Assays for enhanced activity of low efficacy partial agonists at the D-2 dopamine receptor

Background and purpose: Low efficacy partial agonists at the D-2 dopamine receptor may be useful for treating schizophrenia. In this report we describe a method for assessing the efficacy of these compounds based on stimulation of [S-35]GTP gamma S binding. Experimental approach: Agonist efficacy was assessed from [S-35]GTP gamma S binding to membranes of CHO cells expressing D2 dopamine receptors in buffers with and without Na+. Effects of Na+ on receptor/G protein coupling were assessed using agonist/[H-3] spiperone competition binding assays. Key results: When [S-35]GTP gamma S binding assays were performed in buffers containing Na+, some agonists (aripiprazole, AJ-76, UH-232) exhibited very low efficacy whereas other agonists exhibited measurable efficacy. When Na+ was substituted by N-methyl D-glucamine, the efficacy of all agonists increased (relative to that of dopamine) but particularly for aripiprazole, aplindore, AJ-76, (-)-3-PPP and UH-232. In ligand binding assays, substitution of Na+ by N-methyl D-glucamine increased receptor/G protein coupling for some agonists -. aplindore, dopamine and (-)-3-PPP-but for aripiprazole, AJ-76 and UH-232 there was little effect on receptor/G protein coupling. Conclusions and implications: Substitution of Na+ by NMDG increases sensitivity in [S-35] GTPgS binding assays so that very low efficacy agonists were detected clearly. For some agonists the effect seems to be mediated via enhanced receptor/G protein coupling whereas for others the effect is mediated at another point in the G protein activation cycle. AJ-76, aripiprazole and UH-232 seem particularly sensitive to this change in assay conditions. This work provides a new method to discover these very low efficacy agonists.

Investigating the mechanism of enhanced cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells

Recently we have described an HPMA copolymer conjugate carrying both the aromatase inhibitor aminoglutethimide (AGM) and doxorubicin (Dox) as combination therapy. This showed markedly enhanced in vitro cytotoxicity compared to the HPMA copolymer-Dox (FCE28068), a conjugate that demonstrated activity in chemotherapy refractory breast cancer patients during early clinical trials. To better understand the superior activity of HPMA copolymer-Dox-AGM, here experiments were undertaken using MCF-7 and MCF-7ca (aromatase-transfected) breast cancer cell lines to: further probe the synergistic cytotoxic effects of AGM and Dox in free and conjugated form; to compare the endocytic properties of HPMA copolymer-Dox-AGM and HPMA copolymer-Dox (binding, rate and mechanism of cellular uptake); the rate of drug liberation by lysosomal thiol-dependant proteases (i.e. conjugate activation), and also, using immunocytochemistry, to compare their molecular mechanism of action. It was clearly shown that attachment of both drugs to the same polymer backbone was a requirement for enhanced cytotoxicity. FACS studies indicated both conjugates have a similar pattern of cell binding and endocytic uptake (at least partially via a cholesterol-dependent pathway), however, the pattern of enzyme-mediated drug liberation was distinctly different. Dox release from PK1 was linear with time, whereas the release of both Dox and AGM from HPMA copolymer-Dox-AGM was not, and the initial rate of AGM release was much faster than that seen for the anthracycline. Immunocytochemistry showed that both conjugates decreased the expression of ki67. However, this effect was more marked for HPMA copolymer-Dox-AGM and, moreover, only this conjugate decreased the expression of the anti-apoptotic protein bcl-2. In conclusion, the superior in vitro activity of HPMA copolymer-Dox-AGM cannot be attributed to differences in endocytic uptake, and it seems likely that the synergistic effect of Dox and AGM is due to the kinetics of intracellular drug liberation which leads to enhanced activity. (c) 2006 Elsevier B.V All rights reserved.

