Showing papers by "University of Groningen published in 2004"
TL;DR: ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV.
Abstract: Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.
4,714 citations
TL;DR: The newest parameter sets, 53A5 and 53A6, were optimized by first fitting to reproduce the thermodynamic properties of pure liquids of a range of small polar molecules and the solvation free enthalpies of amino acid analogs in cyclohexane.
Abstract: Successive parameterizations of the GROMOS force field have been used successfully to simulate biomolecular systems over a long period of time. The continuing expansion of computational power with time makes it possible to compute ever more properties for an increasing variety of molecular systems with greater precision. This has led to recurrent parameterizations of the GROMOS force field all aimed at achieving better agreement with experimental data. Here we report the results of the latest, extensive reparameterization of the GROMOS force field. In contrast to the parameterization of other biomolecular force fields, this parameterization of the GROMOS force field is based primarily on reproducing the free enthalpies of hydration and apolar solvation for a range of compounds. This approach was chosen because the relative free enthalpy of solvation between polar and apolar environments is a key property in many biomolecular processes of interest, such as protein folding, biomolecular association, membrane formation, and transport over membranes. The newest parameter sets, 53A5 and 53A6, were optimized by first fitting to reproduce the thermodynamic properties of pure liquids of a range of small polar molecules and the solvation free enthalpies of amino acid analogs in cyclohexane (53A5). The partial charges were then adjusted to reproduce the hydration free enthalpies in water (53A6). Both parameter sets are fully documented, and the differences between these and previous parameter sets are discussed.
3,383 citations
TL;DR: The data indicate that the size itself of (ligand-devoid) particles can determine the pathway of entry in non-phagocytic B16 cells, and kinetic parameters may determine the almost exclusive internalization of such particles along this pathway rather than via caveolae.
Abstract: Non-phagocytic eukaryotic cells can internalize particles <1 microm in size, encompassing pathogens, liposomes for drug delivery or lipoplexes applied in gene delivery. In the present study, we have investigated the effect of particle size on the pathway of entry and subsequent intracellular fate in non-phagocytic B16 cells, using a range of fluorescent latex beads of defined sizes (50-1000 nm). Our data reveal that particles as large as 500 nm were internalized by cells via an energy-dependent process. With an increase in size (50-500 nm), cholesterol depletion increased the efficiency of inhibition of uptake. The processing of the smaller particles was significantly perturbed upon microtubule disruption, while displaying a negligible effect on that of the 500 nm beads. Inhibitor and co-localization studies revealed that the mechanism by which the beads were internalized, and their subsequent intracellular routing, was strongly dependent on particle size. Internalization of microspheres with a diameter <200 nm involved clathrin-coated pits. With increasing size, a shift to a mechanism that relied on caveolae-mediated internalization became apparent, which became the predominant pathway of entry for particles of 500 nm in size. At these conditions, delivery to the lysosomes was no longer apparent. The data indicate that the size itself of (ligand-devoid) particles can determine the pathway of entry. The clathrin-mediated pathway of endocytosis shows an upper size limit for internalization of approx. 200 nm, and kinetic parameters may determine the almost exclusive internalization of such particles along this pathway rather than via caveolae.
2,613 citations
TL;DR: In this article, a coarse-grained (CG) model for lipid and surfactant systems is presented, where only a small number of coarse grained atom types interact using a few discrete levels of interaction.
Abstract: This paper describes the parametrization of a new coarse grained (CG) model for lipid and surfactant systems. Reduction of the number of degrees of freedom together with the use of short range potentials makes it computationally very efficient. Compared to atomistic models a gain of 3-4 orders of magnitude can be achieved. Micrometer length scales or millisecond time scales are therefore within reach. To encourage applications, the model is kept very simple. Only a small number of coarse grained atom types are defined, which interact using a few discrete levels of interaction. Despite the computational speed and the simplistic nature of the model, it proves to be both versatile in its applications and accurate in its predictions. We show that densities of liquid alkanes from decane up to eicosane can be reproduced to within 5%, and the mutual solubilities of alkanes in water and water in alkanes can be reproduced within 0.5 kT of the experimental values. The CG model for dipalmitoylphosphatidylcholine (DPPC) is shown to aggregate spontaneously into a bilayer. Structural properties such as the area per headgroup and the phosphate-phosphate distance match the experimentally measured quantities closely. The same is true for elastic properties such as the bending modulus and the area compressibility, and dynamic properties such as the lipid lateral diffusion coefficient and the water permeation rate. The distribution of the individual lipid components along the bilayer normal is very similar to distributions obtained from atomistic simulations. Phospholipids with different headgroup (ethanolamine) or different tail lengths (lauroyl, stearoyl) or unsaturated tails (oleoyl) can also be modeled with the CG force field. The experimental area per headgroup can be reproduced for most lipids within 0.02 nm(2). Finally, the CG model is applied to nonbilayer phases. Dodecylphosphocholine (DPC) aggregates into small micelles that are structurally very similar to ones modeled atomistically, and DOPE forms an inverted hexagonal phase with structural parameters in agreement with experimental data.
2,062 citations
TL;DR: It is claimed that the fundamental mechanism at the basis of the experiential understanding of others' actions is the activation of the mirror neuron system, and a similar mechanism, but involving theactivation of viscero-motor centers, underlies the experience of the emotions of others.
1,934 citations
TL;DR: To describe the 12‐month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries, a large number of countries with high prevalence of these disorders have been surveyed.
Abstract: Objective: To describe the 12-month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries.
Method: A representative random sample of non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older (n = 21425) were interviewed between January 2001 and August 2003. DSM-IV disorders were assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview (WMH-CIDI).
Results: Fourteen per cent reported a lifetime history of any mood disorder, 13.6% any anxiety disorder and 5.2% a lifetime history of any alcohol disorder. More than 6% reported any anxiety disorder, 4.2% any mood disorder, and 1.0% any alcohol disorder in the last year. Major depression and specific phobia were the most common single mental disorders. Women were twice as likely to suffer 12-month mood and anxiety disorders as men, while men were more likely to suffer alcohol abuse disorders.
Conclusion: ESEMeD is the first study to highlight the magnitude of mental disorders in the six European countries studied. Mental disorders were frequent, more common in female, unemployed, disabled persons, or persons who were never married or previously married. Younger persons were also more likely to have mental disorders, indicating an early age of onset for mood, anxiety and alcohol disorders.
1,780 citations
TL;DR: Investigating ‘chronotypes' observed an abrupt change in the timing of sleep at around the age of 20 and propose this change as the first biological marker of the end of adolescence.
1,218 citations
Western Infirmary1, University of Gothenburg2, Cornell University3, Boston University4, Hannover Medical School5, University of Pittsburgh6, University of Copenhagen7, Alfred Hospital8, University of Toronto9, University of Helsinki10, University of Groningen11, Umeå University12, Amgen13, University of Washington14
TL;DR: The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.
Abstract: Background— Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. Methods and Results— Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction ≤0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE ( P =0.17) or RECOVER ( P =0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P =0.33). Conclusions— The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.
1,088 citations
Istanbul University1, University of Bergen2, University of Manchester3, University of Kiel4, Autonomous University of Barcelona5, University of Groningen6, University College London7, Innsbruck Medical University8, Université de Montréal9, University of Lisbon10, VU University Amsterdam11, Novartis12
TL;DR: In this paper, the effects of the dual cholinesterase inhibitor rivastigmine in patients with mild-to-moderate dementia associated with Parkinson's disease were investigated.
Abstract: background Cholinergic deficits are prominent in patients who have dementia associated with Parkinson’s disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. methods Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson’s disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and Alzheimer’s Disease Cooperative Study–Clinician’s Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer’s Disease Cooperative Study–Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini–Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. results A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer’s disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). conclusions In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson’s disease but also with higher rates of nausea, vomiting, and tremor.
1,082 citations
TL;DR: This work identifies the nature of the ferroelectric phase transition in the hexagonal manganite, YMnO3, using a combination of single-crystal X-ray diffraction, thorough structure analysis and first-principles density-functional calculations, and suggests an avenue for designing novel magnetic ferroelectrics.
Abstract: Understanding the ferroelectrocity in magnetic ferroelectric oxides is of both fundamental and technological importance. Here, we identify the nature of the ferroelectric phase transition in the hexagonal manganite, YMnO3, using a combination of single-crystal X-ray diffraction, thorough structure analysis and first-principles density-functional calculations. The ferroelectric phase is characterized by a buckling of the layered MnO5 polyhedra, accompanied by displacements of the Y ions, which lead to a net electric polarization. Our calculations show that the mechanism is driven entirely by electrostatic and size effects, rather than the usual changes in chemical bonding associated with ferroelectric phase transitions in perovskite oxides. As a result, the usual indicators of structural instability, such as anomalies in Born effective charges on the active ions, do not hold. In contrast to the chemically stabilized ferroelectrics, this mechanism for ferroelectricity permits the coexistence of magnetism and ferroelectricity, and so suggests an avenue for designing novel magnetic ferroelectrics.
1,042 citations
Vanderbilt University1, University of Southern California2, University of Texas MD Anderson Cancer Center3, University of Wisconsin-Madison4, University of California, Los Angeles5, National Center for Genome Resources6, Portland VA Medical Center7, University of Colorado Boulder8, University of Pennsylvania9, Hannover Medical School10, Johns Hopkins University11, Oregon Health & Science University12, Cornell University13, University of Michigan14, University of Tennessee Health Science Center15, Washington University in St. Louis16, University of Toronto17, University of Memphis18, Medical Research Council19, University of Massachusetts Medical School20, Hebrew University of Jerusalem21, Université de Montréal22, Purdue University23, University of California, Davis24, Academy of Sciences of the Czech Republic25, University at Buffalo26, Emory University27, University of Cincinnati28, University of Texas Southwestern Medical Center29, New York University30, University of Groningen31, Rutgers University32, Stanford University33, Max Planck Society34, National Institutes of Health35, University of Alabama at Birmingham36, International Livestock Research Institute37, Heidelberg University38, Medical College of Wisconsin39, Icahn School of Medicine at Mount Sinai40, Oak Ridge National Laboratory41, Charité42, University of Antwerp43, RWTH Aachen University44, Paul Sabatier University45, University of California, San Francisco46, McGill University47, Pasteur Institute48, University of Western Australia49, Yale University50, University of Oxford51, Case Western Reserve University52, Roswell Park Cancer Institute53, University of Kentucky54, University of Helsinki55, University of Nebraska–Lincoln56, Harvard University57, Merck & Co.58, King's College London59, Northwestern University60, Shriners Hospitals for Children61, Thomas Jefferson University62, Novartis63, University of North Carolina at Chapel Hill64, Southern Illinois University Carbondale65, University of Rochester66
TL;DR: The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way the authors approach human health and disease.
Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.
TL;DR: These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer by demonstrating the sensitivity and specificity of a multivariate model combining the three biomarkers.
Abstract: Early detection remains the most promising approach to improve long-term survival of patients with ovarian cancer. In a five-center case-control study, serum proteomic expressions were analyzed on 153 patients with invasive epithelial ovarian cancer, 42 with other ovarian cancers, 166 with benign pelvic masses, and 142 healthy women. Data from patients with early stage ovarian cancer and healthy women at two centers were analyzed independently and the results cross-validated to discover potential biomarkers. The results were validated using the samples from two of the remaining centers. After protein identification, biomarkers for which an immunoassay was available were tested on samples from the fifth center, which included 41 healthy women, 41 patients with ovarian cancer, and 20 each with breast, colon, and prostate cancers. Three biomarkers were identified as follows: (a) apolipoprotein A1 (down-regulated in cancer); (b) a truncated form of transthyretin (down-regulated); and (c) a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (up-regulated). In independent validation to detect early stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of a multivariate model combining the three biomarkers and CA125 [74% (95% CI, 52-90%)] was higher than that of CA125 alone [65% (95% CI, 43-84%)] at a matched specificity of 97% (95% CI, 89-100%). When compared at a fixed sensitivity of 83% (95% CI, 61-95%), the specificity of the model [94% (95% CI, 85-98%)] was significantly better than that of CA125 alone [52% (95% CI, 39-65%)]. These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer.
TL;DR: A model based on Onsager's theory of geminate charge recombination explains the observed field and temperature dependence of the photocurrent in PPV:PCBM blends.
Abstract: The photocurrent in conjugated polymer-fullerene blends is dominated by the dissociation efficiency of bound electron-hole pairs at the donor-acceptor interface. A model based on Onsager's theory of geminate charge recombination explains the observed field and temperature dependence of the photocurrent in $\mathrm{P}\mathrm{P}\mathrm{V}\ensuremath{\mathbin:}\mathrm{P}\mathrm{C}\mathrm{B}\mathrm{M}$ blends. At room temperature only 60% of the generated bound electron-hole pairs are dissociated and contribute to the short-circuit current, which is a major loss mechanism in photovoltaic devices based on this material system.
TL;DR: In this paper, the authors compared the chemistries of stars in the Milky Way dwarf spheroidal (dSph) satellite galaxies with stars from the Galaxy, and found that the [α/Fe] ratios of most stars in dSph galaxies are generally lower than similar metallicity Galactic stars in this extended sample.
Abstract: To compare the chemistries of stars in the Milky Way dwarf spheroidal (dSph) satellite galaxies with stars in the Galaxy, we have compiled a large sample of Galactic stellar abundances from the literature. When kinematic information is available, we have assigned the stars to standard Galactic components through Bayesian classification based on Gaussian velocity ellipsoids. As found in previous studies, the [α/Fe] ratios of most stars in the dSph galaxies are generally lower than similar metallicity Galactic stars in this extended sample. Our kinematically selected stars confirm this for the Galactic halo, thin-disk, and thick-disk components. There is marginal overlap in the low [α/Fe] ratios between dSph stars and Galactic halo stars on extreme retrograde orbits (V < -420 km s-1), but this is not supported by other element ratios. Other element ratios compared in this paper include r- and s-process abundances, where we find a significant offset in the [Y/Fe] ratios, which results in a large overabundance in [Ba/Y] in most dSph stars compared with Galactic stars. Thus, the chemical signatures of most of the dSph stars are distinct from the stars in each of the kinematic components of the Galaxy. This result rules out continuous merging of low-mass galaxies similar to these dSph satellites during the formation of the Galaxy. However, we do not rule out very early merging of low-mass dwarf galaxies, since up to one-half of the most metal-poor stars ([Fe/H] ≤ -1.8) have chemistries that are in fair agreement with Galactic halo stars. We also do not rule out merging with higher mass galaxies, although we note that the LMC and the remnants of the Sgr dwarf galaxy are also chemically distinct from the majority of the Galactic halo stars. Formation of the Galaxy's thick disk by heating of an old thin disk during a merger is also not ruled out; however, the Galaxy's thick disk itself cannot be comprised of the remnants from a low-mass (dSph) dwarf galaxy, nor of a high-mass dwarf galaxy like the LMC or Sgr, because of differences in chemistry. The new and independent environments offered by the dSph galaxies also allow us to examine fundamental assumptions related to the nucleosynthesis of the elements. The metal-poor stars ([Fe/H] ≤ -1.8) in the dSph galaxies appear to have