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

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 48 min 15 sec ago

Partially 13C-labeled mouse tissue as reference for LC-MS based untargeted metabolomics.

Sun, 01/07/2018 - 13:00
Partially 13C-labeled mouse tissue as reference for LC-MS based untargeted metabolomics. Anal Biochem. 2018 Jun 26;: Authors: Dethloff F, Bueschl C, Heumann H, Schuhmacher R, Turck CW Abstract The inclusion of stable isotope-labeled reference standards in the sample is an established method for the detection and relative quantification of metabolic features in untargeted metabolomics. In order to quantify as many metabolites as possible, the reference should ideally include the same metabolites in their stable isotope-labeled form as the sample under investigation. We present here an attempt to use partially 13C-labeled mouse material as internal standard for relative metabolite quantification of mouse and human samples in untargeted metabolomics. We fed mice for 14 days with a13C-labeled Ralstonia eutropha based diet. Tissue and blood amino acids from these mice showed 13C enrichment levels that ranged from 6% to 75%. We used MetExtract II software to automatically detect native and labeled peak pairs in an untargeted manner. In a dilution series and with the implementation of a correction factor, partially 13C-labeled mouse plasma resulted in accurate relative quantification of human plasma amino acids using liquid chromatography coupled to mass spectrometry, The coefficient of variation for the relative quantification is reduced from 27% without internal standard to 10% with inclusion of partially 13C-labeled internal standard. We anticipate the method to be of general use for the relative metabolite quantification of human specimens. PMID: 29958846 [PubMed - as supplied by publisher]

2-hydroxycaproate predicts cardiovascular mortality in patients with atherosclerotic disease.

Sun, 01/07/2018 - 13:00
2-hydroxycaproate predicts cardiovascular mortality in patients with atherosclerotic disease. Atherosclerosis. 2018 Jun 12;: Authors: Cardellini M, Ballanti M, Davato F, Cardolini I, Guglielmi V, Rizza S, Pecchioli C, Casagrande V, Mavilio M, Porzio O, Legramante JM, Ippoliti A, Farcomeni A, Sbraccia P, Menghini R, Dumas MED, Kappel BA, Federici M Abstract BACKGROUND AND AIMS: We aimed to identify novel biomarkers for cardiovascular mortality through a non-targeted metabolomics approach in patients with established atherosclerotic disease from the Tor Vergata Atherosclerosis Registry (TVAR). METHODS: We compared the serum baseline metabolome of 19 patients with atherosclerosis suffering from cardiovascular death during follow-up with the baseline serum metabolome of 20 control patients matched for age, gender, body mass index (BMI) and atherosclerotic disease status, who survived during the observation period. RESULTS: Three metabolites were significantly different in the cardiovascular mortality (CVM) group compared to controls: 2-hydroxycaproate, gluconate and sorbitol. 2-hydroxycaproate (otherwise known as alpha hydroxy caproate) was also significantly correlated with time to death. The metabolites performed better when combined together rather than singularly on the identification of CVM status. CONCLUSIONS: Our analysis led to identify few metabolites potentially amenable of translation into the clinical practice as biomarkers for specific metabolic changes in the cardiovascular system in patients with established atherosclerotic disease. PMID: 29958653 [PubMed - as supplied by publisher]

metabolomics; +16 new citations

Sat, 30/06/2018 - 15:30
16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/06/30PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +16 new citations

Sat, 30/06/2018 - 12:29
16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/06/30PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +22 new citations

Fri, 29/06/2018 - 14:34
22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/06/29PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Analyses of the genetic diversity and protein expression variation of the acyl: CoA medium-chain ligases, ACSM2A and ACSM2B.

