Systematic Exploration of Synergistic Drug Pairs

Drug synergy allows a therapeutic effect to be achieved with lower doses of component drugs. Drug synergy can result when drugs target the products of genes that act in parallel pathways (‘specific synergy’). Such cases of drug synergy should tend to correspond to synergistic genetic interaction between the corresponding target genes. Alternatively, ‘promiscuous synergy’ can arise when one drug non-specifically increases the effects of many other drugs, for example, by increased bioavailability. To assess the relative abundance of these drug synergy types, we examined 200 pairs of antifungal drugs in S. cerevisiae. We found 38 antifungal synergies, 37 of which were novel. While 14 cases of drug synergy corresponded to genetic interaction, 92% of the synergies we discovered involved only six frequently synergistic drugs. Although promiscuity of four drugs can be explained under the bioavailability model, the promiscuity of Tacrolimus and Pentamidine was completely unexpected. While many drug synergies correspond to genetic interactions, the majority of drug synergies appear to result from non-specific promiscuous synergy

Prioritizing causal disease genes using unbiased genomic features

Background: Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits. Results: To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM. Conclusion: Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0534-8) contains supplementary material, which is available to authorized users

Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism

Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases

A critical assessment of Mus musculus gene function prediction using integrated genomic evidence

Background: Several years after sequencing the human genome and the mouse genome, much remains to be discovered about the functions of most human and mouse genes. Computational prediction of gene function promises to help focus limited experimental resources on the most likely hypotheses. Several algorithms using diverse genomic data have been applied to this task in model organisms; however, the performance of such approaches in mammals has not yet been evaluated. Results: In this study, a standardized collection of mouse functional genomic data was assembled; nine bioinformatics teams used this data set to independently train classifiers and generate predictions of function, as defined by Gene Ontology (GO) terms, for 21,603 mouse genes; and the best performing submissions were combined in a single set of predictions. We identified strengths and weaknesses of current functional genomic data sets and compared the performance of function prediction algorithms. This analysis inferred functions for 76% of mouse genes, including 5,000 currently uncharacterized genes. At a recall rate of 20%, a unified set of predictions averaged 41% precision, with 26% of GO terms achieving a precision better than 90%. Conclusion: We performed a systematic evaluation of diverse, independently developed computational approaches for predicting gene function from heterogeneous data sources in mammals. The results show that currently available data for mammals allows predictions with both breadth and accuracy. Importantly, many highly novel predictions emerge for the 38% of mouse genes that remain uncharacterized

Genome Analysis Reveals Interplay between 5′UTR Introns and Nuclear mRNA Export for Secretory and Mitochondrial Genes

In higher eukaryotes, messenger RNAs (mRNAs) are exported from the nucleus to the cytoplasm via factors deposited near the 5′ end of the transcript during splicing. The signal sequence coding region (SSCR) can support an alternative mRNA export (ALREX) pathway that does not require splicing. However, most SSCR–containing genes also have introns, so the interplay between these export mechanisms remains unclear. Here we support a model in which the furthest upstream element in a given transcript, be it an intron or an ALREX–promoting SSCR, dictates the mRNA export pathway used. We also experimentally demonstrate that nuclear-encoded mitochondrial genes can use the ALREX pathway. Thus, ALREX can also be supported by nucleotide signals within mitochondrial-targeting sequence coding regions (MSCRs). Finally, we identified and experimentally verified novel motifs associated with the ALREX pathway that are shared by both SSCRs and MSCRs. Our results show strong correlation between 5′ untranslated region (5′UTR) intron presence/absence and sequence features at the beginning of the coding region. They also suggest that genes encoding secretory and mitochondrial proteins share a common regulatory mechanism at the level of mRNA export

Interpreting Cancer Genomes Using Systematic Host Perturbations by Tumour Virus Proteins

Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations associated with cancer predisposition and large numbers of somatic genomic alterations. However, it remains challenging to distinguish between background, or “passenger” and causal, or “driver” cancer mutations in these datasets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. To test the hypothesis that genomic variations and tumour viruses may cause cancer via related mechanisms, we systematically examined host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways that go awry in cancer, such as Notch signalling and apoptosis. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches result in increased specificity for cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate prioritization of cancer-causing driver genes so as to advance understanding of the genetic basis of human cancer

Determination of FA Composition and Total Trans FA of Turkish Margarines by Capillary GLC

