Gelatinase A (MMP-2) activation by skin fibroblasts : dependence on MT1-MMP expression and fibrillar collagen form

The respective requirements of collagen and MT1-MMP in the activation of MMP-2 by primary fibroblast cultures were explored further. Three-dimensional gels enriched in human collagen types I and III or composed of recombinant human type II or III collagen, caused increased MT1-MMP production (mRNA and protein) and induced MMP-2 activation. Only marginal induction was seen with dried monomeric collagen confirming the need for collagen fibrillar organisation for activation. To our surprise, relatively low amounts (as low as 25 μg/ml) of acid soluble type I collagen added to fibroblast cultures also induced potent MMP-2 activation. However, the requirement for collagen fibril formation by the added collagen was indicated by the inhibition seen when the collagen was pre-incubated with a fibril-blocking peptide, and the reduced activation seen with alkali-treated collagen preparations known to have impaired fibrilisation. Pre-treatment of the collagen with sodium periodate also abrogated MMP-2 activation induction. Further evidence of the requirement for collagen fibril formation was provided by the lack of activation when type IV collagen, which does not form collagen fibrils, was added in the cultures. Fibroblasts derived from MT1-MMP-deficient mice were unable to activate MMP-2 in response to either three-dimensional collagen gel or added collagen solutions, compared to their littermate controls. Collectively, these data indicate that the fibrillar structure of collagen and MT1-MMP are essential for the MMP-2 activational response in fibroblasts.

The Wzy O-antigen polymerase of Yersinia pseudotuberculosis O:2a has a dependence on the Wzz chain-length determinant for efficient polymerization

Lipopolysaccharide is a major immunogenic structure for the pathogen Yersinia pseudotuberculosis, which contains the O-specific polysaccharide (OPS) that is presented on the cell surface. The OPS contains many repeats of the oligosaccharide O-unit and exhibits a preferred modal chain length that has been shown to be crucial for cell protection in Yersinia. It is well established that the Wzz protein determines the preferred chain length of the OPS, and in its absence, the polymerization of O units by the Wzy polymerase is uncontrolled. However, for Y. pseudotuberculosis, a wzz mutation has never been described. In this study, we examine the effect of Wzz loss in Y. pseudotuberculosis serotype O:2a and compare the lipopolysaccharide chain-length profile to that of Escherichia coli serotype O111. In the absence of Wzz, the lipopolysaccharides of the two species showed significant differences in Wzy polymerization. Yersinia pseudotuberculosis O:2a exhibited only OPS with very short chain lengths, which is atypical of wzz-mutant phenotypes that have been observed for other species. We hypothesise that the Wzy polymerase of Y. pseudotuberculosis O:2a has a unique default activity in the absence of the Wzz, revealing the requirement of Wzz to drive O-unit polymerization to greater lengths.

Effect of representation size and visual ambiguity on RatSLAM system performance

RatSLAM is a vision-based SLAM system based on extended models of the rodent hippocampus. RatSLAM creates environment representations that can be processed by the experience mapping algorithm to produce maps suitable for goal recall. The experience mapping algorithm also allows RatSLAM to map environments many times larger than could be achieved with a one to one correspondence between the map and environment, by reusing the RatSLAM maps to represent multiple sections of the environment. This paper describes experiments investigating the effects of the environment-representation size ratio and visual ambiguity on mapping and goal navigation performance. The experiments demonstrate that system performance is weakly dependent on either parameter in isolation, but strongly dependent on their joint values.

Attribute exclusion strategies in airline choice : accounting for exogenous information on decision maker processing strategies in models of discrete choice

We examine the impact of individual-specific information processing strategies (IPSs) on the inclusion/exclusion of attributes on the parameter estimates and behavioural outputs of models of discrete choice. Current practice assumes that individuals employ a homogenous IPS with regards to how they process attributes of stated choice (SC) experiments. We show how information collected exogenous of the SC experiment on whether respondents either ignored or considered each attribute may be used in the estimation process, and how such information provides outputs that are IPS segment specific. We contend that accounting the inclusion/exclusion of attributes will result in behaviourally richer population parameter estimates.

