Showing papers by "Radboud University Nijmegen published in 2009"
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TL;DR: An evaluation of double-blind reviewed journals through important academic publishing databases revealed that more than 30 academic articles in the domain of international marketing (in a broad sense) used PLS path modeling as means of statistical analysis.
Abstract: Purpose: This paper discusses partial least squares path modeling (PLS), a powerful structural equation modeling technique for research on international marketing. While a significant body of research provides guidance for the use of covariance-based structural equation modeling (CBSEM) in international marketing, there are no subject-specific guidelines for the use of PLS so far.Methodology/approach: A literature review of the use of PLS in international marketing reveals the increasing application of this methodology.Findings: This paper reveals the strengths and weaknesses of PLS in the context of research on international marketing, and provides guidance for multi-group analysis.Originality/value of paper: The paper assists researchers in making well-grounded decisions regarding the application of PLS in certain research situations and provides specific implications for an appropriate application of the methodology.
7,536 citations
06 Mar 2009
TL;DR: In this article, the authors conducted an exhaustive literature review to determine the status quo of PLS path modeling in international marketing research and found that more than 30 academic articles in the domain of international marketing used PLS as a means of statistical analysis.
Abstract: In order to determine the status quo of PLS path modeling in international marketing research, we conducted an exhaustive literature review. An evaluation of double-blind reviewed journals through important academic publishing databases (e.g., ABI/Inform, Elsevier ScienceDirect, Emerald Insight, Google Scholar, PsycINFO, Swetswise) revealed that more than 30 academic articles in the domain of international marketing (in a broad sense) used PLS path modeling as means of statistical analysis. We assessed what the main motivation for the use of PLS was in respect of each article. Moreover, we checked for applications of PLS in combination with one or more additional methods, and whether the main reason for conducting any additional method(s) was mentioned.
5,282 citations
TL;DR: This work illustrates the concept of graphene as a robust atomic-scale scaffold on the basis of which new two-dimensional crystals with designed electronic and other properties can be created by attaching other atoms and molecules.
Abstract: Although graphite is known as one of the most chemically inert materials, we have found that graphene, a single atomic plane of graphite, can react with atomic hydrogen, which transforms this highly conductive zero-overlap semimetal into an insulator. Transmission electron microscopy reveals that the obtained graphene derivative (graphane) is crystalline and retains the hexagonal lattice, but its period becomes markedly shorter than that of graphene. The reaction with hydrogen is reversible, so that the original metallic state, the lattice spacing, and even the quantum Hall effect can be restored by annealing. Our work illustrates the concept of graphene as a robust atomic-scale scaffold on the basis of which new two-dimensional crystals with designed electronic and other properties can be created by attaching other atoms and molecules.
3,735 citations
University of Alabama at Birmingham1, University of Michigan2, University of Wisconsin-Madison3, Duke University4, University of Lausanne5, University of California, Los Angeles6, Georgia Regents University7, Radboud University Nijmegen8, University of Texas at Austin9, Rowan University10, AstraZeneca11, National Institutes of Health12, Wayne State University13
TL;DR: These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections.
Abstract: Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections. Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised document.
3,016 citations
TL;DR: In this paper, a large-scale Monte-Carlo simulation was conducted to compare the performance of covariance-based and partial least squares (PLS) analysis with PLS and CBSEM.
1,864 citations
TL;DR: In addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
Abstract: Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Furthermore, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
1,793 citations
TL;DR: It is proposed that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes and is described as a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global Chromatin interactions.
Abstract: Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally Many transcription factors bind to regulatory DNA elements distant from gene promoters Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor α (ER-α) in the human genome We found that most high-confidence remote ER-α-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-α functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes © 2009 Macmillan Publishers Limited All rights reserved
1,602 citations
TL;DR: It is argued that gamma-band synchronization is a fundamental process that subserves an elemental operation of cortical computation and brings about both selectivity and invariance of neuronal responses.
Abstract: Neuronal gamma-band synchronization is found in many cortical areas, is induced by different stimuli or tasks, and is related to several cognitive capacities. Thus, it appears as if many different gamma-band synchronization phenomena subserve many different functions. I argue that gamma-band synchronization is a fundamental process that subserves an elemental operation of cortical computation. Cortical computation unfolds in the interplay between neuronal dynamics and structural neuronal connectivity. A core motif of neuronal connectivity is convergence, which brings about both selectivity and invariance of neuronal responses. However, those core functions can be achieved simultaneously only if converging neuronal inputs are functionally segmented and if only one segment is selected at a time. This segmentation and selection can be elegantly achieved if structural connectivity interacts with neuronal synchronization. I propose that this process is at least one of the fundamental functions of gamma-band synchronization, which then subserves numerous higher cognitive functions.
1,551 citations
TL;DR: In this article, a large-scale Monte-Carlo simulation was conducted to compare the performance of covariance-based and partial least squares (PLS) analysis with PLS.
Abstract: Variance-based SEM, also known under the term partial least squares (PLS) analysis, is an approach that has gained increasing interest among marketing researchers in recent years. During the last 25 years, more than 30 articles have been published in leading marketing journals that have applied this approach instead of the more traditional alternative of covariance-based SEM (CBSEM). However, although an analysis of these previous publications shows that there seems to be at least an implicit agreement about the factors that should drive the choice between PLS analysis and CBSEM, no research has until now empirically compared the performance of these approaches given a set of different conditions. Our study addresses this open question by conducting a large-scale Monte-Carlo simulation. We show that justifying the choice of PLS due to a lack of assumptions regarding indicator distribution and measurement scale is often inappropriate, as CBSEM proves extremely robust with respect to violations of its underlying distributional assumptions. Additionally, CBSEM clearly outperforms PLS in terms of parameter consistency and is preferable in terms of parameter accuracy as long as the sample size exceeds a certain threshold (250 observations). Nevertheless, PLS analysis should be preferred when the emphasis is on prediction and theory development, as the statistical power of PLS is always larger than or equal to that of CBSEM; already, 100 observations can be sufficient to achieve acceptable levels of statistical power given a certain quality of the measurement model.
1,378 citations
TL;DR: In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 × 10−7 and included previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
Abstract: Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
1,340 citations
TL;DR: The addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life.
Abstract: Background Fluoropyrimidine-based chemotherapy plus the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab is standard first-line treatment for metastatic colorectal cancer. We studied the effect of adding the anti–epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for metastatic colorectal cancer. Methods We randomly assigned 755 patients with previously untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). The primary end point was progression-free survival. The mutation status of the KRAS gene was evaluated as a predictor of outcome. Results The median progression-free survival was 10.7 months in the CB group and 9.4 in the CBC group (P=0.01). Quality-of-life scores were lower in the CBC group. The overall survival and response rates did not differ significantly in the two groups. Treated ...
TL;DR: The results point to routeing of information as a possible function of gamma frequency variations in the brain and provide a mechanism for temporal segregation of potentially interfering information from different sources.
Abstract: Gamma oscillations are thought to transiently link distributed cell assemblies that are processing related information, a function that is probably important for network processes such as perception, attentional selection and memory. This 'binding' mechanism requires that spatially distributed cells fire together with millisecond range precision; however, it is not clear how such coordinated timing is achieved given that the frequency of gamma oscillations varies substantially across space and time, from approximately 25 to almost 150 Hz. Here we show that gamma oscillations in the CA1 area of the hippocampus split into distinct fast and slow frequency components that differentially couple CA1 to inputs from the medial entorhinal cortex, an area that provides information about the animal's current position, and CA3, a hippocampal subfield essential for storage of such information. Fast gamma oscillations in CA1 were synchronized with fast gamma in medial entorhinal cortex, and slow gamma oscillations in CA1 were coherent with slow gamma in CA3. Significant proportions of cells in medial entorhinal cortex and CA3 were phase-locked to fast and slow CA1 gamma waves, respectively. The two types of gamma occurred at different phases of the CA1 theta rhythm and mostly on different theta cycles. These results point to routeing of information as a possible function of gamma frequency variations in the brain and provide a mechanism for temporal segregation of potentially interfering information from different sources.
TL;DR: The strongest links were found for parental monitoring, psychological control, and negative aspects of support such as rejection and hostility, accounting for up to 11% of the variance in delinquency.
Abstract: This meta-analysis of 161 published and unpublished manuscripts was conducted to determine whether the association between parenting and delinquency exists and what the magnitude of this linkage is. The strongest links were found for parental monitoring, psychological control, and negative aspects of support such as rejection and hostility, accounting for up to 11% of the variance in delinquency. Several effect sizes were moderated by parent and child gender, child age, informant on parenting, and delinquency type, indicating that some parenting behaviors are more important for particular contexts or subsamples. Although both dimensions of warmth and support seem to be important, surprisingly very few studies focused on parenting styles. Furthermore, fewer than 20% of the studies focused on parenting behavior of fathers, despite the fact that the effect of poor support by fathers was larger than poor maternal support, particularly for sons. Implications for theory and parenting are discussed.
