Risk management in the Lusoponte concession : a case study of the two bridges in Lisbon, Portugal

The case study of Lusoponte illustrates the concession awarded by the Portuguese Government to finance, design, build and operate two bridges over the Tagus in Lisbon, Portugal. It includes an overview of the project's background and an analysis of the main risk categories stating both the actual risks encountered and the mitigation measures adopted. Throughout the project a great attention was given to whole life cycle costs, and gains in efficiency and cost control. Among the lessons that can be learned from both the public and private sector is that a complete risk management analysis must include not only the technical factors but also a realistic assessment of environmental and social risks. These were the risks that were somewhat overseen and that caused the main problems to the project's development.

Proton-transfer versus nontransfer in compounds of the diazo-dye precursor 4-(phenyldiazenyl) aniline (aniline yellow) with strong organic acids: the 5-sulfosalicylate and the dichroic benzenesulfonate salts, and the 1:2 adduct with 3,5-dinitrobenzoic

The structures of two 1:1 proton-transfer red-black dye compounds formed by reaction of aniline yellow [4-(phenyldiazenyl)aniline] with 5-sulfosalicylic acid and benzenesulfonic acid, and a 1:2 nontransfer adduct compound with 3,5-dinitrobenzoic acid have been determined at either 130 or 200 K. The compounds are 2-(4-aminophenyl)-1-phenylhydrazin-1-ium 3-carboxy-4-hydroxybenzenesulfonate methanol solvate, C12H12N3+.C7H5O6S-.CH3OH (I), 2-(4-aminophenyl)-1-hydrazin-1-ium 4-(phenydiazinyl)anilinium bis(benzenesulfonate), 2C12H12N3+.2C6H5O3S-, (II) and 4-(phenyldiazenyl)aniline-3,5-dinitrobenzoic acid (1/2) C12H11N3.2C~7~H~4~N~2~O~6~, (III). In compound (I) the diaxenyl rather than the aniline group of aniline yellow is protonated and this group subsequently akes part in a primary hydrogen-bonding interaction with a sulfonate O-atom acceptor, producing overall a three-dimensional framework structure. A feature of the hydrogen bonding in (I) is a peripheral edge-on cation-anion association involving aromatic C--H...O hydrogen bonds, giving a conjoint R1/2(6)R1/2(7)R2/1(4)motif. In the dichroic crystals of (II), one of the two aniline yellow species in the asymmetric unit is diazenyl-group protonated while in the other the aniline group is protonated. Both of these groups form hydrogen bonds with sulfonate O-atom acceptors and thee, together with other associations give a one-dimensional chain structure. In compound (III), rather than proton-transfer, there is a preferential formation of a classic R2/2(8) cyclic head-to-head hydrogen-bonded carboxylic acid homodimer between the two 3,5-dinitrobenzoic acid molecules, which in association with the aniline yellow molecule that is disordered across a crystallographic inversion centre, result in an overall two-dimensional ribbon structure. This work has shown the correlation between structure and observed colour in crystalline aniline yellow compounds, illustrated graphically in the dichroic benzenesulfonate compound.

Art and the sublime : the paradox of indeterminacy unknowing and (dis)orientation in the presentation of the unpresentable

the (dis)orientation of thought in its encounter with art can be understood as the direct result of an encounter with indeterminacy as a lack in meaning. As an artist I am aware of how this indeterminacy impacts on the perceived value and authority of the artistic voice and in particular its value as a research voice. This paper explores this indeterminacy of meaning, as a profound and disturbing unknowing characteristic of the sublime and argues its value to advanced thought and for any methodological understanding of practice-led research. Lyotard described the sublime as an ‘understanding’ through which art and its associated practices may be able to resist an all too easy assimilation by the public as just a consumer commodity. His thought represents an attempt to both politically and philosophically understand art’s, and particularly abstract painting’s, affect as a state of profound and positive unknowing. To talk of the sublime in art is to speak of the suspension of any comfortable certainty in being and instead to engage with the real as a limit to meaning and knowing. It is to talk of the presentation of the unpresentable as a momentary but significant dissolution of representation. This understanding of the sublime is then further explored through the cultural phenomena of the monochrome painting and applied to the work of the two contemporary artists, Franz Erhard Walter and Günter Umberg. Initially the monochrome was understood as an attempt to go beyond traditional representation and present the unpresentable. In the one hundred years or so since that initial move this understanding has broadened. The monochrome now presents itself as a genre or even project within visual art but it still has much to teach us. In the concretely abstract and performative artworks of Franz Erhard Walter and Günter Umberg, traces of this ambition remain and their work can be seen to pose questions probing our understandings and experiences of artistic meaning, its value and the real.