Thu, 28/06/2018 - 14:09
Related Articles Analyses of the genetic diversity and protein expression variation of the acyl: CoA medium-chain ligases, ACSM2A and ACSM2B. Mol Genet Genomics. 2018 Jun 14;: Authors: van der Sluis R Abstract Benzoate (found in milk and widely used as preservative), salicylate (present in fruits and the active component of aspirin), dietary polyphenols produced by gut microbiota, metabolites from organic acidemias, and medium-chain fatty acids (MCFAs) are all metabolised/detoxified by the glycine conjugation pathway. Xenobiotics are first activated to an acyl-CoA by the mitochondrial xenobiotic/medium-chain fatty acid: CoA ligases (ACSMs) and subsequently conjugated to glycine by glycine N-acyltransferase (GLYAT). The MCFAs are activated to acyl-CoA by the ACSMs before entering mitochondrial β-oxidation. This two-step enzymatic pathway has, however, not been thoroughly investigated and the biggest gap in the literature remains the fact that studies continuously characterise the pathway as a one-step reaction. There are no studies available on the interaction/competition of the various substrates involved in the pathway, whilst very little research has been done on the ACSM ligases. To identify variants/haplotypes that should be characterised in future detoxification association studies, this study assessed the naturally observed sequence diversity and protein expression variation of ACSM2A and ACSM2B. The allelic variation, haplotype diversity, Tajima's D values, and phylogenetic analyses indicated that ACSM2A and ACSM2B are highly conserved. This confirmed an earlier hypothesis that the glycine conjugation pathway is highly conserved and essential for life as it maintains the CoA and glycine homeostasis in the liver mitochondria. The protein expression analyses showed that ACSM2A is the predominant transcript in liver. Future studies should investigate the effect of the variants identified in this study on the substrate specificity of these proteins. PMID: 29948332 [PubMed - as supplied by publisher]

Metabolomics profiling reveals the mechanism of increased pneumocandin B0 production by comparing mutant and parent strains.

Thu, 28/06/2018 - 14:09
Related Articles Metabolomics profiling reveals the mechanism of increased pneumocandin B0 production by comparing mutant and parent strains. J Ind Microbiol Biotechnol. 2018 Jun 14;: Authors: Song P, Yuan K, Qin T, Zhang K, Ji XJ, Ren L, Guan R, Wen J, Huang H Abstract Metabolic profiling was used to discover mechanisms of increased pneumocandin B0 production in a high-yield strain by comparing it with its parent strain. Initially, 79 intracellular metabolites were identified, and the levels of 15 metabolites involved in six pathways were found to be directly correlated with pneumocandin B0 biosynthesis. Then by combining the analysis of key enzymes, acetyl-CoA and NADPH were identified as the main factors limiting pneumocandin B0 biosynthesis. Other metabolites, such as pyruvate, α-ketoglutaric acid, lactate, unsaturated fatty acids and previously unreported metabolite γ-aminobutyric acid were shown to play important roles in pneumocandin B0 biosynthesis and cell growth. Finally, the overall metabolic mechanism hypothesis was formulated and a rational feeding strategy was implemented that increased the pneumocandin B0 yield from 1821 to 2768 mg/L. These results provide practical and theoretical guidance for strain selection, medium optimization, and genetic engineering for pneumocandin B0 production. PMID: 29948195 [PubMed - as supplied by publisher]

Imaging and the completion of the omics paradigm in breast cancer.

