ALBERT

Description: Background: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. Methods: Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. Results: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained

Description: Background Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. Methods Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. Results Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained

Description: Background: Innate immune responses are evolutionarily conserved processes that provide crucial protection against invading organisms. Gene activation by potent NF-kappaB transcription factors is essential both in mammals and Drosophila during infection and stress challenges. If not strictly controlled this potent defense system can activate autoimmune and inflammatory stress reactions, with deleterious consequences for the organism. Negative regulation to prevent gene activation in healthy organisms, in the presence of the commensal gut flora, is however not well understood. Results: We show that the Drosophila homolog of mammalian Oct1/POU2F1 transcription factor, called Nubbin (Nub) is a repressor of NF-kappaB/Relish-driven antimicrobial peptide gene expression in flies. In nub1 mutants, which lack Nub-PD protein, excessive expression of antimicrobial peptide genes occurs in the absence of infection, leading to significant reduction of the numbers of cultivatable gut commensal bacteria. This aberrant immune gene expression was effectively blocked by expression of Nub from a transgene. We have identified an upstream regulatory region, containing a cluster of octamer sites, which is required for repression of antimicrobial peptide gene expression in healthy flies. Chromatin immuno-precipitation experiments demonstrated that Nub binds to octamer-containing promoter fragments of several immune genes. Gene expression profiling revealed that Drosophila Nub negatively regulates many genes that are involved in immune and stress responses, while it is a positive regulator of genes involved in differentiation and metabolism. Conclusions: This study demonstrates that a large number of genes that are activated by NF-kappaB/Relish in response to infection are normally repressed by the evolutionarily conserved Oct/POU transcription factor Nub. This prevents uncontrolled gene activation and supports the existence of a normal gut flora. We suggest that Nub protein plays an ancient role, shared with mammalian Oct/POU transcription factors, to moderate responses to immune challenge, thereby increasing the tolerance to biotic stress.

Description: Background: The Sequence Read Archive (SRA) is the largest public repository of sequencing data from the nextgeneration of sequencing platforms including Illumina (Genome Analyzer, HiSeq, MiSeq, .etc),Roche 454 GS System, Applied Biosystems SOLiD System, Helicos Heliscope, PacBio RS, andothers. Results: SRAdb is an attempt to make query of the metadata associated with SRA submission, study, sample,experiment and run more robust and precise, and make access to sequencing data in the SRA easier.We have parsed all the SRA metadata into a SQLite database that is routinely updated and can beeasily distributed. The SRAdb R/Bioconductor package then utilizes this SQLite database forquerying and accessing metadata. Full text search functionality makes querying metadata veryflexible and powerful. Fastq files associated with query results can be downloaded easily for localanalysis. The package also includes an interface from R to a popular genome browser, the IntegratedGenomics Viewer. Conclusions: SRAdb Bioconductor package provides a convenient and integrated framework to query and accessSRA metadata quickly and powerfully from within R.

Description: Background: One of the most widely accepted ecomorphological relationships in vertebrates is the negative correlation between intestinal length and proportion of animal prey in diet. While many fish groups exhibit this general pattern, other clades demonstrate minimal, and in some cases contrasting, associations between diet and intestinal length. Moreover, this relationship and its evolutionary derivation have received little attention from a phylogenetic perspective. This study documents the phylogenetic development of intestinal length variability, and resultant correlation with dietary habits, within a molecular phylogeny of 28 species of terapontid fishes. The Terapontidae (grunters), an ancestrally euryhaline-marine group, is the most trophically diverse of Australia's freshwater fish families, with widespread shifts away from animal-prey-dominated diets occurring since their invasion of fresh waters. Results: Description of ontogenetic development of intestinal complexity of terapontid fishes, in combination with ancestral character state reconstruction, demonstrated that complex intestinal looping (convolution) has evolved independently on multiple occasions within the family. This modification of ontogenetic development drives much of the associated interspecific variability in intestinal length evident in terapontids. Phylogenetically informed comparative analyses (phylogenetic independent contrasts) showed that the interspecific differences in intestinal length resulting from these ontogenetic developmental mechanisms explained ~65% of the variability in the proportion of animal material in terapontid diets. Conclusions: The ontogenetic development of intestinal complexity appears to represent an important functional innovation underlying the extensive trophic differentiation seen in Australia's freshwater terapontids, specifically facilitating the pronounced shifts away from carnivorous (including invertebrates and vertebrates) diets evident across the family. The capacity to modify intestinal morphology and physiology may also be an important facilitator of trophic diversification during other phyletic radiations.

