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For many years I have kept on my writing desk the statuette of a holy woman warrior. Clad in a wrap-around cloak, looking intently into infinity through slightly downcast eyes, she cuts a rather sad but awe-inspiring figure. She is resting her left hand on a mighty down-turned sword, while holding up a book in her right. I choose to believe it is just any book, though it shows clear signs of bring the book of books – the holy scripture of the Christian faith. This statuette is very special as it was given to me by someone I love and lost. We bought it during a day trip to Antwerp and when I first got it, I did not know who she was. Not many people know about Dympna.

Purpose The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL. Participants and Methods Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction–based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples. Results Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10−4 (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis. Conclusion High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.

Background B-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms. Methods We investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts. Results Our analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection. Conclusions This is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Resignation by individual cabinet ministers is a major political event. Little is known, however, about the incidence, the patterns and the causes of ministerial resignations. This article works towards a political survival model of individual (junior and senior) ministers in the Netherlands, a country characterized by proportional representation and coalition governments. It does so on the basis of data for all 719 cabinet members serving between 1946 and 2010. It first establishes the turnover rate of individual cabinet members. On average, 15.0 per cent of all ministers step down individually before the end of their term. A total of 5.3 per cent resigns for political reasons, such as an internal conflict within the cabinet or losing the confidence of the party or parliament. With regard to political resignations, the Balkenende-era was the most turbulent of Dutch post-war political history. We then tried to explain the resignation hazard for individual ministers on the basis of recent comparative research. The analysis shows that previous experience in parliament makes the largest difference. Ministers lacking such experience are currently 51 per cent less likely to survive in office.

Rationale Social factors influence drug abuse. Conversely, drugs of abuse alter social behavior. This is especially pertinent during post-weaning development, when there are profound changes in the social repertoire, and the sensitivity to the positive and negative effects of drugs of abuse is altered. Objectives This study aimed to provide an overview of our current understanding of the interaction between drugs of abuse and juvenile/adolescent social behavior. Methods We first provide evidence that a characteristic form of juvenile and adolescent social behavior, i.e., social play behavior, has reinforcing properties and is affected by drugs of abuse. Next, social risk factors for drug use and addiction are described, including antisocial personality traits and early social insults. Last, we discuss research that investigates social influences on drug use, as well as the consequences of perinatal drug exposure on later social interactions. Results Social play behavior is highly rewarding in laboratory animals, and it is affected by low doses of opioids, cannabinoids, ethanol, nicotine, and psychostimulants. In humans, antisocial personality traits, most prominently in the form of conduct disorder, are a prominent risk factor for drug addiction. Preclinical studies have consistently shown altered sensitivity to drugs as a result of social isolation during post-weaning development. The social environment of an individual has a profound, but complex, influence on drug use, and perinatal drug exposure markedly alters later social interactions. Conclusions The studies reviewed here provide a framework to understand the interaction between drugs of abuse and adolescent social interaction, at the preclinical and the clinical level.

ObjectivesThe Illness Invalidation Inventory (3*I) assesses patients’ perception of responses of others that are perceived as denying, lecturing, not supporting and not acknowledging the condition of the patient. It includes two factors: ‘discounting’ and ‘lack of understanding’. In order to use the 3*I to compare and pool scores across groups and countries, the questionnaire must have measurement invariance; that is, it should measure identical concepts with the same factor structure across groups. The aim of this study was to examine measurement invariance of the 3*I across rheumatic diseases, gender and languages.MethodsParticipants with rheumatic disease from various countries completed an online study using the 3*I, which was presented in Dutch, English, French, German, Portuguese and Spanish; 6057 people with rheumatic diseases participated. Single and multiple group confirmatory factor analyses were used to test the factorial structure and measurement invariance of the 3*I with Mplus.ResultsThe model with strong measurement invariance, that is, equal factor loadings and thresholds (distribution cut-points) across gender and rheumatic disease (fibromyalgia vs other rheumatic diseases) had the best fit estimates for the Dutch version, and good fit estimates across the six language versions.ConclusionsThe 3*I showed measurement invariance across gender, rheumatic disease and language. Therefore, it is appropriate to compare and pool scores of the 3*I across groups. Future research may use the questionnaire to examine antecedents and consequences of invalidation as well as the effect of treatments targeting invalidation.

Background: The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest because more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory agents to improve symptoms of schizophrenia. This study provides an update regarding the efficacy of anti-inflammatory agents on schizophrenic symptoms in clinical studies performed so far. Methods: An electronic search was performed using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. Only randomized, double-blind, placebo-controlled studies that investigated clinical outcome were included. Results: Our search yielded 26 double-blind randomized controlled trials that provided information on the efficacy on symptom severity of the following components: aspirin, celecoxib, davunetide, fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06–0.537, I2 = 0), estrogens (ES: 0.51, n = 262, 95% CI: 0.043–0.972, I2 = 69%), and NAC (ES: 0.45, n = 140, 95% CI: 0.112–0.779) showed significant effects. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect. Conclusion: The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.

Cells control their volume through the accumulation of compatible solutes. The bacterial ATP-binding cassette transporter OpuA couples compatible solute uptake to ATP hydrolysis. Here, we study the gating mechanism and energy coupling of OpuA reconstituted in lipid nanodiscs. We show that anionic lipids are essential both for the gating and the energy coupling. The tight coupling between substrate binding on extracellular domains and ATP hydrolysis by cytoplasmic nucleotide-binding domains allows the study of transmembrane signaling in nanodiscs. From the tight coupling between processes at opposite sides of the membrane, we infer that the ATPase activity of OpuA in nanodiscs reflects solute translocation. Intriguingly, the substrate-dependent, ionic strength-gated ATPase activity of OpuA in nanodiscs is at least an order of magnitude higher than in lipid vesicles (i.e. with identical membrane lipid composition, ionic strength, and nucleotide and substrate concentrations). Even with the chemical components the same, the lateral pressure (profile) of the nanodiscs will differ from that of the vesicles. We thus propose that membrane tension limits translocation in vesicular systems. Increased macromolecular crowding does not activate OpuA but acts synergistically with ionic strength, presumably by favoring gating interactions of like-charged surfaces via excluded volume effects.

Rationale Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated. Objective In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats. Results The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine. Conclusions Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.

Targeted transparency has become a popular regulatory instrument, but its effects are fuzzy because disclosure does not always lead to better compliance. To understand this fuzziness, it is necessary to study the meanings managers attribute to disclosure systems. An empirical analysis of disclosure systems for food safety in Denmark and for environmental safety in the Netherlands confirms that the range of managerial reactions is broader than expected on the basis of rational-choice theory, but can be explained by focusing on local meanings. The article illustrates the shortcomings of a homogeneous approach to targeted transparency policy. Regulators should adopt a bottom-up rather than a top-down approach and develop differentiated policies based on a more nuanced understanding of the meanings managers attribute to targeted transparency.

The emergence of publications on extracellular RNA (exRNA) and extracellular vesicles (EV) has highlighted the potential of these molecules and vehicles as biomarkers of disease and therapeutic targets. These findings have created a paradigm shift, most prominently in the field of oncology, prompting expanded interest in the field and dedication of funds for EV research. At the same time, understanding of EV subtypes, biogenesis, cargo and mechanisms of shuttling remains incomplete. The techniques that can be harnessed to address the many gaps in our current knowledge were the subject of a special workshop of the International Society for Extracellular Vesicles (ISEV) in New York City in October 2012. As part of the “ISEV Research Seminar: Analysis and Function of RNA in Extracellular Vesicles (evRNA)”, 6 round-table discussions were held to provide an evidence-based framework for isolation and analysis of EV, purification and analysis of associated RNA molecules, and molecular engineering of EV for therapeutic intervention. This article arises from the discussion of EV isolation and analysis at that meeting. The conclusions of the round table are supplemented with a review of published materials and our experience. Controversies and outstanding questions are identified that may inform future research and funding priorities. While we emphasize the need for standardization of specimen handling, appropriate normative controls, and isolation and analysis techniques to facilitate comparison of results, we also recognize that continual development and evaluation of techniques will be necessary as new knowledge is amassed. On many points, consensus has not yet been achieved and must be built through the reporting of well-controlled experiments. Keywords: extracellular vesicle; exosome; microvesicle; standardization; isolation (Published: 27 May 2013) Citation: Journal of Extracellular Vesicles 2013, 2 : 20360 - http://dx.doi.org/10.3402/jev.v2i0.20360

Transparency is considered a key value for trustworthy governments. However, the effect of transparency on citizens’ trust across different national cultures is overlooked in current research. This article compares the effect of transparency on trust in government between the Netherlands and South Korea. The effect is investigated by two similar series of three experiments. We hypothesize that the effect of transparency differs, because both countries have different cultural values regarding power distance and short and long-term orientation. Results reveal similar patterns in both countries: transparency has a subdued and sometimes negative effect on trust in government. However, the negative effect in South Korea is much stronger. This implies a subdued and negative effect of transparency on trust in the short term in both countries. Nevertheless, the difference in the magnitude of transparency’s effect suggests that national cultural values play a significant role in how people perceive and appreciate government transparency.

This article presents data from a project exploring women's experiences of work and care. It focuses primarily on work-life balance as a problematic concept. Social and economic transformations across advanced post-industrial economies have resulted in concerns about how individuals manage their lives across the two spheres of work and family and achieve a work-life balance. Governments across the European Union have introduced various measures to address how families effectively combine care with paid work. Research within this area has tended to focus on work-life balance as an objective concept, which implies a static and fixed state fulfilled by particular criteria and measured quantitatively. Qualitative research on women's experiences reveals work-life balance as a fluctuating and intangible process. This article highlights the subjective and variable nature of work-life balance and questions taken-for-granted assumptions, exploring problems of definition and the differential coping strategies which women employ when negotiating the boundaries between work and family.

SummaryIn neurons, the distinct molecular composition of axons and dendrites is established through polarized targeting mechanisms, but it is currently unclear how nonpolarized cargoes, such as mitochondria, become uniformly distributed over these specialized neuronal compartments. Here, we show that TRAK family adaptor proteins, TRAK1 and TRAK2, which link mitochondria to microtubule-based motors, are required for axonal and dendritic mitochondrial motility and utilize different transport machineries to steer mitochondria into axons and dendrites. TRAK1 binds to both kinesin-1 and dynein/dynactin, is prominently localized in axons, and is needed for normal axon outgrowth, whereas TRAK2 predominantly interacts with dynein/dynactin, is more abundantly present in dendrites, and is required for dendritic development. These functional differences follow from their distinct conformations: TRAK2 preferentially adopts a head-to-tail interaction, which interferes with kinesin-1 binding and axonal transport. Our study demonstrates how the molecular interplay between bidirectional adaptor proteins and distinct microtubule-based motors drives polarized mitochondrial transport.

