Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

geneSurv: An interactive web-based tool for survival analysis in genomics research.

Mon, 11/09/2017 - 12:55
geneSurv: An interactive web-based tool for survival analysis in genomics research. Comput Biol Med. 2017 Sep 05;89:487-496 Authors: Korkmaz S, Goksuluk D, Zararsiz G, Karahan S Abstract Survival analysis methods are often used in cancer studies. It has been shown that the combination of clinical data with genomics increases the predictive performance of survival analysis methods. But, this leads to a high-dimensional data problem. Fortunately, new methods have been developed in the last decade to overcome this problem. However, there is a strong need for easily accessible, user-friendly and interactive tool to perform survival analysis in the presence of genomics data. We developed an open-source and freely available web-based tool for survival analysis methods that can deal with high-dimensional data. This tool includes classical methods, such as Kaplan-Meier, Cox proportional hazards regression, and advanced methods, such as penalized Cox regression and Random Survival Forests. It also offers an optimal cutoff determination method based on maximizing several test statistics. The tool has a simple and interactive interface, and it can handle high dimensional data through feature selection and ensemble methods. To dichotomize gene expressions, geneSurv can identify optimal cutoff points. Users can upload their microarray, RNA-Seq, chip-Seq, proteomics, metabolomics or clinical data as a nxp dimensional data matrix, where n refers to samples and p refers to genes. This tool is available free at www.biosoft.hacettepe.edu.tr/geneSurv. All source code is available at https://github.com/selcukorkmaz/geneSurv under the GPL-3 license. PMID: 28889076 [PubMed - as supplied by publisher]

Imazalil exposure induces gut microbiota dysbiosis and hepatic metabolism disorder in zebrafish.

Mon, 11/09/2017 - 12:55
Imazalil exposure induces gut microbiota dysbiosis and hepatic metabolism disorder in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol. 2017 Sep 06;: Authors: Jin C, Luo T, Zhu Z, Pan Z, Yang J, Wang W, Fu Z, Jin Y Abstract The fungicide imazalil (IMZ) is used extensively to preserve freshness, prevent decay and control fungal infections in fruits, vegetables or other plants. Recently, some studies have reported that the real in aquatic systems have reached very high levels. Here, male adult zebrafish were exposed to 100 and 1000μg/L IMZ for 1, 7, 21days, and the gut microbiota and hepatic metabolism were evaluated. Exposure to a high concentration of IMZ for 21days decreased mucin secretion in the gut. Sequencing of the V3-V4 region of the bacterial 16S rRNA gene revealed a significant increase in the diversity of gut microbiota in male zebrafish. At the phylum level, the composition of Proteobacteria and Bacteroidetes was decreased, while those Fusobacteria and Firmicutes increased in the gut after exposure to 1000μg/L IMZ for 21days. At the genus level, 29 species of microorganisms were significantly changed after IMZ exposure. Based on GC/MS metabolomics analysis, 101 metabolites were observably significantly altered in the 1000μg/L IMZ-treatment group. These changed metabolites were mainly associated with the pathway of glycolysis, amino acid metabolism, and lipid metabolism. In addition, the transcription of some genes related to glycolysis and lipid metabolism, including Aco, Cpt1, Acc1, Srebp1a and Fas, was decreased significantly in the liver of zebrafish when exposed to 100 and 1000μg/L IMZ for 7 or 21days. These results indicated that exposure to IMZ could cause gut microbiota dysbiosis and metabolic disorders in adult zebrafish. PMID: 28888875 [PubMed - as supplied by publisher]

Impact of boiling on free and bound phenolic profile and antioxidant activity of commercial gluten-free pasta.

