Ryanodine receptor phosphorylation in human heart failure

Heart failure is a complex disorder, characterized by activation of the sympathetic nervous system, leading to dysregulated Ca2+ homeostasis in cardiac myocytes and tissue remodeling. In a variety of diseases, cardiac malfunction is associated with aberrant fluxes of Ca2+ across both the surface membrane and the internal Ca2+ store, the sarcoplasmic reticulum (SR). One prominent hypothesis residues is that in heart failure, the activity of the ryanodine receptor (RyR2) Ca2+ release channel in the SR is increased due to excess phosphorylation and that this contributes to excess SR Ca2+ leak in diastole, reduced SR Ca2+ load and decreased contractility (Huke & Bers, 2008). There is controversy over which serine residues in RyR2 are hyperphosphorylated in animal models of heart failure and whether this is via the CaMKII or the PKA-linked signaling pathway. S2808, S2814 and S2030 in RyR2 have been variously claimed to be hyperphosphorylated. Our aim was to examine the degree of phosphorylation of these residues in RyR2 from failing human hearts. The use of human tissue was approved by the Human Research Ethics Committee, The Prince Charles Hospital, EC28114. Left ventricular tissue samples were obtained from an explanted heart of a patient with endstage heart failure (Emery Dreifuss Muscular Dystrophy with cardiomyopathy) and non-failing tissue was from a patient with cystic fibrosis undergoing heart-lung transplantation with no history of heart disease. SR vesicles were prepared as described by Laver et al. (1995) and examined with SDS-Page and Western Blot. Transferred proteins were probed with antibodies to detect total protein phosphorylation, phosphorylation of RyR2 serine residues S2808, S2814, S2030 and for the key proteins calsequestrin, triadin, junctin and FKBP12.6. To avoid membrane stripping artifact, each membrane was exposed to one phosphorylation-specific antibody and signal densities quantified using Bio-Rad Quantity One software. We found no distinguishable difference between failing and healthy hearts in the protein expression levels of RyR2, triadin, junctin or calsequestrin. We found an expected upregulation of total RyR2 phosphorylation in the failing heart sample, compared to a matched amount of RyR2 (quantified using densiometry) in healthy heart. Probing with antibodies detecting only the phosphorylated form of the specific RyR2 residues showed that the increase in total RyR2 phosphorylation in the failing heart was due to hyperphosphorylation of S2808 and S2814. We found that S2030 phosphorylation levels were unchanged in human heart failure. Interestingly, we found that S2030 has a basal level of phosphorylation in the healthy human heart, different from the absence of basal phosphorylation recently reported in rodent heart (Huke & Bers, 2008). Finally, preliminary results indicate that less FKBP 12.6 is associated with RyR2 in the failing heart, possibly as a consequence of PKA activation. In conclusion, residues S2808 and S2814 are hyperphosphorylated in human heart failure, presumably due to upregulation of the CaMKII and/or PKA signaling pathway as a result of chronic activation of the sympathetic nervous system. Such changes in RyR2 phosphorylation are believed to contribute to the leaky RyR2 phenotype associated with heart failure, which increases the incidence of arrhythmia and contributes to the severely impaired contractile performance of the failing heart. Huke S & Bers DM. (2008). Ryanodine receptor phosphorylation at serine 2030, 2808 and 2814 in rat cardiomyocytes. Biochemical and Biophysical Research Communications 376, 80-85. Laver DR, Roden LD, Ahern GP, Eager KR, Junankar PR & Dulhunty AF. (1995). Cytoplasmic Ca2+ inhibits the ryanodine receptor from cardiac muscle. Journal of Membrane Biology 147, 7-22. Proceedings

