Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform

OBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoform

Generating confidence intervals on biological networks

<p>Abstract</p> <p>Background</p> <p>In the analysis of networks we frequently require the statistical significance of some network statistic, such as measures of similarity for the properties of interacting nodes. The structure of the network may introduce dependencies among the nodes and it will in general be necessary to account for these dependencies in the statistical analysis. To this end we require some form of Null model of the network: generally rewired replicates of the network are generated which preserve only the degree (number of interactions) of each node. We show that this can fail to capture important features of network structure, and may result in unrealistic significance levels, when potentially confounding additional information is available.</p> <p>Methods</p> <p>We present a new network resampling Null model which takes into account the degree sequence as well as available biological annotations. Using gene ontology information as an illustration we show how this information can be accounted for in the resampling approach, and the impact such information has on the assessment of statistical significance of correlations and motif-abundances in the <it>Saccharomyces cerevisiae </it>protein interaction network. An algorithm, GOcardShuffle, is introduced to allow for the efficient construction of an improved Null model for network data.</p> <p>Results</p> <p>We use the protein interaction network of <it>S. cerevisiae</it>; correlations between the evolutionary rates and expression levels of interacting proteins and their statistical significance were assessed for Null models which condition on different aspects of the available data. The novel GOcardShuffle approach results in a Null model for annotated network data which appears better to describe the properties of real biological networks.</p> <p>Conclusion</p> <p>An improved statistical approach for the statistical analysis of biological network data, which conditions on the available biological information, leads to qualitatively different results compared to approaches which ignore such annotations. In particular we demonstrate the effects of the biological organization of the network can be sufficient to explain the observed similarity of interacting proteins.</p

Phosphorus Is Associated with Coronary Artery Disease in Patients with Preserved Renal Function

High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m2. Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score ≤10 (3.63±0.55 versus 3.49±0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6±0.5 versus 3.5±0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score (p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function

Development and validation of Videogame Addiction Scale for Children (VASC)

The aim of the present study was to develop a valid and reliable Videogame Addiction Scale for Children (VASC). The data were derived from 780 children who completed the Videogame Addiction Scale (405 girls and 375 boys; 48.1% ranging in age from 9 to 12 years). The sample was randomly split into two different sub-samples (sample 1, n=400; sample 2, n= 380). Sample 1 was used to perform exploratory factor analysis (EFA) to define the factorial structure of VASC. As a result of EFA, a four-factor structure comprising 21 items was obtained and explained 55% of the total variance (the four factors being "self-control," "reward/reinforcement", "problems," and "involvement"). The internal consistency reliability of VASC has found 0.89. Confirmatory factor analysis (CFA) was performed to confirm the factorial structure obtained by EFA in the remaining half of sample (n= 390). The obtained fit indices from the CFA confirmed the structure of the EFA. The 21-item VASC has good psychometric properties that can be used among Turkish schoolchildren populations

The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD. Methodology/Principal Findings: Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status. Conclusions/Significance: Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies. © 2009 Bon et al

Plasticity of the Muscle Stem Cell Microenvironment

Satellite cells (SCs) are adult muscle stem cells capable of repairing damaged and creating new muscle tissue throughout life. Their functionality is tightly controlled by a microenvironment composed of a wide variety of factors, such as numerous secreted molecules and different cell types, including blood vessels, oxygen, hormones, motor neurons, immune cells, cytokines, fibroblasts, growth factors, myofibers, myofiber metabolism, the extracellular matrix and tissue stiffness. This complex niche controls SC biology-quiescence, activation, proliferation, differentiation or renewal and return to quiescence. In this review, we attempt to give a brief overview of the most important players in the niche and their mutual interaction with SCs. We address the importance of the niche to SC behavior under physiological and pathological conditions, and finally survey the significance of an artificial niche both for basic and translational research purposes

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes