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Showing papers by "Utrecht University published in 2003"


Journal ArticleDOI
TL;DR: The results of a single-crystal structure determination when in CIF format can now be validated routinely by automatic procedures, and the concepts of validation and the classes of checks carried out by the program PLATON as part of the IUCr checkCIF facility are described.
Abstract: The results of a single-crystal structure determination when in CIF format can now be validated routinely by automatic procedures. In this way, many errors in published papers can be avoided. The validation software generates a set of ALERTS detailing issues to be addressed by the experimenter, author, referee and publication journal. Validation was pioneered by the IUCr journal Acta Crystallographica Section C and is currently standard procedure for structures submitted for publication in all IUCr journals. The implementation of validation procedures by other journals is in progress. This paper describes the concepts of validation and the classes of checks that are carried out by the program PLATON as part of the IUCr checkCIF facility. PLATON validation can be run at any stage of the structure refinement, independent of the structure determination package used, and is recommended for use as a routine tool during or at least at the completion of every structure determination. Two examples are discussed where proper validation procedures could have avoided the publication of incorrect structures that had serious consequences for the chemistry involved.

12,231 citations


Journal ArticleDOI
17 Oct 2003-Science
TL;DR: Retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
Abstract: We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

3,514 citations


Journal ArticleDOI
TL;DR: This paper provides an international methodological protocol aimed at standardising this research effort, based on consensus among a broad group of scientists in this field, and features a practical handbook with step-by-step recipes, for 28 functional traits recognised as critical for tackling large-scale ecological questions.
Abstract: There is growing recognition that classifying terrestrial plant species on the basis of their function (into 'functional types') rather than their higher taxonomic identity, is a promising way forward for tackling important ecological questions at the scale of ecosystems, landscapes or biomes. These questions include those on vegetation responses to and vegetation effects on, environmental changes (e.g. changes in climate, atmospheric chemistry, land use or other disturbances). There is also growing consensus about a shortlist of plant traits that should underlie such functional plant classifications, because they have strong predictive power of important ecosystem responses to environmental change and/or they themselves have strong impacts on ecosystem processes. The most favoured traits are those that are also relatively easy and inexpensive to measure for large numbers of plant species. Large international research efforts, promoted by the IGBP–GCTE Programme, are underway to screen predominant plant species in various ecosystems and biomes worldwide for such traits. This paper provides an international methodological protocol aimed at standardising this research effort, based on consensus among a broad group of scientists in this field. It features a practical handbook with step-by-step recipes, with relatively brief information about the ecological context, for 28 functional traits recognised as critical for tackling large-scale ecological questions.

3,288 citations


Journal ArticleDOI
TL;DR: An overview is presented of the medical image processing literature on mutual-information-based registration, an introduction for those new to the field, an overview for those working in the field and a reference for those searching for literature on a specific application.
Abstract: An overview is presented of the medical image processing literature on mutual-information-based registration. The aim of the survey is threefold: an introduction for those new to the field, an overview for those working in the field, and a reference for those searching for literature on a specific application. Methods are classified according to the different aspects of mutual-information-based registration. The main division is in aspects of the methodology and of the application. The part on methodology describes choices made on facets such as preprocessing of images, gray value interpolation, optimization, adaptations to the mutual information measure, and different types of geometrical transformations. The part on applications is a reference of the literature available on different modalities, on interpatient registration and on different anatomical objects. Comparison studies including mutual information are also considered. The paper starts with a description of entropy and mutual information and it closes with a discussion on past achievements and some future challenges.