Situation Review of Barley Yellow Dwarf Virus in West Asia and North Africa

Symptoms of barley yellow dwarf (BYD) have been observed on cereals in nearly all countries of West Asia and North Africa. Its incidence. however, has varied during the last 15 years. Observations from field surveys are summarized. Since symptoms of barley yellow dwarf virus (BYDV) are of low diagnostic value, especially in wheat (Triticum aestivum L.), more precise qualitative and quantitative detection was derived by vector transmission and serology. In 1985 and 1986. preliminary surveys by enzyme-linked immunosorbent assay (ELlS A) indicated that BYDV incidence in the regions surveyed in Syria, Morocco, and Tunisia was around 7. 22. and 24%. respectively. By vector transmission PAV-, RPV-, and RMV-like isolates ofBYDV were identified in Morocco and the PAV-like isolate in Syria. By serology PAV-like isolates were identified in Ethiopia, Lebanon. Morocco. Syria. and Tunisia. and MA V-like isolates were identified from Morocco and Tunisia. The PAV-like type was the most common in all countries surveyed. Screening for BYDV resistance by natural infection has been carried out in a number of countries of the region during the last few years. Screening for resistance by aphid inoculation was initiated in Syria in 1986 at the International Center for Agricultural Research in the Dry Areas (ICARDA). Such screening is expected to follow in other countries of the region soon.

A conceptual framework for ethical decision making in project procurement

There is a lack of research which identifies the role of the public-sector client in relation to ethical practice in plan procurement. This paper discusses a conceptual framework for ethical decision making in project procurement, focusing on public sector clients within the Malaysian construction industry. A framework is proposed to ensure that effective ethical decision making strategies are deployed to ensure that plan procurement is carried out with a transparent process so that the public sector clients are able to adopt. The conceptual framework adopts various factors that contribute to ethical decision making at the early stage of procurement and consists of the procurement system, individual factors, project characteristics, and organizational culture as the internal factors and professional code of conduct and government policies as the external factors. This framework rationalizes the relationships between systems, psychology and organizational theory to form an innovative understanding of making ethical decisions in plan procurement. It is expected that this proposed framework will be useful as a foundation for identifying the factors that contribute to ethical decision making focusing on the planning stage of procurement process.

Robust tracking control of autonomous underwater vehicles in the presence of disturbance inputs

An autonomous underwater vehicle (AUV) is expected to operate in an ocean in the presence of poorly known disturbance forces and moments. The uncertainties of the environment makes it difficult to apply open-loop control scheme for the motion planning of the vehicle. The objective of this paper is to develop a robust feedback trajectory tracking control scheme for an AUV that can track a prescribed trajectory amidst such disturbances. We solve a general problem of feedback trajectory tracking of an AUV in SE(3). The feedback control scheme is derived using Lyapunov-type analysis. The results obtained from numerical simulations confirm the asymptotic tracking properties of the feedback control law. We apply the feedback control scheme to different mission scenarios, with the disturbances being initial errors in the state of the AUV.

Can hybridization cause local extinction : the case for demographic swamping of the Australian native, Senecio pinnatifolius, by the invasive, S. madagascariensis?

The outcome of interspecific hybridization between native and invasive species depends on the relative frequencies of parental taxa and viability of hybrid progeny. We investigated individual and population level consequences of hybridization between the Australian native, Senecio pinnatifolius, and the exotic S. madagascariensis, with AFLP markers and used this information to simulate the expected outcome of hybridization.A high frequency (range 8.3-75.6 %) of hybrids was detected in open pollinated seeds of both species, but mature hybrids were absent from sympatric populations indicating that sympatric populations represent tension zones. A hybridization advantage was observed for S. madagascariensis,where significantly more progeny than expected were sired based on proportional representation of the two species in sympatric populations. Simulations indicated S. pinnatifolius could be replaced in sympatric populations if hybridization was density dependent.For this native-exotic pair, prezygotic isolating barriers are weak, but low hybrid viability maintains a strong postzygotic barrier to introgression. Due to asymmetric hybridization, S. pinnatifolius appears under threat from demographic swamping, and local extinction is possible where it occurs in sympatry with S. madagascariensis.

