Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085.

The synthesis and cytotoxic evaluation of a series of benzodioxole substituted titanocenes

Using 6-benzo[1,3]dioxolefulvene (1a), a series of benzodioxole substituted titanocenes was synthesized. The benzyl-substituted titanocene bis[(benzo[1,3]dioxole)-5-methylcyclopentadienyl] titanium (IV) dichloride (2a) was synthesized from the reaction of Super Hydride with 1a. An X-ray determined crystal structure was obtained for 2a. The ansa-titanocene (1,2-di(cyclopentadienyl)1,2-di-(benzo[1,3]dioxole)-ethanediyl) titanium(IV) dichloride (2b) was synthesized by reductive dimerisation of la with titanium dichloride. The diarylmethyl substituted titanocene bis(di(benzo[1,3]dioxole)-S-methylcyclopentadienyl) titanium(IV) dichloride (20 was synthesized by reacting la with the para-lithiated benzodioxole followed by transmetallation with titanium tetrachloride. When titanocenes 2a-c were tested against pig kidney (LLC-PK) cells inhibitory concentrations (IC50) of 2.8 X 10(-4), 1.6 x 10(-4) and 7.6 x 10(-5) m, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, when compared with unsubstituted titanocene dichloride, but are not as impressive as values obtained for titanocenes previously synthesized using the above methods. Copyright (c) 2006 John Wiley & Sons, Ltd.

Electronic transitions and bonding properties in a series of five-coordinate “16-electron” complexes [Mn(CO)3(L2)]− (L2=chelating redox-active π-donor ligand)

In this article we present for the first time accurate density functional theory (DFT) and time-dependent (TD) DFT data for a series of electronically unsaturated five-coordinate complexes [Mn(CO)(3)(L-2)](-), where L-2 stands for a chelating strong pi-donor ligand represented by catecholate, dithiolate, amidothiolate, reduced alpha-diimine (1,4-dialkyl-1,4-diazabutadiene (R-DAB), 2,2'-bipyridine) and reduced 2,2'-biphosphinine types. The single-crystal X-ray structure of the unusual compound [Na(BPY)][Mn(CO)(3)(BPY)]center dot Et2O and the electronic absorption spectrum of the anion [Mn(CO)(3)(BPY)](-) are new in the literature. The nature of the bidentate ligand determines the bonding in the complexes, which varies between two limiting forms: from completely pi-delocalized diamagnetic {(CO)(3)Mn-L-2}(-) for L-2 = alpha-diimine or biphosphinine, to largely valence-trapped {(CO)(3)Mn-1-L-2(2-)}(-) for L-2(2-) = catecholate, where the formal oxidation states of Mn and L-2 can be assigned. The variable degree of the pi-delocalization in the Mn(L-2) chelate ring is indicated by experimental resonance Raman spectra of [Mn(CO)(3)(L-2)](-) (L-2=3,5-di-tBu-catecholate and iPr-DAB), where accurate assignments of the diagnostically important Raman bands have been aided by vibrational analysis. The L-2 = catecholate type of complexes is known to react with Lewis bases (CO substitution, formation of six-coordinate adducts) while the strongly pi-delocalized complexes are inert. The five-coordinate complexes adopt usually a distorted square pyramidal geometry in the solid state, even though transitions to a trigonal bipyramid are also not rare. The experimental structural data and the corresponding DFT-computed values of bond lengths and angles are in a very good agreement. TD-DFT calculations of electronic absorption spectra of the studied Mn complexes and the strongly pi-delocalized reference compound [Fe(CO)(3)(Me-DAB)] have reproduced qualitatively well the experimental spectra. Analyses of the computed electronic transitions in the visible spectroscopic region show that the lowest-energy absorption band always contains a dominant (in some cases almost exclusive) contribution from a pi(HOMO) -> pi*(LUMO) transition within the MnL2 metallacycle. The character of this optical excitation depends strongly on the composition of the frontier orbitals, varying from a partial L-2 -> Mn charge transfer (LMCT) through a fully delocalized pi(MnL2) -> pi*(MnL2) situation to a mixed (CO)Mn -> L-2 charge transfer (LLCT/MLCT). The latter character is most apparent in the case of the reference complex [Fe(CO)(3)(Me-DAB)]. The higher-lying, usually strongly mixed electronic transitions in the visible absorption region originate in the three lower-lying occupied orbitals, HOMO - 1 to HOMO - 3, with significant metal-d contributions. Assignment of these optical excitations to electronic transitions of a specific type is difficult. A partial LLCT/MLCT character is encountered most frequently. The electronic absorption spectra become more complex when the chelating ligand L-2, such as 2,2'-bipyridine, features two or more closely spaced low-lying empty pi* orbitals.