lower [Ca/Fe] and [Ti/Fe] than [Mg/Fe] ratios, unlike similar metallicity stars in the Galaxy. Predictions from the α-process (α-rich freeze-out) would be consistent with this result if there have been a lack of hypernovae in dSph galaxies. The α-process could also be responsible for the very low Y abundances in the metal-poor stars in dSph's; since [La/Eu] (and possibly [Ba/Eu]) are consistent with pure r-process results, the low [Y/Eu] suggests a separate r-process site for this light (first-peak) r-process element. We also discuss SNe II rates and yields as other alternatives, however. In stars with higher metallicities ([Fe/H] ≥ -1.8), contributions from the s-process are expected; [(Y, La, and Ba)/Eu] all rise as expected, and yet [Ba/Y] is still much higher in the dSph stars than similar metallicity Galactic stars. This result is consistent with s-process contributions from lower metallicity AGB stars in dSph galaxies, and is in good agreement with the slower chemical evolution expected in the low-mass dSph galaxies relative to the Galaxy, such that the build-up of metals occurs over much longer timescales. Future investigations of nucleosynthetic constraints (as well as galaxy formation and evolution) will require an examination of many stars within individual dwarf galaxies. Finally, the Na-Ni trend reported in 1997 by Nissen & Schuster is confirmed in Galactic halo stars, but we discuss this in terms of the general nucleosynthesis of neutron-rich elements. We do not confirm that the Na-Ni trend is related to the accretion of dSph galaxies in the Galactic halo.
TL;DR: It is shown that selection on a personality trait with high heritability fluctuates across years within a natural bird population, and it is expected that the observed fluctuations in environmental factors lead to fluctuations in competition for space and food, and these, in association with variations in population density, lead to a variation in selection pressure, which maintains genetic variation in personalities.
Abstract: Individual animals differ in the way they cope with challenges in their environment, comparable with variation in human personalities. The proximate basis of variation in personality traits has received considerable attention, and one general finding is that personality traits have a substantial genetic basis. This poses the question of how variation in personality is maintained in natural populations. We show that selection on a personality trait with high heritability fluctuates across years within a natural bird population. Annual adult survival was related to this personality trait (behaviour in novel environments) but the effects were always opposite for males and females, and reversed between years. The number of offspring surviving to breeding was also related to their parents' personalities, and again selection changed between years. The observed annual changes in selection pressures coincided with changes in environmental conditions (masting of beeches) that affect the competitive regimes of the birds. We expect that the observed fluctuations in environmental factors lead to fluctuations in competition for space and food, and these, in association with variations in population density, lead to a variation in selection pressure, which maintains genetic variation in personalities.
TL;DR: It is found using fMRI that the secondary but not the primary somatosensory cortex is activated both when the participants were touched and when they observed someone or something else getting touched by objects.
TL;DR: Albuminuria is an important factor predicting cardiovascular risk in patients with type 2 diabetic nephropathy, and reducing albuminuria in the first 6 months appears to afford cardiovascular protection in these patients.
Abstract: Background— Albuminuria is an established risk marker for both cardiovascular and renal outcomes. Albuminuria can be reduced with drugs that block the renin-angiotensin system (RAS). We questioned whether the short-term drug-induced change in albuminuria would predict the long-term cardioprotective efficacy of RAS intervention. Methods and Results— We analyzed data from Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL), a double-blind, randomized trial in 1513 type 2 diabetic patients with nephropathy, focusing on the relationship between the prespecified cardiovascular end point (composite) or hospitalization for heart failure and baseline or reduction in albuminuria. Patients with high baseline albuminuria (≥3 g/g creatinine) had a 1.92-fold (95% CI, 1.54 to 2.38) higher risk for the cardiovascular end point and a 2.70-fold (95% CI, 1.94 to 3.75) higher risk for heart failure compared with patients with low albuminuria (<1.5 g/g). Amon...
TL;DR: The SCAS-P is recommended as a screening instrument for normal children and as a diagnostic instrument in clinical settings and for both convergent and divergent validity: the measure correlated well with the parent report for internalizing symptoms, and lower with externalizing symptoms.
TL;DR: During random locomotion, human neutrophils and Dictyostelium discoideum amoebae repeatedly extend and retract cytoplasmic processes, and how these molecules become localized in the cell is now becoming clear.
Abstract: During random locomotion, human neutrophils and Dictyostelium discoideum amoebae repeatedly extend and retract cytoplasmic processes. During directed cell migration — chemotaxis — these pseudopodia form predominantly at the leading edge in response to the local accumulation of certain signalling molecules. Concurrent changes in actin and myosin enable the cell to move towards the stimulus. Recent studies are beginning to identify an intricate network of signalling molecules that mediate these processes, and how these molecules become localized in the cell is now becoming clear.
TL;DR: The Autofluorescence Reader (AFR) offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin and may prove to be a useful clinical tool for rapid risk assessment of A GE-related long-term complications in diabetes mellitus and in other conditions associated with A GE accumulation.
Abstract: Aims/hypothesis
The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects.
TL;DR: In this article, a combination of techniques was used to resolve the morphology of spin cast films of poly(p-phenylene vinylene)/methanofullerene blends in three dimensions on a nanometer scale and relate the results to the performance of the corresponding solar cells.
Abstract: The performance of bulk-heterojunction solar cells based on a phase-separated mixture of donor and acceptor materials is known to be critically dependent on the morphology of the active layer. Here we use a combination of techniques to resolve the morphology of spin cast films of poly(p-phenylene vinylene)/methanofullerene blends in three dimensions on a nanometer scale and relate the results to the performance of the corresponding solar cells. Atomic force microscopy (AFM), transmission electron microscopy (TEM), and depth profiling using dynamic time-of-flight secondary ion mass spectrometry (TOF-SIMS) clearly show that for the two materials used in this study, 1-(3-methoxycarbonyl)propyl-1-phenyl-[6,6]-methanofullerene (PCBM) and poly[2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylene vinylene] (MDMO-PPV), phase separation is not observed up to 50 wt.-% PCBM. Nanoscale phase separation throughout the film sets in for concentrations of more than 67 wt.-% PCBM, to give domains of rather pure PCBM in a homogenous matrix of 50:50 wt.-% MDMO-PPV/PCBM. Electrical characterization, under illumination and in the dark, of the corresponding photovoltaic devices revealed a strong increase of power conversion efficiency when the phase-separated network develops, with a sharp increase of the photocurrent and fill factor between 50 and 67 wt.-% PCBM. As the phase separation sets in, enhanced electron transport and a reduction of bimolecular charge recombination provide the conditions for improved performance. The results are interpreted in terms of a model that proposes a hierarchical build up of two cooperative interpenetrating networks at different length scales.
Katholieke Universiteit Leuven1, Beth Israel Medical Center2, French Institute of Health and Medical Research3, Columbia University4, University of Melbourne5, Saint Louis University6, University of Florida7, University of Birmingham8, Boston Children's Hospital9, Cedars-Sinai Medical Center10, University of Groningen11, University of Cambridge12, Kurume University13, Kanazawa University14, University of Western Australia15, Yonsei University16, Indiana University17, Royal Free Hospital18, Icahn School of Medicine at Mount Sinai19, Toronto General Hospital20, New York University21
TL;DR: This international group of liver pathologists and hepatologists seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of the field.
TL;DR: This manuscript examines the impact of mental health state and specific mental and physical disorders on work role disability and quality of life in six European countries.
