The mechanism of maturation of insulin-like growth factor-1

This study, to elucidate the role of des(1-3)IGF-I in the maturation of IGF-I,used two strategies. The first was to detect the presence of enzymes in tissues, which would act on IGF-I to produce des(1-3)IGF-I, and the second was to detect the potential products of such enzymic activity, namely Gly-Pro-Glu(GPE), Gly-Pro(GP) and des(l- 3)IGF-I. No neutral tripeptidyl peptidase (TPP II), which would release the tripeptide GPE from IGF-I, was detected in brain, urine nor in red or white blood cells. The TPPlike activity which was detected, was attributed to a combined action of a dipeptidyl peptidase (DPP N) and an aminopeptidase (AP A). A true TPP II was, however, detected in platelets. Two purified TPP II enzymes were investigated but they did not release GPE from IGF-I under a variety of conditions. Consequently, TPP II seemed unlikely to participate in the formation of des(1-3)IGF-I. In contrast, an acidic tripeptidyl peptidase activity (TPP I) was detected in brain and colostrum, the former with a pH optimum of 4.5 and the latter 3.8. It seems likely that such an enzyme would participate in the formation of des( 1-3 )IGF-I in these tissues in vitro, ie. that des(1-3)IGF-I may have been produced as an artifact in the isolation of IGF-I from brain and colostrum in acidic conditions. This contrasts with suggestions of an in vivo role for des(1-3)IGF-I, as reported by others. The activity of a dipeptidyl peptidase N (DPP N) from urine, which should release the dipeptide GP from IGF-I, was assessed under a variety of conditions and with a variety of additives and potential enzyme stimulants, but there was no release of GP. The DPP N also exhibited a transferase activity with synthetic substrates in the presence of dipeptides, at lower concentrations than previously reported for other acceptors or other proteolytic enzymes. In addition, a low concentration of a product,possibly the tetrapeptide Gly-Pro-Gly-Leu, was detected with the action of the enzyme on IGF-I in the presence of the dipeptide Gly-Leu. As part of attempts to detect tissue production of des(1-3)IGF-I, a monoclonal antibody (MAb ), directed towards the GPE- end ofiGF-I was produced by immunisation with a 10-mer covalently attached to a carrier protein. By the use of indirect ELISA and inhibitor studies, the MAb was shown to selectively recognise peptides with anNterminal GPE- sequence, and applied to the indirect detection of des(1-3)IGF-I. The concentration of GPE in brain, measured by mass spectrometry ( MS), was low, and the concentration of total IGF-I (measured by ELISA with a commercial polyclonal antibody [P Ab]) was 40 times higher at 50 nmol/kg. This also, was not consistent with the action of a tripeptidyl peptidase in brain that converted all IGF-I to des(1-3)IGF-I plus GPE. Contrasting ELISA results, using the MAb prepared in this study, suggest an even higher concentration of intact IGF-I of 150 nmollkg. This would argue against the presence of any des( 1-3 )IGF-I in brain, but in turn, this indicates either the presence of other substances containing a GPE amino-terminus or other cross reacting epitope. Although the results of the specificity studies reported in Chapter 5 would make this latter possibility seem unlikely, it cannot be completely excluded. No GP was detected in brain by MS. No GPE was detected in colostrum by capillary electrophoresis (CE) but the interference from extraneous substances reduced the detectability of GPE by CE and this approach would require further, prior, purification and concentration steps. A molecule, with a migration time equal to that of the peptide GP, was detected in colostrum by CE, but the concentration (~ 10 11mo/L) was much higher than the IGF-I concentration measured by radio-immunoassay using a PAb (80 nmol/L) or using a Mab (300-400 nmolL). A DPP IV enzyme was detected in colostrum and this could account for the GP, derived from substrates other than IGF-1. Based on the differential results of the two antibody assays, there was no indication of the presence of des(1-3)IGF-I in brain or colostrum. In the absence of any enzyme activity directed towards the amino terminus of IGF-I and the absence any potential products, IGF-I, therefore, does not appear to "mature" via des(1-3)IGF-I in the brain, nor in the neutral colostrum. In spite of these results which indicate the absence of an enzymic attack on IGF-I and the absence of the expected products in tissues, the possibility that the conversion of IGF-I may occur in neutral conditions in limited amounts, cannot be ruled out. It remains possible that in the extracellular environment of the membrane, a complex interaction of IGF-I, binding protein, aminopeptidase(s) and receptor, produces des(1- 3)IGF-I as a transient product which is bound to the receptor and internalised.

The differential impact of holocaust trauma across three generations

In the current thesis, the reasons for the differential impact of Holocaust trauma on Holocaust survivors, and the differential intergenerational transmission of this trauma to survivors’ children and grandchildren were explored. A model specifically related to Holocaust trauma and its transmission was developed based on trauma, family systems and attachment theories as well as theoretical and anecdotal conjecture in the Holocaust literature. The Model of the Differential Impact of Holocaust Trauma across Three Generations was tested firstly by extensive meta-analyses of the literature pertaining to the psychological health of Holocaust survivors and their descendants and secondly via analysis of empirical study data. The meta-analyses reported in this thesis represent the first conducted with research pertaining to Holocaust survivors and grandchildren of Holocaust survivors. The meta-analysis of research conducted with children of survivors is the first to include both published and unpublished research. Meta-analytic techniques such as meta-regression and sub-set meta-analyses provided new information regarding the influence of a number of unmeasured demographic variables on the psychological health of Holocaust survivors and descendants. Based on the results of the meta-analyses it was concluded that Holocaust survivors and their children and grandchildren suffer from a statistically significantly higher level or greater severity of psychological symptoms than the general population. However it was also concluded that there is statistically significant variation in psychological health within the Holocaust survivor and descendant populations. Demographic variables which may explain a substantial amount of this variation have been largely under-assessed in the literature and so an empirical study was needed to clarify the role of demographics in determining survivor and descendant mental health. A total of 124 participants took part in the empirical study conducted for this thesis with 27 Holocaust survivors, 69 children of survivors and 28 grandchildren of survivors. A worldwide recruitment process was used to obtain these participants. Among the demographic variables assessed in the empirical study, aspects of the survivors’ Holocaust trauma (namely the exact nature of their Holocaust experiences, the extent of family bereavement and their country of origin) were found to be particularly potent predictors of not only their own psychological health but continue to be strongly influential in determining the psychological health of their descendants. Further highlighting the continuing influence of the Holocaust was the finding that number of Holocaust affected ancestors was the strongest demographic predictor of grandchild of survivor psychological health. Apart from demographic variables, the current thesis considered family environment dimensions which have been hypothesised to play a role in the transmission of the traumatic impact of the Holocaust from survivors to their descendants. Within the empirical study, parent-child attachment was found to be a key determinant in the transmission of Holocaust trauma from survivors to their children and insecure parent-child attachment continues to reverberate through the generations. In addition, survivors’ communication about the Holocaust and their Holocaust experiences to their children was found to be more influential than general communication within the family. Ten case studies (derived from the empirical study data set) are also provided; five Holocaust survivors, three children of survivors and two grandchildren of survivors. These cases add further to the picture of heterogeneity of the survivor and descendant populations in both experiences and adaptations. It is concluded that the legacy of the Holocaust continues to leave its mark on both its direct survivors and their descendants. Even two generations removed, the direct and indirect effects of the Holocaust have yet to be completely nullified. Research with Holocaust survivor families serves to highlight the differential impacts of state-based trauma and the ways in which its effects continue to be felt for generations. The revised and empirically tested Model of the Differential Impact of Holocaust Trauma across Three Generations presented at the conclusion of this thesis represents a further clarification of existing trauma theories as well as the first attempt at determining the relative importance of both cognitive, interpersonal/interfamilial interaction processes and demographic variables in post-trauma psychological health and transmission of traumatic impact.

Conifer defence against insects: microarray gene expression profiling of Sitka spruce (Picea sitchensis) induced by mechanical wounding or feeding by spruce budworms (Choristoneura occidentalis) or white pine weevils (Pissodes strobi) reveals large

Conifers are resistant to attack from a large number of potential herbivores or pathogens. Previous molecular and biochemical characterization of selected conifer defence systems support a model of multigenic, constitutive and induced defences that act on invading insects via physical, chemical, biochemical or ecological (multitrophic) mechanisms. However, the genomic foundation of the complex defence and resistance mechanisms of conifers is largely unknown. As part of a genomics strategy to characterize inducible defences and possible resistance mechanisms of conifers against insect herbivory, we developed a cDNA microarray building upon a new spruce (Picea spp.) expressed sequence tag resource. This first-generation spruce cDNA microarray contains 9720 cDNA elements representing c. 5500 unique genes. We used this array to monitor gene expression in Sitka spruce (Picea sitchensis) bark in response to herbivory by white pine weevils (Pissodes strobi, Curculionidae) or wounding, and in young shoot tips in response to western spruce budworm (Choristoneura occidentalis, Lepidopterae) feeding. Weevils are stem-boring insects that feed on phloem, while budworms are foliage feeding larvae that consume needles and young shoot tips. Both insect species and wounding treatment caused substantial changes of the host plant transcriptome detected in each case by differential gene expression of several thousand array elements at 1 or 2 d after the onset of treatment. Overall, there was considerable overlap among differentially expressed gene sets from these three stress treatments. Functional classification of the induced transcripts revealed genes with roles in general plant defence, octadecanoid and ethylene signalling, transport, secondary metabolism, and transcriptional regulation. Several genes involved in primary metabolic processes such as photosynthesis were down-regulated upon insect feeding or wounding, fitting with the concept of dynamic resource allocation in plant defence. Refined expression analysis using gene-specific primers and real-time PCR for selected transcripts was in agreement with microarray results for most genes tested. This study provides the first large-scale survey of insect-induced defence transcripts in a gymnosperm and provides a platform for functional investigation of plant-insect interactions in spruce. Induction of spruce genes of octadecanoid and ethylene signalling, terpenoid biosynthesis, and phenolic secondary metabolism are discussed in more detail.

