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Sample records for human brain metabolites

  1. The effect of ethanol on human brain metabolites longitudinally characterized by proton MR spectroscopy.

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    Biller, Armin; Bartsch, Andreas J; Homola, György; Solymosi, László; Bendszus, Martin

    2009-05-01

    The effect ethanol exerts on the human brain has not yet been addressed by longitudinal magnetic resonance (MR) spectroscopic experiments. Therefore, we longitudinally characterized cerebral metabolite changes in 15 healthy individuals by proton magnetic resonance spectroscopy ((1)H-MRS) subsequent to the ingestion of a standard beverage (mean peak blood alcohol concentration (BAC): 51.43 +/- 10.27 mg/dL). Each participant was examined before, over 93.71 +/- 11.17 mins immediately after and 726.36 +/- 94.96 mins (12.11 +/ -1.58 h) past per os alcohol exposure. Fronto-mesial and cerebellar ethanol concentrations over time were similar as determined by the LCModel analysis of spectral data. Alcohol-induced changes of fronto-mesial creatine, choline, glucose, inositol and aspartate levels at 5.79 +/- 2.94 [corrected] mins upon ingestion as well as cerebellar choline and inositol levels at 8.64 +/- 2.98 [corrected] mins past exposure. Closely associated with ethanol concentrations, supratentorial creatine, choline, inositol and aspartate levels decreased after ethanol administration, whereas glucose levels increased. Similarly, infratentorial choline and inositol concentrations were negatively correlated with ethanol levels over time. There were no changes in N-acetyl-aspartate levels upon alcohol exposure. Furthermore, no influence of ethanol on brain water integrals was detected. Ethanol consumption may directly increase oxidative stress and the neuronal vulnerability to it. In addition, our results are compatible with ethanol-induced cell membrane modifications and alternative energy substrate usage upon alcohol exposure.

  2. Faster metabolite (1H transverse relaxation in the elder human brain.

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    Małgorzata Marjańska

    Full Text Available (1H magnetic resonance spectroscopy (MRS is unique among imaging modalities because signals from several metabolites are measured during a single examination period. Each metabolite reflects a distinct intracellular process. Furthermore transverse (T2 relaxation times probe the viability of the cell microenvironment, e.g., the viscosity of the cellular fluids, the microscopic susceptibility distribution within the cells, and the iron content. In this study, T2s of brain metabolites were measured in the occipital lobe of eighteen young and fourteen elderly subjects at a field strength of 4 tesla. The T2s of N-acetylaspartate, total creatine, and total choline were 23%, 16% and 10% shorter in elderly than in young subjects. The findings of this study suggest that noninvasive detection of T2 provides useful biological information on changes in the cellular microenvironment that take place during aging.

  3. Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite.

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    Varsha Agarwal

    2008-06-01

    Full Text Available Cytochrome P450 (P450 is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP in brain and liver, relatively more alpha-hydroxy alprazolam (alpha-OHALP is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both alpha-OHALP and 4-hydroxy alprazolam (4-OHALP while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of alpha-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of alpha-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differentially in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.

  4. Comparison of human brain metabolite levels using 1H MRS at 1.5T and 3.0T

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    Fernando Fernandes Paiva

    Full Text Available ABSTRACT Proton magnetic resonance spectroscopy (MRS of the human brain has proven to be a useful technique in several neurological and psychiatric disorders and benefits from higher field scanners as signal intensity and spectral resolution are proportional to the magnetic field strength. Objective: To investigate the effects of the magnetic field on the measurement of brain metabolites in a typical routine clinical setting. Methods: Single voxel spectra were acquired from the posterior cingulate cortex in 26 healthy subjects. Each subject was scanned consecutively at 1.5T and 3.0T in a randomly distributed order. Results: SNR and peak width improvements were observed at higher fields. However, SNR improvement was lower than the theoretical two-fold improvement. Other than the values obtained for creatine (Cre and myo-Inositol (mI, which were both higher at 3.0T, all metabolite concentrations obtained were roughly the same at both field strengths. All the metabolite concentrations were estimated with a Cramer Rao lower bounds (CRLB lower than 15% of the calculated concentrations. Conclusions: Even though the present study supports the expected benefits of higher field strength for MRS, there are several factors that can lead to different quantitative results when comparing 1.5T to 3.0T MRS. Future comparative studies are necessary to refine the metabolite thresholds for early detection and quantification of distinct neurological and psychiatric disorders using 3.0T MRS.

  5. Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

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    Matej Orešič

    2016-10-01

    Full Text Available Traumatic brain injury (TBI is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n = 22, moderate (moTBI; n = 14 or mild TBI (mTBI; n = 108 according to Glasgow Coma Scale. The control group (n = 28 comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n = 23, moTBI (n = 7, mTBI (n = 37 patients and controls (n = 27. We show that two medium-chain fatty acids (decanoic and octanoic acids and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC = 0.84 in validation cohort. Addition of the metabolites to the established clinical model (CRASH, comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified ‘TBI metabotype’ in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs.

  6. Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

    NARCIS (Netherlands)

    M. Oresic (Matej); Posti, J.P. (Jussi P.); Kamstrup-Nielsen, M.H. (Maja H.); Takala, R.S.K. (Riikka S.K.); H.F. Lingsma (Hester); Mattila, I. (Ismo); Jäntti, S. (Sirkku); A. Katila (Ari); K.L.H. Carpenter (Keri L.H.); Ala-Seppälä, H. (Henna); Kyllönen, A. (Anna); Maanpää, H.-R. (Henna-Riikka); Tallus, J. (Jussi); J.P. Coles (Jonathan P.); Heino, I. (Iiro); J. Frantzén (Janek); P.J. Hutchinson (Peter J.); D.K. Menon (David ); O. Tenovuo (Olli); Hyötyläinen, T. (Tuulia)

    2016-01-01

    textabstractTraumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of

  7. Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain.

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    Keevil, S F; Barbiroli, B; Brooks, J C; Cady, E B; Canese, R; Carlier, P; Collins, D J; Gilligan, P; Gobbi, G; Hennig, J; Kügel, H; Leach, M O; Metzler, D; Mlynárik, V; Moser, E; Newbold, M C; Payne, G S; Ring, P; Roberts, J N; Rowland, I J; Thiel, T; Tkác, I; Topp, S; Wittsack, H J; Podo, F

    1998-11-01

    We have performed a multicentre trial to assess the performance of three techniques for absolute quantification of cerebral metabolites using in vivo proton nuclear magnetic resonance (NMR). The techniques included were 1) an internal water standard method, 2) an external standard method based on phantom replacement, and 3) a more sophisticated method incorporating elements of both the internal and external standard approaches, together with compartmental analysis of brain water. Only the internal water standard technique could be readily implemented at all participating sites and gave acceptable precision and interlaboratory reproducibility. This method was insensitive to many of the experimental factors affecting the performance of the alternative techniques, including effects related to loading, standing waves and B1 inhomogeneities; and practical issues of phantom positioning, user expertise and examination duration. However, the internal water standard method assumes a value for the concentration of NMR-visible water within the spectroscopic volume of interest. In general, it is necessary to modify this assumed concentration on the basis of the grey matter, white matter and cerebrospinal fluid (CSF) content of the volume, and the NMR-visible water content of the grey and white matter fractions. Combining data from 11 sites, the concentrations of the principal NMR-visible metabolites in the brains of healthy subjects (age range 20-35 years) determined using the internal water standard method were (mean+/-SD): [NAA]=10.0+/-3.4 mM (n=53), [tCho]=1.9+/-1.0 mM (n=51), [Cr + PCr]=6.5+/-3.7 mM (n=51). Evidence of system instability and other sources of error at some participating sites reinforces the need for rigorous quality assurance in quantitative spectroscopy.

  8. Magnetic resonance spectroscopy of the human brain

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    Strózik-Kotlorz, D.

    2014-01-01

    I give a brief description of the magnetic resonance spectroscopy (MRS) in the human brain examinations. MRS allows a noninvasive chemical analysis of the brain using a standard high field MR system. Nowadays, the dominant form of MR brain spectroscopy is proton spectroscopy. Two main techniques of MRS, which utilize the chemical shift of metabolites in the external magnetic field, are SVS (single voxel) and CSI (single slice). The major peaks in the spectrum of a normal brain include NAA, Cr, Cho and m-Ins, which are neuronal, energetic, membrane turnover and glial markers, respectively. In disease, two pathological metabolites can be found in the brain spectra: Lac, which is end product of anaerobic glycolysis and Lip, which is a marker of membrane breakdown, occurring in necrosis. The common way to analyze clinical spectra is to determine metabolite ratios, e.g. NAA/Cr, Cho/Cr, Cho/NAA. This analysis permits a safe and noninvasive examination of the brain tissue as each disease state has its own characteristic spectroscopic image. MRS is a valuable diagnostic tool in such clinical applications as detecting brain tumors and differentiating tumors from inflammatory and infectious processes. Proton MRS is also very helpful in diagnostic of ischemic lesions, Alzheimer's disease and hepatic encephalopathy. The MRS brain spectra should always be correlated with the Magnetic Resonance Imaging (MRI) results and alone cannot make neurological diagnosis.

  9. Metabolomics of Neurotransmitters and Related Metabolites in Post-Mortem Tissue from the Dorsal and Ventral Striatum of Alcoholic Human Brain.

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    Kashem, Mohammed Abul; Ahmed, Selina; Sultana, Nilufa; Ahmed, Eakhlas U; Pickford, Russell; Rae, Caroline; Šerý, Omar; McGregor, Iain S; Balcar, Vladimir J

    2016-02-01

    We report on changes in neurotransmitter metabolome and protein expression in the striatum of humans exposed to heavy long-term consumption of alcohol. Extracts from post mortem striatal tissue (dorsal striatum; DS comprising caudate nucleus; CN and putamen; P and ventral striatum; VS constituted by nucleus accumbens; NAc) were analysed by high performance liquid chromatography coupled with tandem mass spectrometry. Proteomics was studied in CN by two-dimensional gel electrophoresis followed by mass-spectrometry. Proteomics identified 25 unique molecules expressed differently by the alcohol-affected tissue. Two were dopamine-related proteins and one a GABA-synthesizing enzyme GAD65. Two proteins that are related to apoptosis and/or neuronal loss (BiD and amyloid-β A4 precursor protein-binding family B member 3) were increased. There were no differences in the levels of dopamine (DA), 3,4-dihydrophenylacetic acid (DOPAC), serotonin (5HT), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), histamine, L-glutamate (Glu), γ-aminobutyric acid (GABA), tyrosine (Tyr) and tryptophan (Tryp) between the DS (CN and P) and VS (NAc) in control brains. Choline (Ch) and acetylcholine (Ach) were higher and norepinephrine (NE) lower, in the VS. Alcoholic striata had lower levels of neurotransmitters except for Glu (30 % higher in the alcoholic ventral striatum). Ratios of DOPAC/DA and HIAA/5HT were higher in alcoholic striatum indicating an increase in the DA and 5HT turnover. Glutathione was significantly reduced in all three regions of alcohol-affected striatum. We conclude that neurotransmitter systems in both the DS (CN and P) and the VS (NAc) were significantly influenced by long-term heavy alcohol intake associated with alcoholism.

  10. Brain metabolite values in children with breath-holding spells

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    Calik M

    2017-06-01

    Full Text Available Mustafa Calik,1 Dilek Sen Dokumaci,2 Suna Sarikaya,3 Mahmut Demir,4 Ilhan Isik,5 Halil Kazanasmaz,4 Cemil Kaya,4 Hasan Kandemir6 1Department of Pediatric Neurology, 2Department of Radiology, 3Department of Neurology, 4Department of Pediatrics, Harran University School of Medicine, 5Department of Pediatric Neurology, Eyyubiye Training and Research Hospital, 6Department of Child and Adolescent Psychiatry, Harran University School of Medicine, Sanliurfa, Turkey Abstract: Breath-holding spells are benign, paroxysmal events with apnea and postural tone changes after a crying episode in infants. The objective of this study was to investigate the pathologies in brain metabolite values in the absence of seizure in children with breath-holding spells by using magnetic resonance spectroscopy (MRS. Brain MRS examination was performed on 18 children with breath-holding spells and 13 neurologically normal children who were included as the control group. There was no significant difference in terms of N-acetyl aspartate (NAA, choline (Cho, creatine (Cr, and myoinositol (mI levels and also in terms of NAA/Cr, Cho/Cr, and mI/Cr ratios between the patients and the control group (all P>0.05. Our study suggested that there is no permanent neuronal damage in patients with breath-holding spells. This result confirms the previous studies, which reported no permanent neuronal damage in patients with breath-holding spells. Keywords: brain metabolite, children, breath holding, magnetic resonance spectroscopy 

  11. Pharmacokinetics of thioridazine and its metabolites in blood plasma and the brain of rats after acute and chronic treatment.

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    Daniel, W A; Syrek, M; Mach, A; Wójcikowski, J; Boksa, J

    1997-01-01

    This study was aimed at investigation of the pharmacokinetics of thioridazine and its metabolites after a single and repeated administrations. Male Wistar rats received thioridazine as a single dose (10 mg/kg i.p.) or they were treated chronically with the neuroleptic (10 mg/kg i.p., twice a day for two weeks). Plasma and brain concentrations of thioridazine and its metabolites (N-desmethylthioridazine, mesoridazine, sulforidazine, and the ring sulfoxide) were determined using the HPLC method. The obtained data showed that sulfoxidation in position 2 of the thiomethyl substituent and in the thiazine ring are main metabolic pathways of thioridazine, and showed that, in contrast to humans, in the rat N-desmethylthioridazine is formed in appreciable amount. The biotransformation of thioridazine was rather fast yielding plasma peak concentrations of metabolites lower than that of the parent compound. The maximum concentrations of thioridazine and its metabolites in the brain appeared later than in plasma. The peak concentrations and AUC values of thioridazine and its metabolites were higher in the brain than in plasma and this corresponded well with their longer half-lives in the brain as compared to plasma. The drug was not taken up by the brain as efficiently as other phenothiazines. Chronic treatment with thioridazine produced significant increases (with the exception of thioridazine ring sulfoxide) in the plasma concentrations of the parent compound and its metabolites which was accompanied with the prolongation of their plasma half-lives. The observed plasma levels of thioridazine were within 'therapeutic range' while the concentrations of its metabolites were relatively lower as compared to those observed in psychiatric patients. The increased plasma concentrations of thioridazine and its metabolites observed in plasma after chronic treatment were not followed by parallel changes in the brain.

  12. Protection of Brain Injury by Amniotic Mesenchymal Stromal Cell-Secreted Metabolites.

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    Pischiutta, Francesca; Brunelli, Laura; Romele, Pietro; Silini, Antonietta; Sammali, Eliana; Paracchini, Lara; Marchini, Sergio; Talamini, Laura; Bigini, Paolo; Boncoraglio, Giorgio B; Pastorelli, Roberta; De Simoni, Maria-Grazia; Parolini, Ornella; Zanier, Elisa R

    2016-11-01

    To define the features of human amniotic mesenchymal stromal cell secretome and its protective properties in experimental models of acute brain injury. Prospective experimental study. Laboratory research. C57Bl/6 mice. Mice subjected to sham or traumatic brain injury by controlled cortical impact received human amniotic mesenchymal stromal cells or phosphate-buffered saline infused intracerebroventricularly or intravenously 24 hours after injury. Organotypic cortical brain slices exposed to ischemic injury by oxygen-glucose deprivation were treated with human amniotic mesenchymal stromal cells or with their secretome (conditioned medium) in a transwell system. Traumatic brain injured mice receiving human amniotic mesenchymal stromal cells intravenously or intracerebroventricularly showed early and lasting functional and anatomical brain protection. cortical slices injured by oxigen-glucose deprivation and treated with human amniotic mesenchymal stromal cells or conditioned medium showed comparable protective effects (neuronal rescue, promotion of M2 microglia polarization, induction of trophic factors) indicating that the exposure of human amniotic mesenchymal stromal cells to the injured tissue is not necessary for the release of bioactive factors. Using sequential size-exclusion and gel-filtration chromatography, we identified a conditioned medium subfraction, which specifically displays these highly protective properties and we found that this fraction was rich in bioactive molecules with molecular weight smaller than 700 Da. Quantitative RNA analysis and mass spectrometry-based peptidomics showed that the active factors are not proteins or RNAs. The metabolomic profiling of six metabolic classes identified a list of molecules whose abundance was selectively elevated in the active conditioned medium fraction. Human amniotic mesenchymal stromal cell-secreted factors protect the brain after acute injury. Importantly, a fraction rich in metabolites, and

  13. Brain metabolite values in children with breath-holding spells.

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    Calik, Mustafa; Sen Dokumaci, Dilek; Sarikaya, Suna; Demir, Mahmut; Isik, Ilhan; Kazanasmaz, Halil; Kaya, Cemil; Kandemir, Hasan

    2017-01-01

    Breath-holding spells are benign, paroxysmal events with apnea and postural tone changes after a crying episode in infants. The objective of this study was to investigate the pathologies in brain metabolite values in the absence of seizure in children with breath-holding spells by using magnetic resonance spectroscopy (MRS). Brain MRS examination was performed on 18 children with breath-holding spells and 13 neurologically normal children who were included as the control group. There was no significant difference in terms of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), and myoinositol (mI) levels and also in terms of NAA/Cr, Cho/Cr, and mI/Cr ratios between the patients and the control group (all P>0.05). Our study suggested that there is no permanent neuronal damage in patients with breath-holding spells. This result confirms the previous studies, which reported no permanent neuronal damage in patients with breath-holding spells.