Abstract: Objective: This manuscript examines the impact of mental health state and specific mental and physical disorders on work role disability and quality of life in six European countries. Method: The ESEMeD study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an in-home computer-assisted interview. Common mental disorders, work loss days (WLD) in the past month and quality of life (QoL) were assessed, using the WMH-2000 version of the CIDI, the WHODAS-II, and the mental and physical component scores (MCS, PCS) of the 12-item short form, respectively. The presence of five chronic physical disorders: arthritis, heart disease, lung disease, diabetes and neurological disease was also assessed. Multivariate regression techniques were used to identify the independent association of mental and physical disorders while controlling for gender, age and Country. Results: In each country, WLD and loss of QoL increased with the number of disorders. Most mental disorders had approximately 1.0 SD-unit lower mean MCS and lost three to four times more work days, compared with people without any 12-month mental disorder. The 10 disorders with the highest independent impact on WLD were: neurological disease, panic disorder, PTSD, major depressive episode, dysthymia, specific phobia, social phobia, arthritis, agoraphobia and heart disease. The impact of mental vs. physical disorders on QoL was specific, with mental disorders impacting more on MCS and physical disorders more on PCS. Compared to physical disorders, mental disorders had generally stronger 'cross-domain' effects. Conclusion: The results suggest that mental disorders are important determinants of work role disability and quality of life, often outnumbering the impact of common chronic physical disorders.
TL;DR: The design, synthesis, and operation of a reversible, photoresponsive, self-assembling molecular system in which molecular and supramolecular chirality communicate and shows exceptional stereoselectivity upon aggregation of the molecules during gel formation with the solvent is reported.
Abstract: In nature, key molecular processes such as communication, replication, and enzyme catalysis all rely on a delicate balance between molecular and supramolecular chirality. Here we report the design, synthesis, and operation of a reversible, photoresponsive, self-assembling molecular system in which molecular and supramolecular chirality communicate. It shows exceptional stereoselectivity upon aggregation of the molecules during gel formation with the solvent. This chirality is locked by photochemical switching, a process that is subsequently used to induce an inverted chiral supramolecular assembly as revealed by circular dichroism spectroscopy. The optical switching between different chiral aggregated states and the interplay of molecular and supramolecular chirality offer attractive new prospects for the development of molecular memory systems and smart functional materials.
TL;DR: Based on the anatomical connections of these areas, and the Hebbian learning rule, a simple but powerful account of how the monkey brain can learn to understand the actions of others by associating them with self-produced actions, at the also discriminating its own actions from those of others is proposed.
TL;DR: Proteomics has yielded a variety of novel leads for the analysis of protein traffic in B. subtilis and other gram-positive bacteria, which will serve to increase the understanding of virulence factor biogenesis in gram- positive pathogens, which is likely to be of high medical relevance.
Abstract: Secretory proteins perform a variety of important "remote-control" functions for bacterial survival in the environment. The availability of complete genome sequences has allowed us to make predictions about the composition of bacterial machinery for protein secretion as well as the extracellular complement of bacterial proteomes. Recently, the power of proteomics was successfully employed to evaluate genome-based models of these so-called secretomes. Progress in this field is well illustrated by the proteomic analysis of protein secretion by the gram-positive bacterium Bacillus subtilis, for which approximately 90 extracellular proteins were identified. Analysis of these proteins disclosed various "secrets of the secretome," such as the residence of cytoplasmic and predicted cell envelope proteins in the extracellular proteome. This showed that genome-based predictions reflect only approximately 50% of the actual composition of the extracellular proteome of B. subtilis. Importantly, proteomics allowed the first verification of the impact of individual secretion machinery components on the total flow of proteins from the cytoplasm to the extracellular environment. In conclusion, proteomics has yielded a variety of novel leads for the analysis of protein traffic in B. subtilis and other gram-positive bacteria. Ultimately, such leads will serve to increase our understanding of virulence factor biogenesis in gram-positive pathogens, which is likely to be of high medical relevance.
TL;DR: In this article, the authors propose a challenging program for researchers eager to explore factors and process mechanisms contributing to the benefits and costs individuals and groups incur from pursuing innovative approaches, such as the characteristics of the innovative idea, the innovator, co-workers, supervisors, broader organizational context and in national culture.