Flagging Spaces : exploring the myth of the Australian beach as an egalitarian space

The Australian beach is now accepted as a significant part of Australian national culture and identity. However, Huntsman (2001) and Booth (2001) both believe that the beach is dying: “intellectuals have failed to apply to the beach the attention they have lavished on the bush…” (Huntsman 2001, 218). Yet the beach remains a prominent image in contemporary literature and film; authors such as Tim Winton and Robert Drewe frequently set their stories in and around the coast. Although initially considered a space of myth (Fiske, Hodge, and Turner 1987), Meaghan Morris labelled the beach as ‘ordinary’ (1998), and as recently as 2001 in the wake of the Sydney Olympic Games, Bonner, McKee, and Mackay termed the beach ‘tacky’ and ‘familiar’. The beach, it appears, defies an easy categorisation. In fact, I believe the beach is more than merely mythic or ordinary, or a combination of the two. Instead it is an imaginative space, seamlessly shifting its metaphorical meanings dependent on readings of the texts. My studies examine the beach through five common beach myths; this paper will explore the myth of the beach as an egalitarian space. Contemporary Australian national texts no longer conform to these mythical representations – (in fact, was the beach ever a space of equality?), instead creating new definitions for the beach space that continually shifts in meaning. Recent texts such as Tim Winton’s Breath (2008) and Stephen Orr’s Time’s Long Ruin (2010) lay a more complex metaphorical meaning upon the beach space. This paper will explore the beach as a space of egalitarianism in conjunction with recent Australian fiction and films in order to discover how the contemporary beach is represented.

A comparison of the psychological, social, and legal factors contributing to speeding and drink driving behaviour