Description: Background: Each omics platform is now able to generate a large amount of data. Genomics, proteomics,metabolomics, interactomics are compiled at an ever increasing pace and now form a core part of thefundamental systems biology framework. Recently, several integrative approaches have beenproposed to extract meaningful information. However, these approaches lack of visualisation outputsto fully unravel the complex associations between different biological entities. Results: The multivariate statistical approaches 'regularized Canonical Correlation Analysis' and 'sparsePartial Least Squares regression' were recently developed to integrate two types of highlydimensional 'omics' data and to select relevant information. Using the results of these methods, wepropose to revisit few graphical outputs to better understand the relationships between two 'omics'data and to better visualise the correlation structure between the different biological entities. Thesegraphical outputs include Correlation Circle plots, Relevance Networks and Clustered Image Maps.We demonstrate the usefulness of such graphical outputs on several biological data sets and furtherassess their biological relevance using gene ontology analysis. Conclusions: Such graphical outputs are undoubtedly useful to aid the interpretation of these promising integrativeanalysis tools and will certainly help in addressing fundamental biological questions andunderstanding systems as a whole. AvailabilityThe graphical tools described in this paper are implemented in the freely available R packagemixOmics and in its associated web application.

Description: Background: Metastasis is characterized by spreading of neoplastic cells to an organ other than where they originated and is the predominant cause of death among cancer patients. This holds true for melanoma, whose incidence is increasing more rapidly than any other cancer and once disseminated has few therapeutic options. Here we performed whole exome sequencing of two sets of matched normal and metastatic tumor DNAs. Results: Using stringent criteria, we evaluated the similarities and differences between the lesions. We find that in both cases, 96% of the single nucleotide variants are shared between the two metastases indicating that clonal populations gave rise to the distant metastases. Analysis of copy number variation patterns of both metastatic sets revealed a trend similar to that seen with our single nucleotide variants. Analysis of pathway enrichment on tumor sets shows commonly mutated pathways enriched between individual sets of metastases and all metastases combined. Conclusions: These data provide a proof-of-concept suggesting that individual metastases may have sufficient similarity for successful targeting of driver mutations.

Description: Background: There has been a considerable increase in studies investigating rates of diversification and character evolution, with one of the promising techniques being the BiSSE method (binary state speciation and extinction). This study uses simulations under a variety of different sample sizes (number of tips) and asymmetries of rate (speciation, extinction, character change) to determine BiSSE's ability to test hypotheses, and investigate whether the method is susceptible to confounding effects. Results: We found that the power of the BiSSE method is severely affected by both sample size and high tip ratio bias (one character state dominates among observed tips). Sample size and high tip ratio bias also reduced accuracy and precision of parameter estimation, and resulted in the inability to infer which rate asymmetry caused the excess of a character state. In low tip ratio bias scenarios with appropriate tip sample size, BiSSE accurately estimated the rate asymmetry causing character state excess, avoiding the issue of confounding effects. Conclusions: Based on our findings, we recommend that future studies utilizing BiSSE that have fewer than 300 terminals and/or have datasets where high tip ratio bias is observed (i.e., fewer than 10% of species are of one character state) should be extremely cautious with the interpretation of hypothesis testing results.

Description: Background: Previously described methods to separate dissolved U(IV) from dissolved U(VI) under acidic anoxic conditions prior to laboratory analysis were ineffective with materials currently available commercially. Three strong anion exchange resins were examined for their efficiency in separating, recovering, and preserving both redox states during separation. Results: Under oxic conditions, recovery of U(VI) from three exchange resins (Bio-Rad AG(R) 1x8 Poly-Prep(R) prefilled columns, Bio-Rad AG(R) 1x8 powder, and Dowex(R) 1x8 powder) ranged from 72% to 100% depending on the dosed mass, eluent volume, and resin selected. Dowex(R) 1x8 resin was the only resin found to provide 100% recovery of U(VI) with fewer than 5 bed volumes of eluent. Under anoxic conditions, all three resins oxidized U(IV) in aqueous solutions with relatively low U(IV) concentrations (

Description: Background: Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer.Recent data suggests excess mortality in mutation carriers beyond that conferred byneoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCAproteins in endothelial and cardiomyocyte function. We therefore tested the association ofBRCA2 variants with clinical cardiovascular disease (CVD). Methods: Using data from 1,170 individuals included in two multi-ethnic population-based studies(SHARE and SHARE-AP), the association between BRCA2 variants and CVD wasevaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) 〉 0.01 had beenpreviously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals(9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI,stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for ageand sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using theMassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the SouthAsian subset of an international case-control study of acute MI (INTERHEART), andrs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk ofMyocardial Infarction Study (PROMIS). Results: Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, wereassociated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) inthe SHARE studies. Analysis by specific ethnicities demonstrated an association with CVDfor both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No associationwas observed in the European and Chinese subgroups. A non-significant trend towards anassociation between rs11571836 and lower risk of MI was observed in South Asians fromINTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS[OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studiesresulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06). Conclusions: Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnicpopulation, these results were not replicated in two South Asian case-control studies ofincident MI. Future studies exploring the association between BRCA variants andcardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVDpathogenesis.