bluuebunny/crossref_metadata_2025 huggingface dataset:
William Swinderby and the Wycliffite Attitude to Excommunication
Authors: FORREST IAN
Published: March 2009

The early Wycliffite William Swinderby expressed some strong criticisms of excommunication. He was alarmed that churchman thought that it was their power, rather than God's power, that consigned a soul to hell. The rhetoric of sentences of excommunication in this period was indeed intended to frighten offenders into compliance with ecclesiastical judgements, but the theory and practice of excommunication was in fact far less simple that the Wycliffite criticism of it allowed. This article examines Swinderby's attitude towards ecclesiastical sanctions in light of Wyclif's own ideas, and the theory and practice of excommunication in the late medieval Church. Swinderby's links with early Wycliffism are elucidated and the relationship between Wycliffism and the Church is looked at in a new light.
Macrobenthic community structure and distribution in the Zwin nature reserve (Belgium and The Netherlands)
Authors: Van Colen Carl , Snoeck Frederik , Struyf Kris , Vincx Magda , Degraer Steven
Published: March 2009

Distribution and structure of intertidal macrobenthic communities in the Zwin nature reserve, a lagoonal inlet consisting of marsh and tidal flat habitats, was investigated using univariate and multivariate analyses. Macrobenthos community structure was related to environmental characteristics and discussed in the framework of the implemented extension of the nature reserve.

Based on explorative multivariate techniques, five different sample groups (SGs) were distinguished, which were, in general, located in different habitats of the Zwin nature reserve. The ecologically most important SGs consisted of the highest macrobenthic density, diversity and highest densities of Nereis diversicolor and Scrobicularia plana; these important prey species for wading birds and fish occurred in the deep tidal inlet channels. This habitat was characterized by fine to medium sand sediment and strong tidal currents, guaranteeing water renewal at each high tide. Other SGs were found in less and erratically submersed and thus stressed areas (i.e. tidal pond, salt pans and shallow flats). These assemblages were characterized by typical r-strategists (i.e. Capitella capitata and Polydora cornuta) and typical supralittoral, mobile species (i.e. Orchestia gammarellus and Collembola spp.). Being ecologically most important, the extension of wide, tidal creeks should be a prime target within the future development and management of the nature reserve.
US Welfare Reform: Rewriting the Social Contract
Authors: GILBERT NEIL
Published: March 2009

This paper analyses recent developments in US welfare policy and their implications for future reforms. The analysis begins by examining how the enactment of the Temporary Assistance for Needy Families (TANF) programme in 1996 changed the essential character of public assistance and the major social forces that accounted for this fundamental shift in US welfare policy. It then shows how the most recent welfare reforms under the Deficit Reduction Act of 2005 broadened and intensified the TANF requirements, leaving four avenues along which issues of conditionality and entitlement are likely to be played out in future welfare reforms. Finally, the discussion highlights how a new social contract is being forged through progressive and conservative proposals, which shift the focus of public assistance from the right to financial support to the right to work and earn a living wage.
Public Values and Public Trust: Responses to Welfare State Reform in the UK
Authors: TAYLOR-GOOBY PETER , WALLACE ANDREW
Published: March 2009

The welfare state faces a number of challenges. Recent reforms in the UK appear broadly successful in attaining targets and improving cost-efficiency, but are nonetheless confronted by public disquiet and unease. This article argues that one difficulty with the new directions in policy is that they rest on a particular and limited understanding of agency. Reformers tend to operate within a theoretical framework that understands behaviour as driven by individual and predominantly rational incentives and pays little attention to the expressive and normative aspects of social action. The problems that arise in these areas when a competitive market logic is applied in social provision tend not to be recognised. Such a logic may contradict established values of social care and commitment to user interests. A qualitative survey of 48 members of the general public is used to examine perceptions of and responses to the NHS reforms, and to show how public discourse in this area is at variance with the instrumental and individual assumptions of policy-makers. The result is that the reform programme damages the legitimacy of the service and that those responsible for the new policies fail to recognise that the individual instrumental agenda is eroding public trust.
Families ‘At Risk’ and the Family Nurse Partnership: The Intrusion of Risk into Social Exclusion Policy
Authors: DODDS ANNELIESE
Published: March 2009

This article considers why the family nurse partnership (FNP) has been promoted as a means of tackling social exclusion in the UK. The FNP consists in a programme of visits by nurses to low-income first-time mothers, both while the mothers are pregnant and for the first two years following birth. The FNP is focused on both teaching parenthood and encouraging mothers back into education and/or into employment. Although the FNP marks a considerable discontinuity with previous approaches to family health, it is congruent with an emerging new approach to social exclusion. This new approach maintains that the most important task of social policy is to identify quickly the most ‘at-risk’ households, individuals and children so that interventions can be targeted more effectively at those ‘at risk’, either to themselves or to others. The article illustrates this new approach by analysing a succession of reports by the Social Exclusion Unit. It indicates that there is a considerable amount of ambiguity about the relationship between specific risk-factors and being ‘at risk of social exclusion’. Nonetheless, this new approach helps to explain why British policy-makers may have chosen to promote the new FNP now.
The Impact of Decriminalisation on the Number of Sex Workers in New Zealand
Authors: ABEL GILLIAN M. , FITZGERALD LISA J. , BRUNTON CHERYL
Published: March 2009

