFD. The result: a DTFD definition that, relative to the existing definitions, better approximates the ideal DTFD. The second contribution is two sets of computationally efficient algorithms to compute the proposed DTFD. The first set of algorithms computes the DTFD exactly; the second set requires less memory than the first set by computing time- and, or frequency-decimated versions of the DTFD. Both sets of algorithms reduce the computational load by exploiting symmetries in the DTFD and by constructing kernel-specific algorithms for four different kernel types. The third, and final, contribution is a biomedical application for the proposed DTFD and algorithms. This application is to accurately detect seizure events in newborn electroencephalogram (EEG) signals. Existing detection methods do not perform well enough for use in a clinical setting. I propose a new method which is more robust than existing methods and show how using the proposed DTFD, comparative to an existing DTFD, improves detection performance for this method. In summary, this dissertation makes practical contributions to the area of time--frequency signal processing by proposing an improved DTFD definition, efficient DTFD algorithms, and an improved newborn EEG seizure detection method using DTFDs.

Most signal processing methods were developed for continuous signals. Digital devices, such as the computer, process only discrete signals. This dissertation proposes new techniques to accurately define and efficiently implement an important signal processing method---the time--frequency distribution (TFD)---using discrete signals. The TFD represents a signal in the joint time--frequency domain. Because these distributions are a function of both time and frequency they, unlike traditional signal processing methods, can display frequency content that changes over time. TFDs have been used successfully in many signal processing applications as almost all real-world signals have time-varying frequency content. Although TFDs are well defined for continuous signals, defining and computing a TFD for discrete signals is problematic. This work overcomes these problems by making contributions to the definition, computation, and application of discrete TFDs. The first contribution is a new discrete definition of TFDs. A discrete TFD (DTFD) should be free from the sampling-related distortion known as aliasing and satisfy all the important mathematical properties that the continuous TFD satisfies. Many different DTFD definitions exist but none come close to attaining this ideal. I propose three new components which make up the DTFD: 1) a new discrete Wigner--Ville distribution (DWVD) definition which satisfies all properties, 2) a new discrete analytic signal which minimises aliasing in the DWVD, and 3) a new method to define and convolve the discrete kernel with the DWVD to produce the DTFD. The result: a DTFD definition that, relative to the existing definitions, better approximates the ideal DTFD. The second contribution is two sets of computationally efficient algorithms to compute the proposed DTFD. The first set of algorithms computes the DTFD exactly; the second set requires less memory than the first set by computing time- and, or frequency-decimated versions of the DTFD. Both sets of algorithms reduce the computational load by exploiting symmetries in the DTFD and by constructing kernel-specific algorithms for four different kernel types. The third, and final, contribution is a biomedical application for the proposed DTFD and algorithms. This application is to accurately detect seizure events in newborn electroencephalogram (EEG) signals. Existing detection methods do not perform well enough for use in a clinical setting. I propose a new method which is more robust than existing methods and show how using the proposed DTFD, comparative to an existing DTFD, improves detection performance for this method. In summary, this dissertation makes practical contributions to the area of time--frequency signal processing by proposing an improved DTFD definition, efficient DTFD algorithms, and an improved newborn EEG seizure detection method using DTFDs.

Most signal processing methods were developed for continuous signals. Digital devices, such as the computer, process only discrete signals. This dissertation proposes new techniques to accurately define and efficiently implement an important signal processing method---the time--frequency distribution (TFD)---using discrete signals. The TFD represents a signal in the joint time--frequency domain. Because these distributions are a function of both time and frequency they, unlike traditional signal processing methods, can display frequency content that changes over time. TFDs have been used successfully in many signal processing applications as almost all real-world signals have time-varying frequency content. Although TFDs are well defined for continuous signals, defining and computing a TFD for discrete signals is problematic. This work overcomes these problems by making contributions to the definition, computation, and application of discrete TFDs. The first contribution is a new discrete definition of TFDs. A discrete TFD (DTFD) should be free from the sampling-related distortion known as aliasing and satisfy all the important mathematical properties that the continuous TFD satisfies. Many different DTFD definitions exist but none come close to attaining this ideal. I propose three new components which make up the DTFD: 1) a new discrete Wigner--Ville distribution (DWVD) definition which satisfies all properties, 2) a new discrete analytic signal which minimises aliasing in the DWVD, and 3) a new method to define and convolve the discrete kernel with the DWVD to produce the DTFD. The result: a DTFD definition that, relative to the existing definitions, better approximates the ideal DTFD. The second contribution is two sets of computationally efficient algorithms to compute the proposed DTFD. The first set of algorithms computes the DTFD exactly; the second set requires less memory than the first set by computing time- and, or frequency-decimated versions of the DTFD. Both sets of algorithms reduce the computational load by exploiting symmetries in the DTFD and by constructing kernel-specific algorithms for four different kernel types. The third, and final, contribution is a biomedical application for the proposed DTFD and algorithms. This application is to accurately detect seizure events in newborn electroencephalogram (EEG) signals. Existing detection methods do not perform well enough for use in a clinical setting. I propose a new method which is more robust than existing methods and show how using the proposed DTFD, comparative to an existing DTFD, improves detection performance for this method. In summary, this dissertation makes practical contributions to the area of time--frequency signal processing by proposing an improved DTFD definition, efficient DTFD algorithms, and an improved newborn EEG seizure detection method using DTFDs.