A Novel Selective Muscarinic Acetylcholine Receptor Subtype 1 Antagonist Reduces Seizures without Impairing Hippocampus-Dependent Learning

Previous studies suggest that selective antagonists of specific subtypes of muscarinic acetylcholine receptors (mAChRs) may provide a novel approach for the treatment of certain central nervous system (CNS) disorders, including epileptic disorders, Parkinson's disease, and dystonia. Unfortunately, previously reported antagonists are not highly selective for specific mAChR subtypes, making it difficult to definitively establish the functional roles and therapeutic potential for individual subtypes of this receptor subfamily. The M 1 mAChR is of particular interest as a potential target for treatment of CNS disorders. We now report the discovery of a novel selective antagonist of M-1 mAChRs, termed VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)benzo[c][1,2,5]thiadiazole-4-sulfonamide]. Equilibrium radioligand binding and functional studies demonstrate a greater than 75-fold selectivity of VU0255035 for M-1 mAChRs relative to M-2-M-5. Molecular pharmacology and mutagenesis studies indicate that VU0255035 is a competitive orthosteric antagonist of M-1 mAChRs, a surprising finding given the high level of M-1 mAChR selectivity relative to other orthosteric antagonists. Whole-cell patch-clamp recordings demonstrate that VU0255035 inhibits potentiation of N-methyl-D-aspartate receptor currents by the muscarinic agonist carbachol in hippocampal pyramidal cells. VU0255035 has excellent brain penetration in vivo and is efficacious in reducing pilocarpine-induced seizures in mice. We were surprised to find that doses of VU0255035 that reduce pilo-carpine-induced seizures do not induce deficits in contextual freezing, a measure of hippocampus-dependent learning that is disrupted by nonselective mAChR antagonists. Taken together, these data suggest that selective antagonists of M-1 mAChRs do not induce the severe cognitive deficits seen with nonselective mAChR antagonists and could provide a novel approach for the treatment certain of CNS disorders.

Working across boundaries to improve health outcomes: a case study of a housing support and outreach service for homeless people living with HIV

This paper reports the findings of an evaluation of the ‘Housing Support, Outreach and Referral’ service developed to support people living with HIV who were homeless or at risk of homelessness. The service was set up as part of the Supporting People Health Pilot programme established to demonstrate the policy links between housing support services and health and social care services by encouraging the development of integrated services. The paper considers the role of housing support in improving people's health, and considers the challenges of working across housing, health and social care boundaries. The evaluation of the health pilot employed two main sources of data collection: quarterly project evaluation reports, which collected process data as well as reporting progress against aims and objectives, and semi-structured interviews with professionals from all key stakeholder groups and agencies, and with people who used services. Over the course of 15 months, 56 referrals were received of which 27 were accepted. Fifteen people received tenancy support of whom 12 were helped to access temporary accommodation. At the end of the 15 months, all of the tenancies had been maintained. In addition, 18 people registered with a general practitioner and 13 registered with an HIV clinic. Interviews with professionals emphasised the importance of the local joint working context, the involvement of the voluntary sector and the role of the support workers as factors that accounted for these outcomes. Those using services placed most emphasis on the flexibility of the support worker role. Importantly, interviews with professionals and those using services suggest that the role of support worker incorporates two dimensions – those of networker/navigator as well as advocate – and that both dimensions are important in determining the effectiveness of the service.

A New Gradient Descent Approach for Local Learning of Fuzzy Neural Models

The majority of reported learning methods for Takagi-Sugeno-Kang fuzzy neural models to date mainly focus on the improvement of their accuracy. However, one of the key design requirements in building an interpretable fuzzy model is that each obtained rule consequent must match well with the system local behaviour when all the rules are aggregated to produce the overall system output. This is one of the distinctive characteristics from black-box models such as neural networks. Therefore, how to find a desirable set of fuzzy partitions and, hence, to identify the corresponding consequent models which can be directly explained in terms of system behaviour presents a critical step in fuzzy neural modelling. In this paper, a new learning approach considering both nonlinear parameters in the rule premises and linear parameters in the rule consequents is proposed. Unlike the conventional two-stage optimization procedure widely practised in the field where the two sets of parameters are optimized separately, the consequent parameters are transformed into a dependent set on the premise parameters, thereby enabling the introduction of a new integrated gradient descent learning approach. A new Jacobian matrix is thus proposed and efficiently computed to achieve a more accurate approximation of the cost function by using the second-order Levenberg-Marquardt optimization method. Several other interpretability issues about the fuzzy neural model are also discussed and integrated into this new learning approach. Numerical examples are presented to illustrate the resultant structure of the fuzzy neural models and the effectiveness of the proposed new algorithm, and compared with the results from some well-known methods.

Radiation-Pressure Acceleration of Ion Beams Driven by Circularly Polarized Laser Pulses

We present experimental studies on ion acceleration from ultrathin diamondlike carbon foils irradiated by ultrahigh contrast laser pulses of energy 0.7 J focused to peak intensities of 5×1019  W/cm2. A reduction in electron heating is observed when the laser polarization is changed from linear to circular, leading to a pronounced peak in the fully ionized carbon spectrum at the optimum foil thickness of 5.3 nm. Two-dimensional particle-in-cell simulations reveal that those C6+ ions are for the first time dominantly accelerated in a phase-stable way by the laser radiation pressure.

A Strain-Driven Morphotropic Phase Boundary in BiFeO3

Piezoelectric materials, which convert mechanical to electrical energy and vice versa, are typically characterized by the intimate coexistence of two phases across a morphotropic phase boundary. Electrically switching one to the other yields large electromechanical coupling coefficients. Driven by global environmental concerns, there is currently a strong push to discover practical lead-free piezoelectrics for device engineering. Using a combination of epitaxial growth techniques in conjunction with theoretical approaches, we show the formation of a morphotropic phase boundary through epitaxial constraint in lead-free piezoelectric bismuth ferrite (BiFeO3) films. Electric field-dependent studies show that a tetragonal-like phase can be reversibly converted into a rhombohedral-like phase, accompanied by measurable displacements of the surface, making this new lead-free system of interest for probe-based data storage and actuator applications.

Stability Analysis and Implementation of a Decentralized Formation Control Strategy for Unmanned Vehicles

This paper presents a new methodology for solving the multi-vehicle formation control problem. It employs a unique extension-decomposition-aggregation scheme to transform the overall complex formation control problem into a group of subproblems, which work via boundary interactions or disturbances. Thus, it is proved that the overall formation system is exponentially stable in the sense of Lyapunov, if all the individual augmented subsystems (IASs) are stable. Linear matrix inequality-based H8 control methodology is employed to design the decentralized formation controllers to reject the impact of the formation changes being treated as boundary disturbances and guarantee the stability of all the IASs, consequently maintaining the stability of the overall formation system. Simulation studies are performed to verify the stability, performance, and effectiveness of the proposed strategy.

Sliding window two-thermocouple sensor characterization for variable flow environments

A two-thermocouple sensor characterization method for use in variable flow applications is proposed. Previous offline methods for constant velocity flow are extended using sliding data windows and polynomials to accommodate variable velocity. Analysis of Monte-Carlo simulation studies confirms that the unbiased and consistent parameter estimator outperforms alternatives in the literature and has the added advantage of not requiring a priori knowledge of the time constant ratio of thermocouples. Experimental results from a test rig are also presented. © 2008 The Institute of Measurement and Control.

Observation of an optical phonon band in situ in TiO electrochemistry:A possible indicator of strongly trapped intermediates in the O evolution reaction

This Letter reports in situ Fourier transform infrared (FTIR) spectroscopic data on thermal TiO films fabricated by heating titanium plates in air at 475, 700 and 800 °C. The films were studied in the dark and under UV-irradiation in aqueous 0.1MNaClO in the presence and absence of 0.1 M Na(OOC) and at 10, 25 and 50 °C. The film fabricated at 800 °C showed a broad feature near 1580cm under UV-irradiation that was not observed in the dark, whilst the films fabricated at lower temperatures, 475 and 700 °C, showed no such feature. This feature appears to be associated with the accumulation of surface-mobile holes at the complex, porous film-electrolyte interface and the capacity of such holes to enhance the absorption cross-section of optical phonons characteristic of the rutile crystal form at and near the surface of the TiO/electrolyte interface. © 2001 Elsevier Science B.V.

An analysis of the masking of speech by competing speech using self-report data (L)

Many of the items in the “Speech, Spatial, and Qualities of Hearing” scale questionnaire [S. Gatehouse and W. Noble, Int. J. Audiol.43, 85–99 (2004)] are concerned with speech understanding in a variety of backgrounds, both speech and nonspeech. To study if this self-report data reflected informational masking, previously collected data on 414 people were analyzed. The lowest scores (greatest difficulties) were found for the two items in which there were two speech targets, with successively higher scores for competing speech (six items), energetic masking (one item), and no masking (three items). The results suggest significant masking by competing speech in everyday listening situations.

Determination of Power System Response during Small Load Fluctuations

This paper proposes a calculation method to determine power system response during small load perturbations or minor disturbances. The method establishes the initial value of active power transient using traditional reduction technique on admittance matrix, which incorporates voltage variations in the determination. The method examines active power distribution among generators when several loads simultaneously change, and verifies that the superposition principle is applicable for this scenario. The theoretical derivation provided in the paper is validated by numerical simulations using a 3-generator 9-bus benchmark model. The results indicate that the inclusion of voltage variation renders an independent and precise measure of active power response during transient conditions.

Modal Extraction for Wind Turbines using Moving Window Subspace Identification

This paper proposes a method for wind turbine mode identification using the multivariable output error statespace (MOESP) identification algorithm. The paper incorporates a fast moving window QR decomposition and propagator method from array signal processing, yielding a moving window subspace identification algorithm. The algorithm assumes that the system order is known as a priori and remains constant during identification. For the purpose of extracting modal information for turbines modelled as a linear parameter varying (LPV) system, the algorithm is applicable since a nonlinear system can be approximated as a piecewise time invariant system in consecutive data windows. The algorithm is exemplified using numerical simulations which show that the moving window algorithm can track the modal information. The paper also demonstrates that the low computational burden of the algorithm, compared to conventional batch subspace identification, has significant implications for online implementation.