  14. Identification of non‐reported bupropion metabolites in human plasma

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    Connarn, Jamie N.; Luo, Ruijuan; Windak, Jim; Zhang, Xinyuan; Babiskin, Andrew; Kelly, Marisa; Harrington, Gloria; Ellingrod, Vicki L.; Kamali, Masoud; McInnis, Melvin

    2016-01-01

    Abstract Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non‐reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non‐reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet. Plasma samples were collected and analysed by LC–MS/MS at 0, 6 and 24 h. Two non‐reported metabolites (M1 and M3) were identified with mass‐to‐charge (m/z) ratios of 276 (M1, hydration of bupropion) and 258 (M3, hydroxylation of threo/erythrohydrobupropion) from human plasma in addition to the known hydroxybupropion, threo/erythrohydrobupropion and the glucuronidation products of the major metabolites (M2 and M4–M7). These new metabolites may provide new insight and broaden the understanding of bupropion's variability in clinical pharmacokinetics. © 2016 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd. PMID:27723114

  15. The Prognostic Value of Brain Extracellular Fluid Nitric Oxide Metabolites After Traumatic Brain Injury

    NARCIS (Netherlands)

    Tisdall, M.M.; Rejdak, K.; Kitchen, N.D.; Smith, M.; Petzold, A.

    2013-01-01

    Background: Nitric oxide (NO) is a compound with both protective and damaging effects on neurons. Quantification of NO metabolites in humans is limited by sample contamination with blood. In vivo cerebral microdialysis may offer an alternative approach as sampling of extracellular fluid (ECF)

  16. Metabolites of alectinib in human: their identification and pharmacological activity

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    Mika Sato-Nakai

    2017-07-01

    Full Text Available Two metabolites (M4 and M1b in plasma and four metabolites (M4, M6, M1a and M1b in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.

  17. Filamentous fungal biofilm for production of human drug metabolites.

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    Amadio, Jessica; Casey, Eoin; Murphy, Cormac D

    2013-07-01

    In drug development, access to drug metabolites is essential for assessment of toxicity and pharmacokinetic studies. Metabolites are usually acquired via chemical synthesis, although biological production is potentially more efficient with fewer waste management issues. A significant problem with the biological approach is the effective half-life of the biocatalyst, which can be resolved by immobilisation. The fungus Cunninghamella elegans is well established as a model of mammalian metabolism, although it has not yet been used to produce metabolites on a large scale. Here, we describe immobilisation of C. elegans as a biofilm, which can transform drugs to important human metabolites. The biofilm was cultivated on hydrophilic microtiter plates and in shake flasks containing a steel spring in contact with the glass. Fluorescence and confocal scanning laser microscopy revealed that the biofilm was composed of a dense network of hyphae, and biochemical analysis demonstrated that the matrix was predominantly polysaccharide. The medium composition was crucial for both biofilm formation and biotransformation of flurbiprofen. In shake flasks, the biofilm transformed 86% of the flurbiprofen added to hydroxylated metabolites within 24 h, which was slightly more than planktonic cultures (76%). The biofilm had a longer effective lifetime than the planktonic cells, which underwent lysis after 2×72 h cycles, and diluting the Sabouraud dextrose broth enabled the thickness of the biofilm to be controlled while retaining transformation efficiency. Thus, C. elegans biofilm has the potential to be applied as a robust biocatalyst for the production of human drug metabolites required for drug development.

  18. Detection of Volatile Metabolites of Garlic in Human Breast Milk

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    Laura Scheffler

    2016-06-01

    Full Text Available The odor of human breast milk after ingestion of raw garlic at food-relevant concentrations by breastfeeding mothers was investigated for the first time chemo-analytically using gas chromatography−mass spectrometry/olfactometry (GC-MS/O, as well as sensorially using a trained human sensory panel. Sensory evaluation revealed a clear garlic/cabbage-like odor that appeared in breast milk about 2.5 h after consumption of garlic. GC-MS/O analyses confirmed the occurrence of garlic-derived metabolites in breast milk, namely allyl methyl sulfide (AMS, allyl methyl sulfoxide (AMSO and allyl methyl sulfone (AMSO2. Of these, only AMS had a garlic-like odor whereas the other two metabolites were odorless. This demonstrates that the odor change in human milk is not related to a direct transfer of garlic odorants, as is currently believed, but rather derives from a single metabolite. The formation of these metabolites is not fully understood, but AMSO and AMSO2 are most likely formed by the oxidation of AMS in the human body. The excretion rates of these metabolites into breast milk were strongly time-dependent with large inter-individual differences.

  19. Preparation of human drug metabolites using fungal peroxygenases

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    Marzena Poraj-Kobielska; Matthias Kinne; René Ullrich; Katrin Scheibner; Gernot Kayser; Kenneth E. Hammel; Martin Hofrichter

    2011-01-01

    The synthesis of hydroxylated and O- or N-dealkylated human drug metabolites (HDMs) via selective monooxygenation remains a challenging task for synthetic organic chemists. Here we report that aromatic peroxygenases (APOs; EC 1.11.2.1) secreted by the agaric fungi Agrocybe aegerita and Coprinellus...

  20. Identification of novel metabolite and its cytotoxic effect on human ...

    African Journals Online (AJOL)

    A novel metabolite of P. polonicum was recently isolated from Cameroonian Zea mays by means of preparative silica gel thin layer chromatographic method. The potential cytotoxic effects of this novel compound was further tested, in vitro, against cultured human mononuclear lymphocyte cells over 18-hr period in ...

  1. Metabolites of amygdalin under simulated human digestive fluids.

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    Shim, Soon-Mi; Kwon, Hoonjeong

    2010-12-01

    In the present study, degradation of amygdalin in the human digestive fluids and absorption of its metabolites by the human small intestine were evaluated by simulating a gastrointestinal digestion model combined with a human intestinal cell culture. Orally administered amygdalin was degraded into prunasin by digestive enzymes after passing through the salivary and gastrointestinal phases. Prunasin, the major metabolite of amygdalin in the digestive fluids, was incubated in a caco-2 cell culture system. Prunasin was degraded into the mandelonitrile by β-glucosidase and then hydroxylated across the small intestinal wall, producing hydroxymandelonitrile (149 Da). Results from this study suggest that risk assessment of amygdalin from food consumption can be done in a more accurate way by determining a pathway of amygdalin metabolism in the simulating human upper gastrointestinal tract.

  2. Changes of brain metabolite concentrations during maturation in different brain regions measured by chemical shift imaging

    Energy Technology Data Exchange (ETDEWEB)

    Bueltmann, Eva; Lanfermann, Heinrich [Hannover Medical School, Institute of Diagnostic and Interventional Neuroradiology, Hannover (Germany); Naegele, Thomas [University of Tuebingen, Department of Diagnostic and Interventional Neuroradiology, Radiological University Hospital, Tuebingen (Germany); Klose, Uwe [University of Tuebingen, Section of Experimental MR of the CNS, Department of Neuroradiology, Radiological University Hospital, Tuebingen (Germany)

    2017-01-15

    We examined the effect of maturation on the regional distribution of brain metabolite concentrations using multivoxel chemical shift imaging. From our pool of pediatric MRI examinations, we retrospectively selected patients showing a normal cerebral MRI scan or no pathologic signal abnormalities at the level of the two-dimensional 1H MRS-CSI sequence and an age-appropriate global neurological development, except for focal neurological deficits. Seventy-one patients (4.5 months-20 years) were identified. Using LC Model, spectra were evaluated from voxels in the white matter, caudate head, and corpus callosum. The concentration of total N-acetylaspartate increased in all regions during infancy and childhood except in the right caudate head where it remained constant. The concentration of total creatine decreased in the caudate nucleus and splenium and minimally in the frontal white matter and genu. It remained largely constant in the parietal white matter. The concentration of choline-containing compounds had the tendency to decrease in all regions except in the parietal white matter where it remained constant. The concentration of myoinositol decreased slightly in the splenium and right frontal white matter, remained constant on the left side and in the caudate nucleus, and rose slightly in the parietal white matter and genu. CSI determined metabolite concentrations in multiple cerebral regions during routine MRI. The obtained data will be helpful in future pediatric CSI measurements deciding whether the ratios of the main metabolites are within the range of normal values or have to be considered as probably pathologic. (orig.)

  3. Educating the Human Brain. Human Brain Development Series

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    Posner, Michael I.; Rothbart, Mary K.

    2006-01-01

    "Educating the Human Brain" is the product of a quarter century of research. This book provides an empirical account of the early development of attention and self regulation in infants and young children. It examines the brain areas involved in regulatory networks, their connectivity, and how their development is influenced by genes and…

  4. Cigarette smoking exacerbates chronic alcohol-induced brain damage: a preliminary metabolite imaging study.

    Science.gov (United States)

    Durazzo, Timothy C; Gazdzinski, Stefan; Banys, Peter; Meyerhoff, Dieter J

    2004-12-01

    Cigarette smoking is common among alcohol-dependent individuals. Nevertheless, previous research has typically not accounted for the potential independent or compounding effects of cigarette smoking on alcohol-induced brain injury and neurocognition. Twenty-four 1-week-abstinent recovering alcoholics (RAs; 14 smokers and 10 nonsmokers) in treatment and 26 light-drinking controls (7 smokers and 19 nonsmokers) were compared on measures of common brain metabolites in gray matter and white matter of the major lobes, basal ganglia, midbrain, and cerebellar vermis, obtained via multislice short-echo time proton magnetic resonance spectroscopic imaging. Smoking and nonsmoking RAs were also contrasted on measures of neurocognitive functioning, as well as laboratory markers of drinking severity and nutritional status. Chronic alcohol dependence, independent of smoking, was associated with lower concentrations of frontal N-acetylaspartate (NAA) and frontal choline-containing compounds, as well as lower parietal and thalamic choline. Smoking RAs had lower NAA concentrations in frontal white matter and midbrain and lower midbrain choline than nonsmoking RAs. A four-group analysis of covariance also demonstrated that chronic cigarette smoking was associated with lower midbrain NAA and choline and with lower vermian choline. In smoking RAs, heavier drinking was associated with heavier smoking, which correlated with numerous subcortical metabolite abnormalities. The 1-week-abstinent smoking and nonsmoking RAs did not differ significantly on a brief neurocognitive battery. In smoking RAs, lower cerebellar vermis NAA was associated with poorer visuomotor scanning speed and incidental learning, and in nonsmoking RAs lower vermis NAA was related to poorer visuospatial learning and memory. These human in vivo proton magnetic resonance spectroscopic imaging findings indicate that chronic cigarette smoking exacerbates chronic alcohol-induced neuronal injury and cell membrane damage in

  5. Acute Ethanol-Induced Changes in Edema and Metabolite Concentrations in Rat Brain

    Directory of Open Access Journals (Sweden)

    Huimin Liu

    2014-01-01

    Full Text Available The aim of this study is to describe the acute effects of EtOH on brain edema and cerebral metabolites, using diffusion weight imaging (DWI and proton magnetic resonance spectroscopy (1H-MRS at a 7.0T MR and to define changes in apparent diffusion coefficient (ADC values and the concentration of metabolites in the rat brain after acute EtOH intoxication. ADC values in each ROI decreased significantly at 1 h and 3 h after ethanol administration. ADC values in frontal lobe were decreased significantly compared with other regions at 3 h. For EtOH/Cr+PCr and cerebral metabolites (Cho, Tau, and Glu differing over time, no significant differences for Ins, NAA, and Cr were observed in frontal lobes. Regression analysis revealed a significant association between TSEtOH/Cr+PCr and TSCho, TSTau, TSGlu, and TSADC. The changes of ADC values in different brain regions reflect the process of the cytotoxic edema in vivo. The characterization of frontal lobes metabolites changes and the correlations between TSEtOH/Cr+PCr and TSCho, TSTau, and TSGlu provide a better understanding for the biological mechanisms in neurotoxic effects of EtOH on the brain. In addition, the correlations between TSEtOH/Cr+PCr and TSADC will help us to understand development of the ethanol-induced brain cytotoxic edema.

  6. Multi-center reproducibility of neurochemical profiles in the human brain at 7T

    NARCIS (Netherlands)

    van de Bank, B. L.; Emir, U. E.; Boer, VO; van Asten, J. J. A.; Maas, M. C.; Wijnen, J. P.; Kan, H. E.; Oz, G.; Klomp, D. W. J.; Scheenen, T. W. J.

    The purpose of this work was to harmonize data acquisition and post-processing of single voxel proton MRS (H-1-MRS) at 7T, and to determine metabolite concentrations and the accuracy and reproducibility of metabolite levels in the adult human brain. This study was performed in compliance with local

  7. Metabolite concentrations in the developing brain estimated with proton MR spectroscopy

    DEFF Research Database (Denmark)

    Toft, P B; Leth, H; Lou, H C

    1995-01-01

    The purpose of the present study was to estimate absolute concentrations and relaxation time constants of metabolites that were detectable with proton magnetic resonance (MR) spectroscopy in the healthy preterm, term, and infant brain. Five MR spectra were recorded for each infant by using STEAM ...... concentration. The concentration of PCr+Cr increased rapidly and reached adolescent values at approximately 4 months of age....

  8. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases.

    Science.gov (United States)

    Mendelsohn, Andrew R; Larrick, James W

    2013-12-01

    Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called "glymphatic system" is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers.

  9. Regional brain volumes, diffusivity, and metabolite changes after electroconvulsive therapy for severe depression

    DEFF Research Database (Denmark)

    Jørgensen, A.; Magnusson, P.; Hanson, Lars G.

    2016-01-01

    , and metabolite changes in 19 patients receiving ECT for severe depression. Other regions of interest included the amygdala, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, and hypothalamus. Patients received a 3T MR scan before ECT (TP1), 1 week (TP2), and 4 weeks (TP3) after ECT. Results......: Hippocampal and amygdala volume increased significantly at TP2 and continued to be increased at TP3. DLPFC exhibited a transient volume reduction at TP2. DTI revealed a reduced anisotropy and diffusivity of the hippocampus at TP2. We found no significant post-ECT changes in brain metabolite concentrations...

  10. Reproducibility of brain metabolite concentration measurements in lesion free white matter at 1.5 T.

    Science.gov (United States)

    Busch, Martin H J; Vollmann, Wolfgang; Mateiescu, Serban; Stolze, Manuel; Deli, Martin; Garmer, Marietta; Grönemeyer, Dietrich H W

    2015-09-29

    Post processing for brain spectra has a great influence on the fit quality of individual spectra, as well as on the reproducibility of results from comparable spectra. This investigation used pairs of spectra, identical in system parameters, position and time assumed to differ only in noise. The metabolite amplitudes of fitted time domain spectroscopic data were tested on reproducibility for the main brain metabolites. Proton spectra of white matter brain tissue were acquired with a short spin echo time of 30 ms and a moderate repetition time of 1500 ms at 1.5 T. The pairs were investigated with one time domain post-processing algorithm using different parameters. The number of metabolites, the use of prior knowledge, base line parameters and common or individual damping were varied to evaluate the best reproducibility. The protocols with most reproducible amplitudes for N-acetylaspartate, creatine, choline, myo-inositol and the combined Glx line of glutamate and glutamine in lesion free white matter have the following common features: common damping of the main metabolites, a baseline using only the points of the first 10 ms, no additional lipid/macromolecule lines and Glx is taken as the sum of separately fitted glutamate and glutamine. This parameter set is different to the one delivering the best individual fit results. All spectra were acquired in "lesion free" (no lesion signs found in MR imaging) white matter. Spectra of brain lesions, for example tumors, can be drastically different. Thus the results are limited to lesion free brain tissue. Nevertheless the application to studies is broad, because small alterations in brain biochemistry of lesion free areas had been detected nearby tumors, in patients with multiple sclerosis, drug abuse or psychiatric disorders. Main metabolite amplitudes inside healthy brain can be quantified with a normalized root mean square deviation around 5 % using CH3 of creatine as reference. Only the reproducibility of myo

  11. H-1 chemical shift imaging characterization of human brain tumor and edema

    NARCIS (Netherlands)

    Sijens, PE; Oudkerk, M

    Longitudinal (T1) and transverse (T2) relaxation times of metabolites in human brain tumor, peritumoral edema, and unaffected brain tissue were assessed from point resolved spectroscopy (PRESS) H-1 chemical shift imaging results at different repetition times (TR = 1500 and 5000 ms; T1: n = 19) and

  12. Distinct arsenic metabolites following seaweed consumption in humans.

    Science.gov (United States)

    Taylor, Vivien F; Li, Zhigang; Sayarath, Vicki; Palys, Thomas J; Morse, Kevin R; Scholz-Bright, Rachel A; Karagas, Margaret R

    2017-06-20

    Seaweeds contain arsenic primarily in the form of arsenosugars, which can be metabolized to a wide range of arsenic compounds. To characterize human exposure to arsenic from seaweed consumption, we determined concentrations of arsenic species in locally available seaweeds, and assessed urinary arsenic compounds in an experimental feeding study. A total of 11 volunteers consumed 10 g per day of three types of seaweeds (nori, kombu, and wakame) for three days each, while abstaining from rice and seafood following a three-day washout period. Urinary arsenosugars and their metabolites (including dimethyl arsenate (DMA), thio-dimethylarsinoylethanol (thio-DMAE), thio-dimethylarsinoylacetate (thio-DMAA), and thio-DMA) were measured in spot urine samples prior to seaweed consumption, and in 24-hour urine samples while consuming seaweed. Commercial products made from whole seaweed had substantial concentrations of arsenic (12-84 µg/g), dominated by arsenosugars. Intact arsenosugars along with DMA, thio-DMAA, thio-DMAE all increased in urine after ingesting each type of seaweed, and varied between seaweed types and between individuals. Only trace levels of the known toxic metabolite, thio-DMA, were observed, across individuals. Thio-DMAE and thio-DMAA are unique products of arsenosugar breakdown, thus assessment of these compounds may help to identify dietary intake of arsenic from seaweed from other exposure pathways.

  13. Somatic transposition in the brain has the potential to influence the biosynthesis of metabolites involved in Parkinson’s disease and schizophrenia

    Directory of Open Access Journals (Sweden)

    Abrusán György

    2012-11-01

    Full Text Available Abstract It has been recently discovered that transposable elements show high activity in the brain of mammals, however, the magnitude of their influence on its functioning is unclear so far. In this paper, I use flux balance analysis to examine the influence of somatic retrotransposition on brain metabolism, and the biosynthesis of its key metabolites, including neurotransmitters. The analysis shows that somatic transposition in the human brain can influence the biosynthesis of more than 250 metabolites, including dopamine, serotonin and glutamate, shows large inter-individual variability in metabolic effects, and may contribute to the development of Parkinson’s disease and schizophrenia. Reviewers This article was reviewed by Dr Kenji Kojima (nominated by Dr Jerzy Jurka and Dr Eugene Koonin.

  14. Mindboggling morphometry of human brains

    Science.gov (United States)

    Bao, Forrest S.; Giard, Joachim; Stavsky, Eliezer; Lee, Noah; Rossa, Brian; Reuter, Martin; Chaibub Neto, Elias

    2017-01-01

    Mindboggle (http://mindboggle.info) is an open source brain morphometry platform that takes in preprocessed T1-weighted MRI data and outputs volume, surface, and tabular data containing label, feature, and shape information for further analysis. In this article, we document the software and demonstrate its use in studies of shape variation in healthy and diseased humans. The number of different shape measures and the size of the populations make this the largest and most detailed shape analysis of human brains ever conducted. Brain image morphometry shows great potential for providing much-needed biological markers for diagnosing, tracking, and predicting progression of mental health disorders. Very few software algorithms provide more than measures of volume and cortical thickness, while more subtle shape measures may provide more sensitive and specific biomarkers. Mindboggle computes a variety of (primarily surface-based) shapes: area, volume, thickness, curvature, depth, Laplace-Beltrami spectra, Zernike moments, etc. We evaluate Mindboggle’s algorithms using the largest set of manually labeled, publicly available brain images in the world and compare them against state-of-the-art algorithms where they exist. All data, code, and results of these evaluations are publicly available. PMID:28231282

  15. The significance of estradiol metabolites in human corpus luteum physiology.

    Science.gov (United States)

    Devoto, Luigi; Henríquez, Soledad; Kohen, Paulina; Strauss, Jerome F

    2017-07-01

    The human corpus luteum (CL) is a temporary endocrine gland derived from the ovulated follicle. Its formation and limited lifespan is critical for steroid hormone production required to support menstrual cyclicity, endometrial receptivity for successful implantation, and the maintenance of early pregnancy. Endocrine and paracrine-autocrine molecular mechanisms associated with progesterone production throughout the luteal phase are critical for the development, maintenance, regression, and rescue by hCG which sustains CL function into early pregnancy. However, the signaling systems driving the regression of the primate corpus luteum in non-conception cycles are not well understood. Recently, there has been interest in the functional roles of estradiol metabolites (EMs), mostly in estrogen-producing tissues. The human CL produces a number of EMs, and it has been postulated that the EMs acting via paracrine-autocrine pathways affect angiogenesis or LH-mediated events. The present review describes advances in understanding the role of EMs in the functional lifespan and regression of the human CL in non-conception cycles. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Drug repositioning for enzyme modulator based on human metabolite-likeness.

    Science.gov (United States)

    Lee, Yoon Hyeok; Choi, Hojae; Park, Seongyong; Lee, Boah; Yi, Gwan-Su

    2017-05-31

    Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for

  17. Sexual differences of human brain

    Directory of Open Access Journals (Sweden)

    Masoud Pezeshki Rad

    2014-04-01

    Full Text Available During the last decades there has been an increasing interest in studying the differences between males and females. These differences extend from behavioral to cognitive to micro- and macro- neuro-anatomical aspects of human biology. There have been many methods to evaluate these differences and explain their determinants. The most studied cause of this dimorphism is the prenatal sex hormones and their organizational effect on brain and behavior. However, there have been new and recent attentions to hormone's activational influences in puberty and also the effects of genomic imprinting. In this paper, we reviewed the sex differences of brain, the evidences for possible determinants of these differences and also the methods that have been used to discover them. We reviewed the most conspicuous findings with specific attention to macro-anatomical differences based on Magnetic Resonance Imaging (MRI data. We finally reviewed the findings and the many opportunities for future studies.

  18. Simultaneous determination of monoamine transmitters, precursors and metabolites in a single mouse brain.

    Science.gov (United States)

    Ishikawa, K; McGaugh, J L

    1982-04-16

    A simple and sensitive procedure for simultaneous determination of monoamine transmitters and related substances including precursors and metabolites has been developed for a single mouse brain. The proposed procedure involves (1) primary butanol extraction, (2) separation of the substances into either acid or alkaline aqueous layers according to their physicochemical properties, and (3) determination by means of high-performance liquid chromatography with electrochemical detection. Three transmitters (noradrenaline, dopamine and 5-hydroxytryptamine) and their precursors (tyrosine, 3,4-dihydroxyphenylalanine and tryptophan) and major metabolites (normethanephrine, 3-methoxy-4-hydroxyphenylethylene glycol, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylacetic acid and 5-hydroxyindoleacetic acid) were selectively separated and sensitively detected in mouse whole brain sample. Although 3-methoxy-4-hydroxymandelic acid was also separated from other substances by authentic chromatography, the substance was not detected in mouse brain. Changes in levels of these substances were examined for drugs whose effects had been previously confirmed. These changes reflected putative effects of the drugs and confirmed that the procedure is effective for neurochemical research into the transmitter system.

  19. Postmortem Brain and Blood Reference Concentrations of Alprazolam, Bromazepam, Chlordiazepoxide, Diazepam, and their Metabolites and a Review of the Literature

    DEFF Research Database (Denmark)

    Skov, Louise; Holm, Karen Marie Dollerup; Johansen, Sys Stybe

    2016-01-01

    , the brain, might be considered. Here we present reference concentrations of femoral blood and brain tissue of selected benzodiazepines (BZDs). Using LC-MS/MS, we quantified alprazolam, bromazepam, chlordiazepoxide, diazepam, and the metabolites desmethyldiazepam, oxazepam and temazepam in postmortem femoral...

  20. Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy

    DEFF Research Database (Denmark)

    Gredal, O; Rosenbaum, S; Topp, S

    1997-01-01

    20-mm3 voxel placed in the motor cortex and in the cerebellum from seven patients with clinically probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial criteria, from three patients with suspected ALS (progressive muscular atrophy), and from eight normal control...... subjects. We estimated the concentrations of the metabolites using the water signal as an internal standard. The concentrations of Cho and Cr/PCr in both brain regions, as well as the concentration of NAA in the cerebellum, were unaltered in the MND patients compared with the controls. Only MND patients...

  1. Oxidative Metabolites of Diisononyl Phthalate as Biomarkers for Human Exposure Assessment

    OpenAIRE

    Silva, Manori J; Reidy, John A; Preau, James L.; Needham, Larry L.; Calafat, Antonia M

    2006-01-01

    Diisononyl phthalate (DINP) is a complex mixture of predominantly nine-carbon branched-chain dialkyl phthalate isomers. Similar to di(2-ethylhexyl) phthalate, a widely used phthalate, DINP causes antiandrogenic effects on developing rodent male fetuses. Traditionally, assessment of human exposure to DINP has been done using monoisononyl phthalate (MINP), the hydrolytic metabolite of DINP, as a biomarker. However, MINP is only a minor urinary metabolite of DINP. Oxidative metabolites, includin...

  2. Brain mechanisms underlying human communication

    Directory of Open Access Journals (Sweden)

    Matthijs L Noordzij

    2009-07-01

    Full Text Available Human communication has been described as involving the coding-decoding of a conventional symbol system, which could be supported by parts of the human motor system (i.e. the “mirror neurons system”. However, this view does not explain how these conventions could develop in the first place. Here we target the neglected but crucial issue of how people organize their non-verbal behavior to communicate a given intention without pre-established conventions. We have measured behavioral and brain responses in pairs of subjects during communicative exchanges occurring in a real, interactive, on-line social context. In two fMRI studies, we found robust evidence that planning new communicative actions (by a sender and recognizing the communicative intention of the same actions (by a receiver relied on spatially overlapping portions of their brains (the right posterior superior temporal sulcus. The response of this region was lateralized to the right hemisphere, modulated by the ambiguity in meaning of the communicative acts, but not by their sensorimotor complexity. These results indicate that the sender of a communicative signal uses his own intention recognition system to make a prediction of the intention recognition performed by the receiver. This finding supports the notion that our communicative abilities are distinct from both sensorimotor processes and language abilities.

  3. Metabolite concentrations in the developing brain estimated with proton MR spectroscopy

    DEFF Research Database (Denmark)

    Toft, P B; Leth, H; Lou, H C

    1995-01-01

    The purpose of the present study was to estimate absolute concentrations and relaxation time constants of metabolites that were detectable with proton magnetic resonance (MR) spectroscopy in the healthy preterm, term, and infant brain. Five MR spectra were recorded for each infant by using STEAM...... of a relatively larger signal overlap with glutamate in the most immature brains. The concentration of NAA almost doubled, whereas the Cho concentration showed only a nonsignificant tendency to decrease; therefore, the well-known increase in the ratio of NAA to Cho appears to be due mostly to an increase in NAA...... concentration. The concentration of PCr+Cr increased rapidly and reached adolescent values at approximately 4 months of age....

  4. Morphine metabolites

    DEFF Research Database (Denmark)

    Christrup, Lona Louring

    1997-01-01

    Morphine is a potent opioid analgesic widely used for the treatment of acute pain and for long-term treatment of severe pain. Morphine is a member of the morphinan-framed alkaloids, which are present in the poppy plant. The drug is soluble in water, but its solubility in lipids is poor. In man...... are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after...... systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear...

  5. NMR identification of endogenous metabolites interacting with fatted and non-fatted human serum albumin in blood plasma: Fatty acids influence the HSA-metabolite interaction

    Science.gov (United States)

    Jupin, Marc; Michiels, Paul J.; Girard, Frederic C.; Spraul, Manfred; Wijmenga, Sybren S.

    2013-03-01

    Metabolites and their concentrations are direct reporters on body biochemistry. Thanks to technical developments metabolic profiling of body fluids, such as blood plasma, by for instance NMR has in the past decade become increasingly accurate enabling successful clinical diagnostics. Human Serum Albumin (HSA) is the main plasma protein (∼60% of all plasma protein) and responsible for the transport of endogenous (e.g. fatty acids) and exogenous metabolites, which it achieves thanks to its multiple binding sites and its flexibility. HSA has been extensively studied with regard to its binding of drugs (exogenous metabolites), but only to a lesser extent with regard to its binding of endogenous (non-fatty acid) metabolites. To obtain correct NMR measured metabolic profiles of blood plasma and/or potentially extract information on HSA and fatty acids content, it is necessary to characterize these endogenous metabolite/plasma protein interactions. Here, we investigate these metabolite-HSA interactions in blood plasma and blood plasma mimics. The latter contain the roughly twenty metabolites routinely detected by NMR (also most abundant) in normal relative concentrations with fatted or non-fatted HSA added or not. First, we find that chemical shift changes are small and seen only for a few of the metabolites. In contrast, a significant number of the metabolites display reduced resonance integrals and reduced free concentrations in the presence of HSA or fatted HSA. For slow-exchange (or strong) interactions, NMR resonance integrals report the free metabolite concentration, while for fast exchange (weak binding) the chemical shift reports on the binding. Hence, these metabolites bind strongly to HSA and/or fatted HSA, but to a limited degree because for most metabolites their concentration is smaller than the HSA concentration. Most interestingly, fatty acids decrease the metabolite-HSA binding quite significantly for most of the interacting metabolites. We further find

  6. Brain evolution and human neuropsychology: the inferential brain hypothesis.

    Science.gov (United States)

    Koscik, Timothy R; Tranel, Daniel

    2012-05-01

    Collaboration between human neuropsychology and comparative neuroscience has generated invaluable contributions to our understanding of human brain evolution and function. Further cross-talk between these disciplines has the potential to continue to revolutionize these fields. Modern neuroimaging methods could be applied in a comparative context, yielding exciting new data with the potential of providing insight into brain evolution. Conversely, incorporating an evolutionary base into the theoretical perspectives from which we approach human neuropsychology could lead to novel hypotheses and testable predictions. In the spirit of these objectives, we present here a new theoretical proposal, the Inferential Brain Hypothesis, whereby the human brain is thought to be characterized by a shift from perceptual processing to inferential computation, particularly within the social realm. This shift is believed to be a driving force for the evolution of the large human cortex. (JINS, 2012, 18, 394-401).

  7. Brain Evolution and Human Neuropsychology: The Inferential Brain Hypothesis

    Science.gov (United States)

    Koscik, Timothy R.; Tranel, Daniel

    2013-01-01

    Collaboration between human neuropsychology and comparative neuroscience has generated invaluable contributions to our understanding of human brain evolution and function. Further cross-talk between these disciplines has the potential to continue to revolutionize these fields. Modern neuroimaging methods could be applied in a comparative context, yielding exciting new data with the potential of providing insight into brain evolution. Conversely, incorporating an evolutionary base into the theoretical perspectives from which we approach human neuropsychology could lead to novel hypotheses and testable predictions. In the spirit of these objectives, we present here a new theoretical proposal, the Inferential Brain Hypothesis, whereby the human brain is thought to be characterized by a shift from perceptual processing to inferential computation, particularly within the social realm. This shift is believed to be a driving force for the evolution of the large human cortex. PMID:22459075

  8. Exposure measurement of aflatoxins and aflatoxin metabolites in human body fluids. A short review.

    Science.gov (United States)

    Leong, Yin-Hui; Latiff, Aishah A; Ahmad, Nurul Izzah; Rosma, Ahmad

    2012-05-01

    Aflatoxins are highly toxic secondary fungal metabolites mainly produced by Aspergillus flavus and A. parasiticus. Human exposure to aflatoxins may result directly from ingestion of contaminated foods, or indirectly from consumption of foods from animals previously exposed to aflatoxins in feeds. This paper focuses on exposure measurement of aflatoxins and aflatoxin metabolites in various human body fluids. Research on different metabolites present in blood, urine, breast milk, and other human fluids or tissues including their detection techniques is reviewed. The association between dietary intake of aflatoxins and biomarker measurement is also highlighted. Finally, aspects related to the differences between aflatoxin determination in food versus the biomarker approach are discussed.

  9. Neurotransmitter and their metabolite concentrations in different areas of the HPRT knockout mouse brain.

    Science.gov (United States)

    Tschirner, Sarah K; Gutzki, Frank; Schneider, Erich H; Seifert, Roland; Kaever, Volkhard

    2016-06-15

    Lesch-Nyhan syndrome (LNS) is characterized by uric acid overproduction and severe neurobehavioral symptoms, such as recurrent self-mutilative behavior. To learn more about the pathophysiology of the disease, we quantified neurotransmitters and their metabolites in the cerebral hemisphere, cerebellum and the medulla oblongata of HPRT knockout mice, an animal model for LNS, in comparison to the corresponding wild-type. Our analyses included l-glutamate, 4-aminobutanoic acid (GABA), acetylcholine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, l-normetanephrine, epinephrine and l-metanephrine and were conducted via high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS). Among these neurotransmitter systems, we did not find any abnormalities in the HPRT knockout mouse brains. On one side, this might indicate that HPRT deficiency most severely affects dopamine signaling, while brain functioning based on other neurotransmitters is more or less spared. On the other hand, our findings may reflect a compensating mechanism for impaired purine salvage that protects the brain in HPRT-deficient mice but not in LNS patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. The immunomodulatory activity of secondary metabolites isolated from Streptomyces calvus on human peripheral blood mononuclear cells.

    Science.gov (United States)

    Mahmoudi, Fariba; Baradaran, Behzad; Dehnad, Alireza; Shanehbandi, Dariush; Mohamed Khosroshahi, Leila; Aghapour, Mahyar

    2016-07-01

    The natural products derived from micro-organisms are potential candidates for the discovery of novel drugs. Streptomyces bacteria are prolific sources of secondary metabolites with a wide variety of biological activities. Streptomyces calvus (S. calvus) is one strain of this genus and may be an appropriate candidate for isolating new compounds. In this study, the immunomodulatory effects of S. calvus secondary metabolites on the expression of various cytokine genes by human peripheral blood mononuclear cells (PBMCs) were evaluated. A bacterial sample was inoculated in Mueller Hinton Broth and secondary metabolites were extracted. PBMCs were isolated from venous blood and were treated with S. calvus secondary metabolites for 48 h. The cell proliferation was assessed by Methyl tetrazolium bromide (MTT) assay and quantitative real-time polymerase chain reaction (qRT-PCR) assays to survey mRNA expressions of selected pro-inflammatory and inhibitory cytokine genes. Secondary metabolites augmented interleukin-2 and interferon-γ gene expression in PBMCs at low doses and also reduced the levels of immunosuppressive cytokine interleukin-10. In addition, the proliferation of PBMCs substantially increased in response to metabolite treatment in a concentration-dependent manner (p secondary metabolites from S. calvus can successfully stimulate human PBMCs. Therefore, these metabolites have the potential to serve as robust immunomodulators.

  11. Computational Intelligence in a Human Brain Model

    Directory of Open Access Journals (Sweden)

    Viorel Gaftea

    2016-06-01

    Full Text Available This paper focuses on the current trends in brain research domain and the current stage of development of research for software and hardware solutions, communication capabilities between: human beings and machines, new technologies, nano-science and Internet of Things (IoT devices. The proposed model for Human Brain assumes main similitude between human intelligence and the chess game thinking process. Tactical & strategic reasoning and the need to follow the rules of the chess game, all are very similar with the activities of the human brain. The main objective for a living being and the chess game player are the same: securing a position, surviving and eliminating the adversaries. The brain resolves these goals, and more, the being movement, actions and speech are sustained by the vital five senses and equilibrium. The chess game strategy helps us understand the human brain better and easier replicate in the proposed ‘Software and Hardware’ SAH Model.

