The Expanded Human Kallikrein (KLK) gene family : genomic organisation, tissue specific expression and potential functions

The tissue kallikreins are serine proteases encoded by highly conserved multigene families. The rodent kallikrein (KLK) families are particularly large, consisting of 13 26 genes clustered in one chromosomal locus. It has been recently recognised that the human KLK gene family is of a similar size (15 genes) with the identification of another 12 related genes (KLK4-KLK15) within and adjacent to the original human KLK locus (KLK1-3) on chromosome 19q13.4. The structural organisation and size of these new genes is similar to that of other KLK genes except for additional exons encoding 5 or 3 untranslated regions. Moreover, many of these genes have multiple mRNA transcripts, a trait not observed with rodent genes. Unlike all other kallikreins, the KLK4-KLK15 encoded proteases are less related (25–44%) and do not contain a conventional kallikrein loop. Clusters of genes exhibit high prostatic (KLK2-4, KLK15) or pancreatic (KLK6-13) expression, suggesting evolutionary conservation of elements conferring tissue specificity. These genes are also expressed, to varying degrees, in a wider range of tissues suggesting a functional involvement of these newer human kallikrein proteases in a diverse range of physiological processes.

Third-sector discourses and the future of (un)employment : skilled labor, new technologies, and the meaning of work

In this paper we analyse a 600,000 word corpus comprised of policy statements produced within supranational, national, state and local legislatures about the nature and causes of(un)employment. We identify significant rhetorical and discursive features deployed by third sector (un)employment policy authors that function to extend their legislative grasp to encompass the most intimate aspects of human association.

Seeing music performance : visual influences on perception and experience

Drawing from ethnographic, empirical, and historical / cultural perspectives, we examine the extent to which visual aspects of music contribute to the communication that takes place between performers and their listeners. First, we introduce a framework for understanding how media and genres shape aural and visual experiences of music. Second, we present case studies of two performances, and describe the relation between visual and aural aspects of performance. Third, we report empirical evidence that visual aspects of performance reliably influence perceptions of musical structure (pitch related features) and affective interpretations of music. Finally, we trace new and old media trajectories of aural and visual dimensions of music, and highlight how our conceptions, perceptions and appreciation of music are intertwined with technological innovation and media deployment strategies.

Predication and propagation : a method for analyzing evaluative meanings in technology policy

In this article I outline and demonstrate a synthesis of the methods developed by Lemke (1998) and Martin (2000) for analyzing evaluations in English. I demonstrate the synthesis using examples from a 1.3-million-word technology policy corpus drawn from institutions at the local, state, national, and supranational levels. Lemke's (1998) critical model is organized around the broad 'evaluative dimensions' that are deployed to evaluate propositions and proposals in English. Martin's (2000) model is organized with a more overtly systemic-functional orientation around the concept of 'encoded feeling'. In applying both these models at different times, whilst recognizing their individual usefulness and complementarity, I found specific limitations that led me to work towards a synthesis of the two approaches. I also argue for the need to consider genre, media, and institutional aspects more explicitly when claiming intertextual and heteroglossic relations as the basis for inferred evaluations. A basic assertion made in this article is that the perceived Desirability of a process, person, circumstance, or thing is identical to its 'value'. But the Desirability of anything is a socially and thus historically conditioned attribution that requires significant amounts of institutional inculcation of other 'types' of value-appropriateness, importance, beauty, power, and so on. I therefore propose a method informed by critical discourse analysis (CDA) that sees evaluation as happening on at least four interdependent levels of abstraction.

Community information literacy : developing an Australian research agenda

The majority of information literacy (IL) research has been con ducted within the confi nes of educational or workplace settings. Little to no research has explored IL in community contexts. This paper will consider the current state of IL research within the community setting. The paper uses three re cent IL studies as a vehicle for developing an Australian com munity IL research agenda. Three observations are made about community information literacy (CIL) and CIL research: (i) it is multi- and inter-disciplinary; (ii) it has a learning lens; and (iii) it has a pluralistic approach. The CIL research agenda should be seen as practical and real – it is about real people, doing real things in real life contexts. To achieve this we must bring to gether a research community that is ready to cross boundar ies and forge relationships with other groups. In addition a coherent and structured research agenda should be established.

Predicting effects of monotony on driver’s vigilance

Monotony has been identified as a contributing factor to road crashes. Drivers’ ability to react to unpredictable events deteriorates when exposed to highly predictable and uneventful driving tasks, such as driving on Australian rural roads, many of which are monotonous by nature. Highway design in particular attempts to reduce the driver’s task to a merely lane-keeping one. Such a task provides little stimulation and is monotonous, thus affecting the driver’s attention which is no longer directed towards the road. Inattention contributes to crashes, especially for professional drivers. Monotony has been studied mainly from the endogenous perspective (for instance through sleep deprivation) without taking into account the influence of the task itself (repetitiveness) or the surrounding environment. The aim and novelty of this thesis is to develop a methodology (mathematical framework) able to predict driver lapses of vigilance under monotonous environments in real time, using endogenous and exogenous data collected from the driver, the vehicle and the environment. Existing approaches have tended to neglect the specificity of task monotony, leaving the question of the existence of a “monotonous state” unanswered. Furthermore the issue of detecting vigilance decrement before it occurs (predictions) has not been investigated in the literature, let alone in real time. A multidisciplinary approach is necessary to explain how vigilance evolves in monotonous conditions. Such an approach needs to draw on psychology, physiology, road safety, computer science and mathematics. The systemic approach proposed in this study is unique with its predictive dimension and allows us to define, in real time, the impacts of monotony on the driver’s ability to drive. Such methodology is based on mathematical models integrating data available in vehicles to the vigilance state of the driver during a monotonous driving task in various environments. The model integrates different data measuring driver’s endogenous and exogenous factors (related to the driver, the vehicle and the surrounding environment). Electroencephalography (EEG) is used to measure driver vigilance since it has been shown to be the most reliable and real time methodology to assess vigilance level. There are a variety of mathematical models suitable to provide a framework for predictions however, to find the most accurate model, a collection of mathematical models were trained in this thesis and the most reliable was found. The methodology developed in this research is first applied to a theoretically sound measure of sustained attention called Sustained Attention Response to Task (SART) as adapted by Michael (2010), Michael and Meuter (2006, 2007). This experiment induced impairments due to monotony during a vigilance task. Analyses performed in this thesis confirm and extend findings from Michael (2010) that monotony leads to an important vigilance impairment independent of fatigue. This thesis is also the first to show that monotony changes the dynamics of vigilance evolution and tends to create a “monotonous state” characterised by reduced vigilance. Personality traits such as being a low sensation seeker can mitigate this vigilance decrement. It is also evident that lapses in vigilance can be predicted accurately with Bayesian modelling and Neural Networks. This framework was then applied to the driving task by designing a simulated monotonous driving task. The design of such task requires multidisciplinary knowledge and involved psychologist Rebecca Michael. Monotony was varied through both the road design and the road environment variables. This experiment demonstrated that road monotony can lead to driving impairment. Particularly monotonous road scenery was shown to have the most impact compared to monotonous road design. Next, this study identified a variety of surrogate measures that are correlated with vigilance levels obtained from the EEG. Such vigilance states can be predicted with these surrogate measures. This means that vigilance decrement can be detected in a car without the use of an EEG device. Amongst the different mathematical models tested in this thesis, only Neural Networks predicted the vigilance levels accurately. The results of both these experiments provide valuable information about the methodology to predict vigilance decrement. Such an issue is quite complex and requires modelling that can adapt to highly inter-individual differences. Only Neural Networks proved accurate in both studies, suggesting that these models are the most likely to be accurate when used on real roads or for further research on vigilance modelling. This research provides a better understanding of the driving task under monotonous conditions. Results demonstrate that mathematical modelling can be used to determine the driver’s vigilance state when driving using surrogate measures identified during this study. This research has opened up avenues for future research and could result in the development of an in-vehicle device predicting driver vigilance decrement. Such a device could contribute to a reduction in crashes and therefore improve road safety.

Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia

The kallikreins and kallikrein-related peptidases are serine proteases that control a plethora of developmental and homeostatic phenomena, ranging from semen liquefaction to skin desquamation and blood pressure. The diversity of roles played by kallikreins has stimulated considerable interest in these enzymes from the perspective of diagnostics and drug design. Kallikreins already have well-established credentials as targets for therapeutic intervention and there is increasing appreciation of their potential both as biomarkers and as targets for inhibitor design. Here, we explore the current status of naturally occurring kallikrein protease-inhibitor complexes and illustrate how this knowledge can interface with strategies for rational re-engineering of bioscaffolds and design of small-molecule inhibitors.