In 2003, New Zealand decriminalised sex work through the enactment of the Prostitution Reform Act. Many opponents to this legislation predicted that there would be increasing numbers of people entering sex work, especially in the street-based sector. The debates within the New Zealand media following the legislation were predominantly moralistic and there were calls for the recriminalisation of the street-based sector. This study estimated the number of sex workers post-decriminalisation in five locations in New Zealand: the three main cities in which sex work takes place as well as two smaller cities. These estimations were compared to existing estimations prior to and at the time of decriminalisation. The research suggests that the Prostitution Reform Act has had little impact on the number of people working in the sex industry.
Interaction as method and result of language learning
Authors: Hall Joan Kelly
Published: March 2009

The premise of this paper is that the interactional practices constituting teacher–student interaction and language learning are interdependent in that the substance of learners' language knowledge is inextricably tied to their extended involvement in the regularly occurring interactional practices constituting their specific contexts of learning. After laying out the central components of a theoretical framework for understanding the interdependent nature of interaction and learning, I provide an overview of the Initiation–Respond–Feedback organization (IRF), a ubiquitous classroom interactional practice, and then examine two instances of the IRF taken from two language classrooms. I pay particular attention to actions in the IRF that give shape to learners' developing understandings of, and skills for, using the target language. After briefly discussing the likely consequences of extended participation in the IRF in terms of L2 outcomes, I suggest directions for future research.
An ontologically-based evaluation of software design methods
Authors: Kannengiesser Udo , Zhu Liming
Published: March 2009

This paper develops an ontological basis for evaluating software design methods, based on the situated function–behaviour–structure framework. This framework accounts for the situatedness of designing, viewing it as a dynamic activity driven by interactions between designers and the artefacts being designed. On the basis of this framework, we derive a general evaluation schema that we apply to five software design methods. The ideas presented in this work contribute to a better understanding of design methods, and uncover opportunities for method integration and development.
Effective use of ontologies in software measurement
Authors: García Félix , Ruiz Francisco , Calero Coral , Bertoa Manuel F. , Vallecillo Antonio , Mora Beatriz , Piattini Mario
Published: March 2009

Ontologies are frequently used in the context of software and technology engineering. These can be grouped into two main categories, depending on whether they are used to describe the knowledge of a domain (domain ontologies) or whether they are used as software artifacts in software development processes. This paper presents some experiences and lessons learnt from the effective use of an ontology for Software Measurement, called software measurement ontology (SMO). The SMO was developed some years ago as a result of a thorough analysis of the software measurement domain. Its use as a domain ontology is presented first, a description of how the SMO can serve as a conceptual basis for comparing international standards related to software measurement. Second, the paper describes several examples of the applications of SMO as a software artifact. In particular, we show how the SMO can be instantiated to define a data quality model for Web portals, and also how it can be used to define a Domain-Specific Language (DSL) for measuring software entities. These examples show the significant role that ontologies can play as software artifacts in the realm of model-driven engineering and domain-specific modeling.
A semantic web environment for components
Authors: Wang Hai H. , Sun Jing
Published: March 2009

Component-based development (CBD) has become an important emerging topic in the software engineering field. It promises long-sought-after benefits such as increased software reuse, reduced development time to market and, hence, reduced software production cost. Despite the huge potential, the lack of reasoning support and development environment of component modeling and verification may hinder its development. Methods and tools that can support component model analysis are highly appreciated by industry. Such a tool support should be fully automated as well as efficient. At the same time, the reasoning tool should scale up well as it may need to handle hundreds or even thousands of components that a modern software system may have. Furthermore, a distributed environment that can effectively manage and compose components is also desirable. In this paper, we present an approach to the modeling and verification of a newly proposed component model using Semantic Web languages and their reasoning tools. We use the Web Ontology Language and the Semantic Web Rule Language to precisely capture the inter-relationships and constraints among the entities in a component model. Semantic Web reasoning tools are deployed to perform automated analysis support of the component models. Moreover, we also proposed a service-oriented architecture (SOA)-based semantic web environment for CBD. The adoption of Semantic Web services and SOA make our component environment more reusable, scalable, dynamic and adaptive.
Image statistics at the point of gaze during human navigation
Authors: ROTHKOPF CONSTANTIN A. , BALLARD DANA H.
Published: March 2009

Theories of efficient sensory processing have considered the regularities of image properties due to the structure of the environment in order to explain properties of neuronal representations of the visual world. The regularities imposed on the input to the visual system due to the regularities of the active selection process mediated by the voluntary movements of the eyes have been considered to a much lesser degree. This is surprising, given that the active nature of vision is well established. The present article investigates statistics of image features at the center of gaze of human subjects navigating through a virtual environment and avoiding and approaching different objects. The analysis shows that contrast can be significantly higher or lower at fixation location compared to random locations, depending on whether subjects avoid or approach targets. Similarly, significant differences in the distribution of responses of model simple and complex cells between horizontal and vertical orientations are found over timescales of tens of seconds. By clustering the model simple cell responses, it is established that gaze was directed toward three distinct features of intermediate complexity the vast majority of time. Thus, this study demonstrates and quantifies how the visuomotor tasks of approaching and avoiding objects during navigation determine feature statistics of the input to the visual system through the combined influence on body and eye movements.
The Economy of France in the Eighteenth and Nineteenth Centuries: Market Opportunity and Labour Productivity in Languedoc
Authors: MILLER STEPHEN J.
Published: March 2009

Recent scholarship makes the case that from the seventeenth through the nineteenth centuries, French peasants were just as effective as the large farmers of England in raising agricultural productivity when they had access to urban markets. This article shows that the peasants of the old regime province of Languedoc had access to urban demand and market opportunities, and brought about economic growth, but only by dint of massive increases of labour inputs. The results were paltry increases in labour productivity and the standard of living. The case of Languedoc demonstrates that the study of the social context helps scholars evaluate a society's potential for economic development far more than does the study of its markets.
Immigrants in the Polder. Rural-Rural Long Distance Migration in North-Western Europe: The Case of Watergraafsmeer
Authors: KAAL HARM , VAN LOTTUM JELLE
Published: March 2009

Long distance emigration of agriculture workers or farmers is usually associated with seasonal migration. Permanent migration of farmers on the other hand, is considered to be a non-European phenomenon and commonly linked to migration to the New World where capital costs were relatively low and institutional barriers limited. Interestingly, in the early modern period, in the wake of the mass migration from continental north-western Europe to the urban areas of the Dutch Republic, a contingent of German market gardeners and their descendants were slowly able to take over the production of farmed vegetable goods for the nation's capital, Amsterdam. In the middle of one of Europe's most densely populated areas, in a polder called Watergraafsmeer, a parish neighbouring, and subsequently part of, Amsterdam, Germans dominated the agricultural sector for over a century. This article will try to answer the question of how these German migrants were able to control a sector that is usually run by locally born producers, for such a long period of time.
A Spectral Approach to Analysing Belief Propagation for 3-Colouring
Authors: COJA-OGHLAN AMIN , MOSSEL ELCHANAN , VILENCHIK DAN
Published: March 2009

Belief propagation (BP) is a message-passing algorithm that computes the exact marginal distributions at every vertex of a graphical model without cycles. While BP is designed to work correctly on trees, it is routinely applied to general graphical models that may contain cycles, in which case neither convergence, nor correctness in the case of convergence is guaranteed. Nonetheless, BP has gained popularity as it seems to remain effective in many cases of interest, even when the underlying graph is ‘far’ from being a tree. However, the theoretical understanding of BP (and its new relative survey propagation) when applied to CSPs is poor.

Contributing to the rigorous understanding of BP, in this paper we relate the convergence of BP to spectral properties of the graph. This encompasses a result for random graphs with a ‘planted’ solution; thus, we obtain the first rigorous result on BP for graph colouring in the case of a complex graphical structure (as opposed to trees). In particular, the analysis shows how belief propagation breaks the symmetry between the 3! possible permutations of the colour classes.
A regional archeomagnetic model for Europe for the last 3000 years, SCHA.DIF.3K: Applications to archeomagnetic dating
Authors: Pavón‐Carrasco F. Javier , Osete Maria Luisa , Torta J. Miquel , Gaya‐Piqué Luis R.
Published: March 2009

The available European database of archeomagnetic field values and instrumental data has been used to produce a regional model for the geomagnetic field in Europe for the last 3000 years (from 1000 B.C. to 1900 A.D., connecting with the epoch covered by the IGRF models). This new model, SCHA.DIF.3K, constitutes an improvement with respect to the previous regional archeomagnetic model SCHA.DI.00‐F, which used relocated values and was only valid for the last 2000 years. The new model has been obtained by least sums of absolute deviation inversion of paleomagnetic data using spherical cap harmonics for the spatial representation of the field and sliding windows in time. An algorithm has been developed to jointly model the three archeomagnetic elements declination, inclination, and intensity. The resulting model provides the direction and intensity of the Earth's magnetic field over the European continent, northern Africa, and western Asia for the last 3000 years. The fit to the European archeomagnetic database is more accurate than that provided by global archeomagnetic models. In addition, this model represents a step forward in archeomagnetic dating studies (since the relocation error is avoided) and can also be used to study the rapid changes of the geomagnetic field (archeomagnetic jerks) that have been recently proposed.
Impact of the latitudinal distribution of tropical cyclones on ocean heat transport
Authors: Jansen Malte , Ferrari Raffaele
Published: March 2009

The heavy winds associated with tropical cyclones generate strong upper ocean mixing. Recent studies suggest that this enhanced mixing significantly contributes to the ocean poleward heat transport, mainly due to a strengthening of the subtropical cells. A general circulation model is used here to show that whether the poleward heat transport is actually increased depends crucially on the latitude band where mixing is enhanced. If upper ocean mixing is enhanced everywhere within 30° of the equator, poleward heat transport is increased. However, if mixing is enhanced solely in the subtropical bands, where tropical cyclones are observed, the poleward heat transport out of the deep tropics is decreased.
Annual balance and seasonal variability of sea‐air CO2 fluxes in the Patagonia Sea: Their relationship with fronts and chlorophyll distribution
Authors: Bianchi Alejandro A. , Pino Diana Ruiz , Perlender Hernán G. Isbert , Osiroff Ana P. , Segura Valeria , Lutz Vivian , Clara Moira Luz , Balestrini Carlos F. , Piola Alberto R.
Published: March 2009

Sea‐air differences of CO2 partial pressures (ΔpCO2) and surface chlorophyll a (chl‐a) concentration have been determined during 22 cruises in various seasons for 2000–2006 over the Patagonia Sea and shelf break. From spring to autumn, the nearshore waters act as a source of atmospheric CO2, while the midshelf and slope are a CO2 sink, leading to highly negative areal means of sea‐air CO2 flux and ΔpCO2. The ΔpCO2 and CO2 flux in spring reach values of −67 μatm and −7 × 10−3 mol m−2 d−1, respectively, and are close to equilibrium in winter. Sea‐air ΔpCO2 and chl‐a over the shelf are negatively correlated, suggesting that photosynthesis is one of the main processes responsible for the large CO2 sequestration. The annual areal mean ΔpCO2 and sea‐air CO2 flux are −31 μatm and −3.7 × 10−3 mol m−2 d−1, respectively, indicating that the Patagonia Sea is one of the strongest CO2 sinks per unit area in the World Ocean.
Evaluation of forest snow processes models (SnowMIP2)
Authors: Rutter Nick , Essery Richard , Pomeroy John , Altimir Nuria , Andreadis Kostas , Baker Ian , Barr Alan , Bartlett Paul , Boone Aaron , Deng Huiping , Douville Hervé , Dutra Emanuel , Elder Kelly , Ellis Chad , Feng Xia , Gelfan Alexander , Goodbody Angus , Gusev Yeugeniy , Gustafsson David , Hellström Rob , Hirabayashi Yukiko , Hirota Tomoyoshi , Jonas Tobias , Koren Victor , Kuragina Anna , Lettenmaier Dennis , Li Wei‐Ping , Luce Charlie , Martin Eric , Nasonova Olga , Pumpanen Jukka , Pyles R. David , Samuelsson Patrick , Sandells Melody , Schädler Gerd , Shmakin Andrey , Smirnova Tatiana G. , Stähli Manfred , Stöckli Reto , Strasser Ulrich , Su Hua , Suzuki Kazuyoshi , Takata Kumiko , Tanaka Kenji , Thompson Erin , Vesala Timo , Viterbo Pedro , Wiltshire Andrew , Xia Kun , Xue Yongkang , Yamazaki Takeshi
Published: March 2009

Thirty‐three snowpack models of varying complexity and purpose were evaluated across a wide range of hydrometeorological and forest canopy conditions at five Northern Hemisphere locations, for up to two winter snow seasons. Modeled estimates of snow water equivalent (SWE) or depth were compared to observations at forest and open sites at each location. Precipitation phase and duration of above‐freezing air temperatures are shown to be major influences on divergence and convergence of modeled estimates of the subcanopy snowpack. When models are considered collectively at all locations, comparisons with observations show that it is harder to model SWE at forested sites than open sites. There is no universal “best” model for all sites or locations, but comparison of the consistency of individual model performances relative to one another at different sites shows that there is less consistency at forest sites than open sites, and even less consistency between forest and open sites in the same year. A good performance by a model at a forest site is therefore unlikely to mean a good model performance by the same model at an open site (and vice versa). Calibration of models at forest sites provides lower errors than uncalibrated models at three out of four locations. However, benefits of calibration do not translate to subsequent years, and benefits gained by models calibrated for forest snow processes are not translated to open conditions.
Linking soils and streams: Sources and chemistry of dissolved organic matter in a small coastal watershed
Authors: Sanderman Jonathan , Lohse Kathleen A. , Baldock Jeffrey A. , Amundson Ronald
Published: March 2009

To understand the hydrologic and biogeochemical controls on the age and recalcitrance of dissolved organic matter (DOM) found in stream waters, we combined hydrometric monitoring along a topographic gradient from ridge to channel with isotopic (13C and 14C) and spectroscopic (UV and 13C nuclear magnetic resonance) analyses of soil and stream water samples in a small coastal watershed in California. With increasing discharge, dissolved organic carbon concentrations increased from 2.2 to 10.9 mg C L−1, Δ14C values increased from −125 to +120‰, δ13C values decreased from −24 to −29‰, C:N ratios increased from 6.5 to 15.4, and specific UV adsorption increased from 1.4 to 3.8 L mg C−1 m−1. These changes in DOM composition are consistent with a shift in source from old and recalcitrant soil organic matter (OM) sources found in deep soil horizons to young and relatively fresh OM sources found in the surface horizons. Results from this study suggest upland soils of the watershed become DOM production limited as indicated by a seasonal depletion and chemical shift in soil DOM, whereas highly productive soils in the hollow act as a near‐infinite DOM source. Hydrologic connectivity of this DOM‐rich riparian source region to the stream ultimately constrains DOM export, and the stream DOM composition reflects the combined influence of soil biogeochemical cycling of OM and hydrologic routing of water through the landscape.
Metrics for assessing snow surface roughness from digital imagery
Authors: Fassnacht S. R. , Stednick J. D. , Deems J. S. , Corrao M. V.
Published: March 2009

Digital image profiles of snowpack surfaces were acquired concurrently with 1‐cm resolution manual measurements. The manual measurements confirmed that unaltered digital images accurately represented a two‐dimensional roughness profile of the snowpack surface. Roughness indices, such as random roughness, that have been used to represent soil surfaces were computed, and their utility for quantifying snowpack surface roughness is illustrated. Variogram analysis was used to determine the fractal dimension and scale break. Surface characteristics were a function of the scale, with a rough snow surface and graupel yielding similar results. A relatively smooth snow surface showed no crystal‐scale features and had a fractal dimension approaching that of a random surface.
Ocean Bottom Array Probes Stagnant Slab Beneath the Philippine Sea
Authors: Shiobara Hajime , Baba Kiyoshi , Utada Hisashi , Fukao Yoshio
Published: March 2009

Global seismic tomography has revealed the existence of a now‐stagnant subducted slab (Figure 1c, inset) in the mantle transition zone (MTZ) of the western Pacific Ocean [e.g., Fukao et al., 2001], where the old Pacific plate subducts at the Kuril/Japan/Mariana Trench system. Fukao et al. [2001] showed that a stagnant slab is a common feature of many subduction systems around the world, although it is still not well understood why and how a subducted slab may or may not become stagnant. In addition to a subducted slab itself, water entrained with the slab may also accumulate in the MTZ in association with stagnation. The MTZ has been thought to play a key role in the Earth's water cycle, with water transported to the MTZ possibly being released and supplied to the upper mantle to drive back‐arc volcanism [e.g., Ichiki et al., 2006].
NASA carbon observatory failure
Authors: Showstack Randy
Published: March 2009

Following the crash landing of NASA's Orbiting Carbon Observatory (OCO) satellite on 24 February 2008 in the ocean near Antarctica, a 5‐member mishap investigation board—led by Rick Obenschain, deputy director at NASA's Goddard Space Flight Center—is looking into the cause of the satellite's launch failure. Preliminary indications are that the payload fairing failed to separate from the rocket. The $273 million satellite was to have collected global measurements of carbon dioxide (CO2) in the Earth's atmosphere to help better forecast changes in CO2 levels and their effect on the Earth's climate. The satellite also would have provided information about sinks that absorb and store CO2.
The Sea Level Conundrum: Insights From Paleo Studies: Empirical Constraints on Future Sea Level Rise; Bern, Switzerland, 25–29 August 2008
Authors: Siddall Mark , Clark Peter , Thompson Bill , Waelbroeck Claire , Gregory Jonathan , Stocker Thomas
Published: March 2009

Eustatic sea level (ESL) rise during the 21st century is perhaps the greatest threat from climate change, but its magnitude is contested. Geological records identify examples of nonlinear ice sheet response to climate forcing, suggesting a strategy for refining estimates of 21st‐century sea level change. In August 2008, Past Global Changes (PAGES), International Marine Past Global Change Study (IMAGES), and the University of Bern cosponsored a workshop to address this possibility. The workshop highlighted several ways that paleoceanography studies can place limits on future sea level rise, and these are enlarged upon here.
Space Weather: Physics and Effects
Authors: Hughes W. Jeffrey
Published: March 2009

With the launching of Sputnik, Explorer 1, and the other early satellites, the new discipline of space physics was born, about 50 years ago. Although earlier ground‐based observations had provided strong hints about the nature of our space environment above the upper atmosphere, those early satellites initiated a series of surprises and discoveries, including Van Allen's discovery of the Earth's radiation belts.

Young scientists were attracted to this new field, and it grew quickly. When the Journal of Geophysical Research was divided into two sections, in 1964, one section was devoted to space physics. The field explored not only new regions of space but also a new state of matter: the rarefied, fully ionized plasma that fills space and interacts intimately with magnetic fields.
Prospects for an influenza vaccine that induces cross‐protective cytotoxic T lymphocytes
Authors: Brown Lorena E , Kelso Anne
Published: March 2009

Our approach to vaccination against influenza is unique. For no other pathogen do we construct and produce a new vaccine every year in the face of uncertainty about the strains that will be circulating when it is used. The huge global cooperative effort that underpins this process reflects our awareness of the need to control this major pathogen. Moreover, the threat of devastation by a pandemic due to a newly emerging viral subtype has triggered an intense effort to improve and accelerate the production of vaccines for use if a pandemic arises. However, type A influenza viruses responsible for seasonal epidemics and those with the potential to cause a pandemic share amino acid sequences that form the targets of cytotoxic T lymphocytes (CTL). CTL activated by currently circulating viruses, therefore, offer a possible means to limit the impact of infection with future variant seasonal strains and even new subtypes. This review examines how cross‐protective CTL can be exploited to improve influenza vaccination and issues that need to be considered when attempting to induce this type of immunity. We discuss the role of CTL responses in viral control and review the current knowledge relating to specificity and longevity of memory CD8+ T cells, how vaccine antigen can be loaded into antigen‐presenting cells to prime these responses and factors influencing the class of response induced. Application of these principles to the next generation of influenza vaccines should lead to much greater control of infection.
Insights into the mechanisms of adenosylcobalamin (coenzyme B12)-dependent enzymes from rapid chemical quench experiments
Authors: Marsh E. Neil G.
Published: March 2009

Glutamate mutase is one of a group of adenosylcobalamin-dependent enzymes that use free radicals to catalyse unusual and chemically difficult rearrangements involving 1,2-migrations of hydrogen atoms. A key mechanistic feature of these enzymes is the transfer of the migrating hydrogen atom between substrate, coenzyme and product. The present review summarizes recent experiments from my laboratory that have used rapid chemical quench techniques to identify intermediates in the reaction and probe the mechanism of hydrogen transfer through a variety of pre-steady-state kinetic isotope effect measurements.
Time-resolved studies of radical pairs
Authors: Woodward Jonathan R. , Foster Timothy J. , Jones Alex R. , Salaoru Adrian T. , Scrutton Nigel S.
Published: March 2009

The effect of magnetic fields on chemical reactions through the RP (radical pair) mechanism is well established, but there are few examples, in the literature, of biological reactions that proceed through RP intermediates and show magnetic field-sensitivity. The present and future relevance of magnetic field effects in biological reactions is discussed.
Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling
Authors: Lodola Alessio , Mor Marco , Sirirak Jitnapa , Mulholland Adrian J.
Published: March 2009

FAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the carbamoylating compound URB524. These are potentially crucial insights for designing new covalent inhibitors of this drug target.
Density functional theory (DFT) and combined quantum mechanical/molecular mechanics (QM/MM) studies on the oxygen activation step in nitric oxide synthase enzymes
Authors: Visser Sam P. de
Published: March 2009

In this review paper, we will give an overview of recent theoretical studies on the catalytic cycle(s) of NOS (nitric oxide synthase) enzymes and in particular on the later stages of these cycles where experimental work is difficult due to the short lifetime of intermediates. NOS enzymes are vital for human health and are involved in the biosynthesis of toxic nitric oxide. Despite many experimental efforts in the field, the catalytic cycle of this important enzyme is still surrounded by many unknowns and controversies. Our theoretical studies were focused on the grey zones of the catalytic cycle, where intermediates are short-lived and experimental detection is impossible. Thus combined QM/MM (quantum mechanics/molecular mechanics) as well as DFT (density functional theory) studies on NOS enzymes and active site models have established a novel mechanism of oxygen activation and the conversion of L-arginine into Nω-hydroxo-arginine. Although NOS enzymes show many structural similarities to cytochrome P450 enzymes, it has long been anticipated that therefore they should have a similar catalytic cycle where molecular oxygen binds to a haem centre and is converted into an Fe(IV)-oxo haem(+•) active species (Compound I). Compound I, however, is elusive in the cytochrome P450s as well as in NOS enzymes, but indirect experimental evidence on cytochrome P450 systems combined with theoretical modelling have shown it to be the oxidant responsible for hydroxylation reactions in cytochrome P450 enzymes. By contrast, in the first catalytic cycle of NOS it has been shown that Compound I is first reduced to Compound II before the hydroxylation of arginine. Furthermore, substrate arginine in NOS enzymes appears to have a dual function, namely first as a proton donor in the catalytic cycle to convert the ferric-superoxo into a ferric-hydroperoxo complex and secondly as the substrate that is hydroxylated in the process leading to Nω-hydroxo-arginine.
Combining X-ray crystallography and single-crystal spectroscopy to probe enzyme mechanisms
Authors: Pearson Arwen R. , Owen Robin L.
Published: March 2009