Local spaces: open minds - inspirational ideas for managing lowland commons and other green spaces

The Chiltern commons are typical of those in the south east of England: small and numerous, but with the potential to provide important natural green space whilst contributing to environmental sustainability. In order to keep commons in good heart, they need to be managed. However, as activities such as grazing and coppicing become unviable on the commons, owners need to find sustainable roles beyond traditional agricultural and silvicultural practices. This paper examines ways of making management pay. It begins by exploring the economic, social and environmental challenges of sustainable management within the context of contemporary life. Section 2 identifies the different ways in which revenue contributions might be made towards the management of commons. Section 3 examines the relevant legal and other restrictions and Section 4 offers insights into where management proposals might offer multiple positive benefits, but also where there is the potential to cause conflict with environmental and social interests. Section 5 explores alternative funding streams for commons. Finally, Section 6 concludes with practical tips for the owners and managers of commons in the Chilterns and identifies areas for further research. Full references, links and resources are provided in the footnotes and appendix.

Bayesian model averaging and identification of structural breaks in time series

Bayesian Model Averaging (BMA) is used for testing for multiple break points in univariate series using conjugate normal-gamma priors. This approach can test for the number of structural breaks and produce posterior probabilities for a break at each point in time. Results are averaged over specifications including: stationary; stationary around trend and unit root models, each containing different types and number of breaks and different lag lengths. The procedures are used to test for structural breaks on 14 annual macroeconomic series and 11 natural resource price series. The results indicate that there are structural breaks in all of the natural resource series and most of the macroeconomic series. Many of the series had multiple breaks. Our findings regarding the existence of unit roots, having allowed for structural breaks in the data, are largely consistent with previous work.

Ancient watercourses and biogeography of the Sahara explain the peopling of the desert

Evidence increasingly suggests that sub-Saharan Africa is at the center of human evolution and understanding routes of dispersal “out of Africa” is thus becoming increasingly important. The Sahara Desert is considered by many to be an obstacle to these dispersals and a Nile corridor route has been proposed to cross it. Here we provide evidence that the Sahara was not an effective barrier and indicate how both animals and humans populated it during past humid phases. Analysis of the zoogeography of the Sahara shows that more animals crossed via this route than used the Nile corridor. Furthermore, many of these species are aquatic. This dispersal was possible because during the Holocene humid period the region contained a series of linked lakes, rivers, and inland deltas comprising a large interlinked waterway, channeling water and animals into and across the Sahara, thus facilitating these dispersals. This system was last active in the early Holocene when many species appear to have occupied the entire Sahara. However, species that require deep water did not reach northern regions because of weak hydrological connections. Human dispersals were influenced by this distribution; Nilo-Saharan speakers hunting aquatic fauna with barbed bone points occupied the southern Sahara, while people hunting Savannah fauna with the bow and arrow spread southward. The dating of lacustrine sediments show that the “green Sahara” also existed during the last interglacial (∼125 ka) and provided green corridors that could have formed dispersal routes at a likely time for the migration of modern humans out of Africa.

Reflections on Beckett: a centenary celebration

The essays in this collection were originally delivered as part of the Samuel Beckett lecture series at Trinity College Dublin, Samuel Beckett's alma mater. The contributors include eminent Beckett scholars such as Linda Ben-Zvi, Enoch Brater, Ruby Cohn and Stan Gontarski, theatre scholars such as Herbert Blau and Joseph Roach, practitioners such as the Irish actor, Barry McGovern, and cultural critics such as Marina Warner and Terry Eagleton. The collection sheds new light on Beckett's enigmatic theater, offering new perspectives on Beckett's use of language and silence, on his attitudes toward the body, on those who influenced him and on those he has influenced (including Suzan-Lori Parks and Femi Osofisan), and on Beckett and the art of self-collaboration. Each contributor places the playwright into a network of genealogies and legacies and his work into important historical, cultural, and aesthetic contexts. Together, the essays demonstrate Beckett's impact on theater, performance, and visual arts during the latter half of the twentieth century and serve to open up new directions for Beckett studies.

Spatial disaggregation and intensity correction of TRMM-based rainfall time series for hydrological applications in dryland catchments

A novel approach is presented for combining spatial and temporal detail from newly available TRMM-based data sets to derive hourly rainfall intensities at 1-km spatial resolution for hydrological modelling applications. Time series of rainfall intensities derived from 3-hourly 0.25° TRMM 3B42 data are merged with a 1-km gridded rainfall climatology based on TRMM 2B31 data to account for the sub-grid spatial distribution of rainfall intensities within coarse-scale 0.25° grid cells. The method is implemented for two dryland catchments in Tunisia and Senegal, and validated against gauge data. The outcomes of the validation show that the spatially disaggregated and intensity corrected TRMM time series more closely approximate ground-based measurements than non-corrected data. The method introduced here enables the generation of rainfall intensity time series with realistic temporal and spatial detail for dynamic modelling of runoff and infiltration processes that are especially important to water resource management in arid regions.

Design and management of sustainable built environments

The United Nation Intergovernmental Panel on Climate Change (IPCC) makes it clear that climate change is due to human activities and it recognises buildings as a distinct sector among the seven analysed in its 2007 Fourth Assessment Report. Global concerns have escalated regarding carbon emissions and sustainability in the built environment. The built environment is a human-made setting to accommodate human activities, including building and transport, which covers an interdisciplinary field addressing design, construction, operation and management. Specifically, Sustainable Buildings are expected to achieve high performance throughout the life-cycle of siting, design, construction, operation, maintenance and demolition, in the following areas: • energy and resource efficiency; • cost effectiveness; • minimisation of emissions that negatively impact global warming, indoor air quality and acid rain; • minimisation of waste discharges; and • maximisation of fulfilling the requirements of occupants’ health and wellbeing. Professionals in the built environment sector, for example, urban planners, architects, building scientists, engineers, facilities managers, performance assessors and policy makers, will play a significant role in delivering a sustainable built environment. Delivering a sustainable built environment needs an integrated approach and so it is essential for built environment professionals to have interdisciplinary knowledge in building design and management . Building and urban designers need to have a good understanding of the planning, design and management of the buildings in terms of low carbon and energy efficiency. There are a limited number of traditional engineers who know how to design environmental systems (services engineer) in great detail. Yet there is a very large market for technologists with multi-disciplinary skills who are able to identify the need for, envision and manage the deployment of a wide range of sustainable technologies, both passive (architectural) and active (engineering system),, and select the appropriate approach. Employers seek applicants with skills in analysis, decision-making/assessment, computer simulation and project implementation. An integrated approach is expected in practice, which encourages built environment professionals to think ‘out of the box’ and learn to analyse real problems using the most relevant approach, irrespective of discipline. The Design and Management of Sustainable Built Environment book aims to produce readers able to apply fundamental scientific research to solve real-world problems in the general area of sustainability in the built environment. The book contains twenty chapters covering climate change and sustainability, urban design and assessment (planning, travel systems, urban environment), urban management (drainage and waste), buildings (indoor environment, architectural design and renewable energy), simulation techniques (energy and airflow), management (end-user behaviour, facilities and information), assessment (materials and tools), procurement, and cases studies ( BRE Science Park). Chapters one and two present general global issues of climate change and sustainability in the built environment. Chapter one illustrates that applying the concepts of sustainability to the urban environment (buildings, infrastructure, transport) raises some key issues for tackling climate change, resource depletion and energy supply. Buildings, and the way we operate them, play a vital role in tackling global greenhouse gas emissions. Holistic thinking and an integrated approach in delivering a sustainable built environment is highlighted. Chapter two demonstrates the important role that buildings (their services and appliances) and building energy policies play in this area. Substantial investment is required to implement such policies, much of which will earn a good return. Chapters three and four discuss urban planning and transport. Chapter three stresses the importance of using modelling techniques at the early stage for strategic master-planning of a new development and a retrofit programme. A general framework for sustainable urban-scale master planning is introduced. This chapter also addressed the needs for the development of a more holistic and pragmatic view of how the built environment performs, , in order to produce tools to help design for a higher level of sustainability and, in particular, how people plan, design and use it. Chapter four discusses microcirculation, which is an emerging and challenging area which relates to changing travel behaviour in the quest for urban sustainability. The chapter outlines the main drivers for travel behaviour and choices, the workings of the transport system and its interaction with urban land use. It also covers the new approach to managing urban traffic to maximise economic, social and environmental benefits. Chapters five and six present topics related to urban microclimates including thermal and acoustic issues. Chapter five discusses urban microclimates and urban heat island, as well as the interrelationship of urban design (urban forms and textures) with energy consumption and urban thermal comfort. It introduces models that can be used to analyse microclimates for a careful and considered approach for planning sustainable cities. Chapter six discusses urban acoustics, focusing on urban noise evaluation and mitigation. Various prediction and simulation methods for sound propagation in micro-scale urban areas, as well as techniques for large scale urban noise-mapping, are presented. Chapters seven and eight discuss urban drainage and waste management. The growing demand for housing and commercial developments in the 21st century, as well as the environmental pressure caused by climate change, has increased the focus on sustainable urban drainage systems (SUDS). Chapter seven discusses the SUDS concept which is an integrated approach to surface water management. It takes into consideration quality, quantity and amenity aspects to provide a more pleasant habitat for people as well as increasing the biodiversity value of the local environment. Chapter eight discusses the main issues in urban waste management. It points out that population increases, land use pressures, technical and socio-economic influences have become inextricably interwoven and how ensuring a safe means of dealing with humanity’s waste becomes more challenging. Sustainable building design needs to consider healthy indoor environments, minimising energy for heating, cooling and lighting, and maximising the utilisation of renewable energy. Chapter nine considers how people respond to the physical environment and how that is used in the design of indoor environments. It considers environmental components such as thermal, acoustic, visual, air quality and vibration and their interaction and integration. Chapter ten introduces the concept of passive building design and its relevant strategies, including passive solar heating, shading, natural ventilation, daylighting and thermal mass, in order to minimise heating and cooling load as well as energy consumption for artificial lighting. Chapter eleven discusses the growing importance of integrating Renewable Energy Technologies (RETs) into buildings, the range of technologies currently available and what to consider during technology selection processes in order to minimise carbon emissions from burning fossil fuels. The chapter draws to a close by highlighting the issues concerning system design and the need for careful integration and management of RETs once installed; and for home owners and operators to understand the characteristics of the technology in their building. Computer simulation tools play a significant role in sustainable building design because, as the modern built environment design (building and systems) becomes more complex, it requires tools to assist in the design process. Chapter twelve gives an overview of the primary benefits and users of simulation programs, the role of simulation in the construction process and examines the validity and interpretation of simulation results. Chapter thirteen particularly focuses on the Computational Fluid Dynamics (CFD) simulation method used for optimisation and performance assessment of technologies and solutions for sustainable building design and its application through a series of cases studies. People and building performance are intimately linked. A better understanding of occupants’ interaction with the indoor environment is essential to building energy and facilities management. Chapter fourteen focuses on the issue of occupant behaviour; principally, its impact, and the influence of building performance on them. Chapter fifteen explores the discipline of facilities management and the contribution that this emerging profession makes to securing sustainable building performance. The chapter highlights a much greater diversity of opportunities in sustainable building design that extends well into the operational life. Chapter sixteen reviews the concepts of modelling information flows and the use of Building Information Modelling (BIM), describing these techniques and how these aspects of information management can help drive sustainability. An explanation is offered concerning why information management is the key to ‘life-cycle’ thinking in sustainable building and construction. Measurement of building performance and sustainability is a key issue in delivering a sustainable built environment. Chapter seventeen identifies the means by which construction materials can be evaluated with respect to their sustainability. It identifies the key issues that impact the sustainability of construction materials and the methodologies commonly used to assess them. Chapter eighteen focuses on the topics of green building assessment, green building materials, sustainable construction and operation. Commonly-used assessment tools such as BRE Environmental Assessment Method (BREEAM), Leadership in Energy and Environmental Design ( LEED) and others are introduced. Chapter nineteen discusses sustainable procurement which is one of the areas to have naturally emerged from the overall sustainable development agenda. It aims to ensure that current use of resources does not compromise the ability of future generations to meet their own needs. Chapter twenty is a best-practice exemplar - the BRE Innovation Park which features a number of demonstration buildings that have been built to the UK Government’s Code for Sustainable Homes. It showcases the very latest innovative methods of construction, and cutting edge technology for sustainable buildings. In summary, Design and Management of Sustainable Built Environment book is the result of co-operation and dedication of individual chapter authors. We hope readers benefit from gaining a broad interdisciplinary knowledge of design and management in the built environment in the context of sustainability. We believe that the knowledge and insights of our academics and professional colleagues from different institutions and disciplines illuminate a way of delivering sustainable built environment through holistic integrated design and management approaches. Last, but not least, I would like to take this opportunity to thank all the chapter authors for their contribution. I would like to thank David Lim for his assistance in the editorial work and proofreading.

