FACIL: Fast and Accurate Genetic Code Inference and Logo

MOTIVATION: The intensification of DNA sequencing will increasingly unveil uncharacterized species with potential alternative genetic codes. A total of 0.65% of the DNA sequences currently in Genbank encode their proteins with a variant genetic code, and these exceptions occur in many unrelated taxa. RESULTS: We introduce FACIL (Fast and Accurate genetic Code Inference and Logo), a fast and reliable tool to evaluate nucleic acid sequences for their genetic code that detects alternative codes even in species distantly related to known organisms. To illustrate this, we apply FACIL to a set of mitochondrial genomic contigs of Globobulimina pseudospinescens. This foraminifer does not have any sequenced close relative in the databases, yet we infer its alternative genetic code with high confidence values. Results are intuitively visualized in a Genetic Code Logo. Availability and implementation: FACIL is available as a web-based service at http://www.cmbi.ru.nl/FACIL/ and as a stand-alone program.     

MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer

The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p<0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p<0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer.     

Mining relational paths in integrated biomedical data

Much life science and biology research requires an understanding of complex relationships between biological entities (genes, compounds, pathways, diseases, and so on). There is a wealth of data on such relationships in publicly available datasets and publications, but these sources are overlapped and distributed so that finding pertinent relational data is increasingly difficult. Whilst most public datasets have associated tools for searching, there is a lack of searching methods that can cross data sources and that in particular search not only based on the biological entities themselves but also on the relationships between them. In this paper, we demonstrate how graph-theoretic algorithms for mining relational paths can be used together with a previous integrative data resource we developed called Chem2Bio2RDF to extract new biological insights about the relationships between such entities. In particular, we use these methods to investigate the genetic basis of side-effects of thiazolinedione drugs, and in particular make a hypothesis for the recently discovered cardiac side-effects of Rosiglitazone (Avandia) and a prediction for Pioglitazone which is backed up by recent clinical studies.     

Copy number variation across European populations

Genome analysis provides a powerful approach to test for evidence of genetic variation within and between geographical regions and local populations. Copy number variants which comprise insertions, deletions and duplications of genomic sequence provide one such convenient and informative source. Here, we investigate copy number variants from genome wide scans of single nucleotide polymorphisms in three European population isolates, the island of Vis in Croatia, the islands of Orkney in Scotland and the South Tyrol in Italy. We show that whereas the overall copy number variant frequencies are similar between populations, their distribution is highly specific to the population of origin, a finding which is supported by evidence for increased kinship correlation for specific copy number variants within populations.     

Dietary lipids modify the age-associated changes in intestinal uptake of fructose in rats

Because reduced nutrient absorption may contribute to malnourishment in the elderly, age and diet modulate fructose uptake in mice, and alterations in fructose uptake may be paralleled by changes in the abundance of fructose transporters, the objectives of this study were to determine 1) the effects of aging on fructose absorption in rats, 2) the effect of feeding diets enriched with saturated fatty acids (SFA) vs. polyunsaturated fatty acids (PUFA), and 3) the mechanisms of these age-and diet-associated changes. Male Fischer 344 rats aged 1, 9, and 24 mo received isocaloric diets enriched with SFA or PUFA. The uptake of (14)C-labeled D-fructose was determined in vitro using the intestinal sheet method. Northern and Western blot analyses and immunohistochemistry were used to determine the abundance of sodium-independent glucose and fructose transporters (GLUT)2 and GLUT5. When expressed on the basis of mucosal surface area, jejunal fructose uptake was increased in 9 and 24 mo compared with 1-mo-old animals fed SFA. PUFA-fed animals demonstrated increased fructose uptake at 24 mo compared with younger animals. Ileal fructose uptake was increased with SFA vs. PUFA in 9-mo-old rats but was reduced with SFA in 1- and 24-mo-old rats. Variations in GLUT2 and GLUT5 abundance did not parallel changes in uptake. These results indicate that 1) age increases fructose uptake when expressed on the basis of mucosal surface area, 2) age influences the adaptive response to dietary lipid modifications, and 3) alterations in fructose uptake are not explained by variations in GLUT2 or GLUT5.     

Modeling allosteric regulation of de novo pyrimidine biosynthesis in Escherichia coli

With the emergence of multifaceted bioinformatics-derived data, it is becoming possible to merge biochemical and physiological information to develop a new level of understanding of the metabolic complexity of the cell. The biosynthetic pathway of de novo pyrimidine nucleotide metabolism is an essential capability of all free-living cells, and it occupies a pivotal position relative to metabolic processes that are involved in the macromolecular synthesis of DNA, RNA and proteins, as well as energy production and cell division. This regulatory network in all enteric bacteria involves genetic, allosteric, and physiological control systems that need to be integrated into a coordinated set of metabolic checks and balances. Allosterically regulated pathways constitute an exciting and challenging biosynthetic system to be approached from a mathematical perspective. However, to date, a mathematical model quantifying the contribution of allostery in controlling the dynamics of metabolic pathways has not been proposed. In this study, a direct, rigorous mathematical model of the de novo biosynthesis of pyrimidine nucleotides is presented. We corroborate the simulations with experimental data available in the literature and validate it with derepression experiments done in our laboratory. The model is able to faithfully represent the dynamic changes in the intracellular nucleotide pools that occur during metabolic transitions of the de novo pyrimidine biosynthetic pathway and represents a step forward in understanding the role of allosteric regulation in metabolic control.     

A kin-selection approach to the resolution of sex-ratio conflict between mates

We investigate an instance of conflict between mates over the sex ratio of their brood. We construct a kin-selection model for the evolution of the sex ratio assuming local resource competition (LRC) among females. We explore two basic scenarios: (a) the case where parents make simultaneous sex-ratio decisions (the simultaneous allocation model); and (b) the case where parental sex-ratio decisions occur one after the other (the sequential allocation model). In the simultaneous investment model, resolution of the conflict between mates depends on the extent to which relative paternal contribution influences the brood sex ratio. In the sequential allocation model, fathers determine primary sex-ratio through fertilization bias; then mothers modify the paternal sex-ratio decision by adjusting the level of investment of some resource that contributes to offspring survival. Under the sequential model, a compromise is always achieved; however this compromise favours one perspective or the other, depending on the extent to which maternal investment influences offspring survival.