Within Australia, motor vehicle injury is the leading cause of hospital admissions and fatalities. Road crash data reveals that among the factors contributing to crashes in Queensland, speed and alcohol continue to be overrepresented. While alcohol is the number one contributing factor to fatal crashes, speeding also contributes to a high proportion of crashes. Research indicates that risky driving is an important contributor to road crashes. However, it has been debated whether all risky driving behaviours are similar enough to be explained by the same combination of factors. Further, road safety authorities have traditionally relied upon deterrence based countermeasures to reduce the incidence of illegal driving behaviours such as speeding and drink driving. However, more recent research has focussed on social factors to explain illegal driving behaviours. The purpose of this research was to examine and compare the psychological, legal, and social factors contributing to two illegal driving behaviours: exceeding the posted speed limit and driving when over the legal blood alcohol concentration (BAC) for the drivers licence type. Complementary theoretical perspectives were chosen to comprehensively examine these two behaviours including Akers’ social learning theory, Stafford and Warr’s expanded deterrence theory, and personality perspectives encompassing alcohol misuse, sensation seeking, and Type-A behaviour pattern. The program of research consisted of two phases: a preliminary pilot study, and the main quantitative phase. The preliminary pilot study was undertaken to inform the development of the quantitative study and to ensure the clarity of the theoretical constructs operationalised in this research. Semi-structured interviews were conducted with 11 Queensland drivers recruited from Queensland Transport Licensing Centres and Queensland University of Technology (QUT). These interviews demonstrated that the majority of participants had engaged in at least one of the behaviours, or knew of someone who had. It was also found among these drivers that the social environment in which both behaviours operated, including family and friends, and the social rewards and punishments associated with the behaviours, are important in their decision making. The main quantitative phase of the research involved a cross-sectional survey of 547 Queensland licensed drivers. The aim of this study was to determine the relationship between speeding and drink driving and whether there were any similarities or differences in the factors that contribute to a driver’s decision to engage in one or the other. A comparison of the participants self-reported speeding and self-reported drink driving behaviour demonstrated that there was a weak positive association between these two behaviours. Further, participants reported engaging in more frequent speeding at both low (i.e., up to 10 kilometres per hour) and high (i.e., 10 kilometres per hour or more) levels, than engaging in drink driving behaviour. It was noted that those who indicated they drove when they may be over the legal limit for their licence type, more frequently exceeded the posted speed limit by 10 kilometres per hour or more than those who complied with the regulatory limits for drink driving. A series of regression analyses were conducted to investigate the factors that predict self-reported speeding, self-reported drink driving, and the preparedness to engage in both behaviours. In relation to self-reported speeding (n = 465), it was found that among the sociodemographic and person-related factors, younger drivers and those who score high on measures of sensation seeking were more likely to report exceeding the posted speed limit. In addition, among the legal and psychosocial factors it was observed that direct exposure to punishment (i.e., being detected by police), direct punishment avoidance (i.e., engaging in an illegal driving behaviour and not being detected by police), personal definitions (i.e., personal orientation or attitudes toward the behaviour), both the normative and behavioural dimensions of differential association (i.e., refers to both the orientation or attitude of their friends and family, as well as the behaviour of these individuals), and anticipated punishments were significant predictors of self-reported speeding. It was interesting to note that associating with significant others who held unfavourable definitions towards speeding (the normative dimension of differential association) and anticipating punishments from others were both significant predictors of a reduction in self-reported speeding. In relation to self-reported drink driving (n = 462), a logistic regression analysis indicated that there were a number of significant predictors which increased the likelihood of whether participants had driven in the last six months when they thought they may have been over the legal alcohol limit. These included: experiences of direct punishment avoidance; having a family member convicted of drink driving; higher levels of Type-A behaviour pattern; greater alcohol misuse (as measured by the AUDIT); and the normative dimension of differential association (i.e., associating with others who held favourable attitudes to drink driving). A final logistic regression analysis examined the predictors of whether the participants reported engaging in both drink driving and speeding versus those who reported engaging in only speeding (the more common of the two behaviours) (n = 465). It was found that experiences of punishment avoidance for speeding decreased the likelihood of engaging in both speeding and drink driving; whereas in the case of drink driving, direct punishment avoidance increased the likelihood of engaging in both behaviours. It was also noted that holding favourable personal definitions toward speeding and drink driving, as well as higher levels of on Type-A behaviour pattern, and greater alcohol misuse significantly increased the likelihood of engaging in both speeding and drink driving. This research has demonstrated that the compliance with the regulatory limits was much higher for drink driving than it was for speeding. It is acknowledged that while speed limits are a fundamental component of speed management practices in Australia, the countermeasures applied to both speeding and drink driving do not appear to elicit the same level of compliance across the driving population. Further, the findings suggest that while the principles underpinning the current regime of deterrence based countermeasures are sound, current enforcement practices are insufficient to force compliance among the driving population, particularly in the case of speeding. Future research should further examine the degree of overlap between speeding and drink driving behaviour and whether punishment avoidance experiences for a specific illegal driving behaviour serve to undermine the deterrent effect of countermeasures aimed at reducing the incidence of another illegal driving behaviour. Furthermore, future work should seek to understand the factors which predict engaging in speeding and drink driving behaviours at the same time. Speeding has shown itself to be a pervasive and persistent behaviour, hence it would be useful to examine why road safety authorities have been successful in convincing the majority of drivers of the dangers of drink driving, but not those associated with speeding. In conclusion, the challenge for road safety practitioners will be to convince drivers that speeding and drink driving are equally risky behaviours, with the ultimate goal to reduce the prevalence of both behaviours.