3,121 citations


Journal ArticleDOI
TL;DR: The term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future and a quantitative method for cumulative risk assessment of vulnerable patients needs to be developed.
Abstract: Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

2,719 citations


Journal ArticleDOI
TL;DR: An approach called HADDOCK (High Ambiguity Driven protein-protein Docking) that makes use of biochemical and/or biophysical interaction data such as chemical shift perturbation data resulting from NMR titration experiments or mutagenesis data to drive the docking process.
Abstract: The structure determination of protein-protein complexes is a rather tedious and lengthy process, by both NMR and X-ray crystallography. Several methods based on docking to study protein complexes have also been well developed over the past few years. Most of these approaches are not driven by experimental data but are based on a combination of energetics and shape complementarity. Here, we present an approach called HADDOCK (High Ambiguity Driven protein-protein Docking) that makes use of biochemical and/or biophysical interaction data such as chemical shift perturbation data resulting from NMR titration experiments or mutagenesis data. This information is introduced as Ambiguous Interaction Restraints (AIRs) to drive the docking process. An AIR is defined as an ambiguous distance between all residues shown to be involved in the interaction. The accuracy of our approach is demonstrated with three molecular complexes. For two of these complexes, for which both the complex and the free protein structures have been solved, NMR titration data were available. Mutagenesis data were used in the last example. In all cases, the best structures generated by HADDOCK, that is, the structures with the lowest intermolecular energies, were the closest to the published structure of the respective complexes (within 2.0 A backbone RMSD).

2,616 citations


Journal ArticleDOI
TL;DR: The sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease has been reported.
Abstract: To the Editor: We recently reported (April 18 issue)1 the sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease. These results have since been confirmed in four additional patients with typical X-linked severe combined immunodeficiency. Of the first four successfully treated patients, three continue to do well up to 3.6 years after gene therapy, whereas a serious adverse event occurred in the fourth patient. At a routine checkup 30 months after gene therapy, lymphocytosis consisting of a monoclonal population . . .

1,869 citations


Journal ArticleDOI
TL;DR: The sparsity of the discretized systems for the computation of limit cycles and their bifurcation points is exploited by using the standard Matlab sparse matrix methods.
Abstract: MATCONT is a graphical MATLAB software package for the interactive numerical study of dynamical systems. It allows one to compute curves of equilibria, limit points, Hopf points, limit cycles, period doubling bifurcation points of limit cycles, and fold bifurcation points of limit cycles. All curves are computed by the same function that implements a prediction-correction continuation algorithm based on the Moore-Penrose matrix pseudo-inverse. The continuation of bifurcation points of equilibria and limit cycles is based on bordering methods and minimally extended systems. Hence no additional unknowns such as singular vectors and eigenvectors are used and no artificial sparsity in the systems is created. The sparsity of the discretized systems for the computation of limit cycles and their bifurcation points is exploited by using the standard Matlab sparse matrix methods. The MATLAB environment makes the standard MATLAB Ordinary Differential Equations (ODE) Suite interactively available and provides computational and visualization tools; it also eliminates the compilation stage and so makes installation straightforward. Compared to other packages such as AUTO and CONTENT, adding a new type of curves is easy in the MATLAB environment. We illustrate this by a detailed description of the limit point curve type.