TL;DR: Analysis of literature data enabled the identification of the most important operational parameters leading to N(2)O emission in WWTPs: (i) low dissolved oxygen concentration in the nitrification and denitrification stages, (ii) increased nitrite concentrations in both nitrified stages, and (iii) low COD/N ratio in theDenitrification stage.
TL;DR: In this paper, the adsorption of graphene on metal substrates using first-principles calculations at the level of density-functional theory was studied, and a simple analytical model was developed that describes the Fermi-level shift in graphene in terms of the metal substrate work function.
Abstract: Measuring the transport of electrons through a graphene sheet necessarily involves contacting it with metal electrodes. We study the adsorption of graphene on metal substrates using first-principles calculations at the level of density-functional theory. The bonding of graphene to Al, Ag, Cu, Au, and Pt (111) surfaces is so weak that its unique “ultrarelativistic” electronic structure is preserved. The interaction does, however, lead to a charge transfer that shifts the Fermi level by up to 0.5 eV with respect to the conical points. The crossover from p-type to n-type doping occurs for a metal with a work function ~5.4 eV, a value much larger than the work function of free-standing graphene, 4.5 eV. We develop a simple analytical model that describes the Fermi-level shift in graphene in terms of the metal substrate work function. Graphene interacts with and binds more strongly to Co, Ni, Pd, and Ti. This chemisorption involves hybridization between graphene pz states and metal d states that opens a band gap in graphene, and reduces its work function considerably. The supported graphene is effectively n-type doped because in a current-in-plane device geometry the work-function lowering will lead to electrons being transferred to the unsupported part of the graphene sheet.
TL;DR: An inverse association of IDH1 and IDH2 mutations of the R132C type are strongly associated with astrocytoma, while IDH 2 mutations predominantly occur in oligodendroglial tumors.
Abstract: Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.
TL;DR: It was found that self-compassion predicted more stable feelings of self-worth than self-esteem and was less contingent on particular outcomes as well as being statistically equivalent predictors of happiness, optimism, and positive affect.
Abstract: This research examined self-compassion and self-esteem as they relate to various aspects of psychological functioning. Self-compassion entails treating oneself with kindness, recognizing one's shared humanity, and being mindful when considering negative aspects of oneself. Study 1 (N=2,187) compared self-compassion and global self-esteem as they relate to ego-focused reactivity. It was found that self-compassion predicted more stable feelings of self-worth than self-esteem and was less contingent on particular outcomes. Self-compassion also had a stronger negative association with social comparison, public self-consciousness, self-rumination, anger, and need for cognitive closure. Self-esteem (but not self-compassion) was positively associated with narcissism. Study 2 (N=165) compared global self-esteem and self-compassion with regard to positive mood states. It was found that the two constructs were statistically equivalent predictors of happiness, optimism, and positive affect. Results from these two studies suggest that self-compassion may be a useful alternative to global self-esteem when considering what constitutes a healthy self-stance.
TL;DR: There is a lack of evidence-based data on the radiation dose for CBCT imaging, and an attempt was made to provide a minimal set of CBCT device-related parameters for dedicated OMF scanners as a guideline for future studies.
TL;DR: In this article, the effects of albuminuria and reduced estimated GFR (eGFR) on the risk for cardiovascular and renal events among individuals with type 2 diabetes were investigated. But, there was no evidence of an interaction between the effect of higher eGFR and lower UACR.
Abstract: There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.
TL;DR: This review deals with the reconstruction of gene regulatory networks (GRNs) from experimental data through computational methods and approaches are discussed that enable the modelling of the dynamics of Gene regulatory systems.
Abstract: Systems biology aims to develop mathematical models of biological systems by integrating experimental and theoretical techniques. During the last decade, many systems biological approaches that base on genome-wide data have been developed to unravel the complexity of gene regulation. This review deals with the reconstruction of gene regulatory networks (GRNs) from experimental data through computational methods. Standard GRN inference methods primarily use gene expression data derived from microarrays. However, the incorporation of additional information from heterogeneous data sources, e.g. genome sequence and protein-DNA interaction data, clearly supports the network inference process. This review focuses on promising modelling approaches that use such diverse types of molecular biological information. In particular, approaches are discussed that enable the modelling of the dynamics of gene regulatory systems. The review provides an overview of common modelling schemes and learning algorithms and outlines current challenges in GRN modelling.
TL;DR: It is demonstrated that human blood monocytes release processed IL-1beta after a one-time stimulation with either TLR2 or TLR4 ligands, resulting from constitutively activated caspase-1 and release of endogenous adenosine triphosphate.
TL;DR: The newly developed Compulsive Internet Use Scale (CIUS) contains 14 items ratable on a 5-point Likert scale and showed good factorial stability across time and across different samples and subsamples.
Abstract: The present study aimed to develop a short, easily administered, psychometrically sound, and valid instrument to assess the severity of compulsive Internet use. A set of criteria was determined based on the addiction literature. Next, the internal consistency and convergent validity were determined, and the set was tested as a one-factor solution in two representative samples of heavy Internet users (n = 447 and n = 229) and in one large convenience sample of regular Internet users (n = 16,925). In these three studies, respondents were asked about their online behavior and about problems related to Internet use. In the first study, the Online Cognition Scale (OCS) was included to determine concurrent validity. The newly developed Compulsive Internet Use Scale (CIUS) contains 14 items ratable on a 5-point Likert scale. The instrument showed good factorial stability across time and across different samples and subsamples. The internal consistency is high, and high correlations with concurrent and c...
TL;DR: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage pointsWith SOD, according to a random-effects logistic-regression model.
Abstract: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. Conclusions In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.)
TL;DR: It is concluded that neurofeedback treatment for ADHD can be considered “Efficacious and Specific” (Level 5) with a large ES for inattention and impulsivity and a medium ES for hyperactivity.
Abstract: Since the first reports of neurofeedback treatment in Attention Deficit Hyperactivity Disorder (ADHD) in 1976, many studies have investigated the effects of neurofeedback on different symptoms of ADHD such as inattention, impulsivity and hyperactivity. This technique is also used by many practitioners, but the question as to the evidencebased level of this treatment is still unclear. In this study selected research on neurofeedback treatment for ADHD was collected and a meta-analysis was performed. Both prospective controlled studies and studies employing a preand post-design found large effect sizes (ES) for neurofeedback on impulsivity and inattention and a medium ES for hyperactivity. Randomized studies demonstrated a lower ES for hyperactivity suggesting that hyperactivity is probably most sensitive to nonspecific treatment factors. Due to the inclusion of some very recent and sound methodological studies in this meta-analysis, potential confounding factors such as small studies, lack of randomization in previous studies and a lack of adequate control groups have been addressed, and the clinical effects of neurofeedback in the treatment of ADHD can be regarded as clinically meaningful. Three randomized studies have employed a semi-active control group which can be regarded as a credible sham control providing an equal level of cognitive training and client-therapist interaction. Therefore, in line with the AAPB and ISNR guidelines for rating clinical efficacy, we conclude that neurofeedback treatment for ADHD can be considered “Efficacious and Specific” (Level 5) with a large ES for inattention and impulsivity and a medium ES for hyperactivity.
TL;DR: A family in which four women who were affected by either recurrent vulvovaginal candidiasis or onychomycosis had the early-stop-codon mutation Tyr238X in the beta-glucan receptor dectin-1, explaining why dectIn-1 deficiency was not associated with invasive fungal infections and highlighting the specific role of dect in human mucosal antifungal defense.
Abstract: Mucocutaneous fungal infections are typically found in patients who have no known immune defects. We describe a family in which four women who were affected by either recurrent vulvovaginal candidiasis or onychomycosis had the early-stop-codon mutation Tyr238X in the β-glucan receptor dectin-1. The mutated form of dectin-1 was poorly expressed, did not mediate β-glucan binding, and led to defective production of cytokines (interleukin-17, tumor necrosis factor, and interleukin-6) after stimulation with β-glucan or Candida albicans. In contrast, fungal phagocytosis and fungal killing were normal in the patients, explaining why dectin-1 deficiency was not associated with invasive fungal infections and highlighting the specific role of dectin-1 in human mucosal antifungal defense.
TL;DR: A combination of bioinformatics, yeast genetics, biochemistry, and human genetics was used to show that a previously uncharacterized mitochondrial protein (Sdh5) is required for the activity of respiratory complex II, leading to the discovery of a human tumor susceptibility gene.
Abstract: Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma, a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.
TL;DR: The Das28 (CRP) has been validated against radiographic progression and physical function and the validation profile was similar to the DAS28 (ESR), indicating that both measures are useful for assessing disease activity in patients with rheumatoid arthritis.