Expression of PSA-RP2, an alternatively spliced variant from the PSA gene, is increased in prostate cancer tissues but the protein is not secreted from prostate cancer cells

PSA-RP2 is a variant transcript expressed from the PSA gene that is conserved in gorillas, chimpanzees and humans suggesting a particular relevance for this transcript in these primates. We demonstrated by qRT-PCR that PSA-RP2 is upregulated in prostate cancer compared with benign prostatic hyperplasia tissues. The PSA-RP2 protein was not detected in seminal fluid and was cytoplasmically localised but not secreted from LNCaP or transfected PC3 prostate cells, despite secretion from transfected Cos-7 and HEK293 kidney cell lines. PSA-RP2-transfected PC3 cells showed slightly decreased proliferation and increased migration towards PC3-conditioned medium that could suggest a functional role in prostate cancer.

Extending client-centered support : counselors’ proposals to shift from email to telephone counseling

The availability and use of online counseling approaches has increased rapidly over the last decade. While research has suggested a range of potential affordances and limitations of online counseling modalities, very few studies have offered detailed examinations of how counselors and clients manage asynchronous email counseling exchanges. In this paper we examine email exchanges involving clients and counselors through Kids Helpline, a national Australian counseling service that offers free online, email and telephone counseling for young people up to the age of 25. We employ tools from the traditions of ethnomethodology and conversation analysis to analyze the ways in which counselors from Kids Helpline request that their clients call them, and hence change the modality of their counseling relationship, from email to telephone counseling. This paper shows the counselors’ three multi-layered approaches in these emails as they negotiate the potentially delicate task of requesting and persuading a client to change the trajectory of their counseling relationship from text to talk without placing that relationship in jeopardy.

Non-combinatorial library screening reveals subsite cooperativity and identifies new high-efficiency substrates for kallikrein-related peptidase 14

An array of substrates link the tryptic serine protease, kallikrein-related peptidase 14 (KLK14), to physiological functions including desquamation and activation of signaling molecules associated with inflammation and cancer. Recognition of protease cleavage sequences is driven by complementarity between exposed substrate motifs and the physicochemical signature of an enzyme's active site cleft. However, conventional substrate screening methods have generated conflicting subsite profiles for KLK14. This study utilizes a recently developed screening technique, the sparse matrix library, to identify five novel high-efficiency sequences for KLK14. The optimal sequence, YASR, was cleaved with higher efficiency (k(cat)/K(m)=3.81 ± 0.4 × 10(6) M(-1) s(-1)) than favored substrates from positional scanning and phage display by 2- and 10-fold, respectively. Binding site cooperativity was prominent among preferred sequences, which enabled optimal interaction at all subsites as indicated by predictive modeling of KLK14/substrate complexes. These simulations constitute the first molecular dynamics analysis of KLK14 and offer a structural rationale for the divergent subsite preferences evident between KLK14 and closely related KLKs, KLK4 and KLK5. Collectively, these findings highlight the importance of binding site cooperativity in protease substrate recognition, which has implications for discovery of optimal substrates and engineering highly effective protease inhibitors.

An exploration of affine group laws for elliptic curves

Several forms of elliptic curves are suggested for an efficient implementation of Elliptic Curve Cryptography. However, a complete description of the group law has not appeared in the literature for most popular forms. This paper presents group law in affine coordinates for three forms of elliptic curves. With the existence of the proposed affine group laws, stating the projective group law for each form becomes trivial. This work also describes an automated framework for studying elliptic curve group law, which is applied internally when preparing this work.

Nangkha Nangdrik in the land of the Thunder Dragon : psychology, religion and the potential of mediation in the Kingdom of Bhutan

This article will consider the role that Alternative Dispute Resolution (‘Dham Kha Chen Ki Khendum’ or ‘Nangkha Nangdrik’) currently plays in resolving legal conflict in Bhutan. With a Constitution that has committed to the pursuit of Gross National Happiness, non-adversarial dispute resolution processes that promote continuing relationships and goodwill assume greater importance. One difficulty for Bhutan is that alternative dispute resolution procedures such as mediation (Dhum Drik) are being referred to in enactments of the Bhutanese National Council and National Assembly (bicameral parliament), without a shared understanding as to the characteristics and functionality of these procedures. This article will focus particularly on the current practice of mediation in Bhutan and investigate whether particular models of mediation are more suited to the Bhutanese context, given the particularities of Bhutanese culture, the search for gross national happiness, psychological understandings of happiness and the omnipresent influence of Mahayana Buddhism.

Kallikrein 14 is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness

Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.