Identifying optimal lipid raft characteristics required to promote nanoscale protein-protein interactions on the plasma membrane

The dynamic lateral segregation of signaling proteins into microdomains is proposed to facilitate signal transduction, but the constraints on microdomain size, mobility, and diffusion that might realize this function are undefined. Here we interrogate a stochastic spatial model of the plasma membrane to determine how microdomains affect protein dynamics. Taking lipid rafts as representative microdomains, we show that reduced protein mobility in rafts segregates dynamically partitioning proteins, but the equilibrium concentration is largely independent of raft size and mobility. Rafts weakly impede small-scale protein diffusion but more strongly impede long-range protein mobility. The long-range mobility of raft-partitioning and raft-excluded proteins, however, is reduced to a similar extent. Dynamic partitioning into rafts increases specific interprotein collision rates, but to maximize this critical, biologically relevant function, rafts must be small (diameter, 6 to 14 nm) and mobile. Intermolecular collisions can also be favored by the selective capture and exclusion of proteins by rafts, although this mechanism is generally less efficient than simple dynamic partitioning. Generalizing these results, we conclude that microdomains can readily operate as protein concentrators or isolators but there appear to be significant constraints on size and mobility if microdomains are also required to function as reaction chambers that facilitate nanoscale protein-protein interactions. These results may have significant implications for the many signaling cascades that are scaffolded or assembled in plasma membrane microdomains.

Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.

The beliefs which motivate young male and female drivers to speed : a comparison of low and high intenders

In Australia, young drivers aged 17 to 24 years, and particularly males, have the highest risk of being involved in a fatal crash. Investigation of young drivers’ beliefs allows for a greater understanding of their involvement in risky behaviours, such as speeding, as beliefs are associated with intentions, the antecedent to behaviour. The theory of planned behaviour (TPB) was used to conceptualise beliefs using a scenario based questionnaire distributed to licensed drivers (N = 398). The questionnaire measured individual’s beliefs and intentions to speed in a particular situation. Consistent with a TPB-based approach, the beliefs of those with low intentions to speed (‘low intenders’) were compared with the beliefs of those with high intentions (‘high intenders’) with such comparisons conducted separately for males and females. Overall, significant differences in the beliefs held by low and high intenders and for both females and males were found. Specifically, for females, it was found that high intenders were significantly more likely to perceive advantages of speeding, less likely to perceive disadvantages, and more likely to be encouraged to speed on familiar and inappropriately signed roads than female low intenders. Females, however, did not differ in their perceptions of support from friends, with all females reporting some level of disapproval from most friends and all females (i.e., low and high intenders) reporting approval to speed from their male friends. The results for males revealed that high intenders were significantly more likely to speed on familiar and inappropriately signed roads as well as having greater perceptions of support from all friends, except from those friends with whom they worked. Low and high intending males did not differ in their perceptions of the advantages and disadvantages of speeding, with the exception of feelings of excitement whereby high intenders reported speeding to be more exciting than low intenders. The findings are discussed in terms of how they may directly inform the content of mass media and public education campaigns aimed at encouraging young drivers to slow down.

Propagation of low power low divergence Gaussian fields in unbiased self-defocusing photorefractive media and their interactions