Thu, 28/06/2018 - 14:09
Related Articles Imaging and the completion of the omics paradigm in breast cancer. Radiologe. 2018 Jun 08;: Authors: Leithner D, Horvat JV, Ochoa-Albiztegui RE, Thakur S, Wengert G, Morris EA, Helbich TH, Pinker K Abstract Within the field of oncology, "omics" strategies-genomics, transcriptomics, proteomics, metabolomics-have many potential applications and may significantly improve our understanding of the underlying processes of cancer development and progression. Omics strategies aim to develop meaningful imaging biomarkers for breast cancer (BC) by rapid assessment of large datasets with different biological information. In BC the paradigm of omics technologies has always favored the integration of multiple layers of omics data to achieve a complete portrait of BC. Advances in medical imaging technologies, image analysis, and the development of high-throughput methods that can extract and correlate multiple imaging parameters with "omics" data have ushered in a new direction in medical research. Radiogenomics is a novel omics strategy that aims to correlate imaging characteristics (i. e., the imaging phenotype) with underlying gene expression patterns, gene mutations, and other genome-related characteristics. Radiogenomics not only represents the evolution in the radiology-pathology correlation from the anatomical-histological level to the molecular level, but it is also a pivotal step in the omics paradigm in BC in order to fully characterize BC. Armed with modern analytical software tools, radiogenomics leads to new discoveries of quantitative and qualitative imaging biomarkers that offer hitherto unprecedented insights into the complex tumor biology and facilitate a deeper understanding of cancer development and progression. The field of radiogenomics in breast cancer is rapidly evolving, and results from previous studies are encouraging. It can be expected that radiogenomics will play an important role in the future and has the potential to revolutionize the diagnosis, treatment, and prognosis of BC patients. This article aims to give an overview of breast radiogenomics, its current role, future applications, and challenges. PMID: 29947931 [PubMed - as supplied by publisher]

Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126.

Thu, 28/06/2018 - 14:09
Related Articles Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126. Arch Toxicol. 2018 Jun 14;: Authors: Mesnage R, Biserni M, Balu S, Frainay C, Poupin N, Jourdan F, Wozniak E, Xenakis T, Mein CA, Antoniou MN Abstract Chemical pollutant exposure is a risk factor contributing to the growing epidemic of non-alcoholic fatty liver disease (NAFLD) affecting human populations that consume a western diet. Although it is recognized that intoxication by chemical pollutants can lead to NAFLD, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. Here, we describe the alterations in gene expression profiles and metabolite levels in the human HepaRG liver cell line, a validated model for cellular steatosis, exposed to the polychlorinated biphenyl (PCB) 126, one of the most potent chemical pollutants that can induce NAFLD. Sparse partial least squares classification of the molecular profiles revealed that exposure to PCB 126 provoked a decrease in polyunsaturated fatty acids as well as an increase in sphingolipid levels, concomitant with a decrease in the activity of genes involved in lipid metabolism. This was associated with an increased oxidative stress reflected by marked disturbances in taurine metabolism. A gene ontology analysis showed hallmarks of an activation of the AhR receptor by dioxin-like compounds. These changes in metabolome and transcriptome profiles were observed even at the lowest concentration (100 pM) of PCB 126 tested. A decrease in docosatrienoate levels was the most sensitive biomarker. Overall, our integrated multi-omics analysis provides mechanistic insight into how this class of chemical pollutant can cause NAFLD. Our study lays the foundation for the development of molecular signatures of toxic effects of chemicals causing fatty liver diseases to move away from a chemical risk assessment based on in vivo animal experiments. PMID: 29947894 [PubMed - as supplied by publisher]

Altered Plasma Amino Acids and Lipids Associated with Abnormal Glucose Metabolism and Insulin Resistance in Older Adults.