In this article, using our original data on party leadership succession in 23 parliamentary democracies, we investigate the determinants of a party leader’s survival rate: how long he/she remains in office. Unlike previous studies, which focus on institutional settings of leadership selection or on situational (political, economic and international) conditions at the time of succession, we propose a perceptual theory of leadership survival, focusing on the expectations of party constituents (or indirectly, the voting public) who have the power to remove a leader. Specifically, we argue that they ‘benchmark’ their expectation of a current party leader’s performance by comparing it against their memory of that leader’s immediate predecessor. Empirically, we show that party leaders who succeeded a (very) long-serving party leader and/or a leader who had also been the head of government experience lower longevity than others, making these types of predecessor ‘hard acts to follow’.

Within a short timeframe, social media have become to be widely used in government organizations. Social media gurus assume that the transformational capacities of social media result in similar communication strategies in different organizations. According to them, government is transforming into a user-generated state. This paper investigates this claim empirically by testing the claim of convergence in social media practices in three North-American police departments (Boston, Washington DC and Toronto). The research shows that the social media strategies are widely different: the Boston Police Department has developed a ‘push strategy’ while the Metropolitan Police Department in DC has developed a ‘push and pull strategy and the Toronto Police Service a ‘networking strategy’. The paper concludes that a combination of contextual and path-dependency factors accounts for differences in the emerging social media strategies of government organizations. Social media have a logic of their own but this logic only manifests itself if it lands on fertile soil in a government bureaucracy.

Guillain-Barr, syndrome (GBS) is a post-infectious disease in which the human peripheral nervous system is affected after infection by specific pathogenic bacteria, including Campylobacter jejuni. GBS is suggested to be provoked by molecular mimicry between sialylated lipooligosaccharide (LOS) structures on the cell envelope of these bacteria and ganglioside epitopes on the human peripheral nerves, resulting in autoimmune-driven nerve destruction. Earlier, the C. jejuni sialyltransferase (Cst-II) was found to be linked to GBS and demonstrated to be involved in the biosynthesis of the ganglioside-like LOS structures. Apart from a role in pathogenicity, we report here that Cst-II-generated ganglioside-like LOS structures confer efficient bacteriophage resistance in C. jejuni. By bioinformatic analysis, it is revealed that the presence of sialyltransferases in C. jejuni and other potential GBS-related pathogens correlated significantly with the apparent degeneration of an alternative anti-virus system: type II Clusters of Regularly Interspaced Short Palindromic Repeat and associated genes (CRISPR-Cas). Molecular analysis of the C. jejuni CRISPR-Cas system confirmed the bioinformatic investigation. CRISPR degeneration and mutations in the cas genes cas2, cas1 and csn1 were found to correlate with Cst-II sialyltransferase presence (p < 0.0001). Remarkably, type II CRISPR-Cas systems are mainly found in mammalian pathogens. To study the potential involvement of this system in pathogenicity, we inactivated the type II CRISPR-Cas marker gene csn1, which effectively reduced virulence in primarily cst-II-positive C. jejuni isolates. Our findings indicate a novel link between viral defence, virulence and GBS in a pathogenic bacterium.

Growth factor receptors are present in the plasma membrane of resting cells as monomers or (pre)dimers. Ligand binding results in higher-order oligomerization of ligand-receptor complexes. To study the regulation of receptor clustering, several experimental techniques have been developed in the last decades. However, many involve invasive approaches that are likely to disturb the integrity of the membrane, thereby affecting receptor interactions. In this chapter, we describe the use of a noninvasive approach to study receptor dimerization and oligomerization. This method is based upon the Förster energy transfer between identical adjacent fluorescent proteins (homo-FRET) and is determined by analyzing the change in fluorescence anisotropy. Homo-FRET takes place within a distance of 10nm, making this an excellent approach for studying receptor-receptor interactions in intact cells. After excitation of monomeric GFP (mGFP) with polarized light, limiting anisotropy values (r(inf)) of the emitted light are determined, where proteins with known cluster sizes are used as references. Dimerization and oligomerization of the epidermal growth factor receptor (EGFR) in response to ligand binding is determined by using receptors that have been fused with mGFP at their C-terminus. In this chapter, we describe the involved technology and discuss the feasibility of homo-FRET experiments for the determination of cluster sizes of growth factor receptors like EGFR.

International audience; The PyGaze toolbox is an open-source software package for Python, a high-level programming language. It is designed for creating eyetracking experiments in Python syntax with the least possible effort, and it offers programming ease and script readability without constraining functionality and flexibility. PyGaze can be used for visual and auditory stimulus presentation; for response collection via keyboard, mouse, joystick, and other external hardware; and for the online detection of eye movements using a custom algorithm. A wide range of eyetrackers of different brands (EyeLink, SMI, and Tobii systems) are supported. The novelty of PyGaze lies in providing an easy-to-use layer on top of the many different software libraries that are required for implementing eyetracking experiments. Essentially, PyGaze is a software bridge for eyetracking research.