1,320 citations


Journal ArticleDOI
TL;DR: The experience with selecting perennial grasses for bioenergy production in both the US and Europe is summarized, and an overview of the characteristics and requirements of the four most investigated perennial rhizomatous grasses; switchgrass, miscanthus, reed canarygrass and giant reed are given.
Abstract: Perennial grasses display many beneficial attributes as energy crops, and there has been increasing interest in their use in the US and Europe since the mid-1980s. In the US, the Herbaceous Energy Crops Research Program (HECP), funded by the US Department of Energy (DOE), was established in 1984. After evaluating 35 potential herbaceous crops of which 18 were perennial grasses it was concluded that switchgrass (Panicum virgatum) was the native perennial grass which showed the greatest potential. In 1991, the DOE's Bioenergy Feedstock Development Program (BFDP), which evolved from the HECP, decided to focus research on a “model” crop system and to concentrate research resources on switchgrass, in order to rapidly attain its maximal output as a biomass crop. In Europe, about 20 perennial grasses have been tested and four perennial rhizomatous grasses (PRG), namely miscanthus (Miscanthus spp.), reed canarygrass (Phalaris arundinacea), giant reed (Arundo donax) and switchgrass (Panicum virgatum) were chosen for more extensive research programs. Reed canarygrass and giant reed are grasses with the C3 photosynthetic pathway, and are native to Europe. Miscanthus, which originated in Southeast Asia, and switchgrass, native to North America, are both C4 grasses. These four grasses differ in their ecological/climatic demands, their yield potentials, biomass characteristics and crop management requirements. Efficient production of bioenergy from such perennial grasses requires the choice of the most appropriate grass species for the given ecological/climatic conditions. In temperate and warm regions, C4 grasses outyield C3 grasses due to their more efficient photosynthetic pathway. However, the further north perennial grasses are planted, the more likely cool season grasses are to yield more than warm season grasses. Low winter temperatures and short vegetation periods are major limits to the growth of C4 grasses in northern Europe. With increasing temperatures towards central and southern Europe, the productivity of C4 grasses and therefore their biomass yields and competitiveness increase. Since breeding of and research on perennial rhizomatous grasses (PRG) is comparatively recent, there is still a significant need for further development. Some of the given limitations, like insufficient biomass quality or the need for adaption to certain ecological/climatic zones, may be overcome by breeding varieties especially for biomass production. Furthermore, sure and cost-effective establishment methods for some of the grasses, and effective crop production and harvest methods, have yet to be developed. This review summarizes the experience with selecting perennial grasses for bioenergy production in both the US and Europe, and gives an overview of the characteristics and requirements of the four most investigated perennial rhizomatous grasses; switchgrass, miscanthus, reed canarygrass and giant reed.

1,318 citations


Journal ArticleDOI
TL;DR: Using biological assays, the HR2 peptide was shown to be a potent inhibitor of virus entry into the cell, as well as of cell-cell fusion.
Abstract: Coronavirus entry is mediated by the viral spike (S) glycoprotein. The 180-kDa oligomeric S protein of the murine coronavirus mouse hepatitis virus strain A59 is posttranslationally cleaved into an S1 receptor binding unit and an S2 membrane fusion unit. The latter is thought to contain an internal fusion peptide and has two 4,3 hydrophobic (heptad) repeat regions designated HR1 and HR2. HR2 is located close to the membrane anchor, and HR1 is some 170 amino acids (aa) upstream of it. Heptad repeat (HR) regions are found in fusion proteins of many different viruses and form an important characteristic of class I viral fusion proteins. We investigated the role of these regions in coronavirus membrane fusion. Peptides HR1 (96 aa) and HR2 (39 aa), corresponding to the HR1 and HR2 regions, were produced in Escherichia coli. When mixed together, the two peptides were found to assemble into an extremely stable oligomeric complex. Both on their own and within the complex, the peptides were highly alpha helical. Electron microscopic analysis of the complex revealed a rod-like structure approximately 14.5 nm in length. Limited proteolysis in combination with mass spectrometry indicated that HR1 and HR2 occur in the complex in an antiparallel fashion. In the native protein, such a conformation would bring the proposed fusion peptide, located in the N-terminal domain of HR1, and the transmembrane anchor into close proximity. Using biological assays, the HR2 peptide was shown to be a potent inhibitor of virus entry into the cell, as well as of cell-cell fusion. Both biochemical and functional data show that the coronavirus spike protein is a class I viral fusion protein.

1,283 citations


Journal ArticleDOI
01 Sep 2003-Stroke
TL;DR: Based on the Fugl-Meyer scores of the flaccid arm, optimal prediction of arm function outcome at 6 months can be made within 4 weeks after onset.
Abstract: Background and Purpose— To improve the accuracy of early postonset prediction of motor recovery in the flaccid hemiplegic arm, the effects of change in motor function over time on the accuracy of prediction were evaluated, and a prediction model for the probability of regaining dexterity at 6 months was developed. Methods— In 102 stroke patients, dexterity and paresis were measured with the Action Research Arm Test, Motricity Index, and Fugl-Meyer motor evaluation. For model development, 23 candidate determinants were selected. Logistic regression analysis was used for prognostic factors and model development. Results— At 6 months, some dexterity in the paretic arm was found in 38%, and complete functional recovery was seen in 11.6% of the patients. Total anterior circulation infarcts, right hemisphere strokes, homonymous hemianopia, visual gaze deficit, visual inattention, and paresis were statistically significant related to a poor arm function. Motricity Index leg scores of at least 25 points in the fi...