Thu, 28/06/2018 - 14:09
Related Articles Altered Plasma Amino Acids and Lipids Associated with Abnormal Glucose Metabolism and Insulin Resistance in Older Adults. J Clin Endocrinol Metab. 2018 Jun 26;: Authors: Semba RD, Gonzalez-Freire M, Moaddel R, Sun K, Fabbri E, Zhang P, Carlson OD, Khadeer M, Chia CW, Salem N, Ferrucci L Abstract Context and Objectives: Glucose metabolism becomes progressively impaired with older age. Fasting glucose and insulin resistance are risk factors for premature death and other adverse outcomes. We aimed to identifying plasma metabolites associated with altered glucose metabolism and insulin resistance in older community-dwelling adults. Participants and Methods: A targeted metabolomics approach was used to identify plasma metabolites associated with impaired fasting plasma glucose, 2-hour plasma glucose on oral glucose tolerance testing, and homeostatic model assessment insulin resistance in 472 participants who participated in the Baltimore Longitudinal Study of Aging, mean (standard deviation) age 70.7 (9.9) years. Results: We measured 143 plasma metabolites. In ordinal logistic regression analyses, using a false discovery rate of 5%, and adjusting for potential confounders: alanine, glutamic acid, and proline were significantly associated with increased odds of abnormal fasting plasma glucose. Phosphatidylcholine (diacyl C34:4, alkyl-acyl C32:1, C32:2, C34:2, C34:3, and C36:3) was associated with decreased odds of abnormal fasting plasma glucose. Glutamic and acid phosphatidylcholine alkyl-acyl C34:2 were associated with increased and decreased odds of 2-hour plasma glucose, respectively. Glutamic acid was associated with increased odds of higher tertiles of HOMA-IR. Glycine, phosphatidylcholine (diacyl C32:0, alkyl-acyl C32:1, C32:2, C34:1, C34:2, C34:3, C36:2, C36:3, C40:5, C40:6, C42:3, C42:4, and C42:5), sphingomyelin C16:0, C24:1, and C26:1, and lysophosphatidylcholine C18:1 were associated with decreased odds of abnormal HOMA-IR. Conclusions: Targeted metabolomics identified four plasma amino acids and sixteen plasma lipid species, primarily containing polyunsaturated fatty acids, that were associated with abnormal glucose metabolism and insulin resistance in older adults. PMID: 29947780 [PubMed - as supplied by publisher]

Tracking down protein-protein interactions via a FRET-system using site-specific thiol-labeling.

Thu, 28/06/2018 - 14:09
Related Articles Tracking down protein-protein interactions via a FRET-system using site-specific thiol-labeling. Org Biomol Chem. 2018 Jun 27;: Authors: Söveges B, Imre T, Póti ÁL, Sok P, Kele Z, Alexa A, Kele P, Németh K Abstract Förster resonance energy transfer is among the most popular tools to follow protein-protein interactions. Although limited to certain cases, site-specific fluorescent labeling of proteins via natural functions by means of chemical manipulations can redeem laborious protein engineering techniques. Herein we report on the synthesis of a heterobifunctional tag and its use in site-specific protein labeling studies aiming at exploring protein-protein interactions. The oxadiazole-methylsulfonyl functionality serves as a thiol specific warhead that enables easy and selective installation of fluorescent labels through a bioorthogonal motif. Mitogen activated protein kinase (MAPK14) and its substrate mitogen activated protein kinase activated kinase (MAPKAP2) or its docking motif, a 22 amino acid-long peptide fragment, were labeled with a donor and an acceptor, respectively. Evolution of strong FRET signals upon protein-protein interactions supported the specific communication between the partners. Using an efficient FRET pair allowed the estimation of dissociation constants for protein-protein and peptide-protein interactions (145 nM and 240 nM, respectively). PMID: 29947400 [PubMed - as supplied by publisher]

Serum metabolites associate with CT findings following TBI.

Thu, 28/06/2018 - 14:09
Related Articles Serum metabolites associate with CT findings following TBI. J Neurotrauma. 2018 Jun 27;: Authors: Dickens AM, Posti JP, Takala RS, Ala-Seppälä HM, Mattila I, Coles JC, Frantzén J, Hutchinson PJ, Katila AJ, Kyllönen A, Maanpää HR, Newcombe V, Outtrim J, Tallus J, Carpenter K, Menon D, Hyotylainen T, Tenovuo O, Oresic M Abstract There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load. PMID: 29947291 [PubMed - as supplied by publisher]

Human metabolome changes after a single dose of 3,4-methylenedioxymethamphetamine (MDMA) with special focus on steroid metabolism and inflammation processes.