Purpose To quantify the effects of barrier precautions and antibiotic mixing on prevalence and acquisition of five drug-resistant microorganisms within a single tetanus intensive care unit at a tertiary referral hospital in Ho Chi Minh City, Vietnam. Methods All patients admitted within the study period were included. After a 1-year baseline period, barrier precautions were implemented and the single empirical treatment ceftazidime was changed to mixing (per consecutive patient) of three different regimens (ceftazidime, ciprofloxacin, piperacillin–tazobactam). Markov chain modeling and genotyping were used to determine the effects of interventions on prevalence levels and the relative importance of cross-transmission and antibiotic-associated selection. Results A total of 190 patients were included in year 1 (2,708 patient days, 17,260 cultures) and 167 patients in year 2 (3,384 patient days, 20,580 cultures). In year 1, average daily prevalence rates for methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (excluding Klebsiella pneumoniae), Pseudomonas aeruginosa, gentamicin-resistant K. pneumoniae, and amikacin-resistant Acinetobacter species were 34.0, 61.3, 53.4, 65.7 and 57.1 %. After intervention, ceftazidime usage decreased by 53 %; the use of piperacillin–tazobactam and ciprofloxacin increased 7.2-fold and 4.5-fold, respectively. Adherence to hand hygiene after patient contact was 54 %. These measures were associated with a reduction of MRSA prevalence by 69.8 % (to 10.3 %), mainly because of less cross-transmission (88 % reduction), and of ESBL-producing Enterobacteriaceae prevalence by 10.3 % (non-significantly). In contrast, prevalence levels of the other three pathogens remained unaffected. Conclusion The combination of simple infection control measures and antibiotic mixing was highly effective in reducing the prevalence of MRSA, but not of Gram-negative microorganisms. Electronic supplementary material The online version of this article (doi:10.1007/s00134-012-2771-1) contains supplementary material.

Multilevel analysis is an appropriate tool for the analysis of hierarchically structured data. There may, however, be reasons to ignore one of the levels of nesting in the data analysis. In this article a three level model with one predictor variable is used as a reference model and the top or intermediate level is ignored in the data analysis. Analytical results show that this has an effect on the estimated variance components and that standard errors of regression coefficients estimators may be overestimated, leading to a lower power of the test of the effect of the predictor variable. The magnitude of these results depends on the ignored level and the level at which the predictor variable varies, and on the values of the variance components and the sample sizes.

Most natural Arabidopsis thaliana accessions are susceptible to one or more isolates of the downy mildew pathogen Hyaloperonospora arabidopsidis (Hpa). However, Arabidopsis C24 has proved resistant to all Hpa isolates tested so far. Here we describe the complex genetic basis of broad-spectrum resistance in C24. The genetics of C24 resistance to three Hpa isolates was analyzed by segregation analysis and quantitative trait locus (QTL) mapping on recombinant inbred and introgression lines. Resistance of C24 to downy mildew was found to be a multigenic trait with complex inheritance. Many identified resistance loci were isolate-specific and located on different chromosomes. Among the C24 resistance QTLs, we found dominant, codominant and recessive loci. Interestingly, none of the identified loci significantly contributed to resistance against all three tested Hpa isolates. Our study demonstrates that broad-spectrum resistance of Arabidopsis C24 to Hpa is based on different combinations of multiple isolate-specific loci. The identified quantitative resistance loci are particularly promising as they provide an important basis for the cloning of susceptibility- and immunity-related genes. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

Physics simulation offers the possibility of truly responsive and realistic animation. Despite wide adoption of physics simulation for the animation of passive phenomena, such as fluids, cloths and rag-doll characters, commercial applications still resort to kinematics-based approaches for the animation of actively controlled characters. However, following a renewed interest in the use of physics simulation for interactive character animation, many recent publications demonstrate tremendous improvements in robustness, visual quality and usability. We present a structured review of over two decades of research on physics-based character animation, as well as point out various open research areas and possible future directions. © 2012 Wiley Periodicals, Inc.

In this work, the prospects of available and new battery technologies for battery electric vehicles (BEVs) are examined. Five selected battery technologies are assessed on battery performance and cost in the short, medium and long term. Driving cycle simulations are carried out to assess the influence of the batteries on the energetic, environmental and economic performance of BEVs in the medium term. Well-to-wheel energy consumption and emissions of BEVs are lowest for lithium-ion batteries; 314-374 Wh km -1 and 76-90 gCO 2eq km -1 (assuming 593 gCO 2 kWh -1 for European electricity mix), compared to 450-760 Wh km -1 and 150-170 gCO 2eq km -1 for petrol and diesel cars. The total driving costs are lowest for ZEBRA batteries (0.43-0.62 $ km -1). But, only if ZEBRA batteries attain a very low cost of 100 $ kWh -1 and driving ranges are below 200 km, BEVs become cost competitive to diesel cars. For all batteries, it remains a challenge to simultaneously meet requirements on specific energy, specific power, efficiency, cycle life, lifetime, safety and costs in the medium or even long term. Only lithium-ion batteries could possibly attain all conditions in the medium term. Batteries that do not contain lithium have best perspectives to attain low costs. © 2012 Elsevier B.V. All rights reserved.

Cells release RNA-carrying vesicles and membrane-free RNA/protein complexes into the extracellular milieu. Horizontal vesicle-mediated transfer of such shuttle RNA between cells allows dissemination of genetically encoded messages, which may modify the function of target cells. Other studies used array analysis to establish the presence of microRNAs and mRNA in cell-derived vesicles from many sources. Here, we used an unbiased approach by deep sequencing of small RNA released by immune cells. We found a large variety of small non-coding RNA species representing pervasive transcripts or RNA cleavage products overlapping with protein coding regions, repeat sequences or structural RNAs. Many of these RNAs were enriched relative to cellular RNA, indicating that cells destine specific RNAs for extracellular release. Among the most abundant small RNAs in shuttle RNA were sequences derived from vault RNA, Y-RNA and specific tRNAs. Many of the highly abundant small non-coding transcripts in shuttle RNA are evolutionary well-conserved and have previously been associated to gene regulatory functions. These findings allude to a wider range of biological effects that could be mediated by shuttle RNA than previously expected. Moreover, the data present leads for unraveling how cells modify the function of other cells via transfer of specific non-coding RNA species.

