Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence

Abstract Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence

Gambling & gaming : power relations in dispute resolution

Who, ultimately, has power? Is it the senior executive with his finger on the off switch, is it the users themselves who make the decision to participate and contribute financially, or is it those who report on the actions of the company with the ability to reach large numbers of existing and potential players? In both the gambling and gaming industries, power is up for grabs. This work undertakes to consider how norms are formed in online gaming communities; that is, how the developers and players negotiate amongst themselves both how the game will operate. Also considered is how to resolve disputes that arise, and what power and limitations each side has when they need to make an impact – from developers switching off the server, to players quitting en-mass or causing disruption within the environment (using the recent example of Eve Online). Outside of the direct sphere of the game however a third party lurks – commentators. These may take the form of well established review sites, community forums or, in the case of the gambling industry, dispute resolution services but their power stake is clear – by publicising and interpreting the acts of both developers and players, they are in a position to influence whether current players stick with a company, whether new players join a company and how the company is perceived in the wider community.

A novel high voltage pulsed power supply based on low voltage switch-capacitor units

This paper presents a high voltage pulsed power system based on low voltage switch-capacitor units connected to a current source for several applications such as plasma systems. A buck-boost converter topology is used to utilize the current source and a series of low voltage switch-capacitor units is connected to the current source in order to provide high voltage with high voltage stress (dv/dt) as demanded by loads. This pulsed power converter is flexible in terms of energy control, in that the stored energy in the current source can be adjusted by changing the current magnitude to significantly improve the efficiency of various systems with different requirements. Output voltage magnitude and stress (dv/dt) can be controlled by a proper selection of components and control algorithm to turn on and off switching devices.

A novel high voltage pulsed power supply based on low voltage switch-capacitor units

This paper presents a high voltage pulsed power system based on low voltage switch-capacitor units connected to a current source for several applications such as plasma systems. A modified positive buck-boost converter topology is used to utilize the current source concept and a series of low voltage switch-capacitor units is connected to the current source in order to provide high voltage with high voltage stress (dv/dt) as demanded by loads. This pulsed power converter is flexible in terms of energy control, in that the stored energy in the current source can be adjusted by changing the current magnitude to significantly improve the efficiency of various systems with different requirements. Output voltage magnitude and stress (dv/dt) can be controlled by a proper selection of components and control algorithm to turn on and off switching devices.

Cooperation using a robotic ad hoc network made from Bluetooth, JXTA, OSGi and other commercial off the shelf (COTS) products

Abstract - Mobile devices in the near future will need to collaborate to fulfill their function. Collaboration will be done by communication. We use a real world example of robotic soccer to come up with the necessary structures required for robotic communication. A review of related work is done and it is found no examples come close to providing a RANET. The robotic ad hoc network (RANET) we suggest uses existing structures pulled from the areas of wireless networks, peer to peer and software life-cycle management. Gaps are found in the existing structures so we describe how to extend some structures to satisfy the design. The RANET design supports robot cooperation by exchanging messages, discovering needed skills that other robots on the network may possess and the transfer of these skills. The network is built on top of a Bluetooth wireless network and uses JXTA to communicate and transfer skills. OSGi bundles form the skills that can be transferred. To test the nal design a reference implementation is done. Deficiencies in some third party software is found, specifically JXTA and JamVM and GNU Classpath. Lastly we look at how to fix the deciencies by porting the JXTA C implementation to the target robotic platform and potentially eliminating the TCP/IP layer, using UDP instead of TCP or using an adaptive TCP/IP stack. We also propose a future areas of investigation; how to seed the configuration for the Personal area network (PAN) Bluetooth protocol extension so a Bluetooth TCP/IP link is more quickly formed and using the STP to allow multi-hop messaging and transfer of skills.

Understanding the physical processes of pollutant build-up and wash-off on roof surfaces

Pollutants originating with roof runoff can have a significant impact to urban stormwater quality. This signifies the importance of understanding pollutant processes on roof surfaces. Additionally, knowledge of pollutant processes on roof surfaces is important as roofs are used as the primary catchment surface for domestic rainwater harvesting. In recent years, rainwater harvesting has become one of the primary sustainable water management techniques to counteract the growing demand for potable water. Similar to all impervious services, pollutants associated with roof runoff undergo two primary processes: build-up and wash-off. The knowledge relating to these processes is limited. This paper presents outcomes of an in-depth research study into pollutant build-up and wash-off for roof surfaces. The knowledge will be important in order to develop appropriate strategies to safeguard rainwater users from possible health risks.

Bayesian versus frequentist statistical inference for investi gating a one-off cancer cluster reported to a health department

Background The problem of silent multiple comparisons is one of the most difficult statistical problems faced by scientists. It is a particular problem for investigating a one-off cancer cluster reported to a health department because any one of hundreds, or possibly thousands, of neighbourhoods, schools, or workplaces could have reported a cluster, which could have been for any one of several types of cancer or any one of several time periods. Methods This paper contrasts the frequentist approach with a Bayesian approach for dealing with silent multiple comparisons in the context of a one-off cluster reported to a health department. Two published cluster investigations were re-analysed using the Dunn-Sidak method to adjust frequentist p-values and confidence intervals for silent multiple comparisons. Bayesian methods were based on the Gamma distribution. Results Bayesian analysis with non-informative priors produced results similar to the frequentist analysis, and suggested that both clusters represented a statistical excess. In the frequentist framework, the statistical significance of both clusters was extremely sensitive to the number of silent multiple comparisons, which can only ever be a subjective "guesstimate". The Bayesian approach is also subjective: whether there is an apparent statistical excess depends on the specified prior. Conclusion In cluster investigations, the frequentist approach is just as subjective as the Bayesian approach, but the Bayesian approach is less ambitious in that it treats the analysis as a synthesis of data and personal judgements (possibly poor ones), rather than objective reality. Bayesian analysis is (arguably) a useful tool to support complicated decision-making, because it makes the uncertainty associated with silent multiple comparisons explicit.

Final report : offsite manufacture in Australia Final report off-site manufacture in Australia

Off-site Manufacture (OSM) has long been recognised, both in Australia and internationally, as offering numerous benefits to all parties in the construction process. More importantly, it is recognised as a key vehicle for driving improvement within the construction industry. The uptake of OSM in construction is however limited, despite well documented benefits. The research aims to determine the ‘state-of-the-art’ of OSM in Australia. It confirms the benefits and identifies the real and perceived barriers to the widespread adoption of OSM. Further the project identifies opportunities for future investment and research. Although numerous reports have been produced in the UK on the state of OSM adoption within that region, no prominent studies exist for the Australian context. This scoping study is an essential component upon which to build any initiatives that can take advantage of the benefits of OSM in construction. The Construction 2020 report predicted that OSM is set to increase in use over the next 5-15 years, further justifying the need for such a study. The long-term goal of this study is to contribute to the improvement of the Australian construction industry through a realisation of the potential benefits of OSM.

Off-site Manufacture in Australia : Current State and Future Directions

Off-site manufacture (OSM) offers numerous benefits to all parties in the construction process. The uptake of OSM in Australia has, however, been limited. This limited uptake corresponds to similar trends in the UK and US, although the level of OSM there appears to be increasing. This project undertook three workshops — one each in Victoria, Queensland and Western Australia — and 18 interviews with key stakeholders to assist in identifying the general benefits and barriers to OSM uptake in the Australian construction industry. Seven case studies were also undertaken, involving construction projects that used OSM, ranging from civil projects through to residential. Each of these case studies has been analysed to identify what worked and what didn’t, and suggest the lessons to be learned from each project.

Drivers constraints and the future of off-site manufacture in Australia.

Much has been written on Off-site Manufacture (OSM) in construction, particularly regarding the perceived benefits and barriers to implementation. However, very little understanding of the state of OSM in the Australian construction industry exists. A ‘scoping study' has recently been undertaken to determine the ‘state-of-the-art’ of OSM in Australia. This involved several industry workshops, interviews and case studies across four major states of Australia. The study surveyed a range of suppliers across the construction supply-chain, incorporating the civil, commercial and housing segments of the market. This revealed that skills shortages and lack of adequate OSM knowledge are generally the greatest issues facing OSM in Australia. The drivers and constraints that emerged from the research were, in large measure, consistent with those found in the US and UK, although some Australian anomalies are evident, such as the geographical disparity of markets. A comparative analysis with similar studies in the UK and US is reported, illustrating both the drivers and constraints confronting the industry in Australia. OSM uptake into the future is however dependent on many factors, not least of which is a better understanding of the construction process and its associated costs.

A grounded theory study of nursing students’ experiences in the off-campus clinical setting

Poor workplace relations are an issue of concern in many workplaces and this phenomenon is not restricted to the nursing profession. The issue of workplace violence in nursing is well documented and there are an increasing number of studies which have investigated the notion of horizontal violence amongst graduate nurses. The impact that poor workplace relations has on the development of a professional identity by nursing students in the off-campus clinical setting is significant in light of the current global shortage of nurses. There is a dearth of knowledge in understanding how Australian undergraduate nursing students experience the off-campus clinical setting and subsequently develop a professional identity as a nurse. Therefore the aim of this study was to discover and describe the phenomena in order to develop a substantive theory that explains the experiences of the undergraduate nursing students in a regional setting. Constructivist grounded theory methods were utilised in the conduct of the study. A sample of 29 participants was recruited permitting the formulation of a substantive theory regarding the development of a professional identity in nursing students. This substantive theory contributes knowledge relevant to the undergraduate nursing students, nurse educators, nursing workforce planners, and the tertiary educational institutions offering nursing. This is achieved through discovering, describing and explaining the phenomenon of ‘anxiety’ which the nursing students experience as a result of the interrelationship and interactions of tradition bearing, staff and student performance. These interactions intersect to form expectations of where the student fits within the hierarchy of the facility and the nursing profession in general. An understanding of the issues associated with tradition bearing, staff performance, and student performance and the impact that the interaction of these conditions has upon the student’s developing professional identity as a nurse is necessary to allow for the implementation of corrective strategies.