A population genomics overview of the neuronal nitric oxide synthase (nNOS) gene and its relationship to migraine susceptibility

The ubiquitous chemical messenger molecule nitric oxide (NO) has been implicated in a diverse range of biological activities including neurotransmission, smooth muscle motility and mediation of nociception. Endogenous synthesis of NO by the neuronal isoform of the nitric oxide synthase gene family has an essential role within the central and peripheral nervous systems in addition to the autonomic innervation of cerebral blood vessels. To investigate the potential role of NO and more specifically the neuronal nitric oxide synthase (nNOS) gene in migraine susceptibility, we investigated two microsatellite repeat variants residing within the 5′ and 3′ regions of the nNOS gene. Population genomic evaluation of the two nNOS repeat variants indicated significant linkage disequilibrium between the two loci. Z-DNA conformational sequence structures within the 5′ region of the nNOS gene have the potential to enhance or repress gene promoter activity. We suggest that genetic analysis of this 5′ repeat variant is the more functional variant expressing gene wide information that could affect endogenous NO synthesis and potentially result in diseased states. However, no association with migraine (with or without aura) was seen in our extensive case-control cohort (n = 579 affected with matched controls), when both the 5′ and 3′ genetic variants were investigated.

Photoelectron spectroscopic study of the oxyallyl diradical

The photoelectron spectrum of the oxyallyl (OXA) radical anion has been measured. The radical anion has been generated in the reaction of the atomic oxygen radical anion (O center dot-) with acetone. Three low-lying electronic states of OXA have been observed in the spectrum. Electronic structure calculations have been performed for the triplet states (B-3(2) and B-3(1)) of OXA and the ground doublet state ((2)A(2)) of the radical anion using density, functional theory (DFT). Spectral simulations have been carried out for the triplet statics based on the results of the DFT calculations. The simulation identifies a vibrational progression of the CCC bending mode of the B-3(2) state of OXA in the lower electron binding energy (eBE) portion of the spectrum. On top of the B-3(2) feature, however, the experimental spectrum exhibits additional photoelectron peaks whose angular distribution is distinct from that for the vibronic peaks of the B-3(2) state. Complete active space self-consistent field (CASSCF) method and second-order perturbation theory based on the CASSCF wave function (CASPT2) have been employed to study the lowest singlet state ((1)A(1)) of OXA. The simulation based on the results of these electronic structure calculations establishes that the overlapping peaks represent the vibrational ground level of the (1)A(1) state and its vibrational progression of the CO stretching mode. The A, state is the lowest electronic state of,OXA, and the electron affinity (EA) of OXA is 1.940 +/- 0.010 eV. The B-3(2) state is the first excited state with an electronic term energy of 55 +/- 2 meV. The widths of the vibronic peaks of the (X) over tilde (1)A(1) state are much broader than those of the (a) over tilde B-3(2) state, implying that the (1)A(1) state is indeed a transition state. The CASSCF and CASPT2 calculations suggest that the (1)A(1) state is at a potential maximum along the nuclear coordinate representing disrotatory motion of the two methylene groups, which leads to three-membered-ring formation, i.e., cydopropanone. The simulation of (b) over tilde B-3(1) OXA reproduces the higher eBE portion of the spectrum very well. The term energy of the B-3(1) state is 0.883 +/- 0.012 eV. Photoelectron spectroscopic measurements have also been conducted for the other ion products of the O center dot- reaction with acetone. The photoelectron imaging spectrum of the acetylcarbene (AC) radical anion exhibits a broad, structureless feature, which is assigned to the (X) over tilde (3)A '' state of AC. The ground ((2)A '') and first excited ((2)A') states of the 1-methylvinoxy (1-MVO) radical have been observed in the photoelectron spectrum of the 1-MVO ion, and their vibronic structure has been analyzed.

Reactions of the hydroperoxide anion with dimethyl methylphosphonate in an ion trap mass spectrometer : evidence for a gas phase alpha-effect

The gas phase degradation reactions of the chemical warfare agent (CWA) simulant, dimethyl methylphosphonate (DMMP), with the hydroperoxide anion (HOO(-)) were investigated using a modified quadrupole ion trap mass spectrometer. The HOO(-) anion reacts readily with neutral DMMP forming two significant product ions at m/z 109 and m/z 123. The major reaction pathways correspond to (i) the nucleophilic substitution at carbon to form \[CH(3)P(O)(OCH(3))O](-) (m/z 109) in a highly exothermic process and (ii) exothermic proton transfer. The branching ratios of the two reaction pathways, 89% and 11% respectively, indicate that the former reaction is significantly faster than the latter. This is in contrast to the trend for the methoxide anion with DMMP, where proton transfer dominates. The difference in the observed reactivities of the HOO(-) and CH(3)O(-) anions can be considered as evidence for an a-effect in the gas phase and is supported by electronic structure calculations at the B3LYP/aug-cc-pVTZ//B3LYP/6-31+G(d) level of theory that indicate the S(N)2(carbon) process has an activation energy 7.8 kJ mol(-1) lower for HOO(-) as compared to CH(3)O(-). A similar alpha-effect was calculated for nucleophilic addition-elimination at phosphorus, but this process an important step in the perhydrolysis degradation of CWAs in solution - was not observed to occur with DMMP in the gas phase. A theoretical investigation revealed that all processes are energetically accessible with negative activation energies. However, comparison of the relative Arrhenius pre-exponential factors indicate that substitution at phosphorus is not kinetically competitive with respect to the S(N)2(carbon) and deprotonation processes.