The combination of X-ray crystallography and rapid cryo-trapping methods has enabled the visualization of catalytic intermediates in a variety of enzyme systems. However, the resolution of the X-ray experiment is not always sufficient to precisely place the structure on the reaction pathway. In addition, many trapped intermediates are X-ray-sensitive and can decay during diffraction data collection, resulting in a final structure that may not be representative of the initial trapped species. Complementary methods, such as single-crystal spectroscopy, provide a means to precisely identify the cryo-trapped species as well as detect any X-ray-induced changes during diffraction data collection.
Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase
Authors: Rafice Sara A. , Chauhan Nishma , Efimov Igor , Basran Jaswir , Raven Emma Lloyd
Published: March 2009

The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.
Mechanism of CB1954 reduction by Escherichia coli nitroreductase
Authors: Christofferson Andrew , Wilkie John
Published: March 2009

NTR (nitroreductase NfsB from Escherichia coli) is a flavoprotein with broad substrate specificity, reducing nitroaromatics and quinones using either NADPH or NADH. One of its substrates is the prodrug CB1954 (5-[aziridin-1-yl]-2,4-dinitrobenzamide), which is converted into a cytotoxic agent; so NTR/CB1954 has potential for use in cancer gene therapy. However, wild-type NTR has poor kinetics and binding with CB1954, and the mechanism for the reduction of CB1954 by NTR is poorly understood. Computational methods have been utilized to study potential underlying reaction mechanisms so as to identify the order of electron and proton transfers that make up the initial reduction step and the sources of the protons. We have used Molecular Dynamics to examine the nature of the active site of the wild-type enzyme and the preferred binding mode of the substrate. A combination of these results has allowed us to unequivocally identify the reaction mechanism for the reduction of CB1954 by NTR.
Miniaturized PCR systems for cancer diagnosis
Authors: Day Philip J.R.
Published: March 2009

PCR retains a pivotal role in making accessible marker nucleic acid sequences for ready analysis in cancer diagnosis. For certain cancers such as acute lymphoblastic leukaemia, the application of quantitative procedures to assess and subsequently direct therapy has given rise to the slowly maturing field of MRD (minimal residual disease) management. Although excellent protocols exist for performing these analyses, akin to all PCR procedures the limit of detection can vary markedly between laboratories. The present paper is an overview that describes how the analytical field relating to miniaturization is likely to identify the missing link that integrates sample processing with downstream PCR, analysis and eventual therapy. Miniaturized devices are suited to the multi-parallelized handling of defined numbers of cells, and PCR-based microfluidic procedures have become reasonably established. The integration of sample processing and PCR in microfluidic devices is beginning to offer reproducible quantitative data that relate the number of biomarker nucleic acids to the defined analysed cell or cells for meaningful clinical assessment. The application of MRD may, through integrated miniaturized PCR, become more reliable and routine with additional applications in defining disease threshold levels for other cancer types. These enabling integrated platforms may facilitate biomarker measurements to predict the response and outcome, which are also of current interest for personalized medical care.
COLD-PCR: a new platform for highly improved mutation detection in cancer and genetic testing
Authors: Li Jin , Makrigiorgos G. Mike
Published: March 2009

PCR is widely employed as the initial DNA amplification step for genetic testing and cancer biomarker detection. However, a key limitation of PCR-based methods, including real-time PCR, is the inability to selectively amplify low levels of variant alleles in a wild-type allele background. As a result, downstream assays are limited in their ability to identify subtle genetic changes that can have a profound impact on clinical decision-making and outcome or that can serve as cancer biomarkers. We developed COLD-PCR (co-amplification at lower denaturation temperature-PCR) [Li, Wang, Mamon, Kulke, Berbeco and Makrigiorgos (2008) Nat. Med. 14, 579–584], a novel form of PCR that amplifies minority alleles selectively from mixtures of wild-type and mutation-containing sequences irrespective of the mutation type or position on the sequence. Consequently, COLD-PCR amplification from genomic DNA yields PCR products containing high-prevalence variant alleles that can be detected. Since PCR constitutes a ubiquitous initial step for almost all genetic analysis, COLD-PCR provides a general platform to improve the sensitivity of essentially all DNA-variation detection technologies including Sanger sequencing, pyrosequencing, single molecule sequencing, mutation scanning, mutation genotyping or methylation assays. COLD-PCR combined with real-time PCR provides a new approach to boost the capabilities of existing real-time mutation detection methods. We replaced regular PCR with COLD-PCR before sequencing or real-time mutation detection assays to improve mutation detection-sensitivity by up to 100-fold and identified novel p53/Kras/EGFR (epidermal growth factor receptor) mutations in heterogeneous cancer samples that were missed by all existing methods. For clinically relevant micro-deletions, COLD-PCR enabled exclusive amplification and isolation of the mutants. COLD-PCR is expected to have diverse applications in the fields of biomarker identification and tracing, genomic instability, infectious diseases, DNA methylation testing and prenatal identification of fetal alleles in maternal blood.
PCR in forensic genetics
Authors: Morling Niels
Published: March 2009

