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This dissertation consists of a review of the N2 component of the ERP and five experiments investigating the role of complex visual object categorization in modulating the N2 and two other ERP components: the P300, and a late prefrontal positivity. In the review, we focus on paradigms that elicit N2 components with an anterior scalp distribution, namely cognitive control, novelty, and sequential matching, arguing that the anterior N2 should be divided into separate control- and mismatch-related subcomponents. The experiments manipulated categorical typicality and the presence of conflicting information as participants categorized multi-featured artificial animals. In Experiments 1 and 2, rule-irrelevant features were correlated with particular categories during training. During transfer, participants applied a one- dimensional rule to stimuli with category-congruent, category-incongruent, or novel rule-irrelevant features. Category-incongruent and novel features delayed RT and P300 latency, but had no effect on the N2. Experiment 3 used a two-dimensional rule to create conflict between rule-relevant features. Conflict resulted in prolonged RTs, P300 latency, and larger amplitudes of a prefrontal positive component, but had no impact on the N2. Novel features did enhance the N2 relative to frequent features. In Experiments 4 and 5, participants categorized stimuli using a more complex three dimensional rule. Conflicting stimuli shared two features with one prototype and one feature with a second prototype while prototypes contained no conflicting information. A third category contained stimuli with either common or novel features. Again, perceptual novelty, but not conflict, increased the amplitude of the N2. Compared to prototypes, stimuli with conflicting information slowed reaction times but had no effect on P300 latency, instead enhancing a late prefrontal positive component. These results suggest limitations on the generality of the N2's sensitivity to conflicting information, while confirming its sensitivity to attended visual novelty. We suggest that, while P300 latency tracks stimulus evaluation time, application of a complex categorization rule requires a later stage of evaluation involving prefrontal cortex. In very complex rules, computations indexed by the P3 may be terminated early in favor of computations in PFC.

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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.

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