  12. Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures.

    Science.gov (United States)

    Pomponio, Giuliana; Zurich, Marie-Gabrielle; Schultz, Luise; Weiss, Dieter G; Romanelli, Luca; Gramowski-Voss, Alexandra; Di Consiglio, Emma; Testai, Emanuela

    2015-12-25

    The difficulty in mimicking nervous system complexity and cell-cell interactions as well as the lack of kinetics information has limited the use of in vitro neurotoxicity data. Here, we assessed the biokinetic profile as well as the neurotoxicity of Amiodarone after acute and repeated exposure in two advanced rodent brain cell culture models, consisting of both neurons and glial cells organized in 2 or 3 dimensions to mimic the brain histiotypic structure and function. A strategy was applied to evidence the abiotic processes possibly affecting Amiodarone in vitro bioavailability, showing its ability to adsorb to the plastic devices. At clinically relevant Amiodarone concentrations, known to induce neurotoxicity in some patients during therapeutic treatment, a complete uptake was observed in both models in 24 h, after single exposure. After repeated treatments, bioaccumulation was observed, especially in the 3D cell model, together with a greater alteration of neurotoxicity markers. After 14 days, Amiodarone major oxidative metabolite (mono-N-desethylamiodarone) was detected at limited levels, indicating the presence of active drug metabolism enzymes (i.e. cytochrome P450) in both models. The assessment of biokinetics provides useful information on the relevance of in vitro toxicity data and should be considered in the design of an Integrated Testing Strategy aimed to identify specific neurotoxic alerts, and to improve the neurotoxicity assay predictivity for human acute and repeated exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Brain metabolism and Alzheimer's disease: the prospect of a metabolite-based therapy.

    Science.gov (United States)

    Thomas, S C; Alhasawi, A; Appanna, V P; Auger, C; Appanna, V D

    2015-01-01

    The brain is one of the most energy-demanding organs in the body. It has evolved intricate metabolic networks to fulfill this need and utilizes a variety of substrates to generate ATP, the universal energy currency. Any disruption in the supply of energy results in various abnormalities including Alzheimer's disease (AD), a condition with markedly diminished cognitive ability. Astrocytes are an important participant in maintaining the cerebral ATP budget. However, under oxidative stress induced by numerous factors including aluminum toxicity, the ability of astroctyes to generate ATP is impaired due to dysfunctional mitochondria. This leads to globular, glycolytic, lipogenic and ATP-deficient astrocytes, cerebral characteristics common in AD patients. The reversal of these perturbations by such natural metabolites as pyruvate, α-ketoglutarate, acetoacetate and L-carnitine provides valuable therapeutic cues against AD.

  14. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein.

    Science.gov (United States)

    Zhang, Chunbo; Zuo, Zhong; Kwan, Patrick; Baum, Larry

    2011-10-01

    Antiepileptic drugs (AEDs) are widely used not only in the treatment of epilepsy but also as treatments for psychiatric disorders. Pharmacoresistance of AEDs in the treatment of epilepsy and psychiatric disorders is a serious problem. Transport of antiepileptic drugs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier, may be a mechanism for resistance of AEDs. For most AEDs, conflicting evidence precludes consensus on whether they are substrates of Pgp. The objective of this study was to evaluate whether analogs and metabolites of the AED carbamazepine are substrates of human Pgp. Polarized cell lines MDCKII and LLC transfected with the human MDR1 gene were used in the bidirectional transport assay and concentration equilibrium transport assay. The expression of Pgp was detected by real-time polymerase chain reaction (PCR) and immunofluorescent staining. Rhodamine-123 uptake was also determined. Pgp did not transport carbamazepine, but it did transport its active metabolite carbamazepine-10,11-epoxide. Pgp also pumped eslicarbazepine acetate and oxcarbazepine, as well as their active metabolite (S)-licarbazepine. Transport of the drugs was in the order of ESL>OXC>S-LC>CBZ-E in concentration equilibrium conditions. The transport of these drugs was blocked by Pgp inhibitors tariquidar and verapamil. All carbamazepine analogs or metabolites tested are Pgp substrates, except for carbamazepine. These data suggest that resistance to carbamazepine, oxcarbazepine, or eslicarbazepine acetate may be attributed to increased efflux function of Pgp because they or their active metabolites are Pgp substrates. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

  15. Nutrikinetic modeling reveals order of genistein phase II metabolites appearance in human plasma.

    Science.gov (United States)

    Smit, Suzanne; Szymańska, Ewa; Kunz, Iris; Gomez Roldan, Victoria; van Tilborg, Marcel W E M; Weber, Peter; Prudence, Kevin; van der Kloet, Frans M; van Duynhoven, John P M; Smilde, Age K; de Vos, Ric C H; Bendik, Igor

    2014-11-01

    Genistein from foods or supplements is metabolized by the gut microbiota and the human body, thereby releasing many different metabolites into systemic circulation. The order of their appearance in plasma and the possible influence of food format are still unknown. This study compared the nutrikinetic profiles of genistein metabolites. In a randomized cross-over trial, 12 healthy young volunteers were administered a single dose of 30 mg genistein provided as a genistein tablet, a genistein tablet in low fat milk, and soy milk containing genistein glycosides. A high mass resolution LC-LTQ-Orbitrap FTMS platform detected and quantified in human plasma: free genistein, seven of its phase-II metabolites and 15 gut-derived metabolites. Interestingly, a novel metabolite, genistein-4'-glucuronide-7-sulfate (G-4'G-7S) was identified. Nutrikinetic analysis using population-based modeling revealed the order of appearance of five genistein phase II metabolites in plasma: (1) genistein-4',7-diglucuronide, (2) genistein-7-sulfate, (3) genistein-4'-sulfate-7-glucuronide, (4) genistein-4'-glucuronide, and (5) genistein-7-glucuronide, independent of the food matrix. The conjugated genistein metabolites appear in a distinct order in human plasma. The specific early appearance of G-4',7-diG suggests a multistep formation process for the mono and hetero genistein conjugates, involving one or two deglucuronidation steps. © 2014 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study

    Science.gov (United States)

    Oommen, Anup M.; Varma, Sudhir; Casanova, Ramon; An, Yang; O’Brien, Richard; Pletnikova, Olga; Kastenmueller, Gabi; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima; Thambisetty, Madhav

    2018-01-01

    Background The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. Methods and findings Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and “asymptomatic Alzheimer’s disease” (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes—sphingolipids and glycerophospholipids—that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that

  17. Male microchimerism in the human female brain.

    Directory of Open Access Journals (Sweden)

    William F N Chan

    Full Text Available In humans, naturally acquired microchimerism has been observed in many tissues and organs. Fetal microchimerism, however, has not been investigated in the human brain. Microchimerism of fetal as well as maternal origin has recently been reported in the mouse brain. In this study, we quantified male DNA in the human female brain as a marker for microchimerism of fetal origin (i.e. acquisition of male DNA by a woman while bearing a male fetus. Targeting the Y-chromosome-specific DYS14 gene, we performed real-time quantitative PCR in autopsied brain from women without clinical or pathologic evidence of neurologic disease (n=26, or women who had Alzheimer's disease (n=33. We report that 63% of the females (37 of 59 tested harbored male microchimerism in the brain. Male microchimerism was present in multiple brain regions. Results also suggested lower prevalence (p=0.03 and concentration (p=0.06 of male microchimerism in the brains of women with Alzheimer's disease than the brains of women without neurologic disease. In conclusion, male microchimerism is frequent and widely distributed in the human female brain.

  18. Expanding the limits of human blood metabolite quantitation using NMR spectroscopy.

    Science.gov (United States)

    Nagana Gowda, G A; Gowda, Yashas N; Raftery, Daniel

    2015-01-06

    A current challenge in metabolomics is the reliable quantitation of many metabolites. Limited resolution and sensitivity combined with the challenges associated with unknown metabolite identification have restricted both the number and the quantitative accuracy of blood metabolites. Focused on alleviating this bottleneck in NMR-based metabolomics, investigations of pooled human serum combining an array of 1D/2D NMR experiments at 800 MHz, database searches, and spiking with authentic compounds enabled the identification of 67 blood metabolites. Many of these (∼1/3) are new compared with those reported previously as a part of the Human Serum Metabolome Database. In addition, considering both the high reproducibility and quantitative nature of NMR as well as the sensitivity of NMR chemical shifts to altered sample conditions, experimental protocols and comprehensive peak annotations are provided here as a guide for identification and quantitation of the new pool of blood metabolites for routine applications. Further, investigations focused on the evaluation of quantitation using organic solvents revealed a surprisingly poor performance for protein precipitation using acetonitrile. One-third of the detected metabolites were attenuated by 10-67% compared with methanol precipitation at the same solvent-to-serum ratio of 2:1 (v/v). Nearly 2/3 of the metabolites were further attenuated by up to 65% upon increasing the acetonitrile-to-serum ratio to 4:1 (v/v). These results, combined with the newly established identity for many unknown metabolites in the NMR spectrum, offer new avenues for human serum/plasma-based metabolomics. Further, the ability to quantitatively evaluate nearly 70 blood metabolites that represent numerous classes, including amino acids, organic acids, carbohydrates, and heterocyclic compounds, using a simple and highly reproducible analytical method such as NMR may potentially guide the evaluation of samples for analysis using mass spectrometry.

  19. Levels of seven urinary phthalate metabolites in a human reference population.

    OpenAIRE

    Blount, B.C.; Silva, M J; Caudill, S P; Needham, L L; Pirkle, J L; Sampson, E.J.; Lucier, G W; Jackson, R. J.; Brock, J W

    2000-01-01

    Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percen...

  20. Consumption of seaweeds and the human brain

    DEFF Research Database (Denmark)

    Cornish, M. Lynn; Critchley, Alan T.; Mouritsen, Ole G.

    2017-01-01

    highlighting the potential impacts of the consumption of a variety of seaweeds on human brain health and includes theories in relation to the benefits to early Homo sapiens. The emphasis is on a varied diet including macroalgae and the gut/microbe/brain axis, the importance of polyunsaturated fatty acids...

  1. Lactate fuels the human brain during exercise

    NARCIS (Netherlands)

    Quistorff, Bjorn; Secher, Niels H.; van Lieshout, Johannes J.

    2008-01-01

    The human brain releases a small amount of lactate at rest, and even an increase in arterial blood lactate during anesthesia does not provoke a net cerebral lactate uptake. However, during cerebral activation associated with exercise involving a marked increase in plasma lactate, the brain takes up

  2. An introduction to human brain anatomy

    NARCIS (Netherlands)

    Forstmann, B.U.; Keuken, M.C.; Alkemade, A.; Forstmann, B.U.; Wagenmakers, E.-J.

    2015-01-01

    This tutorial chapter provides an overview of the human brain anatomy. Knowledge of brain anatomy is fundamental to our understanding of cognitive processes in health and disease; moreover, anatomical constraints are vital for neurocomputational models and can be important for psychological

  3. Interoperable atlases of the human brain.

    Science.gov (United States)

    Amunts, K; Hawrylycz, M J; Van Essen, D C; Van Horn, J D; Harel, N; Poline, J-B; De Martino, F; Bjaalie, J G; Dehaene-Lambertz, G; Dehaene, S; Valdes-Sosa, P; Thirion, B; Zilles, K; Hill, S L; Abrams, M B; Tass, P A; Vanduffel, W; Evans, A C; Eickhoff, S B

    2014-10-01

    The last two decades have seen an unprecedented development of human brain mapping approaches at various spatial and temporal scales. Together, these have provided a large fundus of information on many different aspects of the human brain including micro- and macrostructural segregation, regional specialization of function, connectivity, and temporal dynamics. Atlases are central in order to integrate such diverse information in a topographically meaningful way. It is noteworthy, that the brain mapping field has been developed along several major lines such as structure vs. function, postmortem vs. in vivo, individual features of the brain vs. population-based aspects, or slow vs. fast dynamics. In order to understand human brain organization, however, it seems inevitable that these different lines are integrated and combined into a multimodal human brain model. To this aim, we held a workshop to determine the constraints of a multi-modal human brain model that are needed to enable (i) an integration of different spatial and temporal scales and data modalities into a common reference system, and (ii) efficient data exchange and analysis. As detailed in this report, to arrive at fully interoperable atlases of the human brain will still require much work at the frontiers of data acquisition, analysis, and representation. Among them, the latter may provide the most challenging task, in particular when it comes to representing features of vastly different scales of space, time and abstraction. The potential benefits of such endeavor, however, clearly outweigh the problems, as only such kind of multi-modal human brain atlas may provide a starting point from which the complex relationships between structure, function, and connectivity may be explored. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Constitutional Aneuploidy in the Normal Human Brain

    National Research Council Canada - National Science Library

    Rehen, Stevens K; Yung, Yun C; McCreight, Matthew P; Kaushal, Dhruv; Yang, Amy H; Almeida, Beatriz S. V; Kingsbury, Marcy A; Cabral, Katia M. S; McConnell, Michael J; Anliker, Brigitte; Fontanoz, Marisa; Chun, Jerold

    2005-01-01

    .... Chromosome 21 aneuploid cells constitute approximately 4% of the estimated one trillion cells in the human brain and include non-neuronal cells and postmitotic neurons identified by the neuronspecific nuclear protein marker...

  5. 168 sections of a human brain

    OpenAIRE

    Biscotti, Rossella

    2015-01-01

    Tiré du site Internet de Boabooks: "The book displays a close up of a human brain with layers of memory and dreams visualized through a method of psychoanalysis and pharmacological propaganda. It is composed of two scientific researches that investigated the theme of memory and psychoanalysis. The first photos ever realized of sections of the human brain by psychiatric G. Jelgersma at the University of Leiden (1908-1911) are paired with the transcript of narcoanalytic sessions conducted by th...

  6. Concurrent profiling of polar metabolites and lipids in human plasma using HILIC-FTMS

    Science.gov (United States)

    Cai, Xiaoming; Li, Ruibin

    2016-11-01

    Blood plasma is the most popularly used sample matrix for metabolite profiling studies, which aim to achieve global metabolite profiling and biomarker discovery. However, most of the current studies on plasma metabolite profiling focused on either the polar metabolites or lipids. In this study, a comprehensive analysis approach based on HILIC-FTMS was developed to concurrently examine polar metabolites and lipids. The HILIC-FTMS method was developed using mixed standards of polar metabolites and lipids, the separation efficiency of which is better in HILIC mode than in C5 and C18 reversed phase (RP) chromatography. This method exhibits good reproducibility in retention times (CVs profiling and smoking-related biomarker discovery in human plasma samples. Heavy smokers could be successfully distinguished from non smokers by univariate and multivariate statistical analysis of the profiling data, and 62 biomarkers for cigarette smoke were found. These results indicate that our concurrent analysis approach could be potentially used for clinical biomarker discovery, metabolite-based diagnosis, etc.

  7. Analysis of a human brain transcriptome map

    Directory of Open Access Journals (Sweden)

    Greene Jonathan R

    2002-04-01

    Full Text Available Abstract Background Genome wide transcriptome maps can provide tools to identify candidate genes that are over-expressed or silenced in certain disease tissue and increase our understanding of the structure and organization of the genome. Expressed Sequence Tags (ESTs from the public dbEST and proprietary Incyte LifeSeq databases were used to derive a transcript map in conjunction with the working draft assembly of the human genome sequence. Results Examination of ESTs derived from brain tissues (excluding brain tumor tissues suggests that these genes are distributed on chromosomes in a non-random fashion. Some regions on the genome are dense with brain-enriched genes while some regions lack brain-enriched genes, suggesting a significant correlation between distribution of genes along the chromosome and tissue type. ESTs from brain tumor tissues have also been mapped to the human genome working draft. We reveal that some regions enriched in brain genes show a significant decrease in gene expression in brain tumors, and, conversely that some regions lacking in brain genes show an increased level of gene expression in brain tumors. Conclusions This report demonstrates a novel approach for tissue specific transcriptome mapping using EST-based quantitative assessment.

  8. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases.

    Science.gov (United States)

    Lin, Lan; Zhang, Jianqiong

    2017-01-06

    A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health. This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA). In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction. A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.

  9. Genetic control of postnatal human brain growth.

    Science.gov (United States)

    van Dyck, Laura I; Morrow, Eric M

    2017-02-01

    Studies investigating postnatal brain growth disorders inform the biology underlying the development of human brain circuitry. This research is becoming increasingly important for the diagnosis and treatment of childhood neurodevelopmental disorders, including autism and related disorders. Here, we review recent research on typical and abnormal postnatal brain growth and examine potential biological mechanisms. Clinically, brain growth disorders are heralded by diverging head size for a given age and sex, but are more precisely characterized by brain imaging, post-mortem analysis, and animal model studies. Recent neuroimaging and molecular biological studies on postnatal brain growth disorders have broadened our view of both typical and pathological postnatal neurodevelopment. Correlating gene and protein function with brain growth trajectories uncovers postnatal biological mechanisms, including neuronal arborization, synaptogenesis and pruning, and gliogenesis and myelination. Recent investigations of childhood neurodevelopmental and neurodegenerative disorders highlight the underlying genetic programming and experience-dependent remodeling of neural circuitry. To understand typical and abnormal postnatal brain development, clinicians and researchers should characterize brain growth trajectories in the context of neurogenetic syndromes. Understanding mechanisms and trajectories of postnatal brain growth will aid in differentiating, diagnosing, and potentially treating neurodevelopmental disorders.

  10. [Effects of amitriptyline, fluoxetine, and tianeptine on the content of monoamines and their metabolites in Wistar rat brain structures].