Thu, 28/06/2018 - 14:09
Related Articles Human metabolome changes after a single dose of 3,4-methylenedioxymethamphetamine (MDMA) with special focus on steroid metabolism and inflammation processes. J Proteome Res. 2018 Jun 27;: Authors: Boxler MI, Streun GL, Liechti ME, Schmid Y, Kraemer T, Steuer AE Abstract The intake of 3,4-methylenedioxymethamphetamine (MDMA) is known to increase several endogenous substances involved in steroid and inflammation pathways. Untargeted metabolomics screening approaches can determine biochemical changes after drug exposure and can reveal new pathways which might be involved in the pharmacology and toxicology of a drug of abuse. We analyzed plasma samples from a placebo-controlled cross-over study of a single intake of MDMA. Plasma samples from a time point before and three time points after the intake of a single dose of 125 mg MDMA were screened for changes of endogenous metabolites. An untargeted metabolomics approach on a high resolution quadrupole time of flight mass spectrometer coupled to liquid chromatography with two different chromatographic systems (reversed phase and hydrophobic interaction liquid chromatography) was applied. Over 10'000 features of the human metabolome were detected. Hence, 28 metabolites were identified which showed significant changes after administration of MDMA compared to placebo. The analysis revealed an upregulation of cortisol and pregnenolone sulfate four hours after MDMA intake suggesting increased stress and serotonergic activity. Further, calcitriol levels were decreased after the intake of MDMA. Calcitriol is involved in the upregulation of trophic factors which have protective effects on brain dopamine neurons. The inflammation mediators hydroxyeicosatetraenoic acid (HETE), dihydroxyeicosatetraenoic acid (diHETE) and octadecadienoic acid (oxoODE) were found to be upregulated after the intake of MDMA compared to placebo which suggested a stimulation of inflammation pathways. PMID: 29947220 [PubMed - as supplied by publisher]

Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study.

Thu, 28/06/2018 - 14:09
Related Articles Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study. Metab Brain Dis. 2018 Jun 26;: Authors: Zhou Q, Zheng H, Chen J, Li C, Du Y, Xia H, Gao H Abstract Alzheimer's disease (AD) has been associated with the disturbance of brain glucose metabolism. The present study investigates brain glucose metabolism using 13C NMR metabolomics in combination with intravenous [1-13C]-glucose infusion in APP/PS1 transgenic mouse model of amyloid pathology at 10 months of age. We found that brain glucose was significantly accumulated in APP/PS1 mice relative to wild-type (WT) mice. Reductions in 13C fluxes into the specific carbon sites of tricarboxylic acid (TCA) intermediate (succinate) as well as neurotransmitters (glutamate, glutamine, γ-aminobutyric acid and aspartate) from [1-13C]-glucose were also detected in the brain of APP/PS1 mice. In addition, our results reveal that the 13C-enrichments of the C3 of alanine were significantly lower and the C3 of lactate have a tendency to be lower in the brain of APP/PS1 mice than WT mice. Taken together, the development of amyloid pathology could cause a reduction in glucose utilization and further result in decreases in energy and neurotransmitter metabolism as well as the lactate-alanine shuttle in the brain. PMID: 29946959 [PubMed - as supplied by publisher]

Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy.