Abstract: Objective: To validate and compare the definition of the Disease Activity Score 28 based on C-reactive protein (DAS28 (CRP)) to the definition based on erythrocyte sedimentation rate (ESR). Methods: Data were analysed from two randomised, double-blind, placebo-controlled trials of abatacept of 6-month and 12-month duration in patients with rheumatoid arthritis. European League Against Rheumatism (EULAR) response criteria and the proportion of patients in remission (DAS28 Results: There was general agreement in determining the EULAR responder state using both DAS28 definitions (κ = 0.80, 95% CI 0.76 to 0.83). Overall, there was 82.4% agreement on the EULAR response criteria; when disagreements occurred, the DAS28 (CRP) yielded a better EULAR response more often then DAS28 (ESR) (12.6% vs 4.9%, respectively). There was also agreement in determining remission: κ = 0.69 (95% CI 0.60 to 0.78). Radiographic progression decreased in patients treated with abatacept across EULAR states (from none to moderate to good) based on both definitions. For patients treated with placebo, the trend was not as pronounced, with radiographic scores higher for moderate vs non-responders. For physical function, similar trends were observed across the EULAR states for both DAS28 definitions. Conclusions: The DAS28 (CRP) has been validated against radiographic progression and physical function. While the DAS28 (CRP) yielded a better EULAR response more often than the DAS28 (ESR), the validation profile was similar to the DAS28 (ESR), indicating that both measures are useful for assessing disease activity in patients with rheumatoid arthritis.
University of Manchester1, University of Leeds2, University of Washington3, Leeds Teaching Hospitals NHS Trust4, Université libre de Bruxelles5, Mater Dei Hospital6, Boston Children's Hospital7, University of Paris8, University of Göttingen9, Mount Sinai St. Luke's and Mount Sinai Roosevelt10, University of Barcelona11, Radboud University Nijmegen12, University of Oslo13, Royal Children's Hospital14, VU University Amsterdam15, Katholieke Universiteit Leuven16, University of São Paulo17, Rabin Medical Center18, University of British Columbia19, Technion – Israel Institute of Technology20, Baylor College of Medicine21, University of Melbourne22, Children's National Medical Center23, Ealing Hospital24, Imperial College London25
TL;DR: Mutations in SAMHD1 are described as the cause of Aicardi-Goutières syndrome at the AGS5 locus and data is presented to show that SAM HD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Abstract: Aicardi-Goutieres syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response
TL;DR: The long-term study shows that between 1988 and 2005, budburst advanced, while between 1985 and 2005 both caterpillars and the hatching date of the passerine species have advanced, whereas raptor hatching dates showed no trend, showing that the response of the consumers is weaker than that of their food.
Abstract: 1. Climate change has been shown to affect the phenology of many organisms, but interestingly these shifts are often unequal across trophic levels, causing a mismatch between the phenology of organisms and their food. 2. We consider two alternative hypotheses: consumers are constrained to adjust sufficiently to the lower trophic level, or prey species react more strongly than their predators to reduce predation. We discuss both hypotheses with our analyses of changes in phenology across four trophic levels: tree budburst, peak biomass of herbivorous caterpillars, breeding phenology of four insectivorous bird species and an avian predator. 3. In our long-term study, we show that between 1988 and 2005, budburst advanced (not significantly) with 0.17 d yr(-1), while between 1985 and 2005 both caterpillars (0.75 d year(-1)) and the hatching date of the passerine species (range for four species: 0.36-0.50 d year(-1)) have advanced, whereas raptor hatching dates showed no trend. 4. The caterpillar peak date was closely correlated with budburst date, as were the passerine hatching dates with the peak caterpillar biomass date. In all these cases, however, the slopes were significantly less than unity, showing that the response of the consumers is weaker than that of their food. This was also true for the avian predator, for which hatching dates were not correlated with the peak availability of fledgling passerines. As a result, the match between food demand and availability deteriorated over time for both the passerines and the avian predators. 5. These results could equally well be explained by consumers' insufficient responses as a consequence of constraints in adapting to climate change, or by them trying to escape predation from a higher trophic level, or both. Selection on phenology could thus be both from matches of phenology with higher and lower levels, and quantifying these can shed new light on why some organisms do adjust their phenology to climate change, while others do not.
deCODE genetics1, Radboud University Nijmegen Medical Centre2, University of Iceland3, University of Turin4, Karolinska Institutet5, German Cancer Research Center6, St James's University Hospital7, University of Brescia8, Katholieke Universiteit Leuven9, University of Birmingham10, Maastricht University11, University of Zaragoza12, Northwestern University13, Radboud University Nijmegen14, University of Gothenburg15, Imperial College London16
TL;DR: It is found that rs401681[C] on chromosome 5p15 satisfied the threshold for genome-wide significance and seems to confer protection against cutaneous melanoma, and investigation of the region led to rs2736098[A], which showed stronger association with some cancer types, but neither variant could fully account for the association of the other.
Abstract: The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.