    Science.gov (United States)

    Kudrin, V S; Mosin, V M; Klodt, P M; Narkevich, V B; Molodavkin, G M; Voronina, T A

    2010-03-01

    The effects of antidepressant drugs belonging to different pharmacological groups--amitriptyline, fluoxetine (prozac), and tianeptine (coaxyl)--on the content of monoamines and their metabolites in Wistar rat brain structures (frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocamp) has been studied using HPLC with electrochemical detection. Tricyclic antidepressant amitriptyline (10 mg/kg) was found to produce a moderate increase in the DOPAC/dopamine turnover index in nucleus accumbens, but did not influence the levels of serotonin (5-HT), dopamine, and its metabolites (5-HIAA, DOPAC, and HVA) in other brain structures studied (frontal cortex, hypothalamus, striatum, hippocamp). Fluoxetine (Prozac) (20 mg/kg) decreased both the 5-HIAA content and the 5-HIAA/5-HT (5-HT turnover index) in all brain structures of Wistar rats. In contrast, the effects of Prozac on the level of catecholamines and their metabolites in various brain regions was more complex. Tianeptine (Coaxyl) was demonstrated to increase both the 5-HIAA content and the 5-HIAA/5-HT ratio in all the structures studied (except for nucleus accumbens), in good agreement with the hypothesis concerning a two-phase mode of tianeptine action with enhanced 5-HT secretion in the synaptic gap in the first stage of pharmacological response.

  11. Comparison of LCModel and SAGE in Analysis of Brain Metabolite Concentrations-A study of Patients with Mild Cognitive Impairment.

    Science.gov (United States)

    Shih, Chiu-Ming; Lai, Jui-Jen; Chang, Chin-Ching; Chen, Cheng-Sheng; Yeh, Yi-Chun; Jaw, Twei-Shiun; Hsu, Jui-Sheng; Li, Chun-Wei

    2017-03-15

    The purpose of this study was to compare brain metabolite concentration ratios determined by LCModel and Spectroscopy Analysis by General Electric (SAGE) quantitative methods to elucidate the advantages and disadvantages of each method. A total of 10 healthy volunteers and 10 patients with mild cognitive impairment (MCI) were recruited in this study. A point-resolved spectroscopy (PRESS) sequence was used to obtain the brain magnetic resonance spectroscopy (MRS) spectra of the volunteers and patients, as well as the General Electric (GE) MRS-HD-sphere phantom. The brain metabolite concentration ratios were estimated based on the peak area obtained from both LCModel and SAGE software. Three brain regions were sampled for each volunteer or patient, and 20 replicates were acquired at different times for the phantom analysis. The metabolite ratios of the GE phantom were estimated to be myo-inositol (mI)/creatine (Cr): 0.70 ± 0.01, choline (Cho)/Cr: 0.37 ± 0.00, N-acetylaspartate (NAA)/Cr: 1.26 ± 0.02, and NAA/mI: 1.81 ± 0.04 by LCModel, and mI/Cr: 0.88 ± 0.15, Cho/Cr: 0.35 ± 0.01, NAA/Cr: 1.33 ± 0.03, and NAA/mI: 1.55 ± 0.26 by SAGE. In the healthy volunteers and MCI patients, the ratios of mI/Cr and Cho/Cr estimated by LCModel were higher than those estimated by SAGE. In contrast, the ratio of NAA/Cr estimated by LCModel was lower than that estimated by SAGE. Both methods were acceptable in estimating brain metabolite concentration ratios. However, LCModel was marginally more accurate than SAGE because of its full automation, basis set, and user independency.

  12. Identification of a sulfate metabolite of PCB 11 in human serum.

    Science.gov (United States)

    Grimm, Fabian A; Lehmler, Hans-Joachim; Koh, Wen Xin; DeWall, Jeanne; Teesch, Lynn M; Hornbuckle, Keri C; Thorne, Peter S; Robertson, Larry W; Duffel, Michael W

    2017-01-01

    Despite increasing evidence for a major role for sulfation in the metabolism of lower-chlorinated polychlorinated biphenyls in vitro and in vivo, and initial evidence for potential bioactivities of the resulting sulfate ester metabolites, the formation of PCB sulfates in PCB exposed human populations had not been explored. The primary goal of this study was to determine if PCB sulfates, and potentially other conjugated PCB derivatives, are relevant classes of PCB metabolites in the serum of humans with known exposures to PCBs. In order to detect and quantify dichlorinated PCB sulfates in serum samples of 46 PCB-exposed individuals from either rural or urban communities, we developed a high-resolution mass spectrometry-based protocol using 4-PCB 11 sulfate as a model compound. The method also allowed the preliminary analysis of these 46 human serum extracts for the presence of other metabolites, such as glucuronic acid conjugates and hydroxylated PCBs. Sulfate ester metabolites derived from dichlorinated PCBs were detectable and quantifiable in more than 20% of analyzed serum samples. Moreover, we were able to utilize this method to detect PCB glucuronides and hydroxylated PCBs, albeit at lower frequencies than PCB sulfates. Altogether, our results provide initial evidence for the presence of PCB sulfates in human serum. Considering the inability of previously employed analytical protocols for PCBs to extract these sulfate ester metabolites and the concentrations of these metabolites observed in our current study, our data support the hypothesis that total serum levels of PCB metabolites in exposed individuals may have been underestimated in the past. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Preventive brain radio-chemotherapy alters plasticity associated metabolite profile in the hippocampus but seems to not affect spatial memory in young leukemia patients.

    Science.gov (United States)

    Brandt, Moritz D; Brandt, Kalina; Werner, Annett; Schönfeld, Robby; Loewenbrück, Kai; Donix, Markus; Schaich, Markus; Bornhäuser, Martin; von Kummer, Rüdiger; Leplow, Bernd; Storch, Alexander

    2015-09-01

    Neuronal plasticity leading to evolving reorganization of the neuronal network during entire lifespan plays an important role for brain function especially memory performance. Adult neurogenesis occurring in the dentate gyrus of the hippocampus represents the maximal way of network reorganization. Brain radio-chemotherapy strongly inhibits adult hippocampal neurogenesis in mice leading to impaired spatial memory. To elucidate the effects of CNS radio-chemotherapy on hippocampal plasticity and function in humans, we performed a longitudinal pilot study using 3T proton magnetic resonance spectroscopy ((1)H-MRS) and virtual water-maze-tests in 10 de-novo patients with acute lymphoblastic leukemia undergoing preventive whole brain radio-chemotherapy. Patients were examined before, during and after treatment. CNS radio-chemotherapy did neither affect recall performance in probe trails nor flexible (reversal) relearning of a new target position over a time frame of 10 weeks measured by longitudinal virtual water-maze-testing, but provoked hippocampus-specific decrease in choline as a metabolite associated with cellular plasticity in (1)H-MRS. Albeit this pilot study needs to be followed up to definitely resolve the question about the functional role of adult human neurogenesis, the presented data suggest that (1)H-MRS allows the detection of neurogenesis-associated plasticity in the human brain.

  14. MR-visible brain water content in human acute stroke

    DEFF Research Database (Denmark)

    Gideon, P; Rosenbaum, S; Sperling, B

    1999-01-01

    Quantification of metabolite concentrations by proton magnetic resonance spectroscopy (1H-MRS) in the human brain using water as an internal standard is based on the assumption that water content does not change significantly in pathologic brain tissue. To test this, we used 1H-MRS to estimate...... brain water content during the course of cerebral infarction. Measurements were performed serially in the acute, subacute, and chronic phase of infarction. Fourteen patients with acute cerebral infarction were examined as well as 9 healthy controls. To correlate with regional cerebral blood flow (r......CBF from Day 0-3 to Day 4-7 (p = 0.050) and from Day 0-3 to Day 8-21 (p = 0.028). No correlation between rCBF and water content was found. Water content in ischemic brain tissue increased significantly between Day 4-7 after stroke. This should be considered when performing quantitative 1H-MRS using water...

  15. The Human Brain Project: Creating a European Research Infrastructure to Decode the Human Brain.

    Science.gov (United States)

    Amunts, Katrin; Ebell, Christoph; Muller, Jeff; Telefont, Martin; Knoll, Alois; Lippert, Thomas

    2016-11-02

    Decoding the human brain is perhaps the most fascinating scientific challenge in the 21st century. The Human Brain Project (HBP), a 10-year European Flagship, targets the reconstruction of the brain's multi-scale organization. It uses productive loops of experiments, medical, data, data analytics, and simulation on all levels that will eventually bridge the scales. The HBP IT architecture is unique, utilizing cloud-based collaboration and development platforms with databases, workflow systems, petabyte storage, and supercomputers. The HBP is developing toward a European research infrastructure advancing brain research, medicine, and brain-inspired information technology. Copyright © 2016. Published by Elsevier Inc.

  16. The Molecular Basis of Human Brain Evolution.

    Science.gov (United States)

    Enard, Wolfgang

    2016-10-24

    Humans are a remarkable species, especially because of the remarkable properties of their brain. Since the split from the chimpanzee lineage, the human brain has increased three-fold in size and has acquired abilities for vocal learning, language and intense cooperation. To better understand the molecular basis of these changes is of great biological and biomedical interest. However, all the about 16 million fixed genetic changes that occurred during human evolution are fully correlated with all molecular, cellular, anatomical and behavioral changes that occurred during this time. Hence, as humans and chimpanzees cannot be crossed or genetically manipulated, no direct evidence for linking particular genetic and molecular changes to human brain evolution can be obtained. Here, I sketch a framework how indirect evidence can be obtained and review findings related to the molecular basis of human cognition, vocal learning and brain size. In particular, I discuss how a comprehensive comparative approach, leveraging cellular systems and genomic technologies, could inform the evolution of our brain in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Oxidative metabolites of diisononyl phthalate as biomarkers for human exposure assessment.

    Science.gov (United States)

    Silva, Manori J; Reidy, John A; Preau, James L; Needham, Larry L; Calafat, Antonia M

    2006-08-01

    Diisononyl phthalate (DINP) is a complex mixture of predominantly nine-carbon branched-chain dialkyl phthalate isomers. Similar to di(2-ethylhexyl) phthalate, a widely used phthalate, DINP causes antiandrogenic effects on developing rodent male fetuses. Traditionally, assessment of human exposure to DINP has been done using monoisononyl phthalate (MINP) , the hydrolytic metabolite of DINP, as a biomarker. However, MINP is only a minor urinary metabolite of DINP. Oxidative metabolites, including mono(carboxyisooctyl) phthalate (MCIOP) , mono(oxoisononyl) phthalate (MOINP) , and mono(hydroxyisononyl) phthalate (MHINP) are the major urinary metabolites in DINP-dosed rats. The urinary concentrations of MINP, MCIOP, MOINP, and MHINP were measured in 129 adult anonymous human volunteers with no known exposure to DINP. Although MINP was not present at detectable levels in any of the samples analyzed, MCIOP, MHINP, and MOINP were detected in 97, 100, and 87% of the urine samples at geometric mean levels equal to 8.6, 11.4, and 1.2 ng/mL, respectively. The concentrations of all three oxidative metabolites were highly correlated with each other (p<0.0001), which confirms a common precursor. MCIOP was excreted predominantly as a free species, whereas MOINP was excreted mostly in its glucuronidated form. The percentage of MHINP excreted either glucuronidated or in its free form was similar. The significantly higher frequency of detection and urinary concentrations of oxidative metabolites than of MINP suggest that these oxidative metabolites are better biomarkers of exposure assessment of DINP than is MINP. Therefore, we concluded that the prevalence of human exposure to DINP is underestimated by using MINP as the sole DINP urinary biomarker.

  18. Detection of Volatile Metabolites Derived from Garlic (Allium sativum in Human Urine

    Directory of Open Access Journals (Sweden)

    Laura Scheffler

    2016-12-01

    Full Text Available The metabolism and excretion of flavor constituents of garlic, a common plant used in flavoring foods and attributed with several health benefits, in humans is not fully understood. Likewise, the physiologically active principles of garlic have not been fully clarified to date. It is possible that not only the parent compounds present in garlic but also its metabolites are responsible for the specific physiological properties of garlic, including its influence on the characteristic body odor signature of humans after garlic consumption. Accordingly, the aim of this study was to investigate potential garlic-derived metabolites in human urine. To this aim, 14 sets of urine samples were obtained from 12 volunteers, whereby each set comprised one sample that was collected prior to consumption of food-relevant concentrations of garlic, followed by five to eight subsequent samples after garlic consumption that covered a time interval of up to 26 h. The samples were analyzed chemo-analytically using gas chromatography-mass spectrometry/olfactometry (GC-MS/O, as well as sensorially by a trained human panel. The analyses revealed three different garlic-derived metabolites in urine, namely allyl methyl sulfide (AMS, allyl methyl sulfoxide (AMSO and allyl methyl sulfone (AMSO2, confirming our previous findings on human milk metabolite composition. The excretion rates of these metabolites into urine were strongly time-dependent with distinct inter-individual differences. These findings indicate that the volatile odorant fraction of garlic is heavily biotransformed in humans, opening up a window into substance circulation within the human body with potential wider ramifications in view of physiological effects of this aromatic plant that is appreciated by humans in their daily diet.

  19. Detection of Volatile Metabolites Derived from Garlic (Allium sativum) in Human Urine

    Science.gov (United States)

    Scheffler, Laura; Sauermann, Yvonne; Heinlein, Anja; Sharapa, Constanze; Buettner, Andrea

    2016-01-01

    The metabolism and excretion of flavor constituents of garlic, a common plant used in flavoring foods and attributed with several health benefits, in humans is not fully understood. Likewise, the physiologically active principles of garlic have not been fully clarified to date. It is possible that not only the parent compounds present in garlic but also its metabolites are responsible for the specific physiological properties of garlic, including its influence on the characteristic body odor signature of humans after garlic consumption. Accordingly, the aim of this study was to investigate potential garlic-derived metabolites in human urine. To this aim, 14 sets of urine samples were obtained from 12 volunteers, whereby each set comprised one sample that was collected prior to consumption of food-relevant concentrations of garlic, followed by five to eight subsequent samples after garlic consumption that covered a time interval of up to 26 h. The samples were analyzed chemo-analytically using gas chromatography-mass spectrometry/olfactometry (GC-MS/O), as well as sensorially by a trained human panel. The analyses revealed three different garlic-derived metabolites in urine, namely allyl methyl sulfide (AMS), allyl methyl sulfoxide (AMSO) and allyl methyl sulfone (AMSO2), confirming our previous findings on human milk metabolite composition. The excretion rates of these metabolites into urine were strongly time-dependent with distinct inter-individual differences. These findings indicate that the volatile odorant fraction of garlic is heavily biotransformed in humans, opening up a window into substance circulation within the human body with potential wider ramifications in view of physiological effects of this aromatic plant that is appreciated by humans in their daily diet. PMID:27916960

  20. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness

    DEFF Research Database (Denmark)

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng

    2014-01-01

    Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees......, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy...... metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized...

  1. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness.

    Directory of Open Access Journals (Sweden)

    Katarzyna Bozek

    2014-05-01

    Full Text Available Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys.

  2. Exceptional Evolutionary Divergence of Human Muscle and Brain Metabolomes Parallels Human Cognitive and Physical Uniqueness

    Science.gov (United States)

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng; Liu, Xiling; Xiong, Jieyi; Sugimoto, Masahiro; Tomita, Masaru; Pääbo, Svante; Pieszek, Raik; Sherwood, Chet C.; Hof, Patrick R.; Ely, John J.; Steinhauser, Dirk; Willmitzer, Lothar; Bangsbo, Jens; Hansson, Ola; Call, Josep; Giavalisco, Patrick; Khaitovich, Philipp

    2014-01-01

    Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys. PMID:24866127

  3. [IMMUNE REGULATORY PROPERTIES OF BIFIDOBACTERIA METABOLITES DURING EUBIOSIS AND DYSBIOSIS OF THE HUMAN COLON].

    Science.gov (United States)

    Bukharin, O V; Ivanova, E V; Perunova, N B; Chainikova, I N; Nikoforov, I A; Bondarenko, T A

    2015-01-01

    Evaluate immune regulatory properties of bifidobacteria metabolites during eubiosis and dysbiosis of the human colon. Anti-cytokine activity of metabolites of bifidobacteria clinical strains and their ability to influence the production of pro- and anti-inflammatory cytokines (IL-10) by peripheral blood mononuclear cells of healthy humans was studied, taking into account microecological state of the human intestine. Determination of final concentration of cytokines in experimental and control samples was carried out by EIA. Sensitive parameters, that are suitable for evaluation of stability of human intestine microsymbiocenosis, were detected. The level of microbial seeding, concentration of TNF-α and anti-lysozyme activity turned out to be informative for bifidobacteria in eubiosis conditions. The ability of bifidoflora metabolites to influence the production of pro-inflammatory cytokines (INF-γ, TNF-α, IL-8) by human mononuclears was a significant parameter during formation of 1 - 3 degree dysbiosis. The maintenance of physiological state of intestine homeostasis is determined by immune regulatory properties of bifidobacteria metabolites, that is realized via their interaction with both cytokines (anti-cytokine activity) and production of cytokines by host immune cells (peripheral blood mononuclears).

  4. Segmentation and Visualisation of Human Brain Structures

    OpenAIRE

    Hult, Roger

    2003-01-01

    In this thesis the focus is mainly on the development of segmentation techniques for human brain structures and of the visualisation of such structures. The images of the brain are both anatomical images (magnet resonance imaging (MRI) and autoradigraphy) and functional images that show blood flow (functional magnetic imaging (fMRI), positron emission tomography (PET), and single photon emission tomograpy (SPECT)). When working with anatomical images, the structures segmented are visible as d...

  5. Seasonality in human cognitive brain responses.

    Science.gov (United States)

    Meyer, Christelle; Muto, Vincenzo; Jaspar, Mathieu; Kussé, Caroline; Lambot, Erik; Chellappa, Sarah L; Degueldre, Christian; Balteau, Evelyne; Luxen, André; Middleton, Benita; Archer, Simon N; Collette, Fabienne; Dijk, Derk-Jan; Phillips, Christophe; Maquet, Pierre; Vandewalle, Gilles

    2016-03-15

    Daily variations in the environment have shaped life on Earth, with circadian cycles identified in most living organisms. Likewise, seasons correspond to annual environmental fluctuations to which organisms have adapted. However, little is known about seasonal variations in human brain physiology. We investigated annual rhythms of brain activity in a cross-sectional study of healthy young participants. They were maintained in an environment free of seasonal cues for 4.5 d, after which brain responses were assessed using functional magnetic resonance imaging (fMRI) while they performed two different cognitive tasks. Brain responses to both tasks varied significantly across seasons, but the phase of these annual rhythms was strikingly different, speaking for a complex impact of season on human brain function. For the sustained attention task, the maximum and minimum responses were located around summer and winter solstices, respectively, whereas for the working memory task, maximum and minimum responses were observed around autumn and spring equinoxes. These findings reveal previously unappreciated process-specific seasonality in human cognitive brain function that could contribute to intraindividual cognitive changes at specific times of year and changes in affective control in vulnerable populations.

  6. Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain.

    Science.gov (United States)

    Lieblein-Boff, Jacqueline C; Johnson, Elizabeth J; Kennedy, Adam D; Lai, Chron-Si; Kuchan, Matthew J

    2015-01-01

    Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510) were excluded. In addition, moderate correlations with xenobiotic relationships (2) or those driven by single outliers (3) were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region-specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development.

  7. Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain.

    Directory of Open Access Journals (Sweden)

    Jacqueline C Lieblein-Boff

    Full Text Available Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510 were excluded. In addition, moderate correlations with xenobiotic relationships (2 or those driven by single outliers (3 were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region-specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development.

  8. In Vivo Detection of Perinatal Brain Metabolite Changes in a Rabbit Model of Intrauterine Growth Restriction (IUGR.

    Directory of Open Access Journals (Sweden)

    Rui V Simões

    Full Text Available Intrauterine growth restriction (IUGR is a risk factor for abnormal neurodevelopment. We studied a rabbit model of IUGR by magnetic resonance imaging (MRI and spectroscopy (MRS, to assess in vivo brain structural and metabolic consequences, and identify potential metabolic biomarkers for clinical translation.IUGR was induced in 3 pregnant rabbits at gestational day 25, by 40-50% uteroplacental vessel ligation in one horn; the contralateral horn was used as control. Fetuses were delivered at day 30 and weighted. A total of 6 controls and 5 IUGR pups underwent T2-w MRI and localized proton MRS within the first 8 hours of life, at 7T. Changes in brain tissue volumes and respective contributions to each MRS voxel were estimated by semi-automated registration of MRI images with a digital atlas of the rabbit brain. MRS data were used for: (i absolute metabolite quantifications, using linear fitting; (ii local temperature estimations, based on the water chemical shift; and (iii classification, using spectral pattern analysis.Lower birth weight was associated with (i smaller brain sizes, (ii slightly lower brain temperatures, and (iii differential metabolite profile changes in specific regions of the brain parenchyma. Specifically, we found estimated lower levels of aspartate and N-acetylaspartate (NAA in the cerebral cortex and hippocampus (suggesting neuronal impairment, and higher glycine levels in the striatum (possible marker of brain injury. Our results also suggest that the metabolic changes in cortical regions are more prevalent than those detected in hippocampus and striatum.IUGR was associated with brain metabolic changes in vivo, which correlate well with the neurostructural changes and neurodevelopment problems described in IUGR. Metabolic parameters could constitute non invasive biomarkers for the diagnosis and abnormal neurodevelopment of perinatal origin.

  9. In Vivo Detection of Perinatal Brain Metabolite Changes in a Rabbit Model of Intrauterine Growth Restriction (IUGR).

    Science.gov (United States)

    Simões, Rui V; Muñoz-Moreno, Emma; Carbajo, Rodrigo J; González-Tendero, Anna; Illa, Miriam; Sanz-Cortés, Magdalena; Pineda-Lucena, Antonio; Gratacós, Eduard

    2015-01-01

    Intrauterine growth restriction (IUGR) is a risk factor for abnormal neurodevelopment. We studied a rabbit model of IUGR by magnetic resonance imaging (MRI) and spectroscopy (MRS), to assess in vivo brain structural and metabolic consequences, and identify potential metabolic biomarkers for clinical translation. IUGR was induced in 3 pregnant rabbits at gestational day 25, by 40-50% uteroplacental vessel ligation in one horn; the contralateral horn was used as control. Fetuses were delivered at day 30 and weighted. A total of 6 controls and 5 IUGR pups underwent T2-w MRI and localized proton MRS within the first 8 hours of life, at 7T. Changes in brain tissue volumes and respective contributions to each MRS voxel were estimated by semi-automated registration of MRI images with a digital atlas of the rabbit brain. MRS data were used for: (i) absolute metabolite quantifications, using linear fitting; (ii) local temperature estimations, based on the water chemical shift; and (iii) classification, using spectral pattern analysis. Lower birth weight was associated with (i) smaller brain sizes, (ii) slightly lower brain temperatures, and (iii) differential metabolite profile changes in specific regions of the brain parenchyma. Specifically, we found estimated lower levels of aspartate and N-acetylaspartate (NAA) in the cerebral cortex and hippocampus (suggesting neuronal impairment), and higher glycine levels in the striatum (possible marker of brain injury). Our results also suggest that the metabolic changes in cortical regions are more prevalent than those detected in hippocampus and striatum. IUGR was associated with brain metabolic changes in vivo, which correlate well with the neurostructural changes and neurodevelopment problems described in IUGR. Metabolic parameters could constitute non invasive biomarkers for the diagnosis and abnormal neurodevelopment of perinatal origin.

  10. Arsenic metabolites in humans after ingestion of wakame seaweed

    Directory of Open Access Journals (Sweden)

    Hata A.

    2013-04-01

    Full Text Available Seaweed contains large amounts of various arsenic compounds such as arsenosugars (AsSugs, but their relative toxicities have not yet been fully evaluated. A risk evaluation of dietary arsenic would be necessary. After developing an arsenic speciation analysis of wakame seaweed (Undaria pinnatifida, we conducted a wakame ingestion experiment using volunteers. Five volunteers ingested 300 g of commercial wakame after refraining from seafood for 5 days. Arsenic metabolites in the urine were monitored over a 5-day period after ingestion. Total arsenic concentration of the wakame seaweed was 34.3 ± 2.1 mg arsenic/kg (dry weight, n = 3. Two AsSugs, 3-[5′-deoxy-5′-(dimethyl-arsinoyl-β-ribofuranosyloxy]-propylene glycol (AsSug328 and 3-[5′-deoxy-5′-(dimethyl-arsinoyl-β- ribofuranosyl-oxy]-2-hydroxypropyl-2,3-dihydroxy-propyl phosphate (AsSug482 were detected, but arsenobetaine, dimethylarsinic acid (DMA, monomethylarsonic acid, and inorganic arsenics (iAs were not detected. The major peak was AsSug328, which comprised 89% of the total arsenic. Approximately 30% of the total arsenic ingested was excreted in the urine during the 5-day observation. Five arsenic compounds were detected in the urine after ingestion, the major one being DMA, which comprised 58.1 ± 5.0% of the total urinary arsenic excreted over the 5 days. DMA was believed to be metabolized not from iAs but from AsSugs, and its biological half-time was approximately 13 h.

  11. Separation of water-soluble metabolites of benzo[a]pyrene formed by cultured human colon

    DEFF Research Database (Denmark)

    1979-01-01

    A method has been developed to separate conjugated metabolites of benzo[a]pyrene into three major fractions: sulfate esters, glucuronides and glutathione conjugates. In cultured human colon, formation of sulfate esters and glutathione conjugates is the major conjugation pathway, while formation o...

  12. Human Ozone (O3) Exposure Alters Serum Profile of Lipid Metabolites

    Science.gov (United States)

    HUMAN OZONE (O3) EXPOSURE ALTERS SERUM PROFILE OF LIPID METABOLITES Miller, D B.1; Kodavanti, U P.2 Karoly, E D.3; Cascio W.E2, Ghio, A J. 21. UNC-Chapel Hill, Chapel Hill, N.C., United States. 2. NHEERL, U.S. EPA, RTP, N.C., United States. 3. METABOLON INC., Durham, N.C., United...

  13. Facilitated Uptake of a Bioactive Metabolite of Maritime Pine Bark Extract (Pycnogenol) into Human Erythrocytes

    Science.gov (United States)

    Kurlbaum, Max; Mülek, Melanie; Högger, Petra

    2013-01-01

    Many plant secondary metabolites exhibit some degree of biological activity in humans. It is a common observation that individual plant-derived compounds in vivo are present in the nanomolar concentration range at which they usually fail to display measurable activity in vitro. While it is debatable that compounds detected in plasma are not the key effectors of bioactivity, an alternative hypothesis may take into consideration that measurable concentrations also reside in compartments other than plasma. We analysed the binding of constituents and the metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone (M1), that had been previously detected in plasma samples of human consumers of pine bark extract Pycnogenol, to human erythrocytes. We found that caffeic acid, taxifolin, and ferulic acid passively bind to red blood cells, but only the bioactive metabolite M1 revealed pronounced accumulation. The partitioning of M1 into erythrocytes was significantly diminished at higher concentrations of M1 and in the presence of glucose, suggesting a facilitated transport of M1 via GLUT-1 transporter. This concept was further supported by structural similarities between the natural substrate α-D-glucose and the S-isomer of M1. After cellular uptake, M1 underwent further metabolism by conjugation with glutathione. We present strong indication for a transporter-mediated accumulation of a flavonoid metabolite in human erythrocytes and subsequent formation of a novel glutathione adduct. The physiologic role of the adduct remains to be elucidated. PMID:23646194

  14. Facilitated uptake of a bioactive metabolite of maritime pine bark extract (pycnogenol into human erythrocytes.

    Directory of Open Access Journals (Sweden)

    Max Kurlbaum

    Full Text Available Many plant secondary metabolites exhibit some degree of biological activity in humans. It is a common observation that individual plant-derived compounds in vivo are present in the nanomolar concentration range at which they usually fail to display measurable activity in vitro. While it is debatable that compounds detected in plasma are not the key effectors of bioactivity, an alternative hypothesis may take into consideration that measurable concentrations also reside in compartments other than plasma. We analysed the binding of constituents and the metabolite δ-(3,4-dihydroxy-phenyl-γ-valerolactone (M1, that had been previously detected in plasma samples of human consumers of pine bark extract Pycnogenol, to human erythrocytes. We found that caffeic acid, taxifolin, and ferulic acid passively bind to red blood cells, but only the bioactive metabolite M1 revealed pronounced accumulation. The partitioning of M1 into erythrocytes was significantly diminished at higher concentrations of M1 and in the presence of glucose, suggesting a facilitated transport of M1 via GLUT-1 transporter. This concept was further supported by structural similarities between the natural substrate α-D-glucose and the S-isomer of M1. After cellular uptake, M1 underwent further metabolism by conjugation with glutathione. We present strong indication for a transporter-mediated accumulation of a flavonoid metabolite in human erythrocytes and subsequent formation of a novel glutathione adduct. The physiologic role of the adduct remains to be elucidated.

  15. In vivo quantitation of metabolite concentrations in the brain by means of proton MRS

    DEFF Research Database (Denmark)

    Henriksen, O

    1995-01-01

    MRS offers unique possibilities for non-invasive studies of biochemistry in the human brain in vivo. A growing body of evidence suggests that proton MRS may contribute to the clinical evaluation of a number of pathologies including ischaemia, tumours, epilepsy, metabolic and neuropaediatric......, selection efficiency, outer volume depression and signal contamination is essential for validation of the measurements. Furthermore, corrections for the influence of relaxation behavior are necessary. The results published so far indicate that the concentrations of NAA, total creatine, Cho and Ins in mmoles...

  16. Urinary profile of catecholamines and metabolites in Parkinson patients with deep brain stimulation.

    Science.gov (United States)

    Guimarães, J; Vieira-Coelho, M A; Moura, E; Afonso, J; Rosas, M J; Vaz, R; Garrett, C

    2014-02-01

    Deep brain stimulation of the subthalamic nucleus (DBS-STN) is thought to continuously alter the activity of STN neurons in Parkinson's disease (PD). A chronic decrease in the levodopa dose with continuous STN stimulation may induce plastic neuronal changes. The objective of this work was to study urinary excretion of catecholamines in patients with PD before and after DBS-STN. Twenty-three patients were submitted to DBS-STN, and evaluated before and after surgery with respect to catecholamines and metabolites in 24-h urine measured by high-performance liquid chromatography with electrochemical detection. Of the 23 patients evaluated, a significant decrease of about 60% in the urinary excretion of L-3,4-dihydroxyphenylalanine (L-DOPA; in nmol/mg creatinine/24 h) was observed 1 week after DBS-STN. Moreover, in 17 patients with a follow-up of 8 weeks after surgery, there was a further 50% decrease in urinary L-DOPA levels, dropping to about 75% of the values before surgery. There was also a significant decrease in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels 1 week after DBS-STN that was no longer present 8 weeks after. A significant increase in the DA/l-DOPA ratio was observed 1 week after surgery, with a further increase 8 weeks after surgery. After DBS-STN, the DA/l-DOPA ratio, an indirect measure of DA synthesis, increased. These results show that DBS-STN may improve the efficacy of oral levodopa. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

  17. Variation of Metabolite and Hormone Contents in Human Milk.

    Science.gov (United States)

    Demmelmair, Hans; Koletzko, Berthold

    2017-03-01

    Animal studies show that the lactation period contributes to metabolic programming of the offspring and that oral leptin and insulin show bioactivity. Stage of lactation, duration of gestation, maternal body composition, and maternal diet seem to influence the concentrations of small molecules in human milk. Variability of small molecule concentrations seems higher in preterm milk than in term milk. Insulin in human milk shows concentrations similar to plasma. Leptin concentration is lower in milk than in plasma and reflects maternal body mass index. Early in lactation, leptin could contribute to mediating the association between maternal and infant body composition. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. MR-visible brain water content in human acute stroke

    DEFF Research Database (Denmark)

    Gideon, P; Rosenbaum, S; Sperling, B

    1999-01-01

    CBF) SPECT-scanning using 99mTc-HMPAO as flow tracer was performed in the patients. Mean water content (SD) in the infarct area was 37.7 (5.1); 41.8 (4.8); 35.2 (5.4); and 39.3 (5.1) mol x [kg wet weight](-1) at 0-3; 4-7; 8-21; and >180 days after stroke, respectively. Water content increased between Day 0......Quantification of metabolite concentrations by proton magnetic resonance spectroscopy (1H-MRS) in the human brain using water as an internal standard is based on the assumption that water content does not change significantly in pathologic brain tissue. To test this, we used 1H-MRS to estimate...... brain water content during the course of cerebral infarction. Measurements were performed serially in the acute, subacute, and chronic phase of infarction. Fourteen patients with acute cerebral infarction were examined as well as 9 healthy controls. To correlate with regional cerebral blood flow (r...

  19. Effects of Secondary Metabolites of Permafrost Bacillus sp. on Cytokine Synthesis by Human Peripheral Blood Mononuclear Cells.

    Science.gov (United States)

    Kalenova, L F; Kolyvanova, S S; Bazhin, A S; Besedin, I M; Mel'nikov, V P

    2017-06-01

    We studied the effects of secondary metabolites of Bacillus sp. isolated from late Neogene permafrost on secretion of proinflammatory (TNF-α, IL-1β, IL-8, IL-2, and IFNγ) and antiinflammatory (IL-4 and IL-10) cytokines by human peripheral blood mononuclear cells. It was found that metabolites of Bacillus sp. produced more potent effect on cytokine secretion than mitogen phytohemagglutinin and metabolites of Bacillus cereus, medicinal strain IP5832. Activity of metabolites depended on the temperature of bacteria incubation. "Cold" metabolites of Bacillus sp. (isolated at -5°C) primarily induced Th1-mediated secretion of IFNγ, while "warm" metabolites (obtained at 37°C) induced Th2-mediated secretion of IL-4. The results suggest that Bacillus sp. metabolites are promising material for the development of immunomodulating drugs.

  20. Borna disease virus infection perturbs energy metabolites and amino acids in cultured human oligodendroglia cells.

    Science.gov (United States)

    Huang, Rongzhong; Gao, Hongchang; Zhang, Liang; Jia, Jianmin; Liu, Xia; Zheng, Peng; Ma, Lihua; Li, Wenjuan; Deng, Jing; Wang, Xiao; Yang, Liu; Wang, Mingju; Xie, Peng

    2012-01-01

    Borna disease virus is a neurotropic, non-cytolytic virus that has been widely employed in neuroscientific research. Previous studies have revealed that metabolic perturbations are associated with Borna disease viral infection. However, the pathophysiological mechanism underlying its mode of action remains unclear. Human oligodendroglia cells infected with the human strain Borna disease virus Hu-H1 and non-infected matched control cells were cultured in vitro. At day 14 post-infection, a proton nuclear magnetic resonance-based metabonomic approach was used to differentiate the metabonomic profiles of 28 independent intracellular samples from Borna disease virus-infected cells (n = 14) and matched control cells (n = 14). Partial least squares discriminant analysis was performed to demonstrate that the whole metabonomic patterns enabled discrimination between the two groups, and further statistical testing was applied to determine which individual metabolites displayed significant differences between the two groups. Metabonomic profiling revealed perturbations in 23 metabolites, 19 of which were deemed individually significant: nine energy metabolites (α-glucose, acetate, choline, creatine, formate, myo-inositol, nicotinamide adenine dinucleotide, pyruvate, succinate) and ten amino acids (aspartate, glutamate, glutamine, glycine, histidine, isoleucine, phenylalanine, threonine, tyrosine, valine). Partial least squares discriminant analysis demonstrated that the whole metabolic patterns enabled statistical discrimination between the two groups. Borna disease viral infection perturbs the metabonomic profiles of several metabolites in human oligodendroglia cells cultured in vitro. The findings suggest that Borna disease virus manipulates the host cell's metabolic network to support viral replication and proliferation.

  1. Distinct arsenic metabolites following seaweed consumption in humans

    OpenAIRE

    Taylor, Vivien F.; Li, Zhigang; Sayarath, Vicki; Palys, Thomas J.; Morse, Kevin R.; Scholz-Bright, Rachel A.; Margaret R Karagas

    2017-01-01

    Seaweeds contain arsenic primarily in the form of arsenosugars, which can be metabolized to a wide range of arsenic compounds. To characterize human exposure to arsenic from seaweed consumption, we determined concentrations of arsenic species in locally available seaweeds, and assessed urinary arsenic compounds in an experimental feeding study. A total of 11 volunteers consumed 10?g per day of three types of seaweeds (nori, kombu, and wakame) for three days each, while abstaining from rice an...

  2. Consumption of pasteurized human lysozyme transgenic goats' milk alters serum metabolite profile in young pigs.

    Science.gov (United States)

    Brundige, Dottie R; Maga, Elizabeth A; Klasing, Kirk C; Murray, James D

    2010-08-01

    Nutrition, bacterial composition of the gastrointestinal tract, and general health status can all influence the metabolic profile of an organism. We previously demonstrated that feeding pasteurized transgenic goats' milk expressing human lysozyme (hLZ) can positively impact intestinal morphology and modulate intestinal microbiota composition in young pigs. The objective of this study was to further examine the effect of consuming hLZ-containing milk on young pigs by profiling serum metabolites. Pigs were placed into two groups and fed a diet of solid food and either control (non-transgenic) goats' milk or milk from hLZ-transgenic goats for 6 weeks. Serum samples were collected at the end of the feeding period and global metabolite profiling was performed. For a total of 225 metabolites (160 known, 65 unknown) semi-quantitative data was obtained. Levels of 18 known and 4 unknown metabolites differed significantly between the two groups with the direction of change in 13 of the 18 known metabolites being almost entirely congruent with improved health status, particularly in terms of the gastrointestinal tract health and immune response, with the effects of the other five being neutral or unknown. These results further support our hypothesis that consumption of hLZ-containing milk is beneficial to health.

  3. Formation of Δ(1) and Δ(6) testosterone metabolites by human hepatocytes.

    Science.gov (United States)

    Fabregat, Andreu; Marcos, Josep; Ventura, Rosa; Casals, Gregori; Jimenez, Wladimiro; Reichenbach, Vedrana; Segura, Jordi; Pozo, Oscar J

    2015-03-01

    The existence of urinary testosterone (T) metabolites conjugated with cysteine has been recently reported. The formation of a ring double bond by a phase I metabolic transformation and the subsequent nucleophilic conjugation with glutathione was proposed as a putative metabolic pathway for the occurrence of these metabolites in urine. The main goal of the present study was to confirm the first step of the postulated pathway. For that purpose, human hepatocyte cells systems were incubated with a pure T standard. The cell culture supernatants were analyzed by liquid chromatography coupled to mass spectrometry using a selected reaction monitoring method. Major T metabolites such as androsterone and 4-androstene-3,17-dione, together with the recently reported Δ(1) and Δ(6) metabolites were simultaneously quantified. The formation of 1,4-androstadien-3,17-dione, 4,6-androstadien-3,17-dione, 17β-hydroxy-4,6-androstadien-3-one and 17β-hydroxy-1,4-androstadien-3-one (boldenone) after incubation of T in hepatocyte cell cultures was demonstrated by comparing the retention times and the ion ratios of the metabolites with those obtained by analysis of commercial standards. Thus, the formation of double bonds Δ(1) and Δ(6) by hepatic phase I metabolism of T was confirmed. Analogously to T, this pathway might also be present in other steroids, opening the possibility of targeting additional biomarkers. Copyright © 2015. Published by Elsevier Inc.

  4. Brain activation during human male ejaculation

    NARCIS (Netherlands)

    Holstege, Ger; Georgiadis, Janniko R.; Paans, Anne M.J.; Meiners, Linda C.; Graaf, Ferdinand H.C.E. van der; Reinders, A.A.T.Simone

    2003-01-01

    Brain mechanisms that control human sexual behavior in general, and ejaculation in particular, are poorly understood. We used positron emission tomography to measure increases in regional cerebral blood flow (rCBF) during ejaculation compared with sexual stimulation in heterosexual male volunteers.

  5. Brain activation during human male ejaculation revisited

    NARCIS (Netherlands)

    Georgiadis, Janniko R.; Reinders, A. A. T. Simone; Van der Graaf, Ferdinand H. C. E.; Paans, Anne M. J.; Kortekaas, Rudie

    2007-01-01

    In a prior [O-15]-H2O positron emission tomographic study we reported brain regions involved in human male ejaculation. Here, we used another, more recently acquired data set to evaluate the methodological approach of this previous study, and discovered that part of the reported activation pattern

  6. Development and validation of a high performance liquid chromatography quantification method of levo-tetrahydropalmatine and its metabolites in plasma and brain tissues: application to a pharmacokinetic study.

    Science.gov (United States)

    Abdallah, Inas A; Huang, Peng; Liu, Jing; Lee, David Y; Liu-Chen, Lee-Yuan; Hassan, Hazem E

    2017-04-01

    Levo-tetrahydropalmatine (l-THP) is an alkaloid isolated from Chinese medicinal herbs of the Corydalis and Stephania genera. It has been used in China for more than 40 years mainly as an analgesic with sedative/hypnotic effects. Despite its extensive use, its metabolism has not been quantitatively studied, nor there a sensitive reliable bioanalytical method for its quantification simultaneously with its metabolites. As such, the objective of this study was to develop and validate a sensitive and selective HPLC method for simultaneous quantification of l-THP and its desmethyl metabolites l-corydalmine (l-CD) and l-corypalmine (l-CP) in rat plasma and brain tissues. Rat plasma and brain samples were processed by liquid-liquid extraction using ethyl acetate. Chromatographic separation was achieved on a reversed-phase Symmetry® C18 column (4.6 × 150 mm, 5 μm) at 25°C. The mobile phase consisted of acetonitrile-methanol-10 mm ammonium phosphate (pH 3) (10:30:60, v/v) and was used at a flow rate of 0.8 mL/min. The column eluent was monitored at excitation and emission wavelengths of 230 and 315 nm, respectively. The calibration curves were linear over the concentration range of 1-10,000 ng/mL. The intra- and interday reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. The validated HPLC method was successfully applied to analyze samples from a pharmacokinetic study of l-THP in rats. Taken together, the developed method can be applied for bioanalysis of l-THP and its metabolites in rodents and potentially can be transferred for bioanalysis of human samples. Copyright © 2016 John Wiley & Sons, Ltd.

  7. MR-visible water content in human brain: a proton MRS study

    DEFF Research Database (Denmark)

    Christiansen, P; Toft, P B; Gideon, P

    1994-01-01

    In vivo measurement of metabolite concentrations in the human brain by means of proton-MRS contributes significantly to the clinical evaluation of patients with diseases of the brain. The fully relaxed water signal has been proposed as an internal standard for calibration of the MRS measurements....... and biochemical data published, suggest that only a small fraction (water may be MR-invisible.(ABSTRACT TRUNCATED AT 250 WORDS)......In vivo measurement of metabolite concentrations in the human brain by means of proton-MRS contributes significantly to the clinical evaluation of patients with diseases of the brain. The fully relaxed water signal has been proposed as an internal standard for calibration of the MRS measurements....... The major drawbacks are the necessity to make the assumptions that the water concentrations in the brain and that all tissue water is MR-visible. A number of in vivo measurements were carried out to estimate the concentration of MR-visible water in the brain of healthy volunteers divided into four age...

  8. Brain metabolites in the hippocampus-amygdala region and cerebellum in autism: an {sup 1}H-MR spectroscopy study

    Energy Technology Data Exchange (ETDEWEB)

    Otsuka, H.; Harada, M.; Hisaoka, S.; Nishitani, H. [Dept. of Radiology, Univ. of Tokushima, Tokushima City (Japan); Mori, K. [Dept. of Pediatrics, Univ. of Tokushima (Japan)

    1999-07-01

    Histological abnormalities of the brain in autism have been investigated extensively. We studied metabolites in the hippocampusamygdala (HA) region and cerebellum. We examined the right HA region and left cerebellar hemisphere of 27 autistic patients 2-18 years old, 21 boys and 6 girls and 10 normal children 6-14 years old, 4 boys and 6 girls, using the STEAM sequence. This sequence was used to minimise the influence of relaxation times. The N-acetyl aspartate (NAA) concentration was significantly lower (P=0.042) in autistic patients than in normal children (9.37 and 10.95 mM, respectively). There was no significant difference in other metabolites. The correlation coefficient (r value) of NAA between the HA region and cerebellum was 0.616. The decreased NAA concentration may be due to neuronal hypofunction or immature neurons. The NAA concentration in the HA region and cerebellum may be related, because of neuronal circuits or networks. (orig.)

  9. Magnetite pollution nanoparticles in the human brain

    Science.gov (United States)

    Maher, Barbara A.; Ahmed, Imad A. M.; Karloukovski, Vassil; MacLaren, Donald A.; Foulds, Penelope G.; Allsop, David; Mann, David M. A.; Torres-Jardón, Ricardo; Calderon-Garciduenas, Lilian

    2016-09-01

    Biologically formed nanoparticles of the strongly magnetic mineral, magnetite, were first detected in the human brain over 20 y ago [Kirschvink JL, Kobayashi-Kirschvink A, Woodford BJ (1992) Proc Natl Acad Sci USA 89(16):7683-7687]. Magnetite can have potentially large impacts on the brain due to its unique combination of redox activity, surface charge, and strongly magnetic behavior. We used magnetic analyses and electron microscopy to identify the abundant presence in the brain of magnetite nanoparticles that are consistent with high-temperature formation, suggesting, therefore, an external, not internal, source. Comprising a separate nanoparticle population from the euhedral particles ascribed to endogenous sources, these brain magnetites are often found with other transition metal nanoparticles, and they display rounded crystal morphologies and fused surface textures, reflecting crystallization upon cooling from an initially heated, iron-bearing source material. Such high-temperature magnetite nanospheres are ubiquitous and abundant in airborne particulate matter pollution. They arise as combustion-derived, iron-rich particles, often associated with other transition metal particles, which condense and/or oxidize upon airborne release. Those magnetite pollutant particles which are iron-bearing nanoparticles, rather than their soluble compounds, can be transported directly into the brain, where they may pose hazard to human health.

  10. The fungus Cunninghamella elegans can produce human and equine metabolites of selective androgen receptor modulators (SARMs).

    Science.gov (United States)

    Rydevik, Axel; Thevis, Mario; Krug, Oliver; Bondesson, Ulf; Hedeland, Mikael

    2013-05-01

    1. Selective androgen receptor modulators (SARMs) are a group of substances that have potential to be used as doping agents in sports. Being a relatively new group not available on the open market means that no reference materials are commercially available for the main metabolites. In the presented study, the in vitro metabolism of SARMs by the fungus Cunninghamella elegans has been investigated with the purpose of finding out if it can produce relevant human and equine metabolites. 2. Three different SARMs, S1, S4 and S24, were incubated for 5 days with C. elegans. The samples were analysed both with and without sample pretreatment using ultra performance liquid chromatography coupled to high resolution mass spectrometry. 3. All the important phase I and some phase II metabolites from human and horse were formed by the fungus. They were formed through reactions such as hydroxylation, deacetylation, O-dephenylation, nitro-reduction, acetylation and sulfonation. 4. The study showed that the fungus produced relevant metabolites of the SARMs and thus can be used to mimic mammalian metabolism. Furthermore, it has the potential to be used for future production of reference material.

  11. Individual differences in human brain development.

    Science.gov (United States)

    Brown, Timothy T

    2017-01-01

    This article discusses recent scientific advances in the study of individual differences in human brain development. Focusing on structural neuroimaging measures of brain morphology and tissue properties, two kinds of variability are related and explored: differences across individuals of the same age and differences across age as a result of development. A recent multidimensional modeling study is explained, which was able to use brain measures to predict an individual's chronological age within about one year on average, in children, adolescents, and young adults between 3 and 20 years old. These findings reveal great regularity in the sequence of the aggregate brain state across different ages and phases of development, despite the pronounced individual differences people show on any single brain measure at any given age. Future research is suggested, incorporating additional measures of brain activity and function. WIREs Cogn Sci 2017, 8:e1389. doi: 10.1002/wcs.1389 For further resources related to this article, please visit the WIREs website. © 2016 The Authors. WIREs Cognitive Science published by Wiley Periodicals, Inc.

  12. [Evolution of human brain and intelligence].

    Science.gov (United States)

    Lakatos, László; Janka, Zoltán

    2008-07-30

    The biological evolution, including human evolution is mainly driven by environmental changes. Accidental genetic modifications and their innovative results make the successful adaptation possible. As we know the human evolution started 7-8 million years ago in the African savannah, where upright position and bipedalism were significantly advantageous. The main drive of improving manual actions and tool making could be to obtain more food. Our ancestor got more meat due to more successful hunting, resulting in more caloric intake, more protein and essential fatty acid in the meal. The nervous system uses disproportionally high level of energy, so better quality of food was a basic condition for the evolution of huge human brain. The size of human brain was tripled during 3.5 million years, it increased from the average of 450 cm3 of Australopithecinae to the average of 1350 cm3 of Homo sapiens. A genetic change in the system controlling gene expression could happen about 200 000 years ago, which influenced the development of nervous system, the sensorimotor function and learning ability for motor processes. The appearance and stabilisation of FOXP2 gene structure as feature of modern man coincided with the first presence and quick spread of Homo sapiens on the whole Earth. This genetic modification made opportunity for human language, as the basis of abrupt evolution of human intelligence. The brain region being responsible for human language is the left planum temporale, which is much larger in left hemisphere. This shows the most typical human brain asymmetry. In this case the anatomical asymmetry means a clearly defined functional asymmetry as well, where the brain hemispheres act differently. The preference in using hands, the lateralised using of tools resulted in the brain asymmetry, which is the precondition of human language and intelligence. However, it cannot be held anymore, that only humans make tools, because our closest relatives, the chimpanzees are

  13. Native Mutant Huntingtin in Human Brain

    Science.gov (United States)

    Sapp, Ellen; Valencia, Antonio; Li, Xueyi; Aronin, Neil; Kegel, Kimberly B.; Vonsattel, Jean-Paul; Young, Anne B.; Wexler, Nancy; DiFiglia, Marian

    2012-01-01

    Huntington disease (HD) is caused by polyglutamine expansion in the N terminus of huntingtin (htt). Analysis of human postmortem brain lysates by SDS-PAGE and Western blot reveals htt as full-length and fragmented. Here we used Blue Native PAGE (BNP) and Western blots to study native htt in human postmortem brain. Antisera against htt detected a single band broadly migrating at 575–850 kDa in control brain and at 650–885 kDa in heterozygous and Venezuelan homozygous HD brains. Anti-polyglutamine antisera detected full-length mutant htt in HD brain. There was little htt cleavage even if lysates were pretreated with trypsin, indicating a property of native htt to resist protease cleavage. A soluble mutant htt fragment of about 180 kDa was detected with anti-htt antibody Ab1 (htt-(1–17)) and increased when lysates were treated with denaturants (SDS, 8 m urea, DTT, or trypsin) before BNP. Wild-type htt was more resistant to denaturants. Based on migration of in vitro translated htt fragments, the 180-kDa segment terminated ≈htt 670–880 amino acids. If second dimension SDS-PAGE followed BNP, the 180-kDa mutant htt was absent, and 43–50 kDa htt fragments appeared. Brain lysates from two HD mouse models expressed native full-length htt; a mutant fragment formed if lysates were pretreated with 8 m urea + DTT. Native full-length mutant htt in embryonic HD140Q/140Q mouse primary neurons was intact during cell death and when cell lysates were exposed to denaturants before BNP. Thus, native mutant htt occurs in brain and primary neurons as a soluble full-length monomer. PMID:22375012

  14. Evaluation of impact of exposure of Sudan azo dyes and their metabolites on human intestinal bacteria.

    Science.gov (United States)

    Pan, Hongmiao; Feng, Jinhui; He, Gui-Xin; Cerniglia, Carl E; Chen, Huizhong

    2012-08-01

    Sudan azo dyes are banned for food usage in most countries, but they are illegally used to maintain or enhance the color of food products due to low cost, bright staining, and wide availability of the dyes. In this report, we examined the toxic effects of these azo dyes and their potential reduction metabolites on 11 prevalent human intestinal bacterial strains. Among the tested bacteria, cell growth of 2, 3, 5, 5, and 1 strains was inhibited by Sudan I, II, III, IV, and Para Red, respectively. At the tested concentration of 100 μM, Sudan I and II inhibited growth of Clostridium perfringens and Lactobacillus rhamnosus with decrease of growth rates from 14 to 47%. Sudan II also affected growth of Enterococcus faecalis. Growth of Bifidobacterium catenulatum, C. perfringens, E. faecalis, Escherichia coli, and Peptostreptococcus magnus was affected by Sudan III and IV with decrease in growth rates from 11 to 67%. C. perfringens was the only strain in which growth was affected by Para Red with 47 and 26% growth decreases at 6 and 10 h, respectively. 1-Amino-2-naphthol, a common metabolite of the dyes, was capable of inhibiting growth of most of the tested bacteria with inhibition rates from 8 to 46%. However, the other metabolites of the dyes had no effect on growth of the bacterial strains. The dyes and their metabolites had less effect on cell viability than on cell growth of the tested bacterial strains. Clostridium indolis and Clostridium ramosum were the only two strains with about a 10 % decrease in cell viability in the presence of Sudan azo dyes. The present results suggested that Sudan azo dyes and their metabolites potentially affect the human intestinal bacterial ecology by selectively inhibiting some bacterial species, which may have an adverse effect on human health. Published by Elsevier Ltd.