Mon, 11/09/2017 - 12:55
Impact of boiling on free and bound phenolic profile and antioxidant activity of commercial gluten-free pasta. Food Res Int. 2017 Oct;100(Pt 2):69-77 Authors: Rocchetti G, Lucini L, Chiodelli G, Giuberti G, Montesano D, Masoero F, Trevisan M Abstract Cooking by boiling dry pasta could have varying degrees of influence on nutritional and functional components. In the present study, its effect on total phenolic content and antioxidant capacity, as well as on the comprehensive profile of free and bound phenolics, was investigated in six commercial gluten-free (GF) pasta products. Overall, the heat treatment caused a significant reduction (P<0.01) of the total phenolic content as well as FRAP reducing power and ORAC radical scavenging, with significant differences among the pasta samples considered. The highest values were recorded in free phenolic fraction remaining in black rice (41mggallic acid equivalents100g(-1) and 25mmolTrolox Equivalents100g(-1)) and quinoa (24mggallic acid equivalents100g(-1) and 14mmolTrolox Equivalents100g(-1)) cooked GF pasta. Significant correlations (P<0.01) could be found between total phenolics and both the antioxidant capacity assays performed. UHPLC-ESI/QTOF-MS mass profiling allowed confirming the spectrophotometric results, while identifying the amount of free and bound fractions. Among phenolic classes, lignans exhibited the highest decrease during the cooking process, followed by stilbenes and flavonoids. However, phenolic acids and other phenolics showed the highest stability. Furthermore, cooking by boiling strongly lowered the bound-to-free ratio of phenolic compounds, by an averaged factor ranging from 14-folds for flavonoids to 5-folds for other classes of phenolics. PMID: 28888460 [PubMed - in process]

ANALYSIS OF EARTHWORM SUB-LETHAL TOXIC RESPONSES TO ATRAZINE EXPOSURE USING (1) H NUCLEAR MAGNETIC RESONANCE (NMR)-BASED METABOLOMICS.

Sun, 10/09/2017 - 12:21
ANALYSIS OF EARTHWORM SUB-LETHAL TOXIC RESPONSES TO ATRAZINE EXPOSURE USING (1) H NUCLEAR MAGNETIC RESONANCE (NMR)-BASED METABOLOMICS. Environ Toxicol Chem. 2017 Sep 09;: Authors: Dani VD, Simpson AJ, Simpson MJ Abstract Atrazine toxicity to earthworms is still not fully understood, particularly at sub-lethal concentrations. Because of the ubiquity of atrazine in the environment, it is imperative to understand the impacts of atrazine presence on soil-dwelling organisms. To examine this in detail, we used (1) H nuclear magnetic resonance (NMR)-based metabolomics to elucidate earthworm (Eisenia fetida) responses after a 48 h of atrazine exposure in contact tests. Earthworms were exposed to four sub-lethal concentrations of 362.4 ng/cm(2) , 181.2 ng/cm(2) , 90.6 ng/cm(2) and 45.3 ng/cm(2) , which correspond to 1/8(th) , 1/16(th) , 1/32(nd) and 1/64(th) of the LC50 value respectively. After exposure, polar metabolites were isolated from earthworm tissues and analyzed using (1) H NMR spectroscopy. Sub-lethal atrazine exposure induced a non-monotonic response with respect to exposure concentration and caused an overall suppression in earthworm metabolism. Maltose, fumarate, malate, threonine/lactate, adenosine-5'-triphosphate (ATP), betaine, scyllo-inositol, glutamate, arginine and glutamine were the metabolites identified as most sensitive to atrazine exposure. These observed fluctuations in the metabolic profile suggest that atrazine reduced ATP synthesis and negatively impacted the health of earthworms with acute sub-lethal exposure. Our study also demonstrates the utility of NMR-based metabolomics for the basic assessment of sub-lethal toxicity which can then be used for more targeted approaches with other molecular techniques. This article is protected by copyright. All rights reserved. PMID: 28888035 [PubMed - as supplied by publisher]

Metabolomics differences between silkworms (Bombyx mori) reared on fresh mulberry (Morus) leaves or artificial diets.

Sun, 10/09/2017 - 12:21
Related Articles Metabolomics differences between silkworms (Bombyx mori) reared on fresh mulberry (Morus) leaves or artificial diets. Sci Rep. 2017 Sep 08;7(1):10972 Authors: Dong HL, Zhang SX, Tao H, Chen ZH, Li X, Qiu JF, Cui WZ, Sima YH, Cui WZ, Xu SQ Abstract Silkworms (Bombyx mori) reared on artificial diets have great potential applications in sericulture. However, the mechanisms underlying the enhancement of metabolic utilization by altering silkworm nutrition are unclear. The aim of this study was to investigate the mechanisms responsible for the poor development and low silk protein synthesis efficiency of silkworms fed artificial diets. After multi-generational selection of the ingestive behavior of silkworms to artificial diets, we obtained two strains, one of which developed well and another in which almost all its larvae starved to death on the artificial diets. Subsequently, we analyzed the metabolomics of larval hemolymph by gas chromatography/liquid chromatography-mass spectrometry, and the results showed that vitamins were in critically short supply, whereas the nitrogen metabolic end product of urea and uric acid were enriched substantially, in the hemolymph of the silkworms reared on the artificial diets. Meanwhile, amino acid metabolic disorders, as well as downregulation of carbohydrate metabolism, energy metabolism, and lipid metabolism, co-occurred. Furthermore, 10 male-dominant metabolites and 27 diet-related metabolites that differed between male and female silkworms were identified. These findings provide important insights into the regulation of silkworm metabolism and silk protein synthesis when silkworms adapt to an artificial diet. PMID: 28887546 [PubMed - in process]

Dormant 5-lipoxygenase in inflammatory macrophages is triggered by exogenous arachidonic acid.

Sun, 10/09/2017 - 12:21
Related Articles Dormant 5-lipoxygenase in inflammatory macrophages is triggered by exogenous arachidonic acid. Sci Rep. 2017 Sep 08;7(1):10981 Authors: Sorgi CA, Zarini S, Martin SA, Sanchez RL, Scandiuzzi RF, Gijón MA, Guijas C, Flamand N, Murphy RC, Faccioli LH Abstract The differentiation of resident tissue macrophages from embryonic precursors and that of inflammatory macrophages from bone marrow cells leads to macrophage heterogeneity. Further plasticity is displayed through their ability to be polarized as subtypes M1 and M2 in a cell culture microenvironment. However, the detailed regulation of eicosanoid production and its involvement in macrophage biology remains unclear. Using a lipidomics approach, we demonstrated that eicosanoid production profiles between bone marrow-derived (BMDM) and peritoneal macrophages differed drastically. In polarized BMDMs, M1 and M2 phenotypes were distinguished by thromboxane B2, prostaglandin (PG) E2, and PGD2 production, in addition to lysophospholipid acyltransferase activity. Although Alox5 expression and the presence of 5-lipoxygenase (5-LO) protein in BMDMs was observed, the absence of leukotrienes production reflected an impairment in 5-LO activity, which could be triggered by addition of exogenous arachidonic acid (AA). The BMDM 5-LO regulatory mechanism was not responsive to PGE2/cAMP pathway modulation; however, treatment to reduce glutathione peroxidase activity increased 5-LO metabolite production after AA stimulation. Understanding the relationship between the eicosanoids pathway and macrophage biology may offer novel strategies for macrophage-associated disease therapy. PMID: 28887514 [PubMed - in process]

Sulfonolipids as novel metabolite markers of Alistipes and Odoribacter affected by high-fat diets.

Sun, 10/09/2017 - 12:21
Related Articles Sulfonolipids as novel metabolite markers of Alistipes and Odoribacter affected by high-fat diets. Sci Rep. 2017 Sep 08;7(1):11047 Authors: Walker A, Pfitzner B, Harir M, Schaubeck M, Calasan J, Heinzmann SS, Turaev D, Rattei T, Endesfelder D, Castell WZ, Haller D, Schmid M, Hartmann A, Schmitt-Kopplin P Abstract The gut microbiota generates a huge pool of unknown metabolites, and their identification and characterization is a key challenge in metabolomics. However, there are still gaps on the studies of gut microbiota and their chemical structures. In this investigation, an unusual class of bacterial sulfonolipids (SLs) is detected in mouse cecum, which was originally found in environmental microbes. We have performed a detailed molecular level characterization of this class of lipids by combining high-resolution mass spectrometry and liquid chromatography analysis. Eighteen SLs that differ in their capnoid and fatty acid chain compositions were identified. The SL called "sulfobacin B" was isolated, characterized, and was significantly increased in mice fed with high-fat diets. To reveal bacterial producers of SLs, metagenome analysis was acquired and only two bacterial genera, i.e., Alistipes and Odoribacter, were revealed to be responsible for their production. This knowledge enables explaining a part of the molecular complexity introduced by microbes to the mammalian gastrointestinal tract and can be used as chemotaxonomic evidence in gut microbiota. PMID: 28887494 [PubMed - in process]

Approaches and techniques to characterize cancer metabolism in vitro and in vivo.