Enhanced priming for trauma-related material in posttraumatic stress disorder

Intrusive reexperiencing in posttraumatic stress disorder (PTSD) has been linked to perceptual priming for trauma-related material. A prospective longitudinal study (N = 69) investigated perceptual priming for trauma-related, general threat, and neutral words in assault survivors with and without PTSD, using a new version of the word-stem completion task. Survivors with PTSD showed enhanced priming for trauma-related words. Furthermore, priming for trauma-related words measured soon after the trauma was associated with subsequent PTSD severity at 3 6, and 9 months. The enhanced priming effect was specific to trauma-related words. Enhanced perceptual priming for traumatic material appears to be one of the cognitive processes operating in PTSD.

Changing patterns of cognitive-motor interference (CMI) over time during recovery from stroke

Objective: To explore the extent and nature of change in cognitive-motor interference (CMI) among rehabilitating stroke patients who showed dual-task gait decrement at initial assessment. Design: Experimental, with in-subjects, repeated measures design. Setting: Rehabilitation centre for adults with acquired, nonprogressive brain injury. Subjects: Ten patients with unilateral stroke, available for reassessment 1-9 months following their participation in a study of CMI after brain injury. Measures: Median stride duration; mean word generation. Methods: Two x one-minute walking trials, two x one-minute word generation trials, two x one-minute trials of simultaneous walking and word generation; 10-metre walking time; Barthel ADL Scale score. Results: Seven out of ten patients showed reduction over time in dual-task gait decrement. Three out of ten showed reduction in cognitive decrement. Only one showed concomitant reduction in gait and word generation decrement. Conclusion: Extent of CMI during relearning to walk after a stroke reduced over time in the majority of patients. Effects were more evident in improved stride duration than improved cognitive performance. Measures of multiple task performance should be included in assessment for functional recovery.

A fuzzy multi-criteria decision approach for enhanced auto-tracking of seismic events

The main activity carried out by the geophysicist when interpreting seismic data, in terms of both importance and time spent is tracking (or picking) seismic events. in practice, this activity turns out to be rather challenging, particularly when the targeted event is interrupted by discontinuities such as geological faults or exhibits lateral changes in seismic character. In recent years, several automated schemes, known as auto-trackers, have been developed to assist the interpreter in this tedious and time-consuming task. The automatic tracking tool available in modem interpretation software packages often employs artificial neural networks (ANN's) to identify seismic picks belonging to target events through a pattern recognition process. The ability of ANNs to track horizons across discontinuities largely depends on how reliably data patterns characterise these horizons. While seismic attributes are commonly used to characterise amplitude peaks forming a seismic horizon, some researchers in the field claim that inherent seismic information is lost in the attribute extraction process and advocate instead the use of raw data (amplitude samples). This paper investigates the performance of ANNs using either characterisation methods, and demonstrates how the complementarity of both seismic attributes and raw data can be exploited in conjunction with other geological information in a fuzzy inference system (FIS) to achieve an enhanced auto-tracking performance.

Suboptimal system recovery from communication loss in a multi-robot localization scenario using EKF algorithms

This paper describes a multi-robot localization scenario where, for a period of time, the robot team loses communication with one of the robots due to system error. In this novel approach, extended Kalman filter (EKF) algorithms utilize relative measurements to localize the robots in space. These measurements are used to reliably compensate "dead-com" periods were no information can be exchanged between the members of the robot group.

Impact of transmission errors in enhanced relay-enabled distributed coordination function

This paper analyzes the performance of Enhanced relay-enabled Distributed Coordination Function (ErDCF) for wireless ad hoc networks under transmission errors. The idea of ErDCF is to use high data rate nodes to work as relays for the low data rate nodes. ErDCF achieves higher throughput and reduces energy consumption compared to IEEE 802.11 Distributed Coordination Function (DCF) in an ideal channel environment. However, there is a possibility that this expected gain may decrease in the presence of transmission errors. In this work, we modify the saturation throughput model of ErDCF to accurately reflect the impact of transmission errors under different rate combinations. It turns out that the throughput gain of ErDCF can still be maintained under reasonable link quality and distance.