Assessment of commercial network RTK user positioning performance over long inter-station distances

The paper provides an assessment of the performance of commercial Real Time Kinematic (RTK) systems over longer than recommended inter-station distances. The experiments were set up to test and analyse solutions from the i-MAX, MAX and VRS systems being operated with three triangle shaped network cells, each having an average inter-station distance of 69km, 118km and 166km. The performance characteristics appraised included initialization success rate, initialization time, RTK position accuracy and availability, ambiguity resolution risk and RTK integrity risk in order to provide a wider perspective of the performance of the testing systems. ----- ----- The results showed that the performances of all network RTK solutions assessed were affected by the increase in the inter-station distances to similar degrees. The MAX solution achieved the highest initialization success rate of 96.6% on average, albeit with a longer initialisation time. Two VRS approaches achieved lower initialization success rate of 80% over the large triangle. In terms of RTK positioning accuracy after successful initialisation, the results indicated a good agreement between the actual error growth in both horizontal and vertical components and the accuracy specified in the RMS and part per million (ppm) values by the manufacturers. ----- ----- Additionally, the VRS approaches performed better than the MAX and i-MAX when being tested under the standard triangle network with a mean inter-station distance of 69km. However as the inter-station distance increases, the network RTK software may fail to generate VRS correction and then may turn to operate in the nearest single-base RTK (or RAW) mode. The position uncertainty reached beyond 2 meters occasionally, showing that the RTK rover software was using an incorrect ambiguity fixed solution to estimate the rover position rather than automatically dropping back to using an ambiguity float solution. Results identified that the risk of incorrectly resolving ambiguities reached 18%, 20%, 13% and 25% for i-MAX, MAX, Leica VRS and Trimble VRS respectively when operating over the large triangle network. Additionally, the Coordinate Quality indicator values given by the Leica GX1230 GG rover receiver tended to be over-optimistic and not functioning well with the identification of incorrectly fixed integer ambiguity solutions. In summary, this independent assessment has identified some problems and failures that can occur in all of the systems tested, especially when being pushed beyond the recommended limits. While such failures are expected, they can offer useful insights into where users should be wary and how manufacturers might improve their products. The results also demonstrate that integrity monitoring of RTK solutions is indeed necessary for precision applications, thus deserving serious attention from researchers and system providers.

Distinguishing forced versus discretionary replacements in new product diffusion models

In many product categories of durable goods such as TV, PC, and DVD player, the largest component of sales is generated by consumers replacing existing units. Aggregate sales models proposed by diffusion of innovation researchers for the replacement component of sales have incorporated several different replacement distributions such as Rayleigh, Weibull, Truncated Normal and Gamma. Although these alternative replacement distributions have been tested using both time series sales data and individual-level actuarial “life-tables” of replacement ages, there is no census on which distributions are more appropriate to model replacement behaviour. In the current study we are motivated to develop a new “modified gamma” distribution by two reasons. First we recognise that replacements have two fundamentally different drivers – those forced by failure and early, discretionary replacements. The replacement distribution for each of these drivers is expected to be quite different. Second, we observed a poor fit of other distributions to out empirical data. We conducted a survey of 8,077 households to empirically examine models of replacement sales for six electronic consumer durables – TVs, VCRs, DVD players, digital cameras, personal and notebook computers. This data allows us to construct individual-level “life-tables” for replacement ages. We demonstrate the new modified gamma model fits the empirical data better than existing models for all six products using both a primary and a hold-out sample.