Sun, 10/09/2017 - 12:21
Related Articles Approaches and techniques to characterize cancer metabolism in vitro and in vivo. Biochim Biophys Acta. 2017 Sep 05;: Authors: Zaimenko I, Lisec J, Stein U, Brenner W Abstract Cancer metabolism is wired to sustain uncontrollable cell proliferation and ensure cell survival. Given the multitude of available approaches to study metabolic alterations it remains a challenging task to select the most appropriate method. In this mini-review we describe how cancer metabolism can be studied in vitro and in vivo providing an overview of available approaches and techniques, discussing their advantages and drawbacks and guiding through selection of an appropriate method to address particular research needs. This work is particularly intended to those cancer researchers who are new in the field but want to investigate metabolic alterations in their cancer model systems. PMID: 28887205 [PubMed - as supplied by publisher]

From direct to indirect lithium targets: a comprehensive review of omics data.

Sat, 09/09/2017 - 12:05
From direct to indirect lithium targets: a comprehensive review of omics data. Metallomics. 2017 Sep 08;: Authors: Roux M, Dosseto A Abstract Metal ions are critical to a wide range of biological processes. Among them, lithium (Li) has been recognised for its benefit as a treatment for bipolar disorder (BD). However, we are yet to grasp the extent of its role in biological processes, despite its molecular targets having been extensively studied. Here we review a wide range of transcriptomic, proteomic and metabolomic studies in order to obtain a full picture of Li effects at various levels. Multifarious patterns of Li-regulated genes, proteins and metabolites are identified. Some of these patterns are explained as the outcomes of individual Li targets. For instance, Li inhibition of GSK-3 has a wide range of effects: axis development in embryos; cell and tissue differentiation, in particular neurogenesis and osteogenesis; or control of apoptosis. This results in neuroprotection and an attenuation of cognitive deficits. Lithium plays an important role in mitochondrial function, which it improves via its role in phospholipid metabolism and inositol depletion. This is also seen in metabolomics, where its role in the mitochondrial respiratory chain influences energy production and oxidative stress. Lithium also affects the proteins involved in the processing of APP, thus highlighting a possible involvement in Alzheimer's disease. Finally, Li also impacts lipid homeostasis, with studies showing that environmental exposure can impact lipid transport and prostaglandin synthesis. It is seldom possible to establish a causal relationship between Li targets at the molecular level and the resulting effects at the system level. For example, Li effects on adenylate cyclase regulation are not easily linked to any omic pattern despite the importance of the adenylate pathway. Nevertheless, refining our knowledge on the cellular functions of individual Li targets would improve our understanding and interpretation of omics data. This review demonstrates that Li is key to a wide range of processes at all levels, from neuroprotection to oxidative stress and energy production. A corollary of this work is the need for an increased awareness of environmental issues related to Li industrial wastes, in particular considering the widespread use of this metal in our modern society. PMID: 28885630 [PubMed - as supplied by publisher]

Dual RNA-Sequencing to Elucidate the Plant-Pathogen Duel.

Sat, 09/09/2017 - 12:05
Dual RNA-Sequencing to Elucidate the Plant-Pathogen Duel. Curr Issues Mol Biol. 2017 Sep 08;27:127-142 Authors: Naidoo S, Visser EA, Zwart L, Toit YD, Bhadauria V, Shuey LS Abstract RNA-sequencing technology has been widely adopted to investigate host responses during infection with pathogens. Dual RNA-sequencing (RNA-seq) allows the simultaneous capture of pathogen specific transcripts during infection, providing a more complete view of the interaction. In this review, we focus on the design of dual RNA-seq experiments and the application of downstream data analysis to gain biological insight into both sides of the interaction. Recent literature in this area demonstrates the power of the dual RNA-seq approach and shows that it is not limited to model systems where genomic resources are available. A reduction in sequencing cost and single cell transcriptomics coupled with protein and metabolite level dual approaches are set to enhance our understanding of plant-pathogen interactions. Sequencing costs continue to decrease and single cell transcriptomics is becoming more feasible. In combination with proteomics and metabolomics studies, these technological advances are likely to contribute to our understanding of the temporal and spatial aspects of dynamic plant-pathogen interactions. PMID: 28885179 [PubMed - as supplied by publisher]

6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates heptatocellular carcinoma in rats with NMR-based metabolic perturbations.

Sat, 09/09/2017 - 12:05
6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates heptatocellular carcinoma in rats with NMR-based metabolic perturbations. Future Sci OA. 2017 Aug;3(3):FSO202 Authors: Kumar P, Singh AK, Raj V, Rai A, Maity S, Rawat A, Kumar U, Kumar D, Prakash A, Guleria A, Saha S Abstract AIM: 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) was synthesized and evaluated for in-vivo antiproliferative action in diethylnitrosamine-induced hepatocarcinogenic rats. MATERIALS & METHODS: The antiproliferative effect of M1 was assessed by various biochemical parameters, histopathology of liver and HPLC analysis. Proton nuclear magnetic resonance-based serum metabolic study was implemented on rat sera to explore the effects of M1 on hepatocellular carcinoma-induced metabolic alterations. RESULTS: M1 showed protective action on liver and restored the arrangement of liver tissues in normal proportion. HPLC analysis displayed a good plasma drug concentration after its oral administration. Score plots of partial least squares discriminate analysis models exhibited that M1 therapy ameliorated hepatocellular carcinoma-induced metabolic alterations which signified its antiproliferative potential. CONCLUSION: M1 manifested notable antiproliferative profile, and warrants further investigation for future anticancer therapy. PMID: 28884001 [PubMed]

Lipidomics of human umbilical cord serum: identification of unique sterol sulfates.

Sat, 09/09/2017 - 12:05
Lipidomics of human umbilical cord serum: identification of unique sterol sulfates. Future Sci OA. 2017 Aug;3(3):FSO193 Authors: Wood PL, Siljander H, Knip M Abstract AIM: There are currently limited lipidomics data for human umbilical cord blood. Therefore, the lipidomes of cord sera from six newborns and sera from six nonpregnant females were compared. MATERIALS & METHODS: Sera lipidomics analyses were conducted using a high-resolution mass spectrometry analytical platform. RESULTS: Cord serum contained a diverse array of glycerophospholipids, albeit generally at lower concentrations than monitored in adult serum. The unexpected observations were that cord serum contained several neurosteroid sulfates and bile acid sulfates that were not detectable in adult serum. CONCLUSION: Our data are the first to demonstrate that cord serum contains bile acid sulfates that are synthesized early in the hydroxylase, neutral and acidic pathways of primary bile acid biosynthesis and support previous publications of cord blood perfluoralkyl toxins in newborns. PMID: 28883994 [PubMed]

Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study.

Sat, 09/09/2017 - 12:05
Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study. BMJ Open Respir Res. 2017;4(1):e000183 Authors: Zhao YD, Yin L, Archer S, Lu C, Zhao G, Yao Y, Wu L, Hsin M, Waddell TK, Keshavjee S, Granton J, de Perrot M Abstract INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause characterised by progressive fibrotic formation in lung tissue. We hypothesise that disrupted metabolic pathways in IPF contribute to disease pathogenesis. METHODS: Metabolomics of human IPF was performed using mass spectroscopy (IPF lung=8; donor lung=8). Gene expression of key metabolic enzymes was measured using microarrays. Of the 108 metabolites whose levels were found altered, 48 were significantly increased, whereas 60 were significantly decreased in IPF samples compared with normal controls. RESULTS: Specific metabolic pathways mediating the IPF remodelling were found with a downregulated sphingolipid metabolic pathway but an upregulated arginine pathway in IPF. In addition, disrupted glycolysis, mitochondrial beta-oxidation and tricarboxylic acid cycle, altered bile acid, haem and glutamate/aspartate metabolism were found in IPF samples compared with control. CONCLUSIONS: Our results show alterations in metabolic pathways for energy consumption during lung structural remodelling, which may contribute to IPF pathogenesis. We believe that this is the first report of simultaneously and systemically measuring changes of metabolites involving nine metabolic pathways in human severe IPF lungs. The measurement of the metabolites may serve in the future diagnosis and prognosis of IPF. PMID: 28883924 [PubMed]

Metabolomic profiling for identification of metabolites and relevant pathways for taurine in hepatic stellate cells.

Sat, 09/09/2017 - 12:05
Metabolomic profiling for identification of metabolites and relevant pathways for taurine in hepatic stellate cells. World J Gastroenterol. 2017 Aug 21;23(31):5713-5721 Authors: Deng X, Liang XQ, Lu FG, Zhao XF, Fu L, Liang J Abstract AIM: To develop a reliable and simple method to identify important biological metabolites and relevant pathways for taurine in hepatic stellate cells (HSCs), in order to provide more data for taurine therapy. METHODS: All the biological samples were analyzed by using high-performance liquid chromatography-time electrospray ionization/quadrupole-time of flight mass spectrometry. Principal component analysis and partial least squares discriminant analysis were used to identify statistically different metabolites for taurine in HSCs, and metabolomic pathway analysis was used to do pathway analysis for taurine in HSCs. The chemical structure of the related metabolites and pathways was identified by comparing the m/z ratio and ion mode with the data obtained from free online databases. RESULTS: A total of 32 significant differential endogenous metabolites were identified, which may be related to the mechanism of action of taurine in HSCs. Among the seven relevant pathways identified, sphingolipid metabolism pathway, glutathione metabolism pathway and thiamine metabolism pathway were found to be the most important metabolic pathways for taurine in HSCs. CONCLUSION: This study showed that there were distinct changes in biological metabolites of taurine in HSCs and three differential metabolic pathways including sphingolipid pathway, glutathione pathway and thiamine metabolism pathway might be of key importance in mediating the mechanism of action of taurine in HSCs. PMID: 28883696 [PubMed - in process]

Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats.

Sat, 09/09/2017 - 12:05
Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats. Eur J Pharm Sci. 2017 Sep 04;: Authors: van den Brink WJ, Elassaiss-Schaap J, Gonzalez-Amoros B, Harms AC, van der Graaf PH, Hankemeier T, de Lange ECM Abstract The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose-response relations for the dopamine D2 antagonist remoxipride. Remoxipride (vehicle, 0.7 or 3.5mg/kg) was administered to rats. Endogenous metabolites were analyzed in plasma using a biogenic amine platform and PKPD models were derived for each single metabolite. These models were clustered on basis of proximity between their PKPD parameter estimates, and PKPD models were subsequently fitted for the individual clusters. Finally, the metabolites were evaluated for being significantly affected by remoxipride. In total 44 metabolites were detected in plasma, many of them showing a dose dependent decrease from baseline. We identified 6 different clusters with different time and dose dependent responses and 18 metabolites were revealed as potential biomarker. The glycine, serine and threonine pathway was associated with remoxipride pharmacology, as well as the brain uptake of the dopamine and serotonin precursors. This is the first time that pharmacometabolomics and PKPD modeling were integrated. The resulting PKPD cluster model described diverse pharmacometabolomics responses and provided a further understanding of remoxipride pharmacodynamics. Future research should focus on the simultaneous pharmacometabolomics analysis in brain and plasma to increase the interpretability of these responses. PMID: 28882765 [PubMed - as supplied by publisher]

Estimation of time-varying growth, uptake and excretion rates from dynamic metabolomics data.

Sat, 09/09/2017 - 12:05
Estimation of time-varying growth, uptake and excretion rates from dynamic metabolomics data. Bioinformatics. 2017 Jul 15;33(14):i301-i310 Authors: Cinquemani E, Laroute V, Cocaign-Bousquet M, de Jong H, Ropers D Abstract Motivation: Technological advances in metabolomics have made it possible to monitor the concentration of extracellular metabolites over time. From these data, it is possible to compute the rates of uptake and excretion of the metabolites by a growing cell population, providing precious information on the functioning of intracellular metabolism. The computation of the rate of these exchange reactions, however, is difficult to achieve in practice for a number of reasons, notably noisy measurements, correlations between the concentration profiles of the different extracellular metabolites, and discontinuties in the profiles due to sudden changes in metabolic regime. Results: We present a method for precisely estimating time-varying uptake and excretion rates from time-series measurements of extracellular metabolite concentrations, specifically addressing all of the above issues. The estimation problem is formulated in a regularized Bayesian framework and solved by a combination of extended Kalman filtering and smoothing. The method is shown to improve upon methods based on spline smoothing of the data. Moreover, when applied to two actual datasets, the method recovers known features of overflow metabolism in Escherichia coli and Lactococcus lactis , and provides evidence for acetate uptake by L. lactis after glucose exhaustion. The results raise interesting perspectives for further work on rate estimation from measurements of intracellular metabolites. Availability and implementation: The Matlab code for the estimation method is available for download at https://team.inria.fr/ibis/rate-estimation-software/ , together with the datasets. Contact: eugenio.cinquemani@inria.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID: 28881984 [PubMed - in process]

MaBoSS 2.0: an environment for stochastic Boolean modeling.

Sat, 09/09/2017 - 12:05
MaBoSS 2.0: an environment for stochastic Boolean modeling. Bioinformatics. 2017 Jul 15;33(14):2226-2228 Authors: Stoll G, Caron B, Viara E, Dugourd A, Zinovyev A, Naldi A, Kroemer G, Barillot E, Calzone L Abstract Motivation: Modeling of signaling pathways is an important step towards the understanding and the treatment of diseases such as cancers, HIV or auto-immune diseases. MaBoSS is a software that allows to simulate populations of cells and to model stochastically the intracellular mechanisms that are deregulated in diseases. MaBoSS provides an output of a Boolean model in the form of time-dependent probabilities, for all biological entities (genes, proteins, phenotypes, etc.) of the model. Results: We present a new version of MaBoSS (2.0), including an updated version of the core software and an environment. With this environment, the needs for modeling signaling pathways are facilitated, including model construction, visualization, simulations of mutations, drug treatments and sensitivity analyses. It offers a framework for automated production of theoretical predictions. Availability and Implementation: MaBoSS software can be found at https://maboss.curie.fr , including tutorials on existing models and examples of models. Contact: gautier.stoll@upmc.fr or laurence.calzone@curie.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID: 28881959 [PubMed - in process]

Isolation and characterization of exosomes derived from fertile sheep hydatid cysts.

Sat, 09/09/2017 - 12:05
Related Articles Isolation and characterization of exosomes derived from fertile sheep hydatid cysts. Vet Parasitol. 2017 Mar 15;236:22-33 Authors: Siles-Lucas M, Sánchez-Ovejero C, González-Sánchez M, González E, Falcón-Pérez JM, Boufana B, Fratini F, Casulli A, Manzano-Román R Abstract Cystic echinococcosis (CE) is a chronic and complex zoonotic disease. Information on the mechanisms involved in parasite establishment, growth and persistence remain limited. These may be modulated by a crosstalk between extracellular vesicles (EVs). EVs including exosomes and microvesicles are able to carry developmental signaling proteins which coordinate growth and establishment of several parasites. Here, an exosome enriched EV fraction was isolated from hydatid fluid (HF) of fertile sheep cysts. A proteomic analysis of this fraction identified a number of parasite-derived vesicle-membrane associated proteins as well as cytosolic proteins. Additionally, the exosomal enriched fraction contained proteins of host origin. Specific proteins -antigen B2 and TSPAN14- in the exosomal fraction were further assayed by immunoblot and transmission electron microscopy. To the best of our knowledge, this is the first report on the presence of parasite exosomes in fertile hydatid cyst fluid. Further characterization of the exosome cargo will allow the discovery of new markers for the detection of CE in humans and animals, and the treatment of CE patients, and provide new insights regarding the role of these EVs in the establishment and persistence of hydatid cysts. PMID: 28288760 [PubMed - indexed for MEDLINE]

Simultaneous quantitation of hydrazine and acetylhydrazine in human plasma by high performance liquid chromatography-tandem mass spectrometry after derivatization with p-tolualdehyde.

