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

Business cycle dynamics with duration dependence and leading indicators

Durland and McCurdy [Durland, J.M., McCurdy, T.H., 1994. Duration-dependent transitions in a Markov model of US GNP growth. Journal of Business and Economic Statistics 12, 279–288] investigated the issue of duration dependence in US business cycle phases using a Markov regime-switching approach, introduced by Hamilton [Hamilton, J., 1989. A new approach to the analysis of time series and the business cycle. Econometrica 57, 357–384] and extended to the case of variable transition parameters by Filardo [Filardo, A.J., 1994. Business cycle phases and their transitional dynamics. Journal of Business and Economic Statistics 12, 299–308]. In Durland and McCurdy’s model duration alone was used as an explanatory variable of the transition probabilities. They found that recessions were duration dependent whilst expansions were not. In this paper, we explicitly incorporate the widely-accepted US business cycle phase change dates as determined by the NBER, and use a state-dependent multinomial Logit modelling framework. The model incorporates both duration and movements in two leading indexes – one designed to have a short lead (SLI) and the other designed to have a longer lead (LLI) – as potential explanatory variables. We find that doing so suggests that current duration is not only a significant determinant of transition out of recessions, but that there is some evidence that it is also weakly significant in the case of expansions. Furthermore, we find that SLI has more informational content for the termination of recessions whilst LLI does so for expansions.

Improving visual noise insensitivity in small vocabulary audio visual speech recognition applications

Visual noise insensitivity is important to audio visual speech recognition (AVSR). Visual noise can take on a number of forms such as varying frame rate, occlusion, lighting or speaker variabilities. The use of a high dimensional secondary classifier on the word likelihood scores from both the audio and video modalities is investigated for the purposes of adaptive fusion. Preliminary results are presented demonstrating performance above the catastrophic fusion boundary for our confidence measure irrespective of the type of visual noise presented to it. Our experiments were restricted to small vocabulary applications.

Beam steering with high front-to-back ratio and high directivity on small platforms using decoupled antenna pairs

Beam steering with high front-to-back ratio and high directivity on a small platform is proposed. Two closely spaced antenna pairs with eigenmode port decoupling are used as the basic radiating elements. Two orthogonal radiation patterns are obtained for each antenna pair. High front-to-back ratio and high directivity are achieved by combining the two orthogonal radiation patterns. With an infinite groundplane, a front-to-back ratio of 21 dB with a directivity of 9.8 dB can be achieved. Beam steering, at the expense of a slight decrease in directivity, is achieved by placing the two antenna pairs 0.5λ apart. The simulated half power beamwidth is 58°. A prototype was designed and the 2-D radiation patterns were measured. The prototype supports three directions of beam steering. The half power beamwidth was measured as 46°, 48°, and 50° for the three respective beam directions. The measured front-to-back ratio in azimuth plane is 8.5 dB, 8.0 dB and 7.6 dB, respectively.

Why adopt now? Multiple case studies and survey studies comparing small, medium and large firms

While a number of factors have been highlighted in the innovation adoption literature, little is known about whether different factors are related to innovation adoption in differently-sized firms. We used preliminary case studies of small, medium and large firms to ground our hypotheses, which were then tested using a survey of 94 firms. We found that external stakeholder pressure and non-financial readiness were related to innovation adoption in SMEs; but that for large firms, adoption was related to the opportunity to innovate. It may be that the difficulties of adopting innovations, including both the financial cost and the effort involved, are too great for SMEs to overcome unless there is either a compelling need (external pressure) or enough in-house capability (non-financial readiness). This suggests that SMEs are more likely to have innovation “pushed” onto them while large firms are more likely to “pull” innovations when they have the opportunity.

A study on acoustic emission signal propagation of a small size multi-cylinder diesel engine

Acoustic emission has been found effective in offering earlier fault detection and improving identification capabilities of faults. However, the sensors are inherently uncalibrated. This paper presents a source to sensor paths calibration technique which can lead to diagnosis of faults in a small size multi-cylinder diesel engine. Preliminary analysis of the acoustic emission (AE) signals is outlined, including time domain, time-frequency domain, and the root mean square (RMS) energy. The results reveal how the RMS energy of a source propagates to the adjacent sensors. The findings lead to allocate the source and estimate its inferences to the adjacent sensor, and finally help to diagnose the small size diesel engines by minimising the crosstalk from multiple cylinders.