Journal ArticleDOI
TL;DR: Important areas that require further research include: potential protective effects of microbial exposures on atopy and atopic diseases, inter-individual susceptibility for biological exposures, interactions of bioaerosols with non-biological agents and other potential health effects such as skin and neurological conditions and birth effects.
Abstract: Exposures to bioaerosols in the occupational environment are associated with a wide range of health effects with major public health impact, including infectious diseases, acute toxic effects, allergies and cancer. Respiratory symptoms and lung function impairment are the most widely studied and probably among the most important bioaerosol-associated health effects. In addition to these adverse health effects some protective effects of microbial exposure on atopy and atopic conditions has also been suggested. New industrial activities have emerged in recent years in which exposures to bioaerosols can be abundant, e.g. the waste recycling and composting industry, biotechnology industries producing highly purified enzymes and the detergent and food industries that make use of these enzymes. Dose-response relationships have not been established for most biological agents and knowledge about threshold values is sparse. Exposure limits are available for some contaminants, e.g. wood dust, subtilisins (bacterial enzymes) and flour dust. Exposure limits for bacterial endotoxin have been proposed. Risk assessment is seriously hampered by the lack of valid quantitative exposure assessment methods. Traditional culture methods to quantify microbial exposures have proven to be of limited use. Non-culture methods and assessment methods for microbial constituents [e.g. allergens, endotoxin, beta(1-->3)-glucans, fungal extracellular polysaccharides] appear more successful; however, experience with these methods is generally limited. Therefore, more research is needed to establish better exposure assessment tools and validate newly developed methods. Other important areas that require further research include: potential protective effects of microbial exposures on atopy and atopic diseases, inter-individual susceptibility for biological exposures, interactions of bioaerosols with non-biological agents and other potential health effects such as skin and neurological conditions and birth effects.

Journal ArticleDOI
TL;DR: In this paper, a study among 214 nutrition production employees uses the Job Demands-Resources (JD-R) model to predict future company registered absenteeism, and the results of structural equation modeling analyses show that job demands are unique predictors of burnout (i.e., exhaustion and cynicism) and indirectly of absence duration.

Journal ArticleDOI
TL;DR: The contribution of biomass in the future global energy supply is discussed in this paper, based on a review of 17 earlier studies on the subject, and a refined modeling of interactions between different uses and bioenergy, food and materials production would facilitate an improved understanding of the prospects for large-scale bioenergy and of future land-use and biomass management.
Abstract: This paper discusses the contribution of biomass in the future global energy supply. The discussion is based on a review of 17 earlier studies on the subject. These studies have arrived at widely different conclusions about the possible contribution of biomass in the future global energy supply (e.g., from below 100 EJ yr-1 to above 400 EJ yr-1 in 2050). The major reason for the differences is that the two most crucial parameters - land availability and yield levels in energy crop production - are very uncertain, and subject to widely different opinions (e.g., the assessed 2050 plantation supply ranges from below 50 EJ yr-1 to almost 240 EJ yr-1). However, also the expectations about future availability of forest wood and of residues from agriculture and forestry vary substantially among the studies. The question how an expanding bioenergy sector would interact with other land uses, such as food production, biodiversity, soil and nature conservation, and carbon sequestration has been insufficiently analyzed in the studies. It is therefore difficult to establish to what extent bioenergy is an attractive option for climate change mitigation in the energy sector. A refined modeling of interactions between different uses and bioenergy, food and materials production - i.e., of competition for resources, and of synergies between different uses - would facilitate an improved understanding of the prospects for large-scale bioenergy and of future land-use and biomass management in general. © 2003 Elsevier Science Ltd. All rights reserved.