Fri, 08/09/2017 - 14:55
Related Articles Simultaneous quantitation of hydrazine and acetylhydrazine in human plasma by high performance liquid chromatography-tandem mass spectrometry after derivatization with p-tolualdehyde. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Aug 30;1063:189-195 Authors: Song L, Gao D, Li S, Wang Y, Liu H, Jiang Y Abstract A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for simultaneous quantitative analysis of hydrazine and acetylhydrazine in human plasma based on the strategy of p-tolualdehyde derivatization. The derivatization reactions were easily realized by ultrasonic manipulation for 40min. Good separation of the derivatization products was achieved using a C18 column by gradient elution. The optimized mass transition ion-pairs (m/z) monitored for the two hydrazine derivatives were m/z 237.1≫>119.9 and m/z 176.9≫>117.8, respectively. The limit of detection (LOD) and limit of quantification (LOQ) for hydrazine were 0.002 and 0.005ngmL(-1) separately. And they were 0.03 and 0.05ngmL(-1) for acetylhydrazine, respectively. The linear range was 0.005-50ngmL(-1) for hydrazine and 0.05-500ngmL(-1) for acetylhydrazine with R(2) greater than 0.999. The recovery range was determined to be 95.38-108.12% with the relative standard deviation (RSD) in the range of 1.24-14.89%. The method was successfully applied to detect 30 clinical plasma samples of pulmonary tuberculosis patients treated with isoniazid. The concentrations were from 0.04-1.99ngmL(-1) for hydrazine and 0.06-142.43ngmL(-1) for acetylhydrazine. The results indicated that our developed method had the potential for the detection of hydrazine toxicology in complex biological samples. Furthermore, the method has an important significance to clinical treatment with drugs. PMID: 28881295 [PubMed - as supplied by publisher]

Assessing biological effects of fluoxetine in developing zebrafish embryos using gas chromatography-mass spectrometry based metabolomics.

Fri, 08/09/2017 - 14:55
Related Articles Assessing biological effects of fluoxetine in developing zebrafish embryos using gas chromatography-mass spectrometry based metabolomics. Chemosphere. 2017 Aug 31;188:157-167 Authors: Mishra P, Gong Z, Kelly BC Abstract Continuous low-dose exposure of pharmaceutically active compounds (PhACs) in aquatic ecosystems is a concern worldwide. In this study, we utilized a gas chromatography mass spectrometry (GC-MS) based metabolomics approach to assess endogenous metabolite changes in developing zebrafish embryos exposed to different concentrations of the widely used antidepressant, fluoxetine. Embryos were exposed from 2 h post fertilization (hpf) until 96 hpf. Using the Fiehn GC-MS library, a total of 31 metabolites were positively identified in embryos. Statistical analyses revealed significant dysregulation of 11 metabolites in fluoxetine exposed embryos. Metabolite classes that were significantly altered included, amino acids, monosaccharides, glycerophosphates, fatty acids, carboxylic acid derivatives and sugars. Concentrations of amino acids, maltose, d-malic acid, 3-phosphoglycerate and d-glucose were significantly reduced in exposed embryos. Conversely, concentrations of citric acid were in some cases significantly elevated in exposed embryos. Metabolic pathway analysis revealed perturbation of five main pathways, including (i) alanine, aspartate and glutamate metabolism, (ii) phenylalanine, tyrosine and tryptophan biosynthesis, (iii) phenylalanine metabolism. (iv) tyrosine metabolism and (v) starch and sucrose metabolism. The results indicate fluoxetine exposure causes perturbation of energy and amino acid metabolism, which may adversely impact embryogenesis due to depletion of energy reserves during this period. Also, the observed alterations in aspartic acid, phenylalanine and tyrosine in fluoxetine exposed embryos suggests potential disruption of normal neurobehavioral and liver function. The results further demonstrate that GC-MS based metabolomics is an effective approach for assessing toxicodynamics and threshold effect levels of environmental pollutants in aquatic organisms. PMID: 28881243 [PubMed - as supplied by publisher]

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