Strategic targeting of the PI3K–NFκB axis in cisplatin-resistant NSCLC

Chemoresistance is a major therapeutic challenge to overcome in NSCLC, in order to improve the current survival rates of <15% at 5 years. We and others have shown increased PI3K signaling in NSCLC to be associated with a more aggressive disease, and a poorer prognosis. In this study, targeted inhibition of three strategic points of the PI3K–NFκB axis was performed with the aim of exploiting vulnerabilities in cisplatin-resistant NSCLC cells. Cisplatin-resistant cell lines were previously generated through prolonged exposure to the drug. Expression of PI3K and NFκB pathway-related genes were compared between cisplatin-resistant cells and their matched parent cells using a gene expression array, qRT-PCR, DNA sequencing, western blot, and immunofluorescence. Targeted inhibition was performed using GDC-0980, a dual PI3K–mTOR inhibitor currently in Phase II clinical trials in NSCLC, and DHMEQ, an inhibitor of NFκB translocation which has been used extensively both in vitro and in vivo. Effects of the two inhibitors were assessed by BrdU proliferation assay and multiparameter viability assay. NFKBIA was shown to be 12-fold overexpressed in cisplatin-resistant cells, with no mutations present in exons 3, 4, or 5 of the gene. Corresponding overexpression of IκBα was also observed. Treatment with DHMEQ (but not GDC-0980) led to significantly enhanced effects on viability and proliferation in cisplatin-resistant cells compared with parent cells. We conclude that NFκB inhibition represents a more promising strategy than PI3K–mTOR inhibition for treatment in the chemoresistance setting in NSCLC.

Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P < 10 4). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P < 10 10) and found evidence for an additional independent association in 4q22/SNCA.A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease. © The Author 2010. Published by Oxford University Press.

Tuning the valence of the cerium center in (Na)phthalocyaninato and porphyrinato cerium double-deckers by changing the nature of the tetrapyrrole ligands

A series of 7 cerium double-decker complexes with various tetrapyrrole ligands including porphyrinates, phthalocyaninates, and 2,3-naphthalocyaninates have been prepared by previously described methodologies and characterized with elemental analysis and a range of spectroscopic methods. The molecular structures of two heteroleptic \[(na)phthalocyaninato](porphyrinato) complexes have also been determined by X-ray diffraction analysis which exhibit a slightly distorted square antiprismatic geometry with two domed ligands. Having a range of tetrapyrrole ligands with very different electronic properties, these compounds have been systematically investigated for the effects of ligands on the valence of the cerium center. On the basis of the spectroscopic (UV−vis, near-IR, IR, and Raman), electrochemical, and structural data of these compounds and compared with those of the other rare earth(III) counterparts reported earlier, it has been found that the cerium center adopts an intermediate valence in these complexes. It assumes a virtually trivalent state in cerium bis(tetra-tert-butylnaphthalocyaninate) as a result of the two electron rich naphthalocyaninato ligands, which facilitate the delocalization of electron from the ligands to the metal center. For the rest of the cerium double-deckers, the cerium center is predominantly tetravalent. The valences (3.59−3.68) have been quantified according to their LIII-edge X-ray absorption near-edge structure (XANES) profiles.

