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.

Optimistic linear programming gives logarithmic regret for irreducible MDPs

We present an algorithm called Optimistic Linear Programming (OLP) for learning to optimize average reward in an irreducible but otherwise unknown Markov decision process (MDP). OLP uses its experience so far to estimate the MDP. It chooses actions by optimistically maximizing estimated future rewards over a set of next-state transition probabilities that are close to the estimates, a computation that corresponds to solving linear programs. We show that the total expected reward obtained by OLP up to time T is within C(P) log T of the reward obtained by the optimal policy, where C(P) is an explicit, MDP-dependent constant. OLP is closely related to an algorithm proposed by Burnetas and Katehakis with four key differences: OLP is simpler, it does not require knowledge of the supports of transition probabilities, the proof of the regret bound is simpler, but our regret bound is a constant factor larger than the regret of their algorithm. OLP is also similar in flavor to an algorithm recently proposed by Auer and Ortner. But OLP is simpler and its regret bound has a better dependence on the size of the MDP.

An empirical study of applying ISO 9001 elements in large size Indonesian contractors

The effective implementation of such an ISO 9001 Quality Management System (QMS) in construction companies requires a proper and full implementation of the system to allow companies to improve the way they operate, by this means increasing profitability and market share, producing innovative and sustainable construction products, or improving employee and customer satisfaction. In light of this, this paper discusses the current status of QMS implementation, particularly related to the twenty elements of ISO 9001 within the grade 7 (G-7) category of Indonesian construction companies. A survey was conducted involving 403 respondents from 77 companies, to solicit an evaluation of the current implementation levels of the ISO 9001 elements. The survey findings indicated that for a large percentage of the sector surveyed they had ‘not so fully implemented’ the elements. Scrutiny of the data had also indicated elements that are ‘minimally implemented’, whilst none of the elements fell in the category of ‘fully implemented’. Based on these findings, it is suggested that the G-7 contractors may need to fully commit to practicing control of customer-supplied product and statistical techniques in order to enhance an effective implementation of ISO 9001 elements for ensuring better quality performance. These two elements are recognized as the least implemented of the quality elements.

Size effects on tensile and fatigue behaviour of polycrystalline metal foils at the micrometer scale

Tensile and fatigue properties of as-rolled and annealed polycrystalline Cu foils with different thicknesses at the micrometer scale were investigated. Uniaxial tensile testing results showed that with decreasing foil thickness the uniform elongation decreases for both as-rolled and annealed foils, whereas the yield strength and ultimate tensile strength increase for as-rolled foils, but decrease for the annealed foils. For both the as-rolled or annealed foils, bending fatigue resistance decreases with decreasing the foil thickness. Deformation and fatigue damage behaviour of the free-standing foils were characterised as a function of foil thickness. In addition, the fatigue strength of various small-scale Cu foils was compared to understand they physical mechanisms of size effects on mechanical properties of the metallic material at micrometer scales.

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.

What determines real-world meal size? Evidence for pre-meal planning

The customary approach to the study of meal size suggests that ‘events’ occurring during a meal lead to its termination. Recent research, however, suggests that a number of decisions are made before eating commences that may affect meal size. The present study sought to address three key research questions around meal size: the extent to which plate cleaning occurs; prevalence of pre-meal planning and its influence on meal size; and the effect of within-meal experiences, notably the development of satiation. To address these, a large-cohort internet-based questionnaire was developed. Results showed that plate cleaning occurred at 91% of meals, and was planned from the outset in 92% of these cases. A significant relationship between plate cleaning and meal planning was observed. Pre meal plans were resistant to modification over the course of the meal: only 18% of participants reported consumption that deviated from expected. By contrast, 28% reported continuing eating beyond satiation, and 57% stated that they could have eaten more at the end of the meal. Logistic regression confirmed pre-meal planning as the most important predictor of consumption. Together, our findings demonstrate the importance of meal planning as a key determinant of meal size and energy intake.