Thu, 28/06/2018 - 14:09
Related Articles Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy. Breast Cancer Res Treat. 2018 Jun 26;: Authors: Sun Y, Kim JH, Vangipuram K, Hayes DF, Smith EML, Yeomans L, Henry NL, Stringer KA, Hertz DL Abstract PURPOSE: Approximately 25% of breast cancer patients experience treatment delays or discontinuation due to paclitaxel-induced peripheral neuropathy (PN). Currently, there are no predictive biomarkers of PN. Pharmacometabolomics is an informative tool for biomarker discovery of drug toxicity. We conducted a secondary whole blood pharmacometabolomics analysis to assess the association between pretreatment metabolome, early treatment-induced metabolic changes, and the development of PN. METHODS: Whole blood samples were collected pre-treatment (BL), just before the end of the first paclitaxel infusion (EOI), and 24 h after the first infusion (24H) from sixty patients with breast cancer receiving (80 mg/m2) weekly treatment. Neuropathy was assessed at BL and prior to each infusion using the sensory subscale (CIPN8) of the EORTC CIPN20 questionnaire. Blood metabolites were quantified from 1-D-1H-nuclear magnetic resonance spectra using Chenomx® software. Metabolite concentrations were normalized in preparation for Pearson correlation and one-way repeated measures ANOVA with multiple comparisons corrected by false discovery rate (FDR). RESULTS: Pretreatment histidine, phenylalanine, and threonine concentrations were inversely associated with maximum change in CIPN8 (ΔCIPN8) (p < 0.02; FDR ≤ 25%). Paclitaxel caused a significant change in concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, pyruvate, o-acetylcarnitine, and several amino acids from BL to EOI and/or 24H (p < 0.05; FDR ≤ 25%), although these changes were not associated with ΔCIPN8. CONCLUSIONS: Whole blood metabolomics is a feasible approach to identify potential biomarker candidates of paclitaxel-induced PN. The findings suggest that pretreatment concentrations of histidine, phenylalanine, and threonine may be predictive of the severity of future PN and paclitaxel-induced metabolic changes may be related to disruption of energy homeostasis. PMID: 29946863 [PubMed - as supplied by publisher]

Prioritization of Candidate Genes in QTL Regions for Physiological and Biochemical Traits Underlying Drought Response in Barley (Hordeum vulgare L.).

Thu, 28/06/2018 - 14:09
Related Articles Prioritization of Candidate Genes in QTL Regions for Physiological and Biochemical Traits Underlying Drought Response in Barley (Hordeum vulgare L.). Front Plant Sci. 2018;9:769 Authors: Gudys K, Guzy-Wrobelska J, Janiak A, Dziurka MA, Ostrowska A, Hura K, Jurczyk B, Żmuda K, Grzybkowska D, Śróbka J, Urban W, Biesaga-Koscielniak J, Filek M, Koscielniak J, Mikołajczak K, Ogrodowicz P, Krystkowiak K, Kuczyńska A, Krajewski P, Szarejko I Abstract Drought is one of the most adverse abiotic factors limiting growth and productivity of crops. Among them is barley, ranked fourth cereal worldwide in terms of harvested acreage and production. Plants have evolved various mechanisms to cope with water deficit at different biological levels, but there is an enormous challenge to decipher genes responsible for particular complex phenotypic traits, in order to develop drought tolerant crops. This work presents a comprehensive approach for elucidation of molecular mechanisms of drought tolerance in barley at the seedling stage of development. The study includes mapping of QTLs for physiological and biochemical traits associated with drought tolerance on a high-density function map, projection of QTL confidence intervals on barley physical map, and the retrievement of positional candidate genes (CGs), followed by their prioritization based on Gene Ontology (GO) enrichment analysis. A total of 64 QTLs for 25 physiological and biochemical traits that describe plant water status, photosynthetic efficiency, osmoprotectant and hormone content, as well as antioxidant activity, were positioned on a consensus map, constructed using RIL populations developed from the crosses between European and Syrian genotypes. The map contained a total of 875 SNP, SSR and CGs, spanning 941.86 cM with resolution of 1.1 cM. For the first time, QTLs for ethylene, glucose, sucrose, maltose, raffinose, α-tocopherol, γ-tocotrienol content, and catalase activity, have been mapped in barley. Based on overlapping confidence intervals of QTLs, 11 hotspots were identified that enclosed more than 60% of mapped QTLs. Genetic and physical map integration allowed the identification of 1,101 positional CGs within the confidence intervals of drought response-specific QTLs. Prioritization resulted in the designation of 143 CGs, among them were genes encoding antioxidants, carboxylic acid biosynthesis enzymes, heat shock proteins, small auxin up-regulated RNAs, nitric oxide synthase, ATP sulfurylases, and proteins involved in regulation of flowering time. This global approach may be proposed for identification of new CGs that underlies QTLs responsible for complex traits. PMID: 29946328 [PubMed]

Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains.