Background Gene variants on chromosome 17q12-21 are associated with an increased risk of childhood-onset asthma, a risk known to be modified by environmental tobacco smoke (ETS). Objectives To assess whether the association of rs2305480 on chromosome 17q12 in the GSDML gene with asthma-like symptoms in the first 4 years of life is modified by smoke exposure during fetal and early postnatal life. Methods We used data from two independent prospective cohort studies from fetal life onwards in the Netherlands. We genotyped rs2305480 and assessed maternal smoking during pregnancy and ETS exposure at the age of 2. Asthma-like symptoms, defined as any reported wheezing, shortness of breath or dry nocturnal cough, were reported by parents when the children were 1, 2, 3, and 4 years. Analyses were based on a total group of 4461 Caucasian children. Results The G risk-allele of rs2305480 was associated with asthma-like symptoms [overall odds ratio 1.17 (1.11, 1.24), 2.66E-9]. The effect of rs2305480 on asthma-like symptoms was stronger among children who were exposed to smoke during fetal life (P-interaction = 0.04). Smoke exposure in early postnatal life was also associated with an increased effect of the 17q12 single nucleotide polymorphism (SNP) on asthma-like symptoms (P-interaction = 5.06E-4). These associations were consistent in both cohorts. Conclusion A 17q12 variant, rs2305480, was associated with asthma-like symptoms in preschool children, and this association was modified by smoke exposure already during fetal life, and in infancy. Further investigation regarding SNPs in linkage disequilibrium with rs2305480 in relation to pathophysiological pathways is needed.

This article explores the possibilities for using TV archive documents for constructing transnational European heritage environments online. It looks closely at one episode of the Dutch popular music programme Combo from the mid-1960s, where artists from inside and outside the Netherlands perform in front of dancing teenagers. It points in particular to the acts of translation that take place within the programme, and argues that such acts must also be key in constructing television heritage online.

The aim of this study was to examine the dynamics of parasite specific antibody development in Trichinella spiralis and Toxoplasma gondii co-infections in pigs and to compare these with antibody dynamics in T. spiralis and T. gondii single infections. In this experiment, fifty-four pigs were divided into five inoculated groups of ten animals, and one control group of four animals. Two groups were inoculated with a single dose of either T. gondii tissue cysts or T. spiralis muscle larvae, one group was inoculated simultaneously with both parasites and two groups were successively inoculated at an interval of four weeks. Specific IgG responses to the parasites were measured by ELISA. T. gondii burden was determined by MC-PCR carried out on heart muscle and T. spiralis burden by artificial digestion of diaphragm samples. Specific IgG responses to T. gondii and T. spiralis in single and simultaneously inoculated animals showed a respective T. gondii and T. spiralis inoculation effect but no significant interaction of these parasites to the development of specific antibodies with the serum dilutions used. Moreover, our data showed that the specific IgG response levels in groups of animals successively or simultaneously co-infected were independent of a respective previous or simultaneous infection with the other parasite. Additionally, no differences in parasite burden were found within groups inoculated with T. gondii and within groups inoculated with T. spiralis. Conclusively, for the infection doses tested in this experiment, the dynamics of specific antibody development does not differ between single and simultaneous or successive infection with T. gondii and T. spiralis. However, lower parasitic doses and other ratios of doses, like low-low, low-high and high-low of T. gondii and T. spiralis in co-infection, in combination with other time intervals between successive infections may have different outcomes and should therefore be studied in further detail.

Youth policy is more than a mere response to the actual behavior of children, but it is equally influenced by values and beliefs of policy makers. These values are however rarely made explicit and, therefore, the authors refer to them as “the hidden curriculum” of youth policy. The study investigation explicates this hidden curriculum by empirically analyzing policy reports and interviews with policy makers. The study design is based on an existing theory on the content and structure of values. The results show that Dutch youth policy is most dominantly guided by security values. The results also show that there are differences between the social groups the policy measures target. Policy measures regarding “normal” families are becoming increasingly empowering, for example, by putting an emphasis on the competencies of parents. For families at risk, however, the focus is on control over these families by both professionals and citizens.

Student portfolios are increasingly used for assessing student competences in higher education, but results about the construct validity of portfolio assessment are mixed. A prerequisite for construct validity is that the portfolio assessment is based on relevant portfolio content. Assessment criteria, are often used to enhance this condition. This study aims to identify whether assessment criteria can improve content, argumentation and communication during teacher moderation while judging student portfolios. Six teachers scored 32 student portfolios in dyads with and without assessment criteria. Their judgement processes were qualitatively analysed. Results indicated that the quality of their judgement processes was low, since teachers based their judgements mainly on their own personal opinion and less on evidence found in the portfolio. Teachers barely paid attention to quality checks and easily agreed with each other. When teachers used assessment criteria, the quality of their judgements slightly improved. They based their judgements more on relevant evidence, used less personal experiences and more often checked the quality of their judgement processes. It is concluded that the quality of teacher portfolio judgement is low, and that the use of assessment criteria can enhance its quality

Motility assessment before birth can be used to evaluate the integrity of the nervous system. Sideways bending (SB) of head and/or rump, the earliest embryonic motility in both humans and guinea pigs, can be visualized sonographically. We know from other species that early embryonic motility is cyclic. This study explores the distribution of SB-to-SB intervals in human and guinea pig embryos before the appearance of more complex movements such as general movements. We hypothesized that the activity in both species is cyclic. We made 15-min sonographic recordings of SBs between 5 weeks and 0 days (5wk0d) and 7wk0d conceptional age (CA) in 18 human embryos of uncomplicated IVF pregnancies (term 38 weeks) and in 20 guinea pig embryos between 3wk4d and 4wk0d CA (term 9 weeks). SB-to-SB interval durations were categorized as long (≥10 s) or short (

