Task Force 7: Training Guidelines for Research in Pediatric Cardiology

Aim of the study. The aim of the study was to analyze the benefit from adjuvant radiotherapy in patients with vulvar cancer and a single positive node without extra capsular spread. Materials and methods. The Study population comprised data of 75 patients with vulvar cancer and one lymph node metastasis. The patients were treated in three different university centers in Amsterdam, Groningen and Rotterdam between 1984 and 2005. Results. Out of 75 patients, 31 (41%) were treated with adjuvant radiotherapy. Both disease-free survival (DFS) and disease-specific survival (DSS) were comparable between the groups who did and who did not receive adjuvant radiotherapy (HR 0.98, 95% CI 0.45-2.14, p=0.97 and HR = 1.02, 95% CI 0.42-2.47, p = 0.96). Conclusion. We could not demonstrate any beneficial effect of adjuvant radiotherapy in the group Of patients with one intra capsular metastasis. (C) 2009 Elsevier Inc. All rights reserved

Integration of GWAS, CNV and sele ction signature reveals candidate genes for abdominal fat regulation in chickens.

Abstract: Carcass fat content is an economically important trait in commercial chickens. The use of genome-wide high density SNPs may improve the power and resolution to identify QTLs, putative candidate genes and copy number variations (CNVs), for selection programs. The main goal of this study was to identify genomic windows and putative candidate genes for carcass fat content. We checked the overlap of QTL with regions demonstrating signatures of selection and inherited CNVs identified in the same population. A total of 497 42 day-old chickens from the EMBRAPA F2 Chicken Resource Population developed for QTL studies were genotyped with the 600K SNP genotyping array (Affymetrix®), and phenotyped for carcass fat content weight (CFCW) and carcass fat content on a dry matter basis (CFCDM). After quality control, a total of 480 samples and 371,557 SNPs annotated in autosomal chromosomes (GGA1-28) based on Gallus_gallus-5.0 (NCBI) were kept for further analysis. GWAS analyses were performed with GenSel software using BayesB method (π=0.9988) to identify genomic windows associated with CFCW or CFC%. We identified 15 genomic windows associated with CFC% on GGA1, 7, 15, 20 and 28, and from those, we identified two adjacent windows on GGA7 considered as the same QTL explaining 1.31 and 2.18% of the genetic variance for CFCW and CFC%, respectively. This QTL overlapped with one regions previsiouly know to regulate abdominal fat in chickens and the QTL region encompassed two putative candidate genes overlapping with signatures of selection and inherited CNVs. Our findings are helpful to better understand the genetic regulation of fatness in chickens. Resumo: O teor de gordura na carcaça é uma característica economicamente importante em frangos comerciais. O uso de SNPs de alta densidade em todo o genoma pode melhorar o poder e a resolução para identificar QTLs, genes candidatos putativos e variações no número de cópias (CNVs), para programas de seleção. O principal objetivo deste estudo foi identificar janelas genômicas e possíveis genes candidatos para o conteúdo de gordura na carcaça. Verificamos a sobreposição de QTL com regiões demonstrando assinaturas de seleção e CNVs herdadas identificadas na mesma população. Um total de 497 galinhas com 42 dias de idade da EMBRAPA F2 Chicken Resource Population desenvolvidas para estudos QTL foram genotipadas com o arranjo de genótipos SNP 600K (Affymetrix®) e fenotipadas para peso de gordura na carcaça (CFCW) e teor de gordura na carcaça seca. matéria básica (CFCDM). Após o controle de qualidade, um total de 480 amostras e 371.557 SNPs anotados em cromossomos autossômicos (GGA1-28) baseados em Gallus_gallus-5.0 (NCBI) foram mantidos para análise posterior. As análises de GWAS foram realizadas com o software GenSel usando o método de BayesB (π = 0,9988) para identificar janelas genômicas associadas ao CFCW ou CFC%. Foram identificadas 15 janelas genômicas associadas a% CFC em GGA1, 7, 15, 20 e 28 e, a partir delas, identificamos duas janelas adjacentes em GGA7 consideradas como os mesmos QTLs explicando 1,31 e 2,18% da variância genética para CFCW e CFC% , respectivamente. Este QTL se sobrepunha a uma das regiões previsamente conhecidas para regular a gordura abdominal em frangos e a região QTL englobava dois supostos genes candidatos que se sobrepunham com assinaturas de seleção e CNVs herdadas. Nossas descobertas são úteis para entender melhor a regulação genética da gordura em frangos