Knowledge management for enterprise systems: observations from small, medium and large organizations

Anecdotal evidence suggests that the lifecycle-wide management of Enterprise System (ES) related knowledge is critical for ES health and longevity. At a time where many ES-vendors now offering solutions to Small and Medium size organizations, this paper investigates the ability of Small and Medium size organizations to maintain a lifecycle-wide knowledge management strategy. The paper explores the alleged differences in the knowledge management practices across 27 small, medium and large organizations that had implemented a market-leading ES. Results suggest that: (1) despite similar knowledge creation efforts in all three organizational sizes, small organizations struggle with retaining, transferring and applying the knowledge. The study also reveals that, (2) the overall goodness of the knowledge management process in larger organizations remains higher than their small and medium counterparts.

Introducing a small and medium enterprises syllabi design: an enterprise systems hands-on approach

There is increasing attention to the importance of Enterprise Systems (ES) and Information Systems (IS) for Small and Medium Enterprises (SMEs). The same attention must be addressed in IS graduate curriculum. Studies reveal that despite healthy demand from the industry for IS management expertise, most IS graduates are ill-equipped to meet the challenges of modern organizations. The majority of contemporary firms, represented by SMEs, seek employees with a balance of business process knowledge and ES software skills. This article describes a curriculum that teaches Information Technology (IT) and IS managementconcepts in a SMEs context. The curriculum conceptualises a ‘learn-by-doing’ approach, to provide business process and ES software specific knowledge for its students. The approach recommends coverage of traditional content related to SMEs’’ operations, strategies, IT investment and management issues while providing an increased focus on strategic use of enterprise IT. The study addresses to an extent, the perennial challenge of updating IS curriculum, given the rapid pace of technological change.

Small animal bone healing models : standards, tips, and pitfalls results of a consensus meeting

Small animal fracture models have gained increasing interest in fracture healing studies. To achieve standardized and defined study conditions, various variables must be carefully controlled when designing fracture healing experiments in mice or rats. The strain, age and sex of the animals may influence the process of fracture healing. Furthermore, the choice of the fracture fixation technique depends on the questions addressed, whereby intra- and extramedullary implants as well as open and closed surgical approaches may be considered. During the last few years, a variety of different, highly sophisticated implants for fracture fixation in small animals have been developed. Rigid fixation with locking plates or external fixators results in predominantly intramembranous healing in both mice and rats. Locking plates, external fixators, intramedullary screws, the locking nail and the pin-clip device allow different degrees of stability resulting in various amounts of endochondral and intramembranous healing. The use of common pins that do not provide rotational and axial stability during fracture stabilization should be discouraged in the future. Analyses should include at least biomechanical and histological evaluations, even if the focus of the study is directed towards the elucidation of molecular mechanisms of fracture healing using the largely available spectrum of antibodies and gene-targeted animals to study molecular mechanisms of fracture healing. This review discusses distinct requirements for the experimental setups as well as the advantages and pitfalls of the different fixation techniques in rats and mice.

Forgotten places : rediscovering the small spaces and laneways of Fortitude Valley

A design Charrette was the starting point for understanding the different scales within the design process of this architectural intervention. The week-long, intense design activity promoted group interaction amongst students while examining local issues of the Fortitude Valley context. The process was an opportunity for the fourth year architectural design students to collaborate on a complex design problem. Students were asked to identify a unique condition of their site beyond the physical built environment. They were asked to consider the political and social context and respond to these by designing a temporary art gallery for underdeveloped areas within Fortitude Valley. The exhibition shows how architecture can invigorate a space by providing new use and new life.

Omnidirectional bearing-only see-and-avoid for small aerial robots

Motivated by the growing interest in unmanned aerial system’s applications in indoor and outdoor settings and the standardisation of visual sensors as vehicle payload. This work presents a collision avoidance approach based on omnidirectional cameras that does not require the estimation of range between two platforms to resolve a collision encounter. It will achieve a minimum separation between the two vehicles involved by maximising the view-angle given by the omnidirectional sensor. Only visual information is used to achieve avoidance under a bearing-only visual servoing approach. We provide theoretical problem formulation, as well as results from real flight using small quadrotors.