The impact of changes to the graduated driver licensing program in Queensland, Australia on the experiences of learner drivers

Purpose: Graduated driver licensing (GDL) has been introduced in numerous jurisdictions in Australia and internationally in an attempt to ameliorate the significantly greater risk of death and injury for young novice drivers arising from road crashes. The GDL program in Queensland, Australia, was extensively modified in July 2007. This paper reports the driving and licensing experiences of Learner drivers progressing through the current-GDL program, and compares them to the experiences of Learners who progressed through the former-GDL program. ----- ----- Method: Young drivers (n = 1032, 609 females, 423 males) aged 17 to 19 years (M = 17.43, SD = 0.67) were recruited as they progressed from a Learner to a Provisional driver’s licence. They completed a survey exploring their sociodemographic characteristics, driving and licensing experiences as a Learner. Key measures for a subsample (n = 183) of the current-GDL drivers were compared with the former-GDL drivers (n = 149) via t-tests and chi-square analyses. ----- ----- Results: As expected, Learner drivers progressing through the current-GDL program gained significantly more driving practice than those in the former program, which was more likely to be provided by mothers than in the past. Female learners in the current-GDL program reported less difficulty obtaining supervision than those in the former program. The number of attempts needed to pass the practical driving assessment did not change, nor did the amount of professional supervision. The current-GDL Learners held their licence for a significantly longer duration than those in the former program, with the majority reporting that their Logbook entries were accurate on the whole. Compared to those in the former program, a significantly smaller proportion of male current-GDL Learners reported being detected for a driving offence while the females reported significantly lower crash involvement. Most current-GDL drivers reported undertaking their supervised practice at the end of the Learner period. ----- ----- Conclusions: The enhancements to the GDL program in Queensland appear to have achieved many of their intended results. The current-GDL learners participating in the study reported obtaining a significantly greater amount of supervised driving experience compared to former-GDL learners. Encouragingly, the current-GDL Learners did not report any greater difficulty in obtaining supervised driving practice, and there was a decline in the proportion of current-GDL Learners engaging in unsupervised driving. In addition, the majority of Learners do not appear to be attempting to subvert logbook recording requirements, as evidenced by high rates of self-reported logbook accuracy. The results have implications for the development and the evaluation of GDL programs in Australia and around the world.

Empirical Bayes method in the study of traffic safety via heterogeneous negative multinomial model

In the study of traffic safety, expected crash frequencies across sites are generally estimated via the negative binomial model, assuming time invariant safety. Since the time invariant safety assumption may be invalid, Hauer (1997) proposed a modified empirical Bayes (EB) method. Despite the modification, no attempts have been made to examine the generalisable form of the marginal distribution resulting from the modified EB framework. Because the hyper-parameters needed to apply the modified EB method are not readily available, an assessment is lacking on how accurately the modified EB method estimates safety in the presence of the time variant safety and regression-to-the-mean (RTM) effects. This study derives the closed form marginal distribution, and reveals that the marginal distribution in the modified EB method is equivalent to the negative multinomial (NM) distribution, which is essentially the same as the likelihood function used in the random effects Poisson model. As a result, this study shows that the gamma posterior distribution from the multivariate Poisson-gamma mixture can be estimated using the NM model or the random effects Poisson model. This study also shows that the estimation errors from the modified EB method are systematically smaller than those from the comparison group method by simultaneously accounting for the RTM and time variant safety effects. Hence, the modified EB method via the NM model is a generalisable method for estimating safety in the presence of the time variant safety and the RTM effects.

Theoretical model of user acceptance : in the view of measuring success in web personalization

This paper attempts to develop a theoretical acceptance model for measuring Web personalization success. Key factors impacting Web personalization acceptance are identified from a detailed literature review. The final model is then cast in a structural equation modeling (SEM) framework comprising nineteen manifest variables, which are grouped into three focal behaviors of Web users. These variables could provide a framework for better understanding of numerous factors that contribute to the success measures of Web personalization technology. Especially, those concerning the quality of personalized features and how personalized information through personalized Website can be delivered to the user. The interrelationship between success constructs is also explained. Empirical validations of this theoretical model are expected on future research.