The role of insulin and IGF2 signalling on metabolic pathways in prostate cancer progression

Prostate cancer (CaP) is the most commonly diagnosed cancer in males in Australia, North America, and Europe. If found early and locally confined, CaP can be treated with radical prostatectomy or radiation therapy; however, 25-40% patients will relapse and go on to advanced disease. The most common therapy in these cases is androgen deprivation therapy (ADT), which suppresses androgen production from the testis. Lack of the testicular androgen supply causes cells of the prostate to undergo apoptosis. However, in some cases the regression initially seen with ADT eventually gives way to a growth of a population of cancerous cells that no longer require testicular androgens. This phenotype is essentially fatal and is termed castrate resistant prostate cancer (CRPC). In addition to eventual regression, there are many undesirable side effects which accompany ADT, including development of a metabolic syndrome, which is defined by the U.S. National Library of Medicine as “a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes.” This project will focus on the effect of ADT induced hyperinsulinemia, as mimicked by treating androgen receptor positive CaP cells with insulin in a serum (hormone) deprived environment. While this side effect is not widely explored, in this thesis it is demonstrated for the first time that insulin upregulates pathways important to CaP progression. Our group has previously shown that during CaP progression, the enzymes necessary for de novo steroidogenesis are upregulated in the LNCaP xenograft model, total steroid levels are increased in tumours compared to pre castrate levels, and de novo steroidogenesis from radio-labelled acetate has been demonstrated. Because of the CaP dependence on AR for survival, we and other groups believe that CaP cells carry out de novo steroidogenesis to survive in androgen deprived conditions. Because (a) men on ADT often develop metabolic syndrome, and (b) men with lifestyle-induced obesity and hyperinsulinemia have worse prognosis and faster disease progression, and because (c) insulin causes steroidogenesis in other cell lines, the hypothesis that insulin may contribute to CaP progression through upregulation of steroidogenesis was explored. Insulin upregulates steroidogenesis enzymes at the mRNA level in three AR positive cell lines, as well as upregulating these enzymes at the protein level in two cell lines. It has also been demonstrated that insulin increases mitochondrial (functional) levels of steroid acute regulatory protein (StAR). Furthermore, insulin causes increased levels of total steroids in and induction of de novo steroid synthesis by insulin has been demonstrated at levels induced sufficient to activate AR. The effect of insulin analogs on CaP steroidogenesis in LNCaP and VCaP cells has also been investigated because epidemiological studies suggest that some of the analogs developed may have more cancer stimulatory effects than normal insulin. In this project, despite the signalling differences between glargine, X10, and insulin, these analogs did not appear to induce steroidogenesis any more potently that normal insulin. The effect of insulin of MCF7breast cancer cells was also investigated with results suggesting that breast cancer cells may be capable of de novo steroidogenesis, and that increase in estradiol production may be exacerbated by insulin. Insulin has also been long known to stimulate lipogenesis in the liver and adipocytes, and has been demonstrated to increase lipogenesis in breast cancer cells; therefore, investigation of the effect of insulin on lipogenesis, which is a hallmark of aggressive cancers, was investigated. In CaP progression sterol regulatory element binding protein (SREBP) is dysregulated and upregulates fatty acid synthase (FASN), acetyl CoA-carboxylase, and other lipogenesis genes. SREBP is important for steroidogenesis and in this project has been shown to be upregulated by insulin in CaP cells. Fatty acid synthesis provides building blocks of membrane growth, provides substrates for acid oxidation, the main energy source for CaP cells, provides building blocks for anti-apoptotic and proinflammatory molecules, and provides molecules that stimulate steroidogenesis. In this project it has been shown that insulin upregulates FASN and ACC, which synthesize fatty acids, as well as upregulating hormone sensitive lipase (HSL), diazepam-binding inhibitor (DBI), and long-chain acyl-CoA synthetase 3 (ACSL3), which contribute to lipid activation of steroidogenesis. Insulin also upregulates total lipid levels and de novo lipogenesis, which can be suppressed by inhibition of the insulin receptor (INSR). The fatty acids synthesized after insulin treatment are those that have been associated with CaP; furthermore, microarray data suggests insulin may upregulate fatty acid biosynthesis, metabolism and arachidonic acid metabolism pathways, which have been implicated in CaP growth and survival. Pharmacological agents used to treat patients with hyperinsulinemia/ hyperlipidemia have gained much interest in regards to CaP risk and treatment; however, the scientific rationale behind these clinical applications has not been examined. This thesis explores whether the use of metformin or simvastatin would decrease either lipogenesis or steroidogenesis or both in CaP cells. Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitor, which blocks synthesis of cholesterol, the building block of steroids/ androgens. It has also been postulated to down regulate SREBP in other metabolic disorders. It has been shown in this thesis, in LNCaP cells, that simvastatin inhibited and decreased insulin induced steroidogenesis and lipogenesis, respectively, but increased these pathways in the absence of insulin. Conversely, metformin, which activates AMP-activated protein kinase (AMPK) to shut down lipogenesis, cholesterol synthesis, and protein synthesis, highly suppresses both steroidogenesis and lipogenesis in the presence and absence of insulin. Lastly, because it has been demonstrated to increase steroidogenesis in other cell lines, and because the elucidation of any factors affecting steroidogenesis is important to understanding CaP, the effect of IGF2 on steroidogenesis in CaP cells was investigated. In patient samples, as men progress to CRPC, IGF2 mRNA and the protein levels of the receptors it may signal through are upregulated. It has also been demonstrated that IGF2 upregulates steroidogenic enzymes at both the mRNA and protein levels in LNCaP cells, increases intracellular and secreted steroid/androgen levels in LNCaPs to levels sufficient to stimulate the AR, and upregulated de novo steroidogenesis in LNCaPs and VCaPs. As well, inhibition of INSR and insulin-like growth factor 1 receptor (IGF1R), which IGF2 signals through, suggests that induction of steroidogenesis may be occurring predominantly through IGF1R. In summary, this project has illuminated for the first time that insulin is likely to play a large role in cancer progression, through upregulation of the steroidogenesis and lipogenesis pathways at the mRNA and protein levels, and production levels, and demonstrates a novel role for IGF-II in CaP progression through stimulation of steroidogenesis. It has also been demonstrated that metformin and simvastatin drugs may be useful in suppressing the insulin induction of these pathways. This project affirms the pathways by which ADT- induced metabolic syndrome may exacerbate CaP progression and strongly suggests that the monitoring and modulation of the metabolic state of CaP patients could have a strong impact on their therapeutic outcomes.

Differential effects of ERP systems on user outcomes : a longitudinal investigation

Adopting a model of job enrichment we report on a longitudinal case investigating the perceived impact of an Enterprise Resource Planning (ERP) system on user job design characteristics. Our results indicated that in the context of an ERP geared towards centralisation and standardisation the extent to which users perceived an increase or decrease in job enrichment was associated with aspects such as formal authority and the nature of their work role. Experienced operational employees proficient in the original legacy system perceived ERP system protocols to constrain their actions, limit training and increase dependence on others in the workflow. Conversely, managerial users reported a number of benefits relating to report availability, improved organisational transparency and increased overall job enrichment. These results supported our argument concerning the relationship between ERPs with a standardisation intent and positive job enrichment outcomes for managerial users and negative job-related outcomes for operational users.

Influence of atmospheric sublimation and evaporation on the heat pump fluid bed drying of bovine intestines

Experiments on atmospheric two-stage fluidized bed drying of bovine intestines with heat pump were carried out. The investigation covers innovative fluidized bed heat pump drying of bovine intestines. The two-stage drying consists of atmospheric moisture sublimation immediately followed by evaporation. Studies were done to establish the influence of the drying condition on the drying characteristics and product quality of bovine intestines and properties focusing on kinetics, diffusion, and color. The investigation of the drying characteristics has been conducted during moisture removal by evaporation and combined sublimation and evaporation. The effect of drying temperature on the drying constants was determined by fitting the experimental data using regression analysis techniques. The investigation revealed that the drying kinetics is most significantly affected by temperature. Correlations expressing the drying constants and effective moisture diffusivity dependence on the drying conditions are reported.

Crisis on impact : responding to cyber attacks on critical information infrastructures

In the developing digital economy, the notion of traditional attack on enterprises of national significance or interest has transcended into different modes of electronic attack, surpassing accepted traditional forms of physical attack upon a target. The terrorist attacks that took place in the United States on September 11, 2001 demonstrated the physical devastation that could occur if any nation were the target of a large-scale terrorist attack. Therefore, there is a need to protect criticalnational infrastructure and critical information infrastructure. In particular,this protection is crucial for the proper functioning of a modern society and for a government to fulfill one of its most important prerogatives – namely, the protection of its people. Computer networks have many benefits that governments, corporations, and individuals alike take advantage of in order to promote and perform their duties and roles. Today, there is almost complete dependence on private sector telecommunication infrastructures and the associated computer hardware and software systems.1 These infrastructures and systems even support government and defense activity.2 This Article discusses possible attacks on critical information infrastructures and the government reactions to these attacks.

Impact of coronary tortuosity on coronary pressure: Numerical simulation study

Background: Coronary tortuosity (CT) is a common coronary angiographic finding. Whether CT leads to an apparent reduction in coronary pressure distal to the tortuous segment of the coronary artery is still unknown. The purpose of this study is to determine the impact of CT on coronary pressure distribution by numerical simulation. Methods: 21 idealized models were created to investigate the influence of coronary tortuosity angle (CTA) and coronary tortuosity number (CTN) on coronary pressure distribution. A 2D incompressible Newtonian flow was assumed and the computational simulation was performed using finite volume method. CTA of 30°, 60°, 90°, 120° and CTN of 0, 1, 2, 3, 4, 5 were discussed under both steady and pulsatile conditions, and the changes of outlet pressure and inlet velocity during the cardiac cycle were considered. Results: Coronary pressure distribution was affected both by CTA and CTN. We found that the pressure drop between the start and the end of the CT segment decreased with CTA, and the length of the CT segment also declined with CTA. An increase in CTN resulted in an increase in the pressure drop. Conclusions: Compared to no-CT, CT can results in more decrease of coronary blood pressure in dependence on the severity of tortuosity and severe CT may cause myocardial ischemia.

Assessment of code bias variations of BDS triple-frequency signals and their impacts on ambiguity resolution for long baselines

Carrier phase ambiguity resolution over long baselines is challenging in BDS data processing. This is partially due to the variations of the hardware biases in BDS code signals and its dependence on elevation angles. We present an assessment of satellite-induced code bias variations in BDS triple-frequency signals and the ambiguity resolutions procedures involving both geometry-free and geometry-based models. First, since the elevation of a GEO satellite remains unchanged, we propose to model the single-differenced fractional cycle bias with widespread ground stations. Second, the effects of code bias variations induced by GEO, IGSO and MEO satellites on ambiguity resolution of extra-wide-lane, wide-lane and narrow-lane combinations are analyzed. Third, together with the IGSO and MEO code bias variations models, the effects of code bias variations on ambiguity resolution are examined using 30-day data collected over the baselines ranging from 500 to 2600 km in 2014. The results suggest that although the effect of code bias variations on the extra-wide-lane integer solution is almost ignorable due to its long wavelength, the wide-lane integer solutions are rather sensitive to the code bias variations. Wide-lane ambiguity resolution success rates are evidently improved when code bias variations are corrected. However, the improvement of narrow-lane ambiguity resolution is not obvious since it is based on geometry-based model and there is only an indirect impact on the narrow-lane ambiguity solutions.

The Alcohol Helplessness Scale and its prediction of depression among problem drinkers

Event-specific scales commonly have greater power than generalized scales in prediction of specific disorders and in testing mediator models for predicting such disorders. Therefore, in a preliminary study, a 6-item Alcohol Helplessness Scale was constructed and found to be reliable for a sample of 98 problem drinkers. Hierarchical multiple regression and its derivative path analysis were used to test whether helplessness and self-efficacy moderate or mediate the link between alcohol dependence and depression, A test of a moderation model was not supported, whereas a test of a mediation model was supported. Helplessness and self-efficacy both significantly and independently mediated between alcohol dependence and depression. Nevertheless, a significant direct effect of alcohol dependence on depression also remained.

Application of a continuum theory to vertical vibrations of a layer of granular material

Many interesting phenomena have been observed in layers of granular materials subjected to vertical oscillations; these include the formation of a variety of standing wave patterns, and the occurrence of isolated features called oscillons, which alternately form conical heaps and craters oscillating at one-half of the forcing frequency. No continuum-based explanation of these phenomena has previously been proposed. We apply a continuum theory, termed the double-shearing theory, which has had success in analyzing various problems in the flow of granular materials, to the problem of a layer of granular material on a vertically vibrating rigid base undergoing vertical oscillations in plane strain. There exists a trivial solution in which the layer moves as a rigid body. By investigating linear perturbations of this solution, we find that at certain amplitudes and frequencies this trivial solution can bifurcate. The time dependence of the perturbed solution is governed by Mathieu’s equation, which allows stable, unstable and periodic solutions, and the observed period-doubling behaviour. Several solutions for the spatial velocity distribution are obtained; these include one in which the surface undergoes vertical velocities that have sinusoidal dependence on the horizontal space dimension, which corresponds to the formation of striped standing waves, and is one of the observed patterns. An alternative continuum theory of granular material mechanics, in which the principal axes of stress and rate-of-deformation are coincident, is shown to be incapable of giving rise to similar instabilities.

Benefits of collaborative ICT adoption for building project management

Purpose : Effective flow of data and communication at every stage of a construction project is essential for achieving required coordination and collaboration between the project participants, leading to successful management of the projects. In present scenario, when project participants are geographically separated, adoption of information communication technology (ICT) enables such effective communication. Thus, the purpose of this paper is to focus on ICT adoption for building project management.---------- Design/methodology/approach : It is difficult to quantitatively evaluate the benefits of ICT adoption in the multiple enterprise scenario of building project management. It requires qualitative analysis based on the perceptions of the construction professionals. The paper utilizes interpretive structural modeling (ISM) technique to assess importance of perceived benefits and their driving power and dependence on other benefits.---------- Findings : The developed ISM model shows that all the categories of benefits, i.e. benefits related to projects, team management, technology, and organization are inter-related and cannot be achieved in isolation. But, organization- and technology-related benefits have high-driving power and these are “strategic benefits” for the project team organizations. Thus, organizations are required to give more attention on strategically increasing these benefits from application of ICT. Originality/value – This analysis provides a road map to managers or project management organizations to decide that if they are planning ICT adoption for achieving certain benefits then which are the other driving benefits that should be achieved prior to that and also which are the dependent benefits that would be achieved by default.