Optically pure, structural and fluorescent analogues of a dimeric Y4 receptor agonist derived by an olefin metathesis approach

The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective Neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors, and as a lead compound for anti-obesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labelled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)- diaminosuberoyl containing peptide, (R,R)-1 had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore the sulfo-Cy5 labelled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors

Methods for interpreting lists of affected genes obstained in a DNA microarray experiment

Background - The aim of this paper was to describe and compare the methods used and the results obtained by the participants in a joint EADGENE (European Animal Disease Genomic Network of Excellence) and SABRE (Cutting Edge Genomics for Sustainable Animal Breeding) workshop focusing on post analysis of microarray data. The participating groups were provided with identical lists of microarray probes, including test statistics for three different contrasts, and the normalised log-ratios for each array, to be used as the starting point for interpreting the affected probes. The data originated from a microarray experiment conducted to study the host reactions in broilers occurring shortly after a secondary challenge with either a homologous or heterologous species of Eimeria. Results - Several conceptually different analytical approaches, using both commercial and public available software, were applied by the participating groups. The following tools were used: Ingenuity Pathway Analysis, MAPPFinder, LIMMA, GOstats, GOEAST, GOTM, Globaltest, TopGO, ArrayUnlock, Pathway Studio, GIST and AnnotationDbi. The main focus of the approaches was to utilise the relation between probes/genes and their gene ontology and pathways to interpret the affected probes/genes. The lack of a well-annotated chicken genome did though limit the possibilities to fully explore the tools. The main results from these analyses showed that the biological interpretation is highly dependent on the statistical method used but that some common biological conclusions could be reached. Conclusion - It is highly recommended to test different analytical methods on the same data set and compare the results to obtain a reliable biological interpretation of the affected genes in a DNA microarray experimen

Regional differences in recombination hotspots between two chicken populations

<p>Abstract</p> <p>Background</p> <p>Although several genetic linkage maps of the chicken genome have been published, the resolution of these maps is limited and does not allow the precise identification of recombination hotspots. The availability of more than 3.2 million SNPs in the chicken genome and the recent advances in high throughput genotyping techniques enabled us to increase marker density for the construction of a high-resolution linkage map of the chicken genome. This high-resolution linkage map allowed us to study recombination hotspots across the genome between two chicken populations: a purebred broiler line and a broiler × broiler cross. In total, 1,619 animals from the two different broiler populations were genotyped with 17,790 SNPs.</p> <p>Results</p> <p>The resulting linkage map comprises 13,340 SNPs. Although 360 polymorphic SNPs that had not been assigned to a known chromosome on chicken genome build WASHUC2 were included in this study, no new linkage groups were found. The resulting linkage map is composed of 31 linkage groups, with a total length of 3,054 cM for the sex-average map of the combined population. The sex-average linkage map of the purebred broiler line is 686 cM smaller than the linkage map of the broiler × broiler cross.</p> <p>Conclusions</p> <p>In this study, we present a linkage map of the chicken genome at a substantially higher resolution than previously published linkage maps. Regional differences in recombination hotspots between the two mapping populations were observed in several chromosomes near the telomere of the p arm; the sex-specific analysis revealed that these regional differences were mainly caused by female-specific recombination hotspots in the broiler × broiler cross.</p

Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients

GM2 and GM1 gangliosidoses are genetic, neurodegenerative lysosomal sphingolipid storage disorders. The earlier the age of onset, the more severe the clinical presentation and progression, with infantile, juvenile and late-onset presentations broadly delineated into separate phenotypic subtypes. Gene and substrate reduction therapies, both of which act directly on sphingolipidosis are entering clinical trials for treatment of these disorders. Simple to use biomarkers for disease monitoring are urgently required to support and expedite these clinical trials. Here, lysosphingolipid and protein biomarkers of sphingolipidosis and neuropathology respectively, were assessed in plasma samples from 33 GM2 gangliosidosis patients, 13 GM1 gangliosidosis patients, and compared to 66 controls. LysoGM2 and lysoGM1 were detectable in 31/33 GM2 gangliosidosis and 12/13 GM1 gangliosidosis patient samples respectively, but not in any controls. Levels of the axonal damage marker Neurofilament light (NF-L) were highly elevated in both GM2 and GM1 gangliosidosis patient plasma samples, with no overlap with controls. Levels of the astrocytosis biomarker Glial fibrillary acidic protein (GFAP) were also elevated in samples from both patient populations, albeit with some overlap with controls. In GM2 gangliosidosis patient plasma NF-L, Tau, GFAP and lysoGM2 were all most highly elevated in infantile onset patients, indicating a relationship to severity and phenotype. Plasma NF-L and liver lysoGM2 were also elevated in a GM2 gangliosidosis mouse model, and were lowered by treatment with a drug that slowed disease progression. These results indicate that lysosphingolipids and NF-L/GFAP have potential to monitor pharmacodynamics and pathogenic processes respectively in GM2 and GM1 gangliosidoses patients

Porcine colonization of the Americas: a 60k SNP story.

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Strong signatures of selection in the domestic pig genome

Domestication of wild boar (Sus scrofa) and subsequent selection have resulted in dramatic phenotypic changes in domestic pigs for a number of traits, including behavior, body composition, reproduction, and coat color. Here we have used whole-genome resequencing to reveal some of the loci that underlie phenotypic evolution in European domestic pigs. Selective sweep analyses revealed strong signatures of selection at three loci harboring quantitative trait loci that explain a considerable part of one of the most characteristic morphological changes in the domestic pig—the elongation of the back and an increased number of vertebrae. The three loci were associated with the NR6A1, PLAG1, and LCORL genes. The latter two have repeatedly been associated with loci controlling stature in other domestic animals and in humans. Most European domestic pigs are homozygous for the same haplotype at these three loci. We found an excess of derived nonsynonymous substitutions in domestic pigs, most likely reflecting both positive selection and relaxed purifying selection after domestication. Our analysis of structural variation revealed four duplications at the KIT locus that were exclusively present in white or white-spotted pigs, carrying the Dominant white, Patch, or Belt alleles. This discovery illustrates how structural changes have contributed to rapid phenotypic evolution in domestic animals and how alleles in domestic animals may evolve by the accumulation of multiple causative mutations as a response to strong directional selection

Altered hippocampal epigenetic regulation underlying reduced cognitive development in response to early life environmental insults

The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, VWF and LRRC32, which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.</p

Accuracy of Predicted Genomic Breeding Values in Purebred and Crossbred Pigs

Genomic selection has been widely implemented in dairy cattle breeding when the aim is to improve performance of purebred animals. In pigs, however, the final product is a crossbred animal. This may affect the efficiency of methods that are currently implemented for dairy cattle. Therefore, the objective of this study was to determine the accuracy of predicted breeding values in crossbred pigs using purebred genomic and phenotypic data. A second objective was to compare the predictive ability of SNPs when training is done in either single or multiple populations for four traits: age at first insemination (AFI); total number of piglets born (TNB); litter birth weight (LBW); and litter variation (LVR). We performed marker-based and pedigree-based predictions. Within-population predictions for the four traits ranged from 0.21 to 0.72. Multi-population prediction yielded accuracies ranging from 0.18 to 0.67. Predictions across purebred populations as well as predicting genetic merit of crossbreds from their purebred parental lines for AFI performed poorly (not significantly different from zero). In contrast, accuracies of across-population predictions and accuracies of purebred to crossbred predictions for LBW and LVR ranged from 0.08 to 0.31 and 0.11 to 0.31, respectively. Accuracy for TNB was zero for across-population prediction, whereas for purebred to crossbred prediction it ranged from 0.08 to 0.22. In general, marker-based outperformed pedigree-based prediction across populations and traits. However, in some cases pedigree-based prediction performed similarly or outperformed marker-based prediction. There was predictive ability when purebred populations were used to predict crossbred genetic merit using an additive model in the populations studied. AFI was the only exception, indicating that predictive ability depends largely on the genetic correlation between PB and CB performance, which was 0.31 for AFI. Multi-population prediction was no better than within-population prediction for the purebred validation set. Accuracy of prediction was very trait-dependent