Proteolytic processes are often mediated by highly orchestrated cascades, through which protease enzymes function coordinately to ensure a stepwise activation. This thesis presents experimental data which supports and complements the previously postulated mechanism of KLK (kallikrein-related protease) activation through proteolytic cascades. Further examination of the seminal KLK cascade has revealed several of its key (patho) physiological roles in human reproductive system. Multiple members of the seminal KLK cascade, in particular KLK14, were shown to play a pivotal role in regulating semen liquefaction. The cascade was further shown to be tightly regulated through a series of highly orchestrated feedback loops, to prevent deleterious effects due to aberrant protease activation. Accordingly, a strong association was observed between the expression level of several seminal KLKs, delayed liquefaction, and other markers of semen quality, including semen hyperviscosity. Furthermore, a strong association was found between delayed liquefaction and abnormal sperm motility. Therefore, dysregulated KLK expressions and/or activities were proposed as an underlying cause of male subfertility. Finally, this thesis has provided initial insights into a novel potential function of multiple members of the seminal KLK cascade in activation of the key immune-deviating agent, TGFβ1, in seminal plasma. TGFβ1 activation is postulated to be mediated directly through complete fragmentation or indirectly through partial cleavage and conformational changes of the LAP propeptide motif of the latent TGFβ1. KLK- mediate proteolytic cleavage of the TGFβ1 binding protein, LTBP1, is also suggested as a potential physiological mechanism for release of the membrane-bound latent TGFβ1. Overall, the data provided here may suggest a common regulatory mechanism, involved co-temporally in the two key processes of semen liquefaction and immune-suppression. This might be critical in protecting motile sperms following their release from semen coagulum. Understanding KLK-mediated proteolytic events in seminal plasma can shed light not only on the physiological role of this family of enzymes, but also on some of causes of male subfertility. Accordingly, therapeutic induction of this cascade may be utilized to supplement the current clinical treatment of male subfertility. Conversely, targeted inhibition of key components of the cascade may have potential pharmaceutical utility as a novel topical contraceptive strategy.

This dissertation consists of four papers aimed at understanding the complex relationship between employment and health. One paper is a systematic review of the return to work literature, while the other three papers used secondary data from three cohorts of people with HIV to examine the association between employment and health-related quality of life. The systematic review looked at longitudinal studies that reported health outcomes associated with return to work in relation to other employment trajectories. This review supported the beneficial effect of return to work on health in a variety of populations, times, and settings, and also found evidence that poor health interferes with the prospects of returning to work. Two other papers looked at the association between employment and health-related quality of life in people with HIV; one paper used a cross-sectional sample of people with HIV, while the other paper used a longitudinal sample of men who have sex with men. These two studies found evidence to support the association between employment and both physical and mental health-related quality of life. They also found that employment had a stronger relationship with physical than mental health, suggesting an adaptation process to the experience of unemployment. Finally, another paper examined the cross-sectional association between job security and quality of life in men and women living with HIV. This study found that job security offered additional mental health quality of life benefits, over and above participation in employment alone, for men living with HIV. On the other hand, women benefited from the availability of work, but the perception of job security failed to offer additional health benefits. The current level of evidence on the relationship between work and health in HIV needs to be strengthened by further research to develop and support practical clinical and policy recommendations.

Thesis (MNurs)--University of South Australia, 1997

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