‘I could eat a horse’! : meal planning determines meal size

Evidence that our food environment can affect meal size is often taken to indicate a failure of ‘conscious control’. By contrast, our research suggests that ‘expected satiation’ (fullness that a food is expected to confer) predicts self-selected meal size. However, the role of meal planning as a determinant of actual meal size remains unresolved, as does the extent to which meal planning is commonplace outside the laboratory. Here, we quantified meal planning and its relation to meal size in a large-cohort study. Participants (N= 764; 25.6 yrs, 78% female) completed a questionnaire containing items relating to their last meal. The majority (91%) of meals were consumed in their entirety. Furthermore, in 92% of these cases the participants decided to consume the whole meal, even before it began. A second major objective was to explore the prospect that meal plans are revised based on within-meal experience (e.g., development of satiation). Only 8% of participants reported ‘unexpected’ satiation that caused them to consume less than anticipated. Moreover, at the end of the meal 57% indicated that they were not fully satiated, and 29% continued eating beyond comfortable satiation (often to avoid wasting food). This pattern was neither moderated by BMI nor dieting status, and was observed across meal types. Together, these data indicate that meals are often planned and that planning corresponds closely with amount consumed. By contrast, we find limited evidence for within-meal modification of these plans, suggesting that ‘pre-meal cognition’ is an important determinant of meal size in humans.

Body composition and appetite : fat-free mass (but not fat mass or BMI) is positively associated with self-determined meal size and daily energy intake in humans

The idea of body weight regulation implies that a biological mechanism exerts control over energy expenditure and food intake. This is a central tenet of energy homeostasis. However, the source and identity of the controlling mechanism have not been identified, although it is often presumed to be some long-acting signal related to body fat, such as leptin. Using a comprehensive experimental platform, we have investigated the relationship between biological and behavioural variables in two separate studies over a 12-week intervention period in obese adults (total n 92). All variables have been measured objectively and with a similar degree of scientific control and precision, including anthropometric factors, body composition, RMR and accumulative energy consumed at individual meals across the whole day. Results showed that meal size and daily energy intake (EI) were significantly correlated with fat-free mass (FFM, P values ,0·02–0·05) but not with fat mass (FM) or BMI (P values 0·11–0·45) (study 1, n 58). In study 2 (n 34), FFM (but not FM or BMI) predicted meal size and daily EI under two distinct dietary conditions (high-fat and low-fat). These data appear to indicate that, under these circumstances, some signal associated with lean mass (but not FM) exerts a determining effect over self-selected food consumption. This signal may be postulated to interact with a separate class of signals generated by FM. This finding may have implications for investigations of the molecular control of food intake and body weight and for the management of obesity.

Multifractal analysis of geomagnetic storm and solar flare indices and their class dependence

The multifractal properties of two indices of geomagnetic activity, D st (representative of low latitudes) and a p (representative of the global geomagnetic activity), with the solar X-ray brightness, X l , during the period from 1 March 1995 to 17 June 2003 are examined using multifractal detrended fluctuation analysis (MF-DFA). The h(q) curves of D st and a p in the MF-DFA are similar to each other, but they are different from that of X l , indicating that the scaling properties of X l are different from those of D st and a p . Hence, one should not predict the magnitude of magnetic storms directly from solar X-ray observations. However, a strong relationship exists between the classes of the solar X-ray irradiance (the classes being chosen to separate solar flares of class X-M, class C, and class B or less, including no flares) in hourly measurements and the geomagnetic disturbances (large to moderate, small, or quiet) seen in D st and a p during the active period. Each time series was converted into a symbolic sequence using three classes. The frequency, yielding the measure representations, of the substrings in the symbolic sequences then characterizes the pattern of space weather events. Using the MF-DFA method and traditional multifractal analysis, we calculate the h(q), D(q), and τ (q) curves of the measure representations. The τ (q) curves indicate that the measure representations of these three indices are multifractal. On the basis of this three-class clustering, we find that the h(q), D(q), and τ (q) curves of the measure representations of these three indices are similar to each other for positive values of q. Hence, a positive flare storm class dependence is reflected in the scaling exponents h(q) in the MF-DFA and the multifractal exponents D(q) and τ (q). This finding indicates that the use of the solar flare classes could improve the prediction of the D st classes.