Partial agonists of the [alpha]3[beta]4[ast] neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2(*) nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.

Estrogen receptor-Beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNF-alpha mediated

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133+ enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

Varenicline, an alpha-4 beta-2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.

Characterizing the signal pattern of a four-cylinder diesel engine using acoustic emission and vibration analysis

Condition monitoring of diesel engines can prevent unpredicted engine failures and the associated consequence. This paper presents an experimental study of the signal characteristics of a 4-cylinder diesel engine under various loading conditions. Acoustic emission, vibration and in-cylinder pressure signals were employed to study the effectiveness of these techniques for condition monitoring and identifying symptoms of incipient failures. An event driven synchronous averaging technique was employed to average the quasi-periodic diesel engine signal in the time domain to eliminate or minimize the effect of engine speed and amplitude variations on the analysis of condition monitoring signal. It was shown that acoustic emission (AE) is a better technique than vibration method for condition monitor of diesel engines due to its ability to produce high quality signals (i.e., excellent signal to noise ratio) in a noisy diesel engine environment. It was found that the peak amplitude of AE RMS signals correlating to the impact-like combustion related events decreases in general due to a more stable mechanical process of the engine as the loading increases. A small shift in the exhaust valve closing time was observed as the engine load increases which indicates a prolong combustion process in the cylinder (to produce more power). On the contrary, peak amplitudes of the AE RMS attributing to fuel injection increase as the loading increases. This can be explained by the increase fuel friction caused by the increase volume flow rate during the injection. Multiple AE pulses during the combustion process were identified in the study, which were generated by the piston rocking motion and the interaction between the piston and the cylinder wall. The piston rocking motion is caused by the non-uniform pressure distribution acting on the piston head as a result of the non-linear combustion process of the engine. The rocking motion ceased when the pressure in the cylinder chamber stabilized.

Experimentally induced diesel engine injector faults and some preliminary acoustic emission signal observations

Diesel engine fuel injector faults can lead to reduced power, increased fuel consumption and greater exhaust emission levels and if left unchecked, can eventually lead to premature engine failure. This paper provides an overview of the Diesel, or compression ignition combustion process, and of the two basic fuel injector nozzle designs used in Diesel engines, namely, the pintle-type and hole-type nozzles. Also described are some common faults associated with these two types of fuel injector nozzles and the techniques previously used to experimentally simulate these faults. This paper also presents a recent experimental campaign undertaken using two different diesel engines whereby various fuel injector nozzle faults were induced into the engines. The first series of tests was undertaken using a turbo-charged 5.9 litre; Cummins Diesel engine whist the second series of tests was undertaken using a naturally aspirated 4 cylinder, 2.216 litre, Perkins Diesel engine. Data corresponding to different injector fault conditions was captured using in-cylinder pressure, and acoustic emission transducers along with both crank-angle encoder and top-dead centre reference signals. Using averaged in-cylinder pressure signals, it was possible to qualify the severity of the faults whilst averaged acoustic emission signals were in turn, used as the basis for wavelets decomposition. Initial observations from this signal decomposition are also presented and discussed.

Aircraft emission reduction through multi-disciplinary flight path optimisation

There is worldwide interest in reducing aircraft emissions. The difficulty of reducing emissions including water vapour, carbon dioxide (CO2) and oxides of nitrogen (NOx) is mainly due from the fact that a commercial aircraft is usually designed for a particular optimal cruise altitude but may be requested or required to operate and deviate at different altitude and speeds to archive a desired or commanded flight plan, resulting in increased emissions. This is a multi- disciplinary problem with multiple trade-offs such as optimising engine efficiency, minimising fuel burnt, minimise emissions while maintaining aircraft separation and air safety. This project presents the coupling of an advanced optimisation technique with mathematical models and algorithms for aircraft emission reduction through flight optimisation. Numerical results show that the method is able to capture a set of useful trade-offs between aircraft range and NOx, and mission fuel consumption and NOx. In addition, alternative cruise operating conditions including Mach and altitude that produce minimum NOx and CO2 (minimum mission fuel weight) are suggested.

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.

Infrared transmission and emission spectroscopic study of selected Chinese palygorskites

Infrared and infrared emission spectroscopy were used to analyze the difference in structure and thermal behavior of two Chinese palygorskites. The position of the main bands identified in the infrared spectra of the palygorskites studied is similar for these two Chinese samples, but there are some differences in their intensity, which is significant. This discrepancy is attributed to various geological environments in different regions and the existence of impurities. The infrared emission spectra clearly show the structural changes and dehydroxylation of the palygorskites when the temperature is raised. The dehydration of the palygorskites is followed by the loss of intensity of the OH stretching vibration bands in the region 3600-3200 cm-1. Dehydroxylation is followed by the decrease in intensity in the bands between 3700 and 3550 cm-1. Dehydration of pure palygorskite was completed by 600 °C. Partial loss of coordinated water was observed at 400 °C. Infrared emission spectroscopy is an effective method to determine the stability of the mineral.

Quantification of particle emission characteristics and development of an emission model for use in transport microenvironments affected by traffic emissions

Vehicle emitted particles are of significant concern based on their potential to influence local air quality and human health. Transport microenvironments usually contain higher vehicle emission concentrations compared to other environments, and people spend a substantial amount of time in these microenvironments when commuting. Currently there is limited scientific knowledge on particle concentration, passenger exposure and the distribution of vehicle emissions in transport microenvironments, partially due to the fact that the instrumentation required to conduct such measurements is not available in many research centres. Information on passenger waiting time and location in such microenvironments has also not been investigated, which makes it difficult to evaluate a passenger’s spatial-temporal exposure to vehicle emissions. Furthermore, current emission models are incapable of rapidly predicting emission distribution, given the complexity of variations in emission rates that result from changes in driving conditions, as well as the time spent in driving condition within the transport microenvironment. In order to address these scientific gaps in knowledge, this work conducted, for the first time, a comprehensive statistical analysis of experimental data, along with multi-parameter assessment, exposure evaluation and comparison, and emission model development and application, in relation to traffic interrupted transport microenvironments. The work aimed to quantify and characterise particle emissions and human exposure in the transport microenvironments, with bus stations and a pedestrian crossing identified as suitable research locations representing a typical transport microenvironment. Firstly, two bus stations in Brisbane, Australia, with different designs, were selected to conduct measurements of particle number size distributions, particle number and PM2.5 concentrations during two different seasons. Simultaneous traffic and meteorological parameters were also monitored, aiming to quantify particle characteristics and investigate the impact of bus flow rate, station design and meteorological conditions on particle characteristics at stations. The results showed higher concentrations of PN20-30 at the station situated in an open area (open station), which is likely to be attributed to the lower average daily temperature compared to the station with a canyon structure (canyon station). During precipitation events, it was found that particle number concentration in the size range 25-250 nm decreased greatly, and that the average daily reduction in PM2.5 concentration on rainy days compared to fine days was 44.2 % and 22.6 % at the open and canyon station, respectively. The effect of ambient wind speeds on particle number concentrations was also examined, and no relationship was found between particle number concentration and wind speed for the entire measurement period. In addition, 33 pairs of average half-hourly PN7-3000 concentrations were calculated and identified at the two stations, during the same time of a day, and with the same ambient wind speeds and precipitation conditions. The results of a paired t-test showed that the average half-hourly PN7-3000 concentrations at the two stations were not significantly different at the 5% confidence level (t = 0.06, p = 0.96), which indicates that the different station designs were not a crucial factor for influencing PN7-3000 concentrations. A further assessment of passenger exposure to bus emissions on a platform was evaluated at another bus station in Brisbane, Australia. The sampling was conducted over seven weekdays to investigate spatial-temporal variations in size-fractionated particle number and PM2.5 concentrations, as well as human exposure on the platform. For the whole day, the average PN13-800 concentration was 1.3 x 104 and 1.0 x 104 particle/cm3 at the centre and end of the platform, respectively, of which PN50-100 accounted for the largest proportion to the total count. Furthermore, the contribution of exposure at the bus station to the overall daily exposure was assessed using two assumed scenarios of a school student and an office worker. It was found that, although the daily time fraction (the percentage of time spend at a location in a whole day) at the station was only 0.8 %, the daily exposure fractions (the percentage of exposures at a location accounting for the daily exposure) at the station were 2.7% and 2.8 % for exposure to PN13-800 and 2.7% and 3.5% for exposure to PM2.5 for the school student and the office worker, respectively. A new parameter, “exposure intensity” (the ratio of daily exposure fraction and the daily time fraction) was also defined and calculated at the station, with values of 3.3 and 3.4 for exposure to PN13-880, and 3.3 and 4.2 for exposure to PM2.5, for the school student and the office worker, respectively. In order to quantify the enhanced emissions at critical locations and define the emission distribution in further dispersion models for traffic interrupted transport microenvironments, a composite line source emission (CLSE) model was developed to specifically quantify exposure levels and describe the spatial variability of vehicle emissions in traffic interrupted microenvironments. This model took into account the complexity of vehicle movements in the queue, as well as different emission rates relevant to various driving conditions (cruise, decelerate, idle and accelerate), and it utilised multi-representative segments to capture the accurate emission distribution for real vehicle flow. This model does not only helped to quantify the enhanced emissions at critical locations, but it also helped to define the emission source distribution of the disrupted steady flow for further dispersion modelling. The model then was applied to estimate particle number emissions at a bidirectional bus station used by diesel and compressed natural gas fuelled buses. It was found that the acceleration distance was of critical importance when estimating particle number emission, since the highest emissions occurred in sections where most of the buses were accelerating and no significant increases were observed at locations where they idled. It was also shown that emissions at the front end of the platform were 43 times greater than at the rear of the platform. The CLSE model was also applied at a signalled pedestrian crossing, in order to assess increased particle number emissions from motor vehicles when forced to stop and accelerate from rest. The CLSE model was used to calculate the total emissions produced by a specific number and mix of light petrol cars and diesel passenger buses including 1 car travelling in 1 direction (/1 direction), 14 cars / 1 direction, 1 bus / 1 direction, 28 cars / 2 directions, 24 cars and 2 buses / 2 directions, and 20 cars and 4 buses / 2 directions. It was found that the total emissions produced during stopping on a red signal were significantly higher than when the traffic moved at a steady speed. Overall, total emissions due to the interruption of the traffic increased by a factor of 13, 11, 45, 11, 41, and 43 for the above 6 cases, respectively. In summary, this PhD thesis presents the results of a comprehensive study on particle number and mass concentration, together with particle size distribution, in a bus station transport microenvironment, influenced by bus flow rates, meteorological conditions and station design. Passenger spatial-temporal exposure to bus emitted particles was also assessed according to waiting time and location along the platform, as well as the contribution of exposure at the bus station to overall daily exposure. Due to the complexity of the interrupted traffic flow within the transport microenvironments, a unique CLSE model was also developed, which is capable of quantifying emission levels at critical locations within the transport microenvironment, for the purpose of evaluating passenger exposure and conducting simulations of vehicle emission dispersion. The application of the CLSE model at a pedestrian crossing also proved its applicability and simplicity for use in a real-world transport microenvironment.

Condition monitoring and diagnosis of injector faults in a diesel engine using in-cylinder pressure and acoustic emission techniques

Failing injectors are one of the most common faults in diesel engines. The severity of these faults could have serious effects on diesel engine operations such as engine misfire, knocking, insufficient power output or even cause a complete engine breakdown. It is thus essential to prevent such faults from occurring by monitoring the condition of these injectors. In this paper, the authors present the results of an experimental investigation on identifying the signal characteristics of a simulated incipient injector fault in a diesel engine using both in-cylinder pressure and acoustic emission (AE) techniques. A time waveform event driven synchronous averaging technique was used to minimize or eliminate the effect of engine speed variation and amplitude fluctuation. It was found that AE is an effective method to detect the simulated injector fault in both time (crank angle) and frequency (order) domains. It was also shown that the time domain in-cylinder pressure signal is a poor indicator for condition monitoring and diagnosis of the simulated injector fault due to the small effect of the simulated fault on the engine combustion process. Nevertheless, good correlations between the simulated injector fault and the lower order components of the enveloped in-cylinder pressure spectrum were found at various engine loading conditions.

Separation of acoustic emission signals from small size multi-cylinder diesel engine

This paper presents techniques which can lead to diagnosis of faults in a small size multi-cylinder diesel engine. Preliminary analysis of the acoustic emission (AE) signals is outline, including time-frequency analysis and selection of optimum frequency band.The results of applying mean field independent component analysis (MFICA) to separate the AE root mean square (RMS) signals and the effects of changing parameter values are also outlined. The results on separation of RMS signals show thsi technique has the potential of increasing the probability to successfully identify the AE events associated with the various mechanical events within the combustion process of multi-cylinder diesel engines.

Acoustic emission for diesel engine monitoring: A review and preliminary

Vibration analysis has been a prime tool in condition monitoring of rotating machines, however, its application to internal combustion engines remains a challenge because engine vibration signatures are highly non-stationary that are not suitable for popular spectrum-based analysis. Signal-to-noise ratio is a main concern in engine signature analysis due to severe background noise being generated by consecutive mechanical events, such as combustion, valve opening and closing, especially in multi-cylinder engines. Acoustic Emission (AE) has been found to give excellent signal-to-noise ratio allowing discrimination of fine detail of normal or abnormal events during a given cycle. AE has been used to detect faults, such as exhaust valve leakage, fuel injection behaviour, and aspects of the combustion process. This paper presents a review of AE application to diesel engine monitoring and preliminary investigation of AE signature measured on an 18-cylinder diesel engine. AE is compared with vibration acceleration for varying operating conditions: load and speed. Frequency characteristics of AE from those events are analysed in time-frequency domain via short time Fourier trasform. The result shows a great potential of AE analysis for detection of various defects in diesel engines.