Reliability evaluations of railway power supplies by fault-tree analysis

High reliability of railway power systems is one of the essential criteria to ensure quality and cost-effectiveness of railway services. Evaluation of reliability at system level is essential for not only scheduling maintenance activities, but also identifying reliability-critical components. Various methods to compute reliability on individual components or regularly structured systems have been developed and proven to be effective. However, they are not adequate for evaluating complicated systems with numerous interconnected components, such as railway power systems, and locating the reliability critical components. Fault tree analysis (FTA) integrates the reliability of individual components into the overall system reliability through quantitative evaluation and identifies the critical components by minimum cut sets and sensitivity analysis. The paper presents the reliability evaluation of railway power systems by FTA and investigates the impact of maintenance activities on overall reliability. The applicability of the proposed methods is illustrated by case studies in AC railways.

Applications on fault tree analysis in railway power supply systems

Fault tree analysis (FTA) is presented to model the reliability of a railway traction power system in this paper. First, the construction of fault tree is introduced to integrate components in traction power systems into a fault tree; then the binary decision diagram (BDD) method is used to evaluate fault trees qualitatively and quantitatively. The components contributing to the reliability of overall system are identified with their relative importance through sensitivity analysis. Finally, an AC traction power system is evaluated by the proposed methods.

Linearity within the SMS4 Block Cipher

We present several new observations on the SMS4 block cipher, and discuss their cryptographic significance. The crucial observation is the existence of fixed points and also of simple linear relationships between the bits of the input and output words for each component of the round functions for some input words. This implies that the non-linear function T of SMS4 does not appear random and that the linear transformation provides poor diffusion. Furthermore, the branch number of the linear transformation in the key scheduling algorithm is shown to be less than optimal. The main security implication of these observations is that the round function is not always non-linear. Due to this linearity, it is possible to reduce the number of effective rounds of SMS4 by four. We also investigate the susceptibility of SMS4 to further cryptanalysis. Finally, we demonstrate a successful differential attack on a slightly modified variant of SMS4. These findings raise serious questions on the security provided by SMS4.

Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis

We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with NrasQ61K to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4R24C did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4R24C mice. Subsequently, in adulthood, these mutants developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.

Discrimination or Differential Involvement? A Review of the Research Exploring the Impact of Indigenous Status on Sentencing

Existing court data suggest that adult Indigenous offenders are more likely than non-Indigenous defendants to be sentenced to prison but once imprisoned generally receive shorter terms. Using findings from international and Australian multivariate statistical analyses, this paper reviews the three key hypotheses advanced as plausible explanations for these differences: 1) differential involvement, 2) negative discrimination, 3) positive discrimination. Overall, prior research shows strong support for the differential involvement thesis, some support for positive discrimination and little foundation for negative discrimination in the sentencing of Indigenous defendants. Where discrimination is found, we argue that this may be explained by the lack of a more complete set of control variables in researchers’ multivariate models.

Directional earth fault relay operation in mutually coupled multiple circuit distribution lines

Many of the power utilities around the world experienced spurious tripping of directional earth fault relays in their mesh distribution networks due to induced circulating currents. This circulating current is zero sequence and induced in the healthy circuit due to the zero sequence current flow resulting from a ground fault of a parallel circuit. This paper quantitatively discusses the effects of mutual coupling on earth fault protection of distribution systems. An actual spurious tripping event is analyzed to support the theory and to present options for improved resilience to spurious tripping.

Attack of the creationist reverberators! Or: the end of the world (as we know it)

This special issue of Popular Communication examines the impact of the global financial crisis and recession on differnt aspects of global and regional media and the cultural industries, changing practices of media production, as well as media consumption, and the interplay of economic challenges and technological change.