Modulation of the SHBG signalling axis

Sex hormone-binding globulin (SHBG) is a homodimeric plasma glycoprotein that is the major sex steroid carrier-protein in the bloodstream and functions also as a key regulator of steroid bioavailability within target tissues, such as the prostate. Additionally, SHBG binds to prostatic cell membranes via the putative and unidentified SHBG receptor (RSHBG), activating a signal transduction pathway implicated in stimulating both proliferation and expression of prostate specific antigen (PSA) in prostate cell lines in vitro. A yeast-two hybrid assay suggested an interaction between SHBG and kallikrein-related protease (KLK) 4, which is a serine protease implicated in the progression of prostate cancer. The potential interaction between these two proteins was investigated in this PhD thesis to determine whether SHBG is a proteolytic substrate of KLK4 and other members of the KLK family including KLK3/PSA, KLK7 and KLK14. Furthermore, the effects from SHBG proteolytic degradation on SHBG-regulated steroid bioavailability and the activation of the putative RSHBG signal transduction pathway were examined in the LNCaP prostate cancer cell line. SHBG was found to be a proteolytic substrate of the trypsin-like KLK4 and KLK14 in vitro, yielding several proteolysis fragments. Both chymotrypsin-like PSA and KLK7 displayed insignificant proteolytic activity against SHBG. The kinetic parameters of SHBG proteolysis by KLK4 and KLK14 demonstrate a strong enzyme-substrate binding capacity, possessing a Km of 1.2 ± 0.7 µM and 2.1 ± 0.6 µM respectively. The catalytic efficiencies (kcat/Km) of KLK4 and KLK14 proteolysis of SHBG were 1.6 x 104 M-1s-1 and 3.8 x 104 M-1s-1 respectively, which were comparable to parameters previously reported for peptide substrates. N-terminal sequencing of the fragments revealed cleavage near the junction of the N- and C-terminal laminin globulin-like (G-like) domains of SHBG, resulting in the division of the two globulins and ultimately the full degradation of these fragments by KLK4 and KLK14 over time. Proteolytic fragments that may retain steroid binding were rapidly degraded by both proteases, while fragments containing residues beyond the steroid binding pocket were less degraded over the same period of time. Degradation of SHBG was inhibited by the divalent metal cations calcium and zinc for KLK4, and calcium, zinc and magnesium for KLK14. The human secreted serine protease inhibitors (serpins), α1-antitrypsin and α2-antiplasmin, inhibited KLK4 and KLK14 proteolysis of SHBG; α1-antichymotrypsin inhibited KLK4 but not KLK14 activity. The inhibition by these serpins was comparable and in some cases more effective than general trypsin protease inhibitors such as aprotinin and phenylmethanesulfonyl fluoride (PMSF). The binding of 5α-dihydrotestosterone (DHT) to SHBG modulated interactions with KLK4 and KLK14. Steroid-free SHBG was more readily digested by both enzymes than DHT-bound SHBG. Moreover, a binding interaction exists between SHBG and pro-KLK4 and pro-KLK14, with DHT strengthening the binding to pro-KLK4 only. The inhibition of androgen uptake by cultured prostate cancer cells, mediated by SHBG steroid-binding, was examined to assess whether SHBG proteolysis by KLK4 and KLK14 modulated this process. Proteolytic digestion eliminated the ability of SHBG to inhibit the uptake of DHT from conditioned media into LNCaP cells. Therefore, the proteolysis of SHBG by KLK4 and KLK14 increased steroid bioavailability in vitro, leading to an increased uptake of androgens by prostate cancer cells. Interestingly, different transcriptional responses of PSA and KLK2, which are androgen-regulated genes, to DHT-bounsd SHBG treatment were observed between low and high passage number LNCaP cells (lpLNCaP and hpLNCaP respectively). HpLNCaP cells treated with DHT-bound SHBG demonstrated a significant synergistic upregulation of PSA and KLK2 above DHT or SHBG treatment alone, which is similar to previously reported downstream responses from RSHBG-mediated signaling activation. As this result was not seen in lpLNCaP cells, only hpLNCaP cells were further investigated to examine the modulation of potential RSHBG activity by KLK4 and KLK14 proteolysis of SHBG. Contrary to reported results, no increase in intracellular cAMP was observed in hpLNCaP cells when treated with SHBG in the presence and absence of either DHT or estradiol. As a result, the modulation of RSHBG-mediated signaling activation could not be determined. Finally, the identification of the RSHBG from both breast (MCF-7) and prostate cancer (LNCaP) cell lines was attempted. Fluorescently labeled peptides corresponding to the putative receptor binding domain (RBD) of SHBG were shown to be internalized by MCF-7 cells. Crosslinking of the RBD peptide to the cell surfaces of both MCF-7 and LNCaP cells, demonstrated the interaction of the peptide with several targets. These targets were then captured using RBD peptides synthesized onto a hydrophilic scaffold and analysed by mass spectrometry. The samples captured by the RBD peptide returned statistically significantly matches for cytokeratin 8, 18 and 19 as well as microtubule-actin crosslinking factor 1, which may indicate a novel interaction between SHBG and these proteins, but ultimately failed to detect a membrane receptor potentially responsible for the putative RSHBG-mediated signaling. This PhD project has reported the proteolytic processing of SHBG by two members of the kallikrein family, KLK4 and KLK14. The effect of SHBG proteolysis by KLK4 and KLK14 on RSHBG-mediated signaling activation was unable to be determined as the reported signal transduction pathway was not activated after treatment with SHBG, in combination with either DHT or estradiol. However, the digestion of SHBG by these two proteases positively regulated androgen bioavailability to prostate cancer cells in vitro. The increased uptake of androgens is deleterious in prostate cancer due to the promotion of proliferation, metastasis, invasion and the inhibition of apoptosis. The increased bioavailability of androgens, from SHBG proteolysis by KLK4 and KLK14, may therefore promote both carcinogenesis and progression of prostate cancer. Finally, this information may contribute to the development of therapeutic treatment strategies for prostate cancer by inhibiting the proteolysis of SHBG, by KLK4 and KLK14, to prevent the increased uptake of androgens by hormone-dependent cancerous tissues.