Expression and connection : the integration of the reflective learning process and the writing process into social network sites

A number of instructors have recently adopted social network sites (SNSs) for learning. However, the learning design of SNSs often remains at a preliminary level similar to a personal log book because it does not properly include reflective learning elements such as individual reflection and collaboration. This article looks at the reflective learning process and the public writing process as a way of improving the quality of reflective learning on SNSs. It proposes a reflective learning model on SNSs based on two key pedagogical concepts for social networking: individual expression and collaborative connection. It is expected that the model would be helpful for instructors in designing a reflective learning process on SNSs in an effective and flexible way.

An evaluation framework for sustaining the impact of educational development

Notwithstanding significant efforts by international aid agencies, aid ineffectiveness became apparent in 1990s as the impact of continued development intervention did not endure the expected outcomes. Conventional monitoring and evaluation by those agencies is critiqued for focusing on measuring project outcomes and giving little attention to aspects of sustainability. As a result, devising a rigorous evaluation framework for educational development has been sought in light of recent paradigm shifts in international development. This paper reports on a case study of an Egyptian educational development project highlighting the importance of transforming the evaluation procedures to process evaluation so as to enhance project impact and longevity. This requires building evaluation capacity of the aid recipient country.

The big picture : an integrated approach to fashion design education

This paper examines current teaching practice within the context of the Bachelor of Design (Fashion) programme at AUT University and compares it to the approach adopted in previous years. In recent years, staff on the Bachelor of Design (Fashion) adopted a holistic approach to the assessment of design projects similar to the successful ideas and methods put forward by Stella Lange at the FINZ conference, 2005. Prior to adopting this holistic approach, the teaching culture at AUT University was modular and divorced the development of conceptual design ideas from the technical processes of patternmaking and garment construction, thus limiting the creative potential of integrated project work. Fashion Design is not just about drawing pretty pictures but is rather an entire process that encapsulates conceptual design ideas and technical processes within the context of a target market. Fashion design at AUT being under the umbrella of a wider Bachelor of Design must encourage a more serious view of Fashion and Fashion Design as a whole. In the development of the Bachelor of Design degree at AUT, the university recognised that design education would be best serviced by an inclusive approach. At inception, Core Studio and Core Theory papers formed the first semester of the programme across the discipline areas of Fashion, Spatial Design, Graphic Design and Digital Design. These core papers reinforce the reality that there is a common skill set that transcends all design disciplines with the differentiation between disciplines being determined by the techniques and processes they adopt. Studio based teaching within the scope of a major design project was recognised and introduced some time ago for students in their graduating year, however it was also expected that by year 3 the student had amassed the basic skills required to be able to work in this way. The opinion concerning teaching these basic skills was that they were best serviced by a modular approach. Prior attempts to manage design project delivery leant towards deconstructing the newly formed integrated papers in order to ensure key technical skills were covered in enough depth. So, whilst design projects have played an integral part in the delivery of fashion design over the year levels, the earlier projects were timetabled by discipline and unconvincingly connected. This paper discusses how the holistic approach to assessment must be coupled with an integrated approach to delivery. The methods and processes used are demonstrated and some recently trialled developments are shown to have resulted in achieving the integrated approach in both delivery and assessment.

Reliability analysis and economic equipment replacement appraisal for substation and sub-transmission systems with explicit inclusion of non-repairable failures