  15. Microchimerism in the human brain: More questions than answers

    OpenAIRE

    Chan, William F.N.; Nelson, J. Lee

    2013-01-01

    Recently, our group reported the presence of microchimerism (Mc) in the human brain by performing quantitative PCR on female human brain tissues to amplify male DNA. We found brain Mc to be relatively frequent in humans and widely distributed in this organ. Our data also suggested a lower prevalence of brain Mc in women without Alzheimer disease than women without neurological disease. Altogether, these findings suggest that Mc could sometimes influence health and disease of the brain. As fur...

  16. Human freedom and the brain.

    Science.gov (United States)

    Kornhuber, Hans Helmut

    2009-06-01

    Freedom of will does exist, it is self-leadership of man based on reason and ethos. Evidence comes from truth. Determinism cannot be proved since if you try, you mean to prove a truth; but there is no truth without freedom. By contrast for freedom there are many pieces of evidence e.g. science, arts, technology. Freedom utilizes creative abstract thinking with phantasy. Freedom is graded, limited, based on nature, but not developed without good will. We perceive reliably freedom by self-consciousness and in other persons as long as we are sober. Freedom needs intelligence, but is more, it is a creative and moral virtue. The basis for freedom is phylogenesis and culture, in the individual learning and experimenting. Factors in the becoming of freedom are not only genes and environment but also self-discipline. But the creativity of free will is dangerous. Man therefore needs morale. Drives and feelings become humanized, cultural interests are developed. There is a humane nobility from long good will.

  17. Puberty and structural brain development in humans.

    Science.gov (United States)

    Herting, Megan M; Sowell, Elizabeth R

    2017-01-01

    Adolescence is a transitional period of physical and behavioral development between childhood and adulthood. Puberty is a distinct period of sexual maturation that occurs during adolescence. Since the advent of magnetic resonance imaging (MRI), human studies have largely examined neurodevelopment in the context of age. A breadth of animal findings suggest that sex hormones continue to influence the brain beyond the prenatal period, with both organizational and activational effects occurring during puberty. Given the animal evidence, human MRI research has also set out to determine how puberty may influence otherwise known patterns of age-related neurodevelopment. Here we review structural-based MRI studies and show that pubertal maturation is a key variable to consider in elucidating sex- and individual- based differences in patterns of human brain development. We also highlight the continuing challenges faced, as well as future considerations, for this vital avenue of research. Copyright © 2016. Published by Elsevier Inc.

  18. Brain metabolite levels assessed by lactate-edited MR spectroscopy in premature neonates with and without pentobarbital sedation.

    Science.gov (United States)

    Wang, Z J; Vigneron, D B; Miller, S P; Mukherjee, P; Charlton, N N; Lu, Y; Barkovich, A J

    2008-04-01

    Pentobarbital is known to affect cerebral metabolism; pentobarbital sedation is, however, frequently used for MR imaging and MR spectroscopy, especially in children. Accurate assessment of the brain metabolite levels is important, particularly in neonates with suspected brain injury. We investigated whether pentobarbital sedation has any effect on the ratios of spectral metabolites lactate, N-acetylaspartate, or choline in a group of premature neonates. MR spectroscopy was performed in 43 premature neonates, all with normal concurrent MR imaging and normal neurodevelopmental outcome at 12 months of age. Of those neonates, 14 (33%) required pentobarbital (Nembutal 1 mg/kg) sedation during MR spectroscopy; the remaining 29 neonates did not receive any sedation. Ratios of lactate, choline, and N-acetylaspartate were calculated in the basal ganglia, thalami, and corticospinal tracts and compared between those neonates with and without sedation. Small amounts of brain lactate were detected in all of the premature neonates. The basal ganglia lactate/choline and lactate/N-acetylaspartate ratios were significantly lower, by 17% and 25% respectively, in the neonates with pentobarbital sedation compared with the age-matched neonates without sedation (P Sedation did not affect the lactate level in the thalami or the corticospinal tracts. The N-acetylaspartate/choline ratios were unaffected by pentobarbital sedation. Pentobarbital sedation is associated with lower lactate/choline and lactate/N-acetylaspartate ratios in the basal ganglia of premature neonates, as determined by proton MR spectroscopy. Investigators should be aware of this phenomenon for accurate interpretation of their MR spectroscopy results.

  19. Viscoelastic parameter identification of human brain tissue.

    Science.gov (United States)

    Budday, S; Sommer, G; Holzapfel, G A; Steinmann, P; Kuhl, E

    2017-10-01

    Understanding the constitutive behavior of the human brain is critical to interpret the physical environment during neurodevelopment, neurosurgery, and neurodegeneration. A wide variety of constitutive models has been proposed to characterize the brain at different temporal and spatial scales. Yet, their model parameters are typically calibrated with a single loading mode and fail to predict the behavior under arbitrary loading conditions. Here we used a finite viscoelastic Ogden model with six material parameters-an elastic stiffness, two viscoelastic stiffnesses, a nonlinearity parameter, and two viscous time constants-to model the characteristic nonlinearity, conditioning, hysteresis and tension-compression asymmetry of the human brain. We calibrated the model under shear, shear relaxation, compression, compression relaxation, and tension for four different regions of the human brain, the cortex, basal ganglia, corona radiata, and corpus callosum. Strikingly, unconditioned gray matter with 0.36kPa and white matter with 0.35kPa were equally stiff, whereas conditioned gray matter with 0.52kPa was three times stiffer than white matter with 0.18kPa. While both unconditioned viscous time constants were larger in gray than in white matter, both conditioned constants were smaller. These rheological differences suggest a different porosity between both tissues and explain-at least in part-the ongoing controversy between reported stiffness differences in gray and white matter. Our unconditioned and conditioned parameter sets are readily available for finite element simulations with commercial software packages that feature Ogden type models at finite deformations. As such, our results have direct implications on improving the accuracy of human brain simulations in health and disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Mechanical characterization of human brain tissue.

    Science.gov (United States)

    Budday, S; Sommer, G; Birkl, C; Langkammer, C; Haybaeck, J; Kohnert, J; Bauer, M; Paulsen, F; Steinmann, P; Kuhl, E; Holzapfel, G A

    2017-01-15

    Mechanics are increasingly recognized to play an important role in modulating brain form and function. Computational simulations are a powerful tool to predict the mechanical behavior of the human brain in health and disease. The success of these simulations depends critically on the underlying constitutive model and on the reliable identification of its material parameters. Thus, there is an urgent need to thoroughly characterize the mechanical behavior of brain tissue and to identify mathematical models that capture the tissue response under arbitrary loading conditions. However, most constitutive models have only been calibrated for a single loading mode. Here, we perform a sequence of multiple loading modes on the same human brain specimen - simple shear in two orthogonal directions, compression, and tension - and characterize the loading-mode specific regional and directional behavior. We complement these three individual tests by combined multiaxial compression/tension-shear tests and discuss effects of conditioning and hysteresis. To explore to which extent the macrostructural response is a result of the underlying microstructural architecture, we supplement our biomechanical tests with diffusion tensor imaging and histology. We show that the heterogeneous microstructure leads to a regional but not directional dependence of the mechanical properties. Our experiments confirm that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry. Using our measurements, we compare the performance of five common constitutive models, neo-Hookean, Mooney-Rivlin, Demiray, Gent, and Ogden, and show that only the isotropic modified one-term Ogden model is capable of representing the hyperelastic behavior under combined shear, compression, and tension loadings: with a shear modulus of 0.4-1.4kPa and a negative nonlinearity parameter it captures the compression-tension asymmetry and the increase in shear stress under superimposed

  1. In vitro metabolism of trans-permethrin and its major metabolites, PBalc and PBacid, in humans.

    Science.gov (United States)

    Takaku, Tomoyuki; Mikata, Kazuki; Matsui, Masayoshi; Nishioka, Kazuhiko; Isobe, Naohiko; Kaneko, Hideo

    2011-05-11

    To estimate the metabolic profile of trans-permethrin in humans, a comparison of the in vitro metabolism of trans-permethrin in humans and rats was conducted using hepatic microsomes, and cytochrome P450 and UDP-glucuronyltransferase isoforms, which catalyze the metabolism of 3-phenoxybenzyl alcohol (PBalc) and 3-phenoxybenzoic acid (PBacid), respectively. In humans and rats, the major metabolic reaction of trans-permethrin in microsomal incubations was the cleavage of ester linkage to give PBalc, followed by oxidation to 4'-OH-PBalc, 4'-OH-PBacid, and PBacid. As to 4'-hydroxylation of PBalc, several CYPs were able to catalyze the reaction, and CYP2E1 was identified as a predominant isoform. PBacid and its conjugates (glucuronide and glycine) are major urinary metabolites of trans-permethrin in mammals. PBacid is also a metabolite of several pyrethroids, and has been used as a biomarker of human exposure to pyrethroids. Our study indicated that there was no difference in glucuronyltransferase activity of PBacid between humans and rats, and that only UGT1A9 can catalyze the glucuronidation of PBacid among human UGTs. Some UGT1A9 variants are known to have poor glucuronidation activity. From these results, it was assumed that deficiency or polymorphism of UGT1A9 might affect the profile of PBacid and its conjugates in urine collected from persons exposed to trans-permethrin or other pyrethroids. These results are helpful for understanding the metabolism of trans-permethrin in humans and determining methods for quantification of target analytes for assessment of human exposure to trans-permethrin and other pyrethroids that give PBacid and its conjugates as urinary metabolites.

  2. Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans

    Science.gov (United States)

    Mitchell, David A; Lambert, Gavin; Secher, Niels H; Raven, Peter B; van Lieshout, Johannes; Esler, Murray D

    2009-01-01

    A novel neurochemical method was applied for studying the activity of sympathetic nerves in the human cerebral vascular system. The aim was to investigate whether noradrenaline plasma kinetic measurements made with internal jugular venous sampling reflect cerebrovascular sympathetic activity. A database was assembled of fifty-six healthy subjects in whom total body noradrenaline spillover (indicative of whole body sympathetic nervous activity), brain noradrenaline spillover and brain lipophlic noradrenaline metabolite (3,4-dihydroxyphenolglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG)) overflow rates were measured. These measurements were also made following ganglion blockade (trimethaphan, n= 6), central sympathetic inhibition (clonidine, n= 4) and neuronal noradrenaline uptake blockade (desipramine, n= 13) and in a group of patients (n= 9) with pure autonomic failure (PAF). The mean brain noradrenline spillover and brain noradrenaline metabolite overflow in healthy subjects were 12.5 ± 1.8, and 186.4 ± 25 ng min−1, respectively, with unilateral jugular venous sampling for both. Total body noradrenaline spillover was 605.8 ng min−1± 34.4 ng min−1. As expected, trimethaphan infusion lowered brain noradrenaline spillover (P= 0.03), but perhaps surprisingly increased jugular overflow of brain metabolites (P= 0.01). Suppression of sympathetic nervous outflow with clonidine lowered brain noradrenaline spillover (P= 0.004), without changing brain metabolite overflow (P= 0.3). Neuronal noradrenaline uptake block with desipramine lowered the transcranial plasma extraction of tritiated noradrenaline (P= 0.001). The PAF patients had 77% lower brain noradrenaline spillover than healthy recruits (P= 0.06), indicating that in them sympathetic nerve degeneration extended to the cerebral circulation, but metabolites overflow was similar to healthy subjects (P= 0.3). The invariable discordance between noradrenline spillover and noradrenaline metabolite overflow

  3. Identification of two main urinary metabolites of (/sup 14/C)omeprazole in humans

    Energy Technology Data Exchange (ETDEWEB)

    Renberg, L.; Simonsson, R.; Hoffmann, K.J.

    1989-01-01

    The excretion and metabolism of (/sup 14/C)omeprazole given orally as a suspension was studied in 10 healthy male subjects. An average of 79% of the dose was recovered in the urine in 96 hr, with most of the radioactivity (76% of dose) being eliminated in the first 24 hr. Pooled urine (0-2 hr) from five subjects, containing about 47% of the dose, was analyzed by reverse phase gradient elution LC with radioisotope detection. Omeprazole was completely metabolized to at least six metabolites. The two major metabolites were extensively purified by LC and their structures were determined by MS with derivatization and use of stable isotopes, 1H NMR, and comparison with synthetic references. They were formed by hydroxylation of a methyl group in the pyridine ring, followed by further oxidation of the alcohol to the corresponding carboxylic acid. Both metabolites retained the sulfoxide group of omeprazole, rendering them as unstable as the parent compound at pH less than 7. They accounted for approximately 28% (hydroxyomeprazole) and 23% (omeprazole acid) of the amount excreted in the 0-2-hr collection interval. Based on in vitro studies with the synthetic metabolites in isolated gastric glands, it is unlikely that M1 and M2 will contribute to the pharmacological effect of omeprazole in humans.

  4. Quantification of metabolites for assessing human exposure to soapberry toxins hypoglycin A and methylenecyclopropylglycine.

    Science.gov (United States)

    Isenberg, Samantha L; Carter, Melissa D; Graham, Leigh Ann; Mathews, Thomas P; Johnson, Darryl; Thomas, Jerry D; Pirkle, James L; Johnson, Rudolph C

    2015-09-21

    Ingestion of soapberry fruit toxins hypoglycin A and methylenecyclopropylglycine has been linked to public health challenges worldwide. In 1976, over 100 years after Jamaican vomiting sickness (JVS) was first reported, the cause of JVS was linked to the ingestion of the toxin hypoglycin A produced by ackee fruit. A structural analogue of hypoglycin A, methylenecyclopropylglycine (MCPG), was implicated as the cause of an acute encephalitis syndrome (AES). Much of the evidence linking hypoglycin A and MCPG to these diseases has been largely circumstantial due to the lack of an analytical method for specific metabolites. This study presents an analytical approach to identify and quantify specific urine metabolites for exposure to hypoglycin A and MCPG. The metabolites are excreted in urine as glycine adducts methylenecyclopropylacetyl-glycine (MCPA-Gly) and methylenecyclopropylformyl-glycine (MCPF-Gly). These metabolites were processed by isotope dilution, separated by reverse-phase liquid chromatography, and monitored by electrospray ionization tandem mass spectrometry. The analytical response ratio was linearly proportional to the concentration of MCPF-Gly and MCPA-Gly in urine from 0.10 to 20 μg/mL with a correlation coefficient of r > 0.99. The assay demonstrated accuracy ≥80% and precision ≤20% RSD across the calibration range. This method has been applied to assess exposure to hypoglycin A and MCPG as part of a larger public health initiative and was used to provide the first reported identification of MCPF-Gly and MCPA-Gly in human urine.

  5. Imaging retinotopic maps in the human brain

    Science.gov (United States)

    Wandell, Brian A.; Winawer, Jonathan

    2010-01-01

    A quarter-century ago visual neuroscientists had little information about the number and organization of retinotopic maps in human visual cortex. The advent of functional magnetic resonance imaging (MRI), a non-invasive, spatially-resolved technique for measuring brain activity, provided a wealth of data about human retinotopic maps. Just as there are differences amongst nonhuman primate maps, the human maps have their own unique properties. Many human maps can be measured reliably in individual subjects during experimental sessions lasting less than an hour. The efficiency of the measurements and the relatively large amplitude of functional MRI signals in visual cortex make it possible to develop quantitative models of functional responses within specific maps in individual subjects. During this last quarter century, there has also been significant progress in measuring properties of the human brain at a range of length and time scales, including white matter pathways, macroscopic properties of gray and white matter, and cellular and molecular tissue properties. We hope the next twenty-five years will see a great deal of work that aims to integrate these data by modeling the network of visual signals. We don’t know what such theories will look like, but the characterization of human retinotopic maps from the last twenty-five years is likely to be an important part of future ideas about visual computations. PMID:20692278

  6. Hierarchical modularity in human brain functional networks

    CERN Document Server

    Meunier, D; Fornito, A; Ersche, K D; Bullmore, E T; 10.3389/neuro.11.037.2009

    2010-01-01

    The idea that complex systems have a hierarchical modular organization originates in the early 1960s and has recently attracted fresh support from quantitative studies of large scale, real-life networks. Here we investigate the hierarchical modular (or "modules-within-modules") decomposition of human brain functional networks, measured using functional magnetic resonance imaging (fMRI) in 18 healthy volunteers under no-task or resting conditions. We used a customized template to extract networks with more than 1800 regional nodes, and we applied a fast algorithm to identify nested modular structure at several hierarchical levels. We used mutual information, 0 < I < 1, to estimate the similarity of community structure of networks in different subjects, and to identify the individual network that is most representative of the group. Results show that human brain functional networks have a hierarchical modular organization with a fair degree of similarity between subjects, I=0.63. The largest 5 modules at ...

  7. Imaging Monoamine Oxidase in the Human Brain

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, J. S.; Volkow, N. D.; Wang, G-J.; Logan, Jean

    1999-11-10

    Positron emission tomography (PET) studies mapping monoamine oxidase in the human brain have been used to measure the turnover rate for MAO B; to determine the minimum effective dose of a new MAO inhibitor drug lazabemide and to document MAO inhibition by cigarette smoke. These studies illustrate the power of PET and radiotracer