Abstract: This introduction essay proposes a challenging program for researchers eager to explore factors and process mechanisms contributing to the benefits and costs individuals and groups incur from pursuing innovative approaches. With respect to individual innovation, such moderating factors might be found in the characteristics of the innovative idea, the innovator, co-workers, supervisors, the broader organizational context, and in national culture. Examples of factors that are likely to shape the beneficial and detrimental outcomes of group innovation include knowledge, skills and ability of group members, group tenure, diversity among group members, group processes (clarifying group objectives, participation, constructive management of competing perspectives), and external demands on groups. This Special Issue contains a state-of-the-science paper, three articles dealing with the benefits and costs of individual innovation, and three articles addressing the bright and dark sides of group innovation. Copyright © 2004 John Wiley & Sons, Ltd.
TL;DR: In microalbuminuric subjects, fosinopril treatment was associated with a trend in reducing cardiovascular events, and treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.
Abstract: BACKGROUND: Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours). METHODS AND RESULTS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51+/-12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8+/-1.0 mmol/L, mean systolic/diastolic blood pressure was 130+/-18/76+/-10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% (P<0.001). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio 0.60 [95% CI 0.33 to 1.10], P=0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57], P=0.649, log-rank). CONCLUSIONS: In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.
TL;DR: The currentvoltage characteristics of ITO/PEDOT:PSS/OC1C10-PPV:PCBM/Al solar cells were measured in the temperature range 125-320 K under variable illumination, between 0.03 and 100 mW cm(-2) (white light), with the aim of determining the efficiency-limiting mechanism in these devices, and the temperature and/or illumination range(s) in which these devices demonstrate optimal performance.
Abstract: The current-voltage characteristics of ITO/PEDOT:PSS/OC1C10-PPV:PCBM/Al solar cells were measured in the temperature range 125-320 K under variable illumination, between 0.03 and 100 mW cm(-2) (white light), with the aim of determining the efficiency-limiting mechanism(s) in these devices, and the temperature and/or illumination range(s) in which these devices demonstrate optimal performance. (ITO: indium tin oxide; PEDOT:PSS: poly(styrene sulfonate)-doped poly(ethylene dioxythiophene); OC1C10-PPV: poly[2-methoxy-5-(3,7-dimethyl octyloxy)-1,4-phenylene vinylene]; PCBM: phenyl-C-61 butyric acid methyl ester.) The short-circuit current density and the fill factor grow monotonically with temperature until 320 K. This is indicative of a thermally activated transport of photogenerated charge carriers, influenced by recombination with shallow traps. A gradual increase of the open-circuit voltage to 0.91 V was observed upon cooling the devices down to 125 K. This fits the picture in which the open-circuit voltage is not limited by the work-function difference of electrode materials used. The overall effect of temperature on solar-cell parameters results in a positive temperature coefficient of the power conversion efficiency, which is 1.9% at T = 320 K and 100 mW cm(-2) (2.5% at 0.7 mW cm(-2)). The almost-linear variation of the short-circuit current density with light intensity confirms that the internal recombination losses are predominantly of monomolecular type under short-circuit conditions. We present evidence that the efficiency of this type of solar cell is limited by a light-dependent shunt resistance. Furthermore, the electronic transport properties of the absorber materials, e.g., low effective charge-carrier mobility with a strong temperature dependence, limit the photogenerated current due to a high series resistance, therefore the active layer thickness must be kept low, which results in low absorption for this particular composite absorber.
TL;DR: Patients with severe asthma are often inadequately controlled on existing anti‐asthma therapy, constituting an unmet clinical need, and this work aims to address that need.
Abstract: Background Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need. Objective This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma. Methods After a run-in period when an optimized fluticasone dose (greater than or equal to1000 mug/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting beta(2)-agonists were allowed as needed. Results Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a greater than or equal to50% dose reduction (P=0.001). Fluticasone dose reduction to less than or equal to500 mug/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo. Conclusion Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use. (Less)