Thu, 28/06/2018 - 14:09
Related Articles Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains. Front Neurosci. 2018;12:399 Authors: Vanaveski T, Narvik J, Innos J, Philips MA, Ottas A, Plaas M, Haring L, Zilmer M, Vasar E Abstract The main goal of the study was to characterize the behavioral and metabolomic profiles of repeated administration (for 11 days) of d-amphetamine (AMPH, 3 mg/kg i. p.), indirect agonist of dopamine (DA), in widely used 129S6/SvEvTac (129Sv) and C57BL/6NTac (Bl6) mouse strains. Acute administration of AMPH (acute AMPH) induced significantly stronger motor stimulation in Bl6. However, repeated administration of AMPH (repeated AMPH) caused stronger motor sensitization in 129Sv compared acute AMPH. Body weight of 129Sv was reduced after repeated saline and AMPH, whereas no change occurred in Bl6. In the metabolomic study, acute AMPH induced an elevation of isoleucine and leucine, branched chain amino acids (BCAA), whereas the level of hexoses was reduced in Bl6. Both BCAAs and hexoses remained on level of acute AMPH after repeated AMPH in Bl6. Three biogenic amines [asymmetric dimethylarginine (ADMA), alpha-aminoadipic acid (alpha-AAA), kynurenine] were significantly reduced after repeated AMPH. Acute AMPH caused in 129Sv a significant reduction of valine, lysophosphatidylcholines (lysoPC a C16:0, lysoPC a C18:2, lysoPC a C20:4), phosphatidylcholine (PC) diacyls (PC aa C34:2, PC aa C36:2, PC aa C36:3, PC aa C36:4) and alkyl-acyls (PC ae C38:4, PC ae C40:4). However, repeated AMPH increased the levels of valine and isoleucine, long-chain acylcarnitines (C14, C14:1-OH, C16, C18:1), PC diacyls (PC aa C38:4, PC aa C38:6, PC aa C42:6), PC acyl-alkyls (PC ae C38:4, PC ae C40:4, PC ae C40:5, PC ae C40:6, PC ae C42:1, PC ae C42:3) and sphingolipids [SM(OH)C22:1, SM C24:0] compared to acute AMPH in 129Sv. Hexoses and kynurenine were reduced after repeated AMPH compared to saline in 129Sv. The established changes probably reflect a shift in energy metabolism toward lipid molecules in 129Sv because of reduced level of hexoses. Pooled data from both strains showed that the elevation of isoleucine and leucine was a prominent biomarker of AMPH-induced behavioral sensitization. Simultaneously a significant decline of hexoses, citrulline, ADMA, and kynurenine occurred. The reduced levels of kynurenine, ADMA, and citrulline likely reflect altered function of N-methyl-D-aspartate (NMDA) and NO systems caused by repeated AMPH. Altogether, 129Sv strain displays stronger sensitization toward AMPH and larger variance in metabolite levels than Bl6. PMID: 29946233 [PubMed]

Dietary Intakes and Circulating Concentrations of Branched-Chain Amino Acids in Relation to Incident Type 2 Diabetes Risk Among High-Risk Women with a History of Gestational Diabetes Mellitus.