Journal ArticleDOI
TL;DR: In this paper, a reflection intensity integration method is presented based upon ab initio calculation of three-dimensional reflection boundaries from a few physical crystal and instrument parameters, which is especially useful in challenging circumstances, such as the case of a crystal that is far from spherical, anisotropic mosaicity, α1α2 peak splitting, interference from close neighbours, twin lattices or satellite reflections, all of which may frustrate the customary profile-learning and fitting procedures.
Abstract: A reflection intensity integration method is presented based upon ab initio calculation of three-dimensional (x, y, ω) reflection boundaries from a few physical crystal and instrument parameters. It is especially useful in challenging circumstances, such as the case of a crystal that is far from spherical, anisotropic mosaicity, α1α2 peak splitting, interference from close neighbours, twin lattices or satellite reflections, and the case of streaks from modulated structures, all of which may frustrate the customary profile-learning and -fitting procedures. The method, called EVAL-14, has been implemented and extensively tested on a Bruker Nonius KappaCCD diffractometer.

Journal ArticleDOI
TL;DR: Analysis of the Arabidopsis mutant npr1 revealed that the antagonistic effect of SA on JA signaling requires the regulatory protein NPR1, indicating that cross-talk between SA and JA is modulated through a novel function of NPR1 in the cytosol.
Abstract: Plant defenses against pathogens and insects are regulated differentially by cross-communicating signal transduction pathways in which salicylic acid (SA) and jasmonic acid (JA) play key roles. In this study, we investigated the molecular mechanism of the antagonistic effect of SA on JA signaling. Arabidopsis plants unable to accumulate SA produced 25-fold higher levels of JA and showed enhanced expression of the JA-responsive genes LOX2, PDF1.2, and VSP in response to infection by Pseudomonas syringae pv tomato DC3000, indicating that in wild-type plants, pathogen-induced SA accumulation is associated with the suppression of JA signaling. Analysis of the Arabidopsis mutant npr1, which is impaired in SA signal transduction, revealed that the antagonistic effect of SA on JA signaling requires the regulatory protein NPR1. Nuclear localization of NPR1, which is essential for SA-mediated defense gene expression, is not required for the suppression of JA signaling, indicating that cross-talk between SA and JA is modulated through a novel function of NPR1 in the cytosol.

Journal ArticleDOI
TL;DR: Empirical evidence is examined concerning the obstacles to memory for medical information and some suggestions for overcoming them as a prerequisite for good adherence to recommended treatment are offered.
Abstract: When important decisions are to be made, the patient must receive detailed information on the illness, treatment options and prognosis. The shortening of hospital stays and the trend towards outpatient care enhance the need of patients and their families for specific information.1 Practitioners are responding to these demands, yet the amount of information correctly recalled by patients is strikingly small.2 In this review I examine empirical evidence concerning the obstacles to memory for medical information and offer some suggestions for overcoming them. Clearly, memory for medical information is a prerequisite for good adherence to recommended treatment. Ley's3 model on effective communication in medical practice (see Figure 1) stresses the importance of memory next to factors such as the understanding of information and satisfaction with the treatment. 40-80% of medical information provided by healthcare practitioners is forgotten immediately. The greater the amount of information presented, the lower the proportion correctly recalled;4 furthermore, almost half of the information that is remembered is incorrect.5 For the forgetting of information there are three basic types of explanation—first, factors related to the clinician, such as use of difficult medical terminology; second, the mode of information (e.g. spoken versus written); and, third, factors related to the patient, such as low education or specific expectations.6 Here, I discuss only the second and third, since the communication skills of clinicians have been thoroughly reviewed elsewhere.7,8 Figure 1 Overview of Ley's model on the interactions between patient-related factors and therapy adherence (see Ref. 3)

Journal ArticleDOI
Claus Feldmann, Thomas Jüstel1, Cees Ronda2, Cees Ronda1, P.J. Schmidt1 
TL;DR: A review of inorganic luminescent materials can be found in this paper, where the authors reviewed a hundred years of research in the field of lighting and display systems. But until approximately 80 years ago, only black-body radiation (including natural sources) was available to illuminate our environment.
Abstract: Up until approximately 80 years ago, only black-body radiation (including natural sources) was available to illuminate our environment. To realise state-of-the-art lamps, TV sets, monitors, and medical scanners, took an enormous scientific and technical effort. Inorganic luminescent materials are key components, which were, are, and will be prerequisite to the functionality and success of many lighting and display systems. In this Highlight, a hundred years of inorganic luminescent material research are reviewed.

Journal ArticleDOI
11 Jul 2003-Langmuir
TL;DR: In this article, a general method to coat colloids with silica is described, which is especially useful for colloidal particles that cannot be covered directly with SiO2 by a Stober-like growth process.
Abstract: A general method to coat colloids with silica is described. The amphiphilic, nonionic polymer poly(vinylpyrrolidone) (PVP) was adsorbed to various colloidal particles such as small gold colloids, gold-shell silica-core particles, small and large silver colloids, boehmite rods, gibbsite platelets, and positively or negatively charged polystyrene. After this functionalization the stabilized particles could be transferred to a solution of ammonia in ethanol and directly coated with smooth and homogeneous silica shells of variable thickness by addition of tetraethoxysilane in a seeded growth process. The length of the polymer used strongly influences the stability of the colloids and the homogeneity and smoothness of the initial silica coating. This method is especially useful for colloidal particles that cannot be covered directly with SiO2 by a Stober-like growth process. Compared to methods known from the literature for the coating of such particles, this new method is faster and requires neither the use o...

Journal ArticleDOI
TL;DR: The results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin and can inhibit β-catenin-mediated signaling.
Abstract: Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.

Journal ArticleDOI
TL;DR: In this paper, the predictive validity of the job demands and resources model for self-reported absenteeism and turnover intentions was examined among 477 employees working in the call centre of a Dutch telecom company.
Abstract: This study among 477 employees working in the call centre of a Dutch telecom company (response 88%) examined the predictive validity of the job demands – resources (JD – R) model for self-reported absenteeism and turnover intentions. The central hypothesis was that job demands would be the most important predictors of absenteeism, through their relationship with health problems (i.e., exhaustion and Repetitive Strain Injury—RSI), whereas job resources would be the most important predictors of turnover intentions, through their relationship with involvement (i.e., organizational commitment and dedication). Results of a series of SEM analyses largely supported these dual processes. In the first energy-driven process, job demands (i.e., work pressure, computer problems, emotional demands, and changes in tasks) were the most important predictors of health problems, which, in turn, were related to sickness absence (duration and long-term absence). In the second motivation-driven process, job resources (i.e., s...

Journal ArticleDOI
TL;DR: Data suggest that recruitment of membrane proteins from the limiting membranes into the internal vesicles of multivesicular bodies may involve their incorporation into tetraspanin-containing detergent-resistant membrane domains.

Journal ArticleDOI
03 Jan 2003-Science
TL;DR: A correlation between geographic distance and cultural difference, a correlation between the abundance of opportunities for social learning and the size of the local cultural repertoire, and no effect of habitat on the content of culture mean that great-ape cultures exist and may have done so for at least 14 million years.
Abstract: Geographic variation in some aspects of chimpanzee behavior has been interpreted as evidence for culture Here we document similar geographic variation in orangutan behaviors Moreover, as expected under a cultural interpretation, we find a correlation between geographic distance and cultural difference, a correlation between the abundance of opportunities for social learning and the size of the local cultural repertoire, and no effect of habitat on the content of culture Hence, great-ape cultures exist, and may have done so for at least 14 million years

