Ca2+-independent phospholipase A2-dependent gating of TRPM8 by lysophospholipids

TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca(2+)-independent phospholipase A(2) (iPLA(2)) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA(2) resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA(2) stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland.

Towards a person-centred ‘culture’: the use of community development approaches in the Independent Youth Counselling Service in West Belfast

This paper is drawn from a qualitative study of clients, counsellors and the supervisors views of the value and impact of the Independent Youth Counselling Service (IYCS) in West Belfast. Data collection combined semi-structured interviews, focus groups and an open-ended questionnaire. The findings indicate the significance of factors above and beyond the person-centred counselling experience, in maximising the potential for growth and development for clients and counsellors. This holistic approach to counselling service provision employs a body of community development processes, which collectively combine to embed the counselling service in a complementary principled approach. This paper explores how these community development features bolster the counselling experience to promote a culture of person-centeredness, thereby increasing the empowerment of the client.

A Novel Multimodal Interface for Improving Visually Impaired People's Web Accessibility

This paper introduces a novel interface designed to help blind and visually impaired people to explore and navigate on the Web. In contrast to traditionally used assistive tools, such as screen readers and magnifiers, the new interface employs a combination of both audio and haptic features to provide spatial and navigational information to users. The haptic features are presented via a low-cost force feedback mouse allowing blind people to interact with the Web, in a similar fashion to their sighted counterparts. The audio provides navigational and textual information through the use of non-speech sounds and synthesised speech. Interacting with the multimodal interface offers a novel experience to target users, especially to those with total blindness. A series of experiments have been conducted to ascertain the usability of the interface and compare its performance to that of a traditional screen reader. Results have shown the advantages that the new multimodal interface offers blind and visually impaired people. This includes the enhanced perception of the spatial layout of Web pages, and navigation towards elements on a page. Certain issues regarding the design of the haptic and audio features raised in the evaluation are discussed and presented in terms of recommendations for future work.

Epipolar geometry estimation based on evolutionary agents

This paper presents a novel approach based on the use of evolutionary agents for epipolar geometry estimation. In contrast to conventional nonlinear optimization methods, the proposed technique employs each agent to denote a minimal subset to compute the fundamental matrix, and considers the data set of correspondences as a 1D cellular environment, in which the agents inhabit and evolve. The agents execute some evolutionary behavior, and evolve autonomously in a vast solution space to reach the optimal (or near optima) result. Then three different techniques are proposed in order to improve the searching ability and computational efficiency of the original agents. Subset template enables agents to collaborate more efficiently with each other, and inherit accurate information from the whole agent set. Competitive evolutionary agent (CEA) and finite multiple evolutionary agent (FMEA) apply a better evolutionary strategy or decision rule, and focus on different aspects of the evolutionary process. Experimental results with both synthetic data and real images show that the proposed agent-based approaches perform better than other typical methods in terms of accuracy and speed, and are more robust to noise and outliers.

Mutational analysis of the active centre of coronavirus 3C-like proteases.

Formation of the coronavirus replication-transcription complex involves the synthesis of large polyprotein precursors that are extensively processed by virus-encoded cysteine proteases. In this study, the coding sequence of the feline infectious peritonitis virus (FIPV) main protease, 3CL(pro), was determined. Comparative sequence analyses revealed that FIPV 3CL(pro) and other coronavirus main proteases are related most closely to the 3C-like proteases of potyviruses. The predicted active centre of the coronavirus enzymes has accepted unique replacements that were probed by extensive mutational analysis. The wild-type FIPV 3CL(pro) domain and 25 mutants were expressed in Escherichia coli and tested for proteolytic activity in a peptide-based assay. The data strongly suggest that, first, the FIPV 3CL(pro) catalytic system employs His(41) and Cys(144) as the principal catalytic residues. Second, the amino acids Tyr(160) and His(162), which are part of the conserved sequence signature Tyr(160)-Met(161)-His(162) and are believed to be involved in substrate recognition, were found to be indispensable for proteolytic activity. Third, replacements of Gly(83) and Asn(64), which were candidates to occupy the position spatially equivalent to that of the catalytic Asp residue of chymotrypsin-like proteases, resulted in proteolytically active proteins. Surprisingly, some of the Asn(64) mutants even exhibited strongly increased activities. Similar results were obtained for human coronavirus (HCoV) 3CL(pro) mutants in which the equivalent Asn residue (HCoV 3CL(pro) Asn(64)) was substituted. These data lead us to conclude that both the catalytic systems and substrate-binding pockets of coronavirus main proteases differ from those of other RNA virus 3C and 3C-like proteases.

Proposed wavelet-neurofuzzy combined system for power qualityviolations detection and diagnosis

A system for the identification of power quality violations is proposed. It is a two-stage system that employs the potentials of the wavelet transform and the adaptive neurofuzzy networks. For the first stage, the wavelet multiresolution signal analysis is exploited to denoise and then decompose the monitored signals of the power quality events to extract its detailed information. A new optimal feature-vector is suggested and adopted in learning the neurofuzzy classifier. Thus, the amount of needed training data is extensively reduced. A modified organisation map of the neurofuzzy classifier has significantly improved the diagnosis efficiency. Simulation results confirm the aptness and the capability of the proposed system in power quality violations detection and automatic diagnosis

Stochastic protein folding simulation in the three-dimensional HP-model

We present results from three-dimensional protein folding simulations in the HP-model on ten benchmark problems. The simulations are executed by a simulated annealing-based algorithm with a time-dependent cooling schedule. The neighbourhood relation is determined by the pull-move set. The results provide experimental evidence that the maximum depth D of local minima of the underlying energy landscape can be upper bounded by D < n(2/3). The local search procedure employs the stopping criterion (In/delta)(D/gamma) where m is an estimation of the average number of neighbouring conformations, gamma relates to the mean of non-zero differences of the objective function for neighbouring conformations, and 1-delta is the confidence that a minimum conformation has been found. The bound complies with the results obtained for the ten benchmark problems. (c) 2008 Elsevier Ltd. All rights reserved.

Laser-Driven Proton Beams: Acceleration Mechanism, Beam Optimization, and Radiographic Applications

This paper reviews recent experimental activity in the area of optimization, control, and application of laser accelerated proton beams, carried out at the Rutherford Appleton Laboratory and the Laboratoire pour l’Utilisation des Lasers Intenses 100 TW facility in France. In particular, experiments have investigated the role of the scale length at the rear of the plasma in reducing target-normal-sheath-acceleration acceleration efficiency. Results match with recent theoretical predictions and provide information in view of the feasibility of proton fast-ignition applications. Experiments aiming to control the divergence of the proton beams have investigated the use of a laser-triggered microlens, which employs laser-driven transient electric fields in cylindrical geometry, enabling to focus the emitted
protons and select monochromatic beam lets out of the broad spectrum beam. This approach could be advantageous in view
of a variety of applications. The use of laser-driven protons as a particle probe for transient field detection has been developed and
applied to a number of experimental conditions. Recent work in this area has focused on the detection of large-scale self-generated magnetic fields in laser-produced plasmas and the investigation of fields associated to the propagation of relativistic electron both on the surface and in the bulk of targets irradiated by high-power laser pulses.

Using signed digit arithmetic for low-power multiplication

Hardware implementations of arithmetic operators using signed digit arithmetic have lost some of their earlier popularity. However, SD is revisited and used to realise an efficient radix-16 generic multiplier, which has particular potential for low-power implementation. The SD multiplier algorithm reduces the number of partial products to as much as 1/4, and in initial tests reduces the estimated power consumption to only about 50% of that of the Booth multiplier. It is different from other previous high-radix methods in that it employs a novel method to generate its partial products with zero arithmetic logic.

94 GHz dual-reflector antenna with reflectarray subreflector

The design, construction and measured performance is described of an offset parabolic reflector antenna which employs a reflectarray subreflector to tilt the focused beam from the boresight direction at 94 GHz. An analysis technique based on the method of moments (MoM) is used to design the dual-reflector antenna. Numerical simulations were employed to demonstrate that the high gain pattern of the antenna can be tilted to a predetermined angle by introducing a progressive phase shift across the aperture of the reflectarray. Experimental validation of the approach was made by constructing a 28 × 28 element patch reflectarray which was designed to deflect the beam 5° from the boresight direction in the azimuth plane. The array was printed on a 115 µm thick metal backed quartz wafer and the radiation patterns of the dual reflector antenna were measured from 92.6-95.5 GHz. The experimental results are used to validate the analysis technique by comparing the radiation patterns and the reduction in the peak gain due to beam deflection from the boresight direction. Moreover the results demonstrate that this design concept can be developed further to create an electronically scanned dual reflector antenna by using a tunable reflectarray subreflector.

Habitat for Humanity: Calibrating Best Practice Against the MDGs

Poverty alleviation lies at the heart of contemporary international initiatives on development. The key to development is the creation of an environment in which people can develop their potential, leading productive, creative lives in accordance with their needs, interests and faith. This entails, on the one hand, protecting the vulnerable from things that threaten their survival, such as inadequate nutrition, disease, conflict, natural disasters and the impact of climate change, thereby enhancing the poor’s capabilities to develop resilience in difficult conditions. On the other hand, it also requires a means of empowering the poor to act on their own behalf, as individuals and communities, to secure access to resources and the basic necessities of life such as water, food, shelter, sanitation, health and education. ‘Development’, from this perspective, seeks to address the sources of human insecurity, working towards ‘freedom from want, freedom from fear’ in ways that empower the vulnerable as agents of development (not passive recipients of benefaction).

Recognition of the magnitude of the problems confronted by the poor and failure of past interventions to tackle basic issues of human security led the United Nations (UN) in September 2000 to set out a range of ambitious, but clearly defined, development goals to be achieved by 2015. These are known as the Millennium Development Goals (MDGs). The intention of the UN was to mobilise multilateral international organisations, non-governmental organisations and the wider international community to focus attention on fulfilling earlier promises to combat global poverty. This international framework for development prioritises: the eradication of extreme poverty and hunger; achieving universal primary education; promoting gender equality and empowering women; reducing child mortality; improving maternal health; combating HIV/AIDS, malaria and other diseases; ensuring environmental sustainability; and developing a global partnership for development. These goals have been mapped onto specific targets (18 in total) against which outcomes of associated development initiatives can be measured and the international community held to account. If the world achieves the MDGs, more than 500 million people will be lifted out of poverty. However, the challenges the goals represent are formidable. Interim reports on the initiative indicate a need to scale-up efforts and accelerate progress.
Only MDG 7, Target 11 explicitly identifies shelter as a priority, identifying the need to secure ‘by 2020 a significant improvement in the lives of at least 100 million slum dwellers’. This raises a question over how Habitat for Humanity’s commitment to tackling poverty housing fits within this broader international framework designed to allievate global poverty. From an analysis of HFH case studies, this report argues that the processes by which Habitat for Humanity tackles poverty housing directly engages with the agenda set by the MDGs. This should not be regarded as a beneficial by-product of the delivery of decent, affordable shelter, but rather understood in terms of the ways in which Habitat for Humanity has translated its mission and values into a participatory model that empowers individuals and communities to address the interdependencies between inadequate shelter and other sources of human insecurity. What housing can deliver is as important as what housing itself is.

Examples of the ways in which Habitat for Humanity projects engage with the MDG framework include the incorporation of sustainable livelihoods strategies, up-grading of basic infrastructure and promotion of models of good governance. This includes housing projects that have also offered training to young people in skills used in the construction industry, microfinanced loans for women to start up their own home-based businesses, and the provision of food gardens. These play an important role in lifting families out of poverty and ensuring the sustainability of HFH projects. Studies of the impact of improved shelter and security of livelihood upon family life and the welfare of children evidence higher rates of participation in education, more time dedicated to study and greater individual achievement. Habitat for Humanity projects also typically incorporate measures to up-grade the provision of basic sanitation facilities and supplies of safe, potable drinking water. These measures not only directly help reduce mortality rates (e.g. diarrheal diseases account for around 2 million deaths annually in children under 5), but also, when delivered through HFH project-related ‘community funds’, empower the poor to mobilise community resources, develop local leadership capacities and even secure de facto security of tenure from government authorities.

In the process of translating its mission and values into practical measures, HFH has developed a range of innovative practices that deliver much more than housing alone. The organisation’s participatory model enables both direct beneficiaries and the wider community to tackle the insecurities they face, unlocking latent skills and enterprise, building sustainable livelihood capabilities. HFH plays an important role as a catalyst for change, delivering through the vehicle of housing the means to address the primary causes of poverty itself. Its contribution to wider development priorities deserves better recognition. In calibrating the success of HFH projects in terms of units completed or renovated alone, the significance of the process by which HFH realises these outcomes is often not sufficiently acknowledged, both within the organisation and externally. As the case studies developed in the report illustrate, the methodologies Habitat for Humanity employs to address the issue of poverty housing within the developing world, place the organisation at the centre of a global strategic agenda to address the root causes of poverty through community empowerment and the transformation of structures of governance.

Given this, the global network of HFH affiliates constitutes a unique organisational framework to faciliate sharing resources, ideas and practical experience across a diverse range of cultural, political and institutional environments. This said, it is apparent that work needs to be done to better to faciliate the pooling of experience and lessons learnt from across its affiliates. Much is to be gained from learning from less successful projects, sharing innovative practices, identifying strategic partnerships with donors, other NGOs and CBOs, and engaging with the international development community on how housing fits within a broader agenda to alleviate poverty and promote good governance.

Carrying religion into a secularising Europe: Montserratian migrants' experiences of global processes in British methodism

Migrants to Europe often perceive themselves as entering a secular society that threatens their religious identities and practices. Whilst some sociological models present their responses in terms of cultural defence, ethnographic analysis reveals a more complex picture of interaction with local contexts. This essay draws upon ethnographic research to explore a relatively neglected situation in migration studies, namely the interactions between distinct migration cohorts - in this case, from the Caribbean island of Montserrat, as examined through their experiences in London Methodist churches. It employs the ideas of Weber and Bourdieu to view these migrants as 'religious carriers', as collective and individual embodiments of religious dispositions and of those socio-cultural processes through which their religion is reproduced. Whilst the strategies of the cohort migrating after the Second World War were restricted through their marginalised social status and experience of racism, the recent cohort of evacuees fleeing volcanic eruptions has had greater scope for strategies which combat secularisation and fading Methodist identity.

Application of proton radiography in experiments of relevance to inertial confinement fusion

Multi-Mev proton beams generated by target normal sheath acceleration (TNSA) during the interaction of an ultra intense laser beam (Ia parts per thousand yen10(19) W/cm(2)) with a thin metallic foil (thickness of the order of a few tens of microns) are particularly suited as a particle probe for laser plasma experiments. The proton imaging technique employs a laser-driven proton beam in a point-projection imaging scheme as a diagnostic tool for the detection of electric fields in such experiments. The proton probing technique has been applied in experiments of relevance to inertial confinement fusion (ICF) such as laser heated gasbags and laser-hohlraum experiments. The data provides direct information on the onset of laser beam filamentation and on the plasma expansion in the hohlraum's interior, and confirms the suitability and usefulness of this technique as an ICF diagnostic.

Hierarchical synthesis of complex DSP functions on FPGAs

SoC systems are now being increasingly constructed using a hierarchy of subsystems or silicon Intellectual Property (IP) cores. The key challenge is to use these cores in a highly efficient manner which can be difficult as the internal core structure may not be known. A design methodology based on synthesizing hierarchical circuit descriptions is presented. The paper employs the MARS synthesis scheduling algorithm within the existing IRIS synthesis flow and details how it can be enhanced to allow for design exploration of IP cores. It is shown that by accessing parameterised expressions for the datapath latencies in the cores, highly efficient FPGA solutions can be achieved. Hardware sharing at both the hierarchical and flattened levels is explored for a normalized lattice filter and results are presented.

Use of breakpoint combination sensitivity testing as a simple and convenient method to evaluate the combined effects of ceftazidime and tobramycin on Pseudomonas aeruginosa and Burkholderia cepacia complex isolates in vitro

An in vitro method of determining the activity of antibiotics in combination which is simple and convenient to perform and which could be used routinely in clinical microbiology laboratories is desirable. We investigated the activity, against Pseudomonas aeruginosa and Burkholderia cepacia complex clinical isolates, of ceftazidime and tobramycin in combination using a broth macrodilution sensitivity method based on breakpoint minimum inhibitory concentrations and compared the results obtained using this method with those obtained using the microtitre checkerboard method. There was good agreement in interpretation of results between the two methods for both P. aeruginosa (90%) and B. cepacia complex isolates (70%) with tobramycin and for P. aeruginosa isolates (70%) with ceftazidime. As the breakpoint combination sensitivity testing method employs only four tubes and does not require initial determination of individual antibiotic minimum inhibitory concentrations, it is simpler and more convenient for determining the activity of antibiotics in combination than the microtitre checkerboard method. The use of this method in routine microbiology laboratories to determine the activity of antibiotic combinations against clinical isolates should optimise treatment of infection by ensuring that appropriate antibiotic combinations are prescribed. (C) 2004 Elsevier B.V. All rights reserved.