Many optical networks are limited in speed and processing capability due to the necessity for the optical signal to be converted to an electrical signal and back again. In addition, electronically manipulated interconnects in an otherwise optical network lead to overly complicated systems. Optical spatial solitons are optical beams that propagate without spatial divergence. They are capable of phase dependent interactions, and have therefore been extensively researched as suitable all optical interconnects for over 20 years. However, they require additional external components, initially high voltage power sources were required, several years later, high power background illumination had replaced the high voltage. However, these additional components have always remained as the greatest hurdle in realising the applications of the interactions of spatial optical solitons as all optical interconnects. Recently however, self-focusing was observed in an otherwise self-defocusing photorefractive crystal. This observation raises the possibility of the formation of soliton-like fields in unbiased self-defocusing media, without the need for an applied electrical field or background illumination. This thesis will present an examination of the possibility of the formation of soliton-like low divergence fields in unbiased self-defocusing photorefractive media. The optimal incident beam and photorefractive media parameters for the formation of these fields will be presented, together with an analytical and numerical study of the effect of these parameters. In addition, preliminary examination of the interactions of two of these fields will be presented. In order to complete an analytical examination of the field propagating through the photorefractive medium, the spatial profile of the beam after propagation through the medium was determined. For a low power solution, it was found that an incident Gaussian field maintains its Gaussian profile as it propagates. This allowed the beam at all times to be described by an individual complex beam parameter, while also allowing simple analytical solutions to the appropriate wave equation. An analytical model was developed to describe the effect of the photorefractive medium on the Gaussian beam. Using this model, expressions for the required intensity dependent change in both the real and imaginary components of the refractive index were found. Numerical investigation showed that under certain conditions, a low powered Gaussian field could propagate in self-defocusing photorefractive media with divergence of approximately 0.1 % per metre. An investigation into the parameters of a Ce:BaTiO3 crystal showed that the intensity dependent absorption is wavelength dependent, and can in fact transition to intensity dependent transparency. Thus, with careful wavelength selection, the required intensity dependent change in both the real and imaginary components of the refractive index for the formation of a low divergence Gaussian field are physically realisable. A theoretical model incorporating the dependence of the change in real and imaginary components of the refractive index on propagation distance was developed. Analytical and numerical results from this model are congruent with the results from the previous model, showing low divergence fields with divergence less than 0.003 % over the propagation length of the photorefractive medium. In addition, this approach also confirmed the previously mentioned self-focusing effect of the self-defocusing media, and provided an analogy to a negative index GRIN lens with an intensity dependent focal length. Experimental results supported the findings of the numerical analysis. Two low divergence fields were found to possess the ability to interact in a Ce:BaTiO3 crystal in a soliton-like fashion. The strength of these interactions was found to be dependent on the degree of divergence of the individual beams. This research found that low-divergence fields are possible in unbiased self-defocusing photorefractive media, and that soliton-like interactions between two of these fields are possible. However, in order for these types of fields to be used in future all optical interconnects, the manipulation of these interactions, together with the ability for these fields to guide a second beam at a different wavelength, must be investigated.

Optimal allocation strategies for the dark pool problem

We study the problem of allocating stocks to dark pools. We propose and analyze an optimal approach for allocations, if continuous-valued allocations are allowed. We also propose a modification for the case when only integer-valued allocations are possible. We extend the previous work on this problem to adversarial scenarios, while also improving on their results in the iid setup. The resulting algorithms are efficient, and perform well in simulations under stochastic and adversarial inputs.

Variable Speed Limits : conceptual design for Queensland practice

Variable Speed Limits (VSL) is an Intelligent Transportation Systems (ITS) control tool which can enhance traffic safety and which has the potential to contribute to traffic efficiency. Queensland's motorways experience a large volume of commuter traffic in peak periods, leading to heavy recurrent congestion and a high frequency of incidents. Consequently, Queensland's Department of Transport and Main Roads have considered deploying VSL to improve safety and efficiency. This paper identifies three types of VSL and three applicable conditions for activating VSL on for Queensland motorways: high flow, queuing and adverse weather. The design objectives and methodology for each condition are analysed, and micro-simulation results are presented to demonstrate the effectiveness of VSL.

Optimal budget allocation in budget-based access control

In dynamic and uncertain environments, where the needs of security and information availability are difficult to balance, an access control approach based on a static policy will be suboptimal regardless of how comprehensive it is. Risk-based approaches to access control attempt to address this problem by allocating a limited budget to users, through which they pay for the exceptions deemed necessary. So far the primary focus has been on how to incorporate the notion of budget into access control rather than what or if there is an optimal amount of budget to allocate to users. In this paper we discuss the problems that arise from a sub-optimal allocation of budget and introduce a generalised characterisation of an optimal budget allocation function that maximises organisations expected benefit in the presence of self-interested employees and costly audit.