Thu, 28/06/2018 - 14:09
Related Articles Dietary Intakes and Circulating Concentrations of Branched-Chain Amino Acids in Relation to Incident Type 2 Diabetes Risk Among High-Risk Women with a History of Gestational Diabetes Mellitus. Clin Chem. 2018 Jun 26;: Authors: Tobias DK, Clish C, Mora S, Li J, Liang L, Hu FB, Manson JE, Zhang C Abstract BACKGROUND: Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, valine) are consistently associated with increased type 2 diabetes (T2D) risk, but the relationship with dietary intake of BCAAs is less clear. METHODS: The longitudinal Nurses' Health Study II cohort conducted a blood collection from 1996 to 1999. We profiled plasma metabolites among 172 incident T2D cases and 175 age-matched controls from women reporting a history of gestational diabetes before blood draw. We estimated dietary energy-adjusted BCAAs from food frequency questionnaires. We used conditional logistic regression models to estimate odds ratios (OR) and 95% CI of T2D risk across quartiles (Q1-Q4) of BCAAs, adjusting for age, body mass index (BMI), physical activity, family history, and other established risk factors. We also assessed joint exposure to below/above medians of diet and plasma concentrations, with lower diet/lower plasma as reference. RESULTS: Dietary and plasma BCAA concentrations were positively associated with incident T2D (diet Q4 vs Q1 OR = 4.6, CI = 1.6, 13.4; plasma Q4 vs Q1 OR = 4.4, CI = 1.4, 13.4). Modeling the joint association indicated that higher diet BCAAs were associated with T2D when plasma concentrations were also higher (OR = 6.0, CI = 2.1, 17.2) but not when concentrations were lower (OR = 1.6, CI = 0.61, 4.1). Conversely, higher plasma BCAAs were associated with increased T2D for either lower or higher diet. CONCLUSIONS: Independent of BMI and other risk factors, higher diet and plasma BCAA concentrations were associated with an increased incident T2D risk among high-risk women with a history of gestational diabetes, supporting impaired BCAA metabolism as conferring T2D risk. PMID: 29945965 [PubMed - as supplied by publisher]

Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies.

Thu, 28/06/2018 - 14:09
Related Articles Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies. Ann Rheum Dis. 2018 Jun 26;: Authors: van Schie KA, Kruithof S, Ooijevaar-de Heer P, Derksen NIL, van de Bovenkamp FS, Saris A, Vidarsson G, Bentlage AEH, Jiskoot W, Romeijn S, Koning RI, Bos E, Stork EM, Koeleman CAM, Wuhrer M, Wolbink G, Rispens T Abstract OBJECTIVES: Therapeutic antibodies can provoke an antidrug antibody (ADA) response, which can form soluble immune complexes with the drug in potentially high amounts. Nevertheless, ADA-associated adverse events are usually rare, although with notable exceptions including infliximab. The immune activating effects and the eventual fate of these 'anti-idiotype' complexes are poorly studied, hampering assessment of ADA-associated risk of adverse events. We investigated the in vitro formation and biological activities of ADA-drug anti-idiotype immune complexes using patient-derived monoclonal anti-infliximab antibodies. METHODS: Size distribution and conformation of ADA-drug complexes were characterised by size-exclusion chromatography and electron microscopy. Internalisation of and immune activation by complexes of defined size was visualised with flow imaging, whole blood cell assay and C4b/c ELISA. RESULTS: Size and conformation of immune complexes depended on the concentrations and ratio of drug and ADA; large complexes (>6 IgGs) formed only with high ADA titres. Macrophages efficiently internalised tetrameric and bigger complexes in vitro, but not dimers. Corroborating these results, ex vivo analysis of patient sera demonstrated only dimeric complexes in circulation.No activation of immune cells by anti-idiotype complexes was observed, and only very large complexes activated complement. Unlike Fc-linked hexamers, anti-idiotype hexamers did not activate complement, demonstrating that besides size, conformation governs immune complex potential for triggering effector functions. CONCLUSIONS: Anti-idiotype ADA-drug complexes generally have restricted immune activation capacity. Large, irregularly shaped complexes only form at high concentrations of both drug and ADA, as may be achieved during intravenous infusion of infliximab, explaining the rarity of serious ADA-associated adverse events. PMID: 29945923 [PubMed - as supplied by publisher]

metabolomics; +18 new citations

Wed, 27/06/2018 - 13:53
18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/06/27PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pages