Letter to the editor

Students in competence-based vocational education are expected to actively construct a personal professional theory, in which they integrate different types of knowledge and beliefs. Students’ personal professional theories are seen as an important learning outcome of competence-based vocational education. However, it is unknown how personal professional theories can be measured. This study focused on measuring the content and nature of students’ personal professional theories using a multi-method triangulation approach, in which 16 students in the domain of Social Work constructed a concept map, an interview and a self-report. The results show that the relatively structured methods (i.e., interviews and concept maps) reveal more insight into students’ personal professional theories than less structured methods (i.e., self-reports). It is concluded that both structure as well as adequate prompts are important in the process of explicating personal professional theories.

Respondents are more likely to disagree with negative survey questions (This text is boring. Yes/No) than to agree with positive ones (This text is interesting. Yes/No). The size of this effect, however, varies largely between word pairs. A semantic classification of adjectives in closed scale/absolute and open scale/relative types was predicted to explain this variation. To classify survey adjectives, a judgment experiment was conducted. Language users (N = 173) rated sentences in which an adjective was modified by the maximizer completely or the approximator almost: it should be possible to combine closed scale/absolute adjectives with these modifiers, in contrast to open scale/relative adjectives for which this is not the case. Results show that language users agree on which adjective and degree modifier combinations are acceptable and which combinations are unacceptable. Moreover, the two methods, almost and fully, show convergent validity. However, the rating of the same combination of a specific adjective and a specific degree modifier varies across contexts. This suggests that neither of the two methods allows for an unambiguous classification of adjectives. Hence, the distinction between closed scale/absolute and open scale/relative adjectives cannot explain variation in survey response effects. For semantics and pragmatics results indicate that context plays a crucial role in the linguistic behavior of adjectives and degree modifiers.

Technology, particularly digitization and the online availability of cultural heritage collections, provides new possibilities for creating new forms of ’European cultural heritage’. This essay analyzes the emerging sphere of European digital heritage as a project of technological harmonization. Drawing on Andrew Barry’s concepts of technological zones, it examines the various ways in which agency and European citizenship are being reconfigured around cultural heritage. It explores the “Europeanization” of digital heritage in three areas. In the first section, it analyzes the recent agenda for digital heritage of the European Union as a harmonizing project to create a smooth space of cultural heritage. In the next sections, the development of a harmonized virtual exhibit on the history of technology in Europe forms a case study to explore processes of harmonization at the level of the web platform, and in the aesthetics of digitized objects. It argues that rather than seeking to elide the points of unevenness and ’dissonance’ that emerge in harmonization processes, we should instead look for ways to embrace them as points of dialogue and discovery.

This paper presents an efficient technique for synthesizing motions by stitching, or splicing, an upper-body motion retrieved from a motion space on top of an existing lower-body locomotion of another motion. Compared to the standard motion splicing problem, motion space splicing imposes new challenges as both the upper and lower body motions might not be known in advance. Our technique is the first motion (space) splicing technique that propagates temporal and spatial properties of the lower-body locomotion to the newly generated upper-body motion and vice versa. Whereas existing techniques only adapt the upper-body motion to fit the lower-body motion, our technique also adapts the lower-body locomotion based on the upper body task for a more coherent full-body motion. In this paper, we will show that our decoupled approach is able to generate high-fidelity full-body motion for interactive applications such as games.

Conformity refers to the act of changing one's behaviour to match that of others. Recent studies in humans have shown that individual differences exist in conformity and that these differences are related to differences in neuronal activity. To understand the neuronal mechanisms in more detail, animal tests to assess conformity are needed. Here, we used a test of conformity in rats that has previously been evaluated in female, but not male, rats and assessed the nature of individual differences in conformity. Male Wistar rats were given the opportunity to learn that two diets differed in palatability. They were subsequently exposed to a demonstrator that had consumed the less palatable food. Thereafter, they were exposed to the same diets again. Just like female rats, male rats decreased their preference for the more palatable food after interaction with demonstrator rats that had eaten the less palatable food. Individual differences existed for this shift, which were only weakly related to an interaction between their own initial preference and the amount consumed by the demonstrator rat. The data show that this conformity test in rats is a promising tool to study the neurobiology of conformity. published

Rationale: Drugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role in sensitization is unclear. Stimulation of dopamine receptors plays an important role in drug reward, but not in the sensitizing properties of cocaine and morphine.Objective: This study aims to evaluate the role of mGlu5 and dopamine receptors in the development of cocaine- and morphine-induced conditioned place preference (CPP) and psychomotor sensitization.Materials and methods: Rats were treated with the mGlu5 receptor antagonist MTEP (0, 1, 3, and 10 mg/kg, i.p.) or the dopamine receptor antagonist α-flupenthixol (0, 0.125, 0.25, and 0.5 mg/kg, i.p.) during place conditioning with either morphine (3 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). Furthermore, MTEP (1 mg/kg, i.p.) or α-flupenthixol (0.5 mg/kg, i.p.) was co-administered during cocaine (30 mg/kg, i.p.) or morphine (3.0 mg/kg, s.c.) pretreatment and psychomotor sensitization was tested 3 weeks post-treatment.Results: MTEP attenuated the development of morphine- but not cocaine-induced CPP. In contrast, MTEP suppressed the development of cocaine- but not morphine-induced psychomotor sensitization. α-Flupenthixol blocked the development of both cocaine- and morphine-induced CPP but did not affect the development of sensitization to either drug.Conclusion: Dopamine receptor stimulation mediates cocaine and morphine reward but not sensitization. In contrast, the role of mGlu5 receptors in reward and sensitization is drug-specific.

It is often assumed that relative adjectives (e.g. ‘long’, ‘old’) evoke unbounded scales and are, therefore, incompatible with maximizers (e.g. ‘completely’) and approximators (e.g. ‘almost’). In contrast, absolute adjectives which are felicitous with maximizers (e.g. ‘completely full’) and approximators (e.g. ‘almost full’) are argued to trigger bounded scales. This paper investigates whether the semantic typology of gradable adjectives developed for Germanic languages can be extended to non-Germanic languages by comparing the distribution of relative adjectives with totality modifiers in English and Russian corpora. In line with previous research, the corpus analysis shows that English relative adjectives are associated with fully unbounded scales and are very infrequent in combination with maximizers and approximators. In contrast, Russian relative adjectives evoke half-bounded scales. Therefore, relative adjectives denoting less of a property (e.g. korotkij “short”, dešëvyj “cheap”) are quite frequently modified by maximizing adverbs in Russian. However, unlike maximum-standard absolute adjectives, Russian relative adjectives are incompatible with approximators. It is concluded that there is no universal one-to-one relationship between adjective types and scale types.

Maximizers - adverbs denoting a maximum degree of a property (e.g. completely) - are often re-conceptualized as boosters denoting a high degree (cf. very). As a result, these degree adverbs come to modify unbounded adjectives which are not compatible with the idea of a maximum value. Although this kind of meaning change proved cross-linguistically robust, the exact mechanisms of this process have never been investigated. The present paper aims to shed more light onto semantic and contextual factors facilitating combinations of open-scale (unbounded) adjectives with closed-scale (bounded) adverbs by analyzing the distribution of the Dutch maximizer helemaal in the Corpus of Spoken Dutch. Following the boundedness hypothesis, we hypothesized that configurational harmony destroyed by combinations of the maximizer helemaal with unbounded adjectives can be restored by either imposing scale boundaries onto, by default, unbounded adjectival scales, or by re-conceptualizing the degree adverb as an unbounded modifier. Both predictions were confirmed by the data in this study. The findings suggest that there is no one-to-one relationship between semantic classes of adjectives and scalar structures associated with them. Rather, scalar meanings are a matter of dynamic construal constrained by semantic properties of adjectives and degree modifiers, as well as by context and world knowledge. © 2010 Elsevier B.V.

Most researchers have specific expectations concerning their research questions. These may be derived from theory, empirical evidence, or both. Yet despite these expectations, most investigators still use null hypothesis testing to evaluate their data, that is, when analysing their data they ignore the expectations they have. In the present article, Bayesian model selection is presented as a means to evaluate the expectations researchers have, that is, to evaluate so called informative hypotheses. Although the methodology to do this has been described in previous articles, these are rather technical and have mainly been published in statistical journals. The main objective of the present article is to provide a basic introduction to the evaluation of informative hypotheses using Bayesian model selection. Moreover, what is new in comparison to previous publications on this topic is that we provide guidelines on how to interpret the results. Bayesian evaluation of informative hypotheses is illustrated using an example concerning psychosocial functioning and the interplay between personality and support from family.

Between 1999 and 2002 religion-related riots took place on the Maluku islands in Indonesia. After the first clash, in January 1999, the conflict disseminated rapidly along religious lines. Religious language was used in order to understand what was going on, inscribing the conflict into specific religious traditions. However, using religious language to understand the conflict also framed the conflict into an essentialist religious battle with an important religious meaning. In this article I will explore the possibility to understand the religious framing of this conflict as a religious variety of what Vamik Volkan has coined ‘chosen trauma’. Applying this term to the situation in Ambon, elucidates the impact of religious language on violent conflicts.

This study examines whether the increase of geographical heterogamy in the nineteenth and early twentieth century is related to modernization. Specifically, we test whether mass communication and mass transport enhanced the likelihood of a geographically heterogamous marriage as well as the distance over which heterogamous marriages took place. Furthermore, we study whether modernization decreased the relationship between social background and geographical heterogamy. We employ individual and municipality level data of some 30,000 marriages in over 40 municipalities in the Dutch province Overijssel between 1823 and 1922. The results from our multi-level analyses suggest that mass communication was more important than mass transport. 1. Introduction Studies of geographical heterogamy in Europe and the United States in the nineteenth and twentieth century show a strong tendency for people to marry someone living nearby (e.g. Bossard 1932; Rogoff Ramsoy 1966; Van Poppel & Ekamper 2005). For example, of all marriages in the first five months of 1931 in the city of Philadelphia, 30% of the couples lived one block or less apart just before marriage, and only 18 % of the couples had one partner coming from outside the city (Bossard 1932). Most studies show that during the nineteenth and twentieth centuries the size of the marriage market increased (Gueresi, Pettener, and Maruzzi Veronesi 2001; Kok and Mandemakers 2008; Van Poppel and Ekamper 2005; but see Kok 1998 and Van de Putte 2003 for exceptions). Geographical heterogamy increased and shows the same development as heterogamy with respect to other ascribed characteristics, such as class of origin and religion (the latter after 1938) (Hendrickx, Lammers and Ultee 1991; Uunk 1996; Zijdeman and Maas forthcoming). But note that age heterogamy decreased during this period (e.g. Van Poppel et al. 2001). Contrary to studies on heterogamy with respect to age, class of origin, and religion, studies on geographical heterogamy are relatively scarce. However studying geographical heterogamy is highly relevant because it is connected to social cohesion in society. If culture or economic prosperity strongly differs between local entities, this is a potential source of conflict. The likelihood of conflict is less if there is exchange of people between localities, either by migration or by marriage. At the same time, as a consequence of the exchange of people, cultural and economic differences diminish. In the nineteenth century differences between regions in the Netherlands were still strong. Protestants lived in the north and Catholics in the south of the country. Between small regions there were differences in manner of speech as well as manner of dress. Municipalities even differed in their measurement of time, although the use of a universal time was requested by the Dutch government (Knippenberg and De Pater 1988: 77-82). Couples from different geographical backgrounds had to deal with these differences and solve the potential local conflicts. Today the cultural and economic differences between local entities in the Netherlands are small, although still existent. By uncovering the causes of increased geographical heterogamy we may come to understand how local differences were overcome. In an attempt to provide an explanation for the increase in heterogamy, with respect to ascribed characteristics in general and geographical heterogamy specifically, researchers refer to the modernization processes, such as the development of new means of mass transport and the appearance of mass communication (Kok and Mandemakers 2008; Van Poppel and Ekamper 2005; Uunk 1996; Zijdeman and Maas forthcoming). These two aspects of modernization affect heterogamy through different mechanisms. Means of mass transport allow people to travel over larger distances and increase the likelihood of finding a partner outside the local region. Mass communication is thought to spread information, such as news on events, technological developments, and fashion, beyond local regions. …

Like human children, most young mammals devote a significant amount of time and energy playing together, and social play is fun. Although social play is very pleasurable, it is more than just a frivolous activity: it is crucial for the development of behavioral flexibility, the acquisition of social and cognitive competence and the maintenance of group cohesion. Social play is a natural reinforcer, and the neurotransmitter systems intimately implicated in the motivational, pleasurable and cognitive aspects of natural and drug rewards, such as opioids, endocannabinoids, dopamine and noradrenaline, play an important modulatory role in the performance of social play as well. In this review, we will address the notion that social play is rewarding, and discuss recent developments in the neuropharmacology of this behavior. This provides a framework to understand how the brain processes social emotions, to make young individuals enjoy social play.

The academic literature on celebrity politics is rarely systematic; more often it is superficial and anecdotal. In addition, most of the literature focuses either upon classifying different types/categories of celebrity politicians and their roles in politics, or upon the question of whether the growth of celebrity politics undermines or enhances democracy. In this article we consider both of these issues more systematically and, in doing so, work towards a more coherent understanding of the mechanisms that influence modern governance and the operation of contemporary democracy.

Contains fulltext : 89979.pdf (Publisher’s version ) (Closed access) This study examines the religious participation of Islamic immigrants in Belgium using data from the Migration History and Social Mobility Survey collected in 1994-1996 from 2,200 men who had immigrated from Turkey and Morocco. Religious participation is measured as mosque attendance, fasting during Ramadan, and sacrificing a sheep at the Festival of Sacrifice. Results show that the religious participation of Islamic immigrants depends on both premigration and postmigration characteristics. Religious participation is higher among immigrants who: (1) attended a Koranic school in their country of origin, (2) were socialized in a religious region of their home country, (3) received little schooling, (4) currently live in an area of Belgium with a greater number of mosques, and (5) associate with a high number of co-ethnics. These results suggest that the religious participation of Islamic immigrants in Belgium is an outcome of characteristics unique to immigrants as well as processes common among the general population.

Glaciers respond to mass balance changes by adjusting their surface elevation and area. These properties in their turn affect the local and area-averaged mass balance. To incorporate this interdependence in the response of glaciers to climate change, models should include an interactive scheme coupling mass balance and ice dynamics. In this study, a spatially distributed mass balance model, comprising surface energy balance calculations, was coupled to a vertically integrated ice-flow model based on the shallow ice approximation. The coupled model was applied to the ice cap Hardangerjøkulen in southern Norway. The available glacio-meteorological records, mass balance and glacier length change measurements were utilized for model calibration and validation. Forced with meteorological data from nearby synoptic weather stations, the coupled model realistically simulated the observed mass balance and glacier length changes during the 20th century. The mean climate for the period 1961–1990, computed from local meteorological data, was used as a basis to prescribe climate projections for the 21st century at Hardangerjøkulen. For a linear temperature increase of 3 °C from 1961–1990 to 2071–2100, the modelled net mass balance soon becomes negative at all altitudes and Hardangerjøkulen disappears around the year 2100. The projected changes in the other meteorological variables could at most partly compensate for the effect of the projected warming.

During the last twenty years, a remarkable new type of service has been developed in the world of sports, which can be described as the indoorisation of outdoor sports. Typical outdoor sports like climbing, skiing, surfing, rowing, and skydiving, which used to be exclusively practiced in a natural environment of mountains, oceans, rivers and the air, are now being offered for consumption in safe, predictable and controlled indoor centers. The present article emphasizes the rise of indoor lifestyle sports, such as rafting, snowboarding, skydiving and surfing. It discusses the conditions under and ways in which commercial entrepreneurs in the Netherlands have created this market, the meanings that they have ascribed to their centers and the dilemmas with which they have been confronted. It is argued that the rise of this economic market cannot be understood if it is solely interpreted as the result of economic, technological or natural developments. These economic activities were also embedded in and influenced by shared understandings and their representations in structured fields of outdoor sports, mainstream sports and leisure experience activities. A better understanding of the indoorisation of outdoor lifestyle sports can be achieved by recognizing how these structures and cultures pervaded the rise of this new market.