Comparison of three expert elicitation methods for logistic regression on predicting the presence of the threatened brush-tailed rock-wallaby petrogale penicillata

Numerous expert elicitation methods have been suggested for generalised linear models (GLMs). This paper compares three relatively new approaches to eliciting expert knowledge in a form suitable for Bayesian logistic regression. These methods were trialled on two experts in order to model the habitat suitability of the threatened Australian brush-tailed rock-wallaby (Petrogale penicillata). The first elicitation approach is a geographically assisted indirect predictive method with a geographic information system (GIS) interface. The second approach is a predictive indirect method which uses an interactive graphical tool. The third method uses a questionnaire to elicit expert knowledge directly about the impact of a habitat variable on the response. Two variables (slope and aspect) are used to examine prior and posterior distributions of the three methods. The results indicate that there are some similarities and dissimilarities between the expert informed priors of the two experts formulated from the different approaches. The choice of elicitation method depends on the statistical knowledge of the expert, their mapping skills, time constraints, accessibility to experts and funding available. This trial reveals that expert knowledge can be important when modelling rare event data, such as threatened species, because experts can provide additional information that may not be represented in the dataset. However care must be taken with the way in which this information is elicited and formulated.

Who's afraid of the dark? Transpower New Zealand Ltd

On 12 June 2006, the lights went out in New Zealand’s largest city and major commercial centre, Auckland. Business was disrupted and many thousands of people inconvenienced. The unscheduled power cut was the latest in a series of electric power problems in New Zealand over the past decade. Attention turned to state-owned enterprise [SOE] Transpower, which was in charge of maintaining and developing New Zealand’s national electricity grid. The problem of 12 June was traced to two shackles in poor condition, small but essential parts of the electricity grid infrastructure. Closer examination of New Zealand’s electricity sector indicated these shackles were merely the tip of a power supply iceberg. Transpower’s Chief Executive, Ralph Craven, was now answerable to the Prime Minister for the issues creating the problems, and a workable solution to fix them. Transpower Chief Executive Ralph Craven needed to produce answers that went well beyond the problem of the two faulty shackles. The power crisis had brought to the fore wider issues of roles, responsibilities, and expectations in relation to the supply of electric power in New Zealand. Transpower was contending with these issues on a daily basis; however, the incident on 12 June publicly highlighted the urgent need for solutions that served the stakeholders in this critical industry.