Performance evaluation of enhanced relay-enabled distributed coordination function

In this paper we evaluate the performance of our earlier proposed enhanced relay-enabled distributed coordination function (ErDCF) for wireless ad hoc networks. The idea of ErDCF is to use high data rate nodes to work as relays for the low data rate nodes. ErDCF achieves higher throughput and reduced energy consumption compared to IEEE 802.11 distributed coordination function (DCF). This is a result of. 1) using relay which helps to increase the throughput and lower overall blocking time of nodes due to faster dual-hop transmission, 2) using dynamic preamble (i.e. using short preamble for the relay transmission) which further increases the throughput and lower overall blocking time and also by 3) reducing unnecessary overhearing (by other nodes not involved in transmission). We evaluate the throughput and energy performance of the ErDCF with different rate combinations. ErDCF (11,11) (ie. R1=R2=11 Mbps) yields a throughput improvement of 92.9% (at the packet length of 1000 bytes) and an energy saving of 72.2% at 50 nodes.

An enhanced relay-enabled medium access control protocol for wireless ad hoc networks

In this paper we propose an enhanced relay-enabled distributed coordination function (rDCF) for wireless ad hoc networks. The idea of rDCF is to use high data rate nodes to work as relays for the low data rate nodes. The relay helps to increase the throughput and lower overall blocking time of nodes due to faster dual-hop transmission. rDCF achieves higher throughput over IEEE 802.11 distributed coordination function (DCF). The protocol is further enhanced for higher throughput and reduced energy. These enhancements result from the use of a dynamic preamble (i.e. using short preamble for the relay transmission) and also by reducing unnecessary overhearing (by other nodes not involved in transmission). We have modeled the energy consumption of rDCF, showing that rDCF provides an energy efficiency of 21.7% at 50 nodes over 802.11 DCF. Compared with the existing rDCF, the enhanced rDCF (ErDCF) scheme proposed in this paper yields a throughput improvement of 16.54% (at the packet length of 1000 bytes) and an energy saving of 53% at 50 nodes.

Analysis of enhanced relay-enabled distributed coordination function under transmission errors

This paper analyzes the performance of enhanced relay-enabled distributed coordination function (ErDCF) for wireless ad hoc networks under transmission errors. The idea of ErDCF is to use high data rate nodes to work as relays for the low data rate nodes. ErDCF achieves higher throughput and reduces energy consumption compared to IEEE 802.11 distributed coordination function (DCF) in an ideal channel environment. However, there is a possibility that this expected gain may decrease in the presence of transmission errors. In this work, we modify the saturation throughput model of ErDCF to accurately reflect the impact of transmission errors under different rate combinations. It turns out that the throughput gain of ErDCF can still be maintained under reasonable link quality and distance.

A tool for replay and analysis of gaze-enhanced multiparty sessions captured in immersive collaborative environments

A desktop tool for replay and analysis of gaze-enhanced multiparty virtual collaborative sessions is described. We linked three CAVE (TM)-like environments, creating a multiparty collaborative virtual space where avatars are animated with 3D gaze as well as head and hand motions in real time. Log files are recorded for subsequent playback and analysis Using the proposed software tool. During replaying the user can rotate the viewpoint and navigate in the simulated 3D scene. The playback mechanism relies on multiple distributed log files captured at every site. This structure enables an observer to experience latencies of movement and information transfer for every site as this is important fir conversation analysis. Playback uses an event-replay algorithm, modified to allow fast traversal of the scene by selective rendering of nodes, and to simulate fast random access. The tool's is analysis module can show each participant's 3D gaze points and areas where gaze has been concentrated.

Proposal of an admittance enhanced redundant joint mechanism to improve backdrivability

This paper describes a proposed admittance enhanced redundant joint mechanism (AERJM) which allows greater flexibility in the design of robotic joints. First, the basic concept of a redundant joint mechanism that reduces joint inertia is explained. Second, the AERJM structure is discussed. AERJM consists of a redundancy introducing mechanism (RIM), the adjustable admittance mechanism (AAM) and an admittance enhancing actuator. The working principles of the AERJM concept are analysed. The design and a working prototype, consisting of a variable reduction mechanism, along with a spring and a damper with constant coefficients, are described.