The modern society has come to expect the electrical energy on demand, while many of the facilities in power systems are aging beyond repair and maintenance. The risk of failure is increasing with the aging equipments and can pose serious consequences for continuity of electricity supply. As the equipments used in high voltage power networks are very expensive, economically it may not be feasible to purchase and store spares in a warehouse for extended periods of time. On the other hand, there is normally a significant time before receiving equipment once it is ordered. This situation has created a considerable interest in the evaluation and application of probability methods for aging plant and provisions of spares in bulk supply networks, and can be of particular importance for substations. Quantitative adequacy assessment of substation and sub-transmission power systems is generally done using a contingency enumeration approach which includes the evaluation of contingencies, classification of the contingencies based on selected failure criteria. The problem is very complex because of the need to include detailed modelling and operation of substation and sub-transmission equipment using network flow evaluation and to consider multiple levels of component failures. In this thesis a new model associated with aging equipment is developed to combine the standard tools of random failures, as well as specific model for aging failures. This technique is applied in this thesis to include and examine the impact of aging equipments on system reliability of bulk supply loads and consumers in distribution network for defined range of planning years. The power system risk indices depend on many factors such as the actual physical network configuration and operation, aging conditions of the equipment, and the relevant constraints. The impact and importance of equipment reliability on power system risk indices in a network with aging facilities contains valuable information for utilities to better understand network performance and the weak links in the system. In this thesis, algorithms are developed to measure the contribution of individual equipment to the power system risk indices, as part of the novel risk analysis tool. A new cost worth approach was developed in this thesis that can make an early decision in planning for replacement activities concerning non-repairable aging components, in order to maintain a system reliability performance which economically is acceptable. The concepts, techniques and procedures developed in this thesis are illustrated numerically using published test systems. It is believed that the methods and approaches presented, substantially improve the accuracy of risk predictions by explicit consideration of the effect of equipment entering a period of increased risk of a non-repairable failure.

Hierarchical Bayesian models for estimating the extent of plant pest invasions

Plant biosecurity requires statistical tools to interpret field surveillance data in order to manage pest incursions that threaten crop production and trade. Ultimately, management decisions need to be based on the probability that an area is infested or free of a pest. Current informal approaches to delimiting pest extent rely upon expert ecological interpretation of presence / absence data over space and time. Hierarchical Bayesian models provide a cohesive statistical framework that can formally integrate the available information on both pest ecology and data. The overarching method involves constructing an observation model for the surveillance data, conditional on the hidden extent of the pest and uncertain detection sensitivity. The extent of the pest is then modelled as a dynamic invasion process that includes uncertainty in ecological parameters. Modelling approaches to assimilate this information are explored through case studies on spiralling whitefly, Aleurodicus dispersus and red banded mango caterpillar, Deanolis sublimbalis. Markov chain Monte Carlo simulation is used to estimate the probable extent of pests, given the observation and process model conditioned by surveillance data. Statistical methods, based on time-to-event models, are developed to apply hierarchical Bayesian models to early detection programs and to demonstrate area freedom from pests. The value of early detection surveillance programs is demonstrated through an application to interpret surveillance data for exotic plant pests with uncertain spread rates. The model suggests that typical early detection programs provide a moderate reduction in the probability of an area being infested but a dramatic reduction in the expected area of incursions at a given time. Estimates of spiralling whitefly extent are examined at local, district and state-wide scales. The local model estimates the rate of natural spread and the influence of host architecture, host suitability and inspector efficiency. These parameter estimates can support the development of robust surveillance programs. Hierarchical Bayesian models for the human-mediated spread of spiralling whitefly are developed for the colonisation of discrete cells connected by a modified gravity model. By estimating dispersal parameters, the model can be used to predict the extent of the pest over time. An extended model predicts the climate restricted distribution of the pest in Queensland. These novel human-mediated movement models are well suited to demonstrating area freedom at coarse spatio-temporal scales. At finer scales, and in the presence of ecological complexity, exploratory models are developed to investigate the capacity for surveillance information to estimate the extent of red banded mango caterpillar. It is apparent that excessive uncertainty about observation and ecological parameters can impose limits on inference at the scales required for effective management of response programs. The thesis contributes novel statistical approaches to estimating the extent of pests and develops applications to assist decision-making across a range of plant biosecurity surveillance activities. Hierarchical Bayesian modelling is demonstrated as both a useful analytical tool for estimating pest extent and a natural investigative paradigm for developing and focussing biosecurity programs.