ABSTRACT: In this research, FA composition and total trans FA contents of 16 different brands of margarine (8 hard-type and 8 soft-type) sold in Turkey were determined by capillary GLC method. According to the results, the contents of saturated FA, monounsaturated FA, and PUFA were within the ranges of 23. 9-32.3, 44.0-61.9, and 14.2-24.1%, respectively, in hardtype margarines, and 27.0-39.9, 21.0-40.9, and 32.0-53.7%, respectively, in soft-type margarines. Hard-type margarines contained total trans FA concentrations of 20.1-34.3%, whereas softtype margarines contained less than 8.9% total trans FA. C 18:1 trans acid content was within the range of 18.5-29.8% in hardtype margarines, and it was significantly higher than the range in soft margarines (0.7-8.1%). C 18:1 trans acid was the major trans FA in all margarines, and C 18:3 trans acid concentrations were less than 0.2%. Trans FA, which are created by the partial hydrogenation of liquid vegetable oils in the manufacturing of margarine and vegetable shortening, increase serum levels of LDL cholesterol and decrease those of HDL cholesterol (1,2). The adverse effects of the trans FA on the ratio of total cholesterol to HDL cholesterol are twice that of saturated FA (3). Some epidemiological studies have also found a positive association between levels of trans FA intake and risk of cardiovascular disease (4,5). Owing to these concerns, the Food and Agriculture Organization and the World Health Organization recommended in 1994 that fats for human consumption contain less than 4% of the total fat as trans and urged the food industry to reduce the presence of trans fats in their products to these levels (6). Vegetable oil production was approximately 1.45 million tons per year between 1995 and 2000 in Turkey. About 30% of this production was used by the margarine industry. Total margarine production was 550 million kg, and consumption was 430 million kg per year. These results indicate that margarines have an important role in the consumption of vegetable oil in Turkey. Vegetable oil consumption is approximately 15.9 kg/person/year, and 6.3 kg of this value is from margarines (7). This paper presents the FA composition and total trans FA contents of Turkish margarines determined by capillary GLC. The trans isomers of the samples were evaluated in relation to health. EXPERIMENTAL PROCEDURES Sample selection. Seven different margarine companies are present in Turkey. Of these, five are major producers. Margarines produced by these companies are sold in all regions of Turkey. The five leading margarine companies produce 23 different brands (10 soft and 13 hard) of margarines. Of these, the top 16 best-selling brands (8 soft and 8 hard), which represented 85% of the market share, were selected for analysis and then purchased locally. Each brand was coded with a number Analysis. Each sample was homogenized and dehydrated with sodium sulfate, and the FA present were converted to methyl esters. Preparation of FAME. FAME were prepared from the margarines after alkaline hydrolysis, followed by methylation in methanol with 12.5% BF 3 as catalyst. The final concentration of the FAME was approximately 7 mg/mL in heptane (8). Capillary GLC. Analyses of the FAME by capillary GLC were carried out on a Hewlett-Packard 6890 chromatograph, equipped with an FID on a split injector (Chrompack, Middleburg, The Netherlands). A fused-silica capillary column (Chrompack) was used for the FAME analysis; CP TM -Sil 88, 50 m × 0.25 mm i.d., 0.2 µm film. GLC operating conditions were: temperature program of 130°C for 5 min, rising to 177°C at a rate of 2°C/min. Other GLC conditions were: injector temperature, 250°C; detector temperature, 250°C; carrier gas, helium at a flow rate of 1 mL/min. RESULTS AND DISCUSSION FA composition and trans FA of Turkish margarines are given i

Distance Based Indexing for String Proximity Search

In many database applications involving string data, it is common to have near neighbor queries (asking for strings that are similar to a query string) or nearest neighbor queries (asking for strings that are most similar to a query string). The similarity between strings is defined in terms of a distance function determined by the application domain. The most popular string distance measures are based on (a weighted) count of (i) character edit or (ii) block edit operations to transform one string into the other. Examples include the Levenshtein edit distance and the recently introduced compression distance. The main goa

Using encapsulatedNannochloropsis oculatain white chocolate as coloring agent

Durmaz, Yasar/0000-0002-1858-5882WOS: 000552158400001Colored chocolate products have gained importance in recent years. This increases the importance of identifying potential natural colorants for chocolate technology. in this study,Nannochloropsis oculatamicroalgae which were grown by using tubular photobioreactor in two different forms (spray-dried and encapsulated by using a spray dryer and maltodextrin (50%)), were used in white chocolate composition (0.00-0.75 g) as a coloring agent. the color stability (Delta E) values for all sample groups were determined below the visibility level of 3.0 under accelerated shelf life conditions (25 degrees C/70% RH) for 28 days. the water activity, moisture and ash content, hardness, yield stress, plastic viscosity, and melting properties of white chocolate samples showed no significant differences (P > 0.05) and the other quality characteristics were found to be acceptable. the chlorophyll-acontent of white chocolate samples was between 9.60-22.9 mu g g(-1). It was found that the sensory properties of the samples as appearance, texture, melting in the mouth, and odor were not affected by level of microalgae use (P > 0.05). However, it was noteworthy that there was a decrease in taste and overall acceptability according to usage level of dried and encapsulated microalgae (P < 0.05). As a result, it was determined that spray-drying technique is preferred for use of microalgae in chocolate composition

Serum IGF-1 and IGFBP-3 levels in subclinical hypothyroid women

Thyroid status is known to influence growth in mammals. The aim of this study is to investigate the possible relationship between autoimmune subclinical hypothyroidism and growth hormone (GH), insulin-like growth factor-1(IGF-1) and insulin-like growth factor binding protein-3(IGFBP-3) levels. Thirty-five women with autoimmune subclinical hypothyroidism, 33 years of age, were used as controls and enrolled in the study. Free triiodothyronin (FT3), free thyroxin(FT4), thyrotropin(TSH), anti-thyroid peroxidase(Anti-TPO), anti-thyroglobuline(Anti-Tg), GH, IGF-1 and IGFBP-3 levels were measured in blood samples and correlations among these parameters were evaluated. We found no significant differences in GH, IGF-1 or IGFBP-3 between patients and controls. In patients and controls, there were no correlations among thyroid hormones and IGF-1 or IGFBP-3 levels, but GH levels were correlated with FT3, FT4 and TSH only in patients' group. In controls, only IGF-1 and IGFBP-3 levels were correlated. The present study suggests that subclinical hypothyroidism with high TSH and antibody status does not affect IGF-1 and IGFBP-3 levels in adult women. To our knowledge, this is the first study concerning the relationship between autoimmune subclinical hypothyroidism and IGF-1 and IGFBP-3 levels