Bioimpedance in the assessment of unilateral lymphedema of a limb: the optimal frequency

Background: Bioimpedance techniques provide a reliable method of assessing unilateral lymphedema in a clinical setting. Bioimpedance devices are traditionally used to assess body composition at a current frequency of 50 kHz. However, these devices are not transferable to the assessment of lymphedema, as the sensitivity of measuring the impedance of extracellular fluid is frequency dependent. It has previously been shown that the best frequency to detect extracellular fluid is 0 kHz (or DC). However, measurement at this frequency is not possible in practice due to the high skin impedance at DC, and an estimate is usually determined from low frequency measurements. This study investigated the efficacy of various low frequency ranges for the detection of lymphedema. Methods and Results: Limb impedance was measured at 256 frequencies between 3 kHz and 1000 kHz for a sample control population, arm lymphedema population, and leg lymphedema population. Limb impedance was measured using the ImpediMed SFB7 and ImpediMed L-Dex® U400 with equipotential electrode placement on the wrists and ankles. The contralateral limb impedance ratio for arms and legs was used to calculate a lymphedema index (L-Dex) at each measurement frequency. The standard deviation of the limb impedance ratio in a healthy control population has been shown to increase with frequency for both the arm and leg. Box and whisker plots of the spread of the control and lymphedema populations show that there exists good differentiation between the arm and leg L-Dex measured for lymphedema subjects and the arm and leg L-Dex measured for control subjects up to a frequency of about 30 kHz. Conclusions: It can be concluded that impedance measurements above a frequency of 30 kHz decrease sensitivity to extracellular fluid and are not reliable for early detection of lymphedema.

High speed rail and regional competitiveness

The presence of High Speed Rail (HSR) systems influences market shares of road and air transport, and the development of cities and regions they serve. With the deployment of HSR infrastructure, changes in accessibility have occurred. These changes have lead researchers to investigate effects on the economic and spatial derived variables. Contention exists when managing the trade off between efficiency, and access points which are usually in the range of hundreds of kilometres apart. In short, it is argued that intermediate cities, bypassed by HSR services, suffer a decline in their accessibility and developmental opportunities. The present Chapter will analyse possible impacts derived from the presence of HSR infrastructure. In particular, it will consider small and medium agglomerations in the vicinity of HSR corridors, not always served by HSR stations. Thus, a methodology is developed to quantify accessibility benefits and their distribution. These benefits will be investigated in relation to different rail transit strategies integrating HSR infrastructure where a HSR station cannot be positioned. These strategies are selected principally for the type of service offered: (i) cadenced, (ii) express, (iii) frequent or (iv) non-stopping. Furthermore, to ground the theoretical approach linking accessibility and competitiveness, a case study in the North-Eastern Italian regions will be used for the application of the accessibility distributive patterns between the HSR infrastructure and the selected strategies. Results indicate that benefits derive from well informed decisions on HSR station positioning and the appropriate blend of complementary services in the whole region to interface HSR infrastructure. The results are significant for all countries in Europe and worldwide, not only for investing in HSR infrastructure, but mostly in terms of building territorial cohesion, while seeking international recognition for developing successful new technology and systems.

Estimating the loading condition of a diesel engine using instantaneous angular speed analysis

Continuing monitoring of diesel engine performance is critical for early detection of fault developments in the engine before they materialize and become a functional failure. Instantaneous crank angular speed (IAS) analysis is one of a few non intrusive condition monitoring techniques that can be utilized for such tasks. In this experimental study, IAS analysis was employed to estimate the loading condition of a 4-stroke 4-cylinder diesel engine in a laboratory condition. It was shown that IAS analysis can provide useful information about engine speed variation caused by the changing piston momentum and crankshaft acceleration during the engine combustion process. It was also found that the major order component of the IAS spectrum directly associated with the engine firing frequency (at twice the mean shaft revolution speed) can be utilized to estimate the engine loading condition regardless of whether the engine is operating at normal running conditions or in a simulated faulty injector case. The amplitude of this order component follows a clear exponential curve as the loading condition changes. A mathematical relationship was established for the estimation of the engine power output based on the amplitude of the major order component of the measured IAS spectrum.