Analysis of distrubances in large interconnected power systems

World economies increasingly demand reliable and economical power supply and distribution. To achieve this aim the majority of power systems are becoming interconnected, with several power utilities supplying the one large network. One problem that occurs in a large interconnected power system is the regular occurrence of system disturbances which can result in the creation of intra-area oscillating modes. These modes can be regarded as the transient responses of the power system to excitation, which are generally characterised as decaying sinusoids. For a power system operating ideally these transient responses would ideally would have a “ring-down” time of 10-15 seconds. Sometimes equipment failures disturb the ideal operation of power systems and oscillating modes with ring-down times greater than 15 seconds arise. The larger settling times associated with such “poorly damped” modes cause substantial power flows between generation nodes, resulting in significant physical stresses on the power distribution system. If these modes are not just poorly damped but “negatively damped”, catastrophic failures of the system can occur. To ensure system stability and security of large power systems, the potentially dangerous oscillating modes generated from disturbances (such as equipment failure) must be quickly identified. The power utility must then apply appropriate damping control strategies. In power system monitoring there exist two facets of critical interest. The first is the estimation of modal parameters for a power system in normal, stable, operation. The second is the rapid detection of any substantial changes to this normal, stable operation (because of equipment breakdown for example). Most work to date has concentrated on the first of these two facets, i.e. on modal parameter estimation. Numerous modal parameter estimation techniques have been proposed and implemented, but all have limitations [1-13]. One of the key limitations of all existing parameter estimation methods is the fact that they require very long data records to provide accurate parameter estimates. This is a particularly significant problem after a sudden detrimental change in damping. One simply cannot afford to wait long enough to collect the large amounts of data required for existing parameter estimators. Motivated by this gap in the current body of knowledge and practice, the research reported in this thesis focuses heavily on rapid detection of changes (i.e. on the second facet mentioned above). This thesis reports on a number of new algorithms which can rapidly flag whether or not there has been a detrimental change to a stable operating system. It will be seen that the new algorithms enable sudden modal changes to be detected within quite short time frames (typically about 1 minute), using data from power systems in normal operation. The new methods reported in this thesis are summarised below. The Energy Based Detector (EBD): The rationale for this method is that the modal disturbance energy is greater for lightly damped modes than it is for heavily damped modes (because the latter decay more rapidly). Sudden changes in modal energy, then, imply sudden changes in modal damping. Because the method relies on data from power systems in normal operation, the modal disturbances are random. Accordingly, the disturbance energy is modelled as a random process (with the parameters of the model being determined from the power system under consideration). A threshold is then set based on the statistical model. The energy method is very simple to implement and is computationally efficient. It is, however, only able to determine whether or not a sudden modal deterioration has occurred; it cannot identify which mode has deteriorated. For this reason the method is particularly well suited to smaller interconnected power systems that involve only a single mode. Optimal Individual Mode Detector (OIMD): As discussed in the previous paragraph, the energy detector can only determine whether or not a change has occurred; it cannot flag which mode is responsible for the deterioration. The OIMD seeks to address this shortcoming. It uses optimal detection theory to test for sudden changes in individual modes. In practice, one can have an OIMD operating for all modes within a system, so that changes in any of the modes can be detected. Like the energy detector, the OIMD is based on a statistical model and a subsequently derived threshold test. The Kalman Innovation Detector (KID): This detector is an alternative to the OIMD. Unlike the OIMD, however, it does not explicitly monitor individual modes. Rather it relies on a key property of a Kalman filter, namely that the Kalman innovation (the difference between the estimated and observed outputs) is white as long as the Kalman filter model is valid. A Kalman filter model is set to represent a particular power system. If some event in the power system (such as equipment failure) causes a sudden change to the power system, the Kalman model will no longer be valid and the innovation will no longer be white. Furthermore, if there is a detrimental system change, the innovation spectrum will display strong peaks in the spectrum at frequency locations associated with changes. Hence the innovation spectrum can be monitored to both set-off an “alarm” when a change occurs and to identify which modal frequency has given rise to the change. The threshold for alarming is based on the simple Chi-Squared PDF for a normalised white noise spectrum [14, 15]. While the method can identify the mode which has deteriorated, it does not necessarily indicate whether there has been a frequency or damping change. The PPM discussed next can monitor frequency changes and so can provide some discrimination in this regard. The Polynomial Phase Method (PPM): In [16] the cubic phase (CP) function was introduced as a tool for revealing frequency related spectral changes. This thesis extends the cubic phase function to a generalised class of polynomial phase functions which can reveal frequency related spectral changes in power systems. A statistical analysis of the technique is performed. When applied to power system analysis, the PPM can provide knowledge of sudden shifts in frequency through both the new frequency estimate and the polynomial phase coefficient information. This knowledge can be then cross-referenced with other detection methods to provide improved detection benchmarks.

Promoting student understanding through complex learning

The world’s increasing complexity, competitiveness, interconnectivity, and dependence on technology generate new challenges for nations and individuals that cannot be met by “continuing education as usual” (The National Academies, 2009). With the proliferation of complex systems have come new technologies for communication, collaboration, and conceptualization. These technologies have led to significant changes in the forms of mathematical thinking that are required beyond the classroom. This paper argues for the need to incorporate future-oriented understandings and competencies within the mathematics curriculum, through intellectually stimulating activities that draw upon multidisciplinary content and contexts. The paper also argues for greater recognition of children’s learning potential, as increasingly complex learners capable of dealing with cognitively demanding tasks.