Journal ArticleDOI
30 Jan 2003-Nature
TL;DR: This work demonstrates a charge- and sterically stabilized colloidal suspension—poly(methyl methacrylate) spheres in a mixture of cycloheptyl (or cyclohexyl) bromide and decalin—where both the repulsive range and the anisotropy of the interparticle interaction potential can be controlled.
Abstract: Monodisperse colloidal suspensions of micrometre-sized spheres are playing an increasingly important role as model systems to study, in real space, a variety of phenomena in condensed matter physics—such as glass transitions and crystal nucleation1,2,3,4. But to date, no quantitative real-space studies have been performed on crystal melting, or have investigated systems with long-range repulsive potentials. Here we demonstrate a charge- and sterically stabilized colloidal suspension—poly(methyl methacrylate) spheres in a mixture of cycloheptyl (or cyclohexyl) bromide and decalin—where both the repulsive range and the anisotropy of the interparticle interaction potential can be controlled. This combination of two independent tuning parameters gives rise to a rich phase behaviour, with several unusual colloidal (liquid) crystalline phases, which we explore in real space by confocal microscopy. The softness of the interaction is tuned in this colloidal suspension by varying the solvent salt concentration; the anisotropic (dipolar) contribution to the interaction potential can be independently controlled with an external electric field ranging from a small perturbation to the point where it completely determines the phase behaviour. We also demonstrate that the electric field can be used as a pseudo-thermodynamic temperature switch to enable real-space studies of melting transitions. We expect studies of this colloidal model system to contribute to our understanding of, for example, electro- and magneto-rheological fluids.

Journal ArticleDOI
TL;DR: In this paper, an overview of the current knowledge available about vanadium oxide-based catalysts is given, including the molecular structure of supported vanadium oxides under hydrated, dehydrated and reduced conditions, including parameters which influence the molecular structures formed at the surface of the support oxide.

Journal ArticleDOI
TL;DR: To quantify the antibacterial properties of five essential oils on a non‐toxigenic strain of Escherichia coli O157:H7 in the presence and absence of a stabilizer and an emulsifier and at three different temperatures.
Abstract: Aims: To quantify the antibacterial properties of five essential oils (EO) on a non-toxigenic strain of Escherichia coli O157:H7 in the presence and absence of a stabilizer and an emulsifier and at three different temperatures. Methods and Results: Five EOs known to exhibit antibacterial properties were screened by disc diffusion assay and the most active were selected for further study in microdilution colorimetric assays. Oregano (Origanum vulgare) and thyme (Thymus vulgaris; light and red varieties) EO had the strongest bacteriostatic and bactericidal properties, followed by bay (Pimenta racemosa) and clove bud (Eugenia caryophyllata synonym: Syzygium aromaticum) EO. Oregano oil was colicidal at 625 μl l−1 at 10, 20 and 37°C. The addition of 0·05% (w/v) agar as stabilizer reinforced the antibacterial properties, particularly at 10°C, whereas 0·25% (w/v) lecithin reduced antibacterial activity. Scanning electron micrographs showed extensive morphological changes to treated cells. Conclusions: Oregano and thyme EO possess significant in vitro colicidal and colistatic properties, which are exhibited in a broad temperature range and substantially improved by the addition of agar as stabilizer. Bay and clove bud EO are less active. Lecithin diminished antibacterial properties. The bactericidal concentration of oregano EO irreversibly damaged E. coli O157:H7 cells within 1 min. Significance and Impact of the Study: Oregano and light thyme EO, particularly when enhanced by agar stabilizer, may be effective in reducing the number or preventing the growth of E. coli O157:H7 in foods.

Journal ArticleDOI
TL;DR: This meta-analysis provides evidence for a sex difference in the risk of developing schizophrenia, as reported in the published literature from the last 2 decades.
Abstract: Background Sex differences in the risk of a particular disorder can yield important clues regarding its pathogenesis. The evidence for a sex difference in the risk of schizophrenia is inconclusive. The purpose of this study was to integrate results from the published literature and to provide a quantitative index of the male-female ratio for the incidence of schizophrenia. Methods The MEDLINE and PsychLIT databases were searched for English-language publications on "incidence and schizophrenia" that appeared during the period between January 1980 and September 2001. Population-based incidence studies using standard clinical diagnostic criteria were included if they reported sex-specific incidence rates. Sex-specific incidence figures were extracted directly from each study. Categorical analyses were conducted on a subset of studies that met specific methodological criteria (to minimize criterion bias, hospital bias, and age bias). Study categorization and data extraction were performed independently by 2 of us (A. A. and J.-P.S.). Results Log risk ratio meta-analysis was conducted using a random-effects model. The incidence risk ratios for men to develop schizophrenia relative to women were 1.42 (95% confidence interval [CI], 1.30-1.56) when all studies were included in the analysis (49 effect sizes), 1.31 (95% CI, 1.13-1.51) when studies that minimized selection biases were analyzed separately (23 effect sizes), and 1.39 (95% CI, 1.15-1.68) when only high-quality studies were included(11 effect sizes). The sex difference was significantly smaller in studies with sample years before 1980 than those with sample years after 1980. No significant sex differences were reported in studies from developing countries. A final analysis, limited to studies with an age cutoff of 64 years or older(16 effect sizes), yielded a mean risk ratio of 1.32 (95% CI, 1.13-1.55). Conclusion This meta-analysis provides evidence for a sex difference in the risk of developing schizophrenia, as reported in the published literature from the last 2 decades.