Since the introduction in the mid-1980s of analyses of minisatellites for DNA analyses, a revolution has taken place in forensic genetics. The subsequent invention of the PCR made it possible to develop forensic genetics tools that allow both very informative routine investigations and still more and more advanced, special investigations in cases concerning crime, paternity, relationship, disaster victim identification etc. The present review gives an update on the use of DNA investigations in forensic genetics.
Genomic DNA amplification by the multiple displacement amplification (MDA) method
Authors: Lasken Roger S.
Published: March 2009

Large amounts of DNA are frequently required for use in detection assays and genomic analysis. The limited availability of DNA can be a critical obstacle to meeting research and clinical needs. DNA amplification methods are often required to generate sufficient material from small specimens or environmental samples with low DNA content. The MDA (multiple displacement amplification) reaction is increasingly the method of choice for many applications because of its extensive coverage of the genome, the generation of extremely long DNA products compared with older whole genome amplification methods and the high DNA yields, even from exceedingly low amounts of starting material. Remarkably, MDA enables genomic sequencing even from single microbial cells. Some of the uses of MDA and its strengths and limitations will be discussed.
Duplex communicable implanted antenna for magnetic direct feeding method: Functional electrical stimulation
Authors: Kato Kentaro , Matsuki Hidetoshi , Sato Fumihiro , Satoh Tadakuni , Handa Nobuyasu
Published: March 2009

Functional electrical stimulation (FES) is the therapy used for the rehabilitation of lost movement function by applying electrical stimulation (ES) to paralyzed extremities. To realize ES, we adapted the implanted direct feeding method (DFM). In this method, small implanted stimulators are placed under the skin at a depth of 10–20 mm and stimulus energy and signals for controlling devices are applied to them by a mounted system using magnetic coupling. This method has the merits of having no percutaneous points and high-precision stimulation. However, since the mounted system and implanted elements are separated, it is necessary to add feedback information from inside the body to confirm the system operation for safety therapy or to rehabilitate motor function smoothly. Satisfying both restrictions, we propose the magnetic connective dual resonance (MCDR) antenna, which has two resonance circuits. Adding the LC serial circuit to the LC parallel circuit gives the sending function. In this paper, we report the principle of the MCDR antenna and verify its duplex communication ability through communication experiment. This antenna enables DFM of FES to rehabilitate more complex movements.
Magnetocaloric effect in spherical La(FexSi1−x)13 and their hydrides for active magnetic regenerator-type refrigerator
Authors: Fujita A. , Koiwai S. , Fujieda S. , Fukamichi K. , Kobayashi T. , Tsuji H. , Kaji S. , Saito A. T.
Published: March 2009

We have fabricated spherical La(FexSi1−x)13 compounds by a rotating electrode process (REP) to provide suitable refrigerants for active magnetic regenerator (AMR)-type systems. In the as-prepared state, the cross section exhibits a dendritic metallographic structure composed of two phases of α-Fe-based alloy with Si and LaFeSi equiatomic compound. After annealing at 1323 K for 5 days, the spheres become a single phase of La(FexSi1−x)13. From the temperature dependence of magnetic entropy change for the hydrogenated spheres, it has been confirmed that the hydrogen concentration in the spheres is homogeneous. In addition, it has also been demonstrated that the itinerant-electron metamagnetic transition appears in the spheres with the higher Fe concentration. Consequently, the spherical La(FexSi1−x)13 fabricated by the REP are suitable for AMR-type refrigerations.
Magnetization dynamics and static properties of Ho-doped Ni0.8Fe0.2
Authors: Benatmane Nadjib , Ambrose T. F. , Clinton T. W.
Published: March 2009

The effect of holmium (Ho) doping in films of Ni0.8Fe0.2 (NiFe) is investigated. The ferromagnetic resonance (FMR) is measured, and the linewidths (Δf) are fit to a model that incorporates broadening from inhomogeneities and intrinsic damping (αLLG). The data reveal a drastic increase in Δf for increasing Ho concentration in the NiFe films, while the fits of this data to the model indicate this is largely due to an increase in αLLG. At Ho concentrations of 10% and greater, the saturation magnetization is reduced by more than 60% while the FMR is no longer observable, which is likely due to the signal falling below the noise floor from further linewidth broadening and decreased magnetization. In general, the saturation magnetization decreases continuously with Ho concentration, presumably due to local ferrimagnetic order induced by the Ho moments. However, the coercivity is essentially unchanged by the doping, while the magnetic anisotropy HK is unchanged out to 2% Ho, beyond which there is an abrupt step-function-like increase. The data suggest Ho concentrations as small as 2% can substantially increase intrinsic damping in NiFe while minimizing change in other practical magnetic properties.