Estimating the loading condition of a diesel engine using instantaneous angular speed analysis

Continuing monitoring of diesel engine performance is critical for early detection of fault developments in the engine before they materialize and become a functional failure. Instantaneous crank angular speed (IAS) analysis is one of a few non intrusive condition monitoring techniques that can be utilized for such tasks. In this experimental study, IAS analysis was employed to estimate the loading condition of a 4-stroke 4-cylinder diesel engine in a laboratory condition. It was shown that IAS analysis can provide useful information about engine speed variation caused by the changing piston momentum and crankshaft acceleration during the engine combustion process. It was also found that the major order component of the IAS spectrum directly associated with the engine firing frequency (at twice the mean shaft revolution speed) can be utilized to estimate the engine loading condition regardless of whether the engine is operating at normal running conditions or in a simulated faulty injector case. The amplitude of this order component follows a clear exponential curve as the loading condition changes. A mathematical relationship was established for the estimation of the engine power output based on the amplitude of the major order component of the measured IAS spectrum.

An improved genetic algorithm and graph theory based method for optimal sectionalizer switch placement in distribution networks with DG

In this paper a new graph-theory and improved genetic algorithm based practical method is employed to solve the optimal sectionalizer switch placement problem. The proposed method determines the best locations of sectionalizer switching devices in distribution networks considering the effects of presence of distributed generation (DG) in fitness functions and other optimization constraints, providing the maximum number of costumers to be supplied by distributed generation sources in islanded distribution systems after possible faults. The proposed method is simulated and tested on several distribution test systems in both cases of with DG and non DG situations. The results of the simulations validate the proposed method for switch placement of the distribution network in the presence of distributed generation.

The impact of taxes on optimal portfolio choice : an Australian study

Taxes are an important component of investing that is commonly overlooked in both the literature and in practice. For example, many understand that taxes will reduce an investment’s return, but less understood is the risk-sharing nature of taxes that also reduces the investment’s risk. This thesis examines how taxes affect the optimal asset allocation and asset location decision in an Australian environment. It advances the model of Horan & Al Zaman (2008), improving the method by which the present value of tax liabilities are calculated, by using an after-tax risk-free discount rate, and incorporating any new or reduced tax liabilities generated into its expected risk and return estimates. The asset allocation problem is examined for a range of different scenarios using Australian parameters, including different risk aversion levels, personal marginal tax rates, investment horizons, borrowing premiums, high or low inflation environments, and different starting cost bases. The findings support the Horan & Al Zaman (2008) conclusion that equities should be held in the taxable account. In fact, these findings are strengthened with most of the efficient frontier maximising equity holdings in the taxable account instead of only half. Furthermore, these findings transfer to the Australian case, where it is found that taxed Australian investors should always invest into equities first through the taxable account before investing in super. However, untaxed Australian investors should invest their equity first through superannuation. With borrowings allowed in the taxable account (no borrowing premium), Australian taxed investors should hold 100% of the superannuation account in the risk-free asset, while undertaking leverage in the taxable account to achieve the desired risk-return. Introducing a borrowing premium decreases the likelihood of holding 100% of super in the risk-free asset for taxable investors. The findings also suggest that the higher the marginal tax rate, the higher the borrowing premium in order to overcome this effect. Finally, as the investor’s marginal tax rate increases, the overall allocation to equities should increase due to the increased risk and return sharing caused by taxation, and in order to achieve the same risk/return level as the lower taxation level, the investor must take on more equity exposure. The investment horizon has a minimal impact on the optimal allocation decision in the absence of factors such as mean reversion and human capital.