The Prophetic Sound: a day and night of noise cabaret(symposium of talks and live performances)

'The Prophetic Sound: a day and night of noise cabaret' is the first event hosted by Agency of Noise. This all day event brought together artists and academics whose subject of focus is noise (in creative practice). Artists from across the UK were invited to consider a future post-digital era in which everything with a microchip has malfunctioned, as a thought exercise and starting point for response through sound. In response to Jacques Attali’s claim that music is prophecy, The Prophetic Sound asks us to consider if noise can communicate in an unbridled, unfiltered, way that is somehow not culturally coded -before it becomes sound that is recognised, refined, manipulated and exploited for musical or other cultured purpose. Featuring students from Reading, Brighton, LCC and Goldsmiths alongside more established artists and academics from across the UK, this event brings into focus locations where pattern, timbre, pitch, organisation and sequencing of sounds become distinguishable from noise and asks us to consider, through diversion within such locations, new origins for future communication systems. The Prophetic Sound included talks, films, presentations and performances from: Ryo Ikeshiro / Inigo Wilkins / Neal Spowage / Dane Sutherland / Poulomi Desai / Benedict Drew / AAS / Polly Fibre / Steven Dickie As part of The Prophetic Sound, POLLYFIBRE (Ellison, C.) performed LIVE RECORDING with Amplified Scissors. This industrial activity by POLLYFIBRE short-circuits the complicated chain that is music production. The distinctive roles of consumer, producer, composer, and performer collapse in a series of live ‘cuts’ where vinyl discs are produced with amplified scissors. Production happens through action and action becomes production. A limited edition of 9 flexi discs were produced and available for special collectors at the event.

Naturally occurring radioactive material (NORM) from a former phosphoric acid processing plant

In recent years there has been an increasing awareness of the radiological impact of non-nuclear industries that extract and/or process ores and minerals containing naturally occurring radioactive material (NORM). These industrial activities may result in significant radioactive contamination of (by-) products, wastes and plant installations. In this study, scale samples were collected from a decommissioned phosphoric acid processing plant. To determine the nature and concentration of NORM retained in pipe-work and associated process plant, four main areas of the site were investigated: (1) the 'Green Acid Plant', where crude acid was concentrated; (2) the green acid storage tanks; (3) the Purified White Acid (PWA) plant, where inorganic impurities were removed; and (4) the solid waste, disposed of on-site as landfill. The scale samples predominantly comprise the following: fluorides (e.g. ralstonite); calcium sulphate (e.g. gypsum); and an assemblage of mixed fluorides and phosphates (e.g. iron fluoride hydrate, calcium phosphate), respectively. The radioactive inventory is dominated by U-238 and its decay chain products, and significant fractionation along the series occurs. Compared to the feedstock ore, elevated concentrations (<= 8.8 Bq/g) of U-238 Were found to be retained in installations where the process stream was rich in fluorides and phosphates. In addition, enriched levels (<= 11 Bq/g) of Ra-226 were found in association with precipitates of calcium sulphate. Water extraction tests indicate that many of the scales and waste contain significantly soluble materials and readily release radioactivity into solution. (c) 2005 Elsevier Ltd. All rights reserved.

Implicit and explicit processes in a second-language learning task

Two experiments examined the learning of a set of Greek pronunciation rules through explicit and implicit modes of rule presentation. Experiment 1 compared the effectiveness of implicit and explicit modes of presentation in two modalities, visual and auditory. Subjects in the explicit or rule group were presented with the rule set, and those in the implicit or natural group were shown a set of Greek words, composed of letters from the rule set, linked to their pronunciations. Subjects learned the Greek words to criterion and were then given a series of tests which aimed to tap different types of knowledge. The results showed an advantage of explicit study of the rules. In addition, an interaction was found between mode of presentation and modality. Explicit instruction was more effective in the visual than in the auditory modality, whereas there was no modality effect for implicit instruction. Experiment 2 examined a possible reason for the advantage of the rule groups by comparing different combinations of explicit and implicit presentation in the study and learning phases. The results suggested that explicit presentation of the rules is only beneficial when it is followed by practice at applying them.

Maize yield and rainfall on different spatial and temporal scales in Southern Brazil

This study aimed to establish relationships between maize yield and rainfall on different temporal and spatial scales, in order to provide a basis for crop monitoring and modelling. A 16-year series of maize yield and daily rainfall from 11 municipalities and micro-regions of Rio Grande do Sul State was used. Correlation and regression analyses were used to determine associations between crop yield and rainfall for the entire crop cycle, from tasseling to 30 days after, and from 5 days before tasseling to 40 days after. Close relationships between maize yield and rainfall were found, particularly during the reproductive period (45-day period comprising the flowering and grain filling). Relationships were closer on a regional scale than at smaller scales. Implications of the crop-rainfall relationships for crop modelling are discussed.