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TL;DR: It is argued that the development of newMOEAs cannot converge onto a single new most efficient MOEA because the performance of MOEAs shows characteristics of multiobjective problems.
Abstract: Over the last decade, a variety of evolutionary algorithms (EAs) have been proposed for solving multiobjective optimization problems. Especially more recent multiobjective evolutionary algorithms (MOEAs) have been shown to be efficient and superior to earlier approaches. An important question however is whether we can expect such improvements to converge onto a specific efficient MOEA that behaves best on a large variety of problems. In this paper, we argue that the development of new MOEAs cannot converge onto a single new most efficient MOEA because the performance of MOEAs shows characteristics of multiobjective problems. While we point out the most important aspects for designing competent MOEAs in this paper, we also indicate the inherent multiobjective tradeoff in multiobjective optimization between proximity and diversity preservation. We discuss the impact of this tradeoff on the concepts and design of exploration and exploitation operators. We also present a general framework for competent MOEAs and show how current state-of-the-art MOEAs can be obtained by making choices within this framework. Furthermore, we show an example of how we can separate nondomination selection pressure from diversity preservation selection pressure and discuss the impact of changing the ratio between these components.

Journal ArticleDOI
01 Jul 2003-Lupus
TL;DR: Anticoagulation, corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most commonly used treatments for catastrophic APS patients.
Abstract: The term 'catastrophic' antiphospholipid syndrome (APS) is used to define an accelerated form of APS resulting in multiorgan failure. Although catastrophic APS patients represent less than 1% of all patients with APS, they are usually in a life-threatening medical situation that requires high clinical awareness. The careful and open discussion of several proposals by all participants in the presymposium workshop on APS consensus, held in Taormina on occasion of the 10th International Congress on aPL and chaired by Munther A Khamashta and Yehuda Shoenfeld (29 September 2002), has allowed the acceptation of a preliminary set of classification criteria. On the other hand, the optimal management of catastrophic APS must have three clear aims: to treat any precipitating factors (prompt use of antibiotics if infection is suspected, amputation for any necrotic organ, high awareness in patients with APS who undergo an operation or an invasive procedure), to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine 'storm'. Anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most commonly used treatments for catastrophic APS patients.

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TL;DR: In this paper, an overview is presented of the different approaches to generate and characterize mesopores in zeolite crystals and establish their impact on the catalytic action, and it is shown that electron tomography, a form of threedimensional transmission electron microscopy, is able to reveal the three-dimensional shape, size, and connectivity of the mesopore.
Abstract: Amongst the current developments in the field of hierarchical pore structures, the creation of mesopores in zeolite crystals is the most frequently employed way to combine micropores with mesopores in one material. In this review an overview is presented of the different approaches to generate and characterize mesopores in zeolite crystals and establish their impact on the catalytic action. Mesopores can be created via several routes from which steaming and acid leaching are the most frequently applied. Novel approaches using secondary carbon templates that are removed after synthesis have recently been launched. For the characterization of mesopores, nitrogen physisorption and electron microscopy are commonly used. More recently, it was shown that electron tomography, a form of three-dimensional transmission electron microscopy, is able to reveal the three-dimensional shape, size, and connectivity of the mesopores. The effect of the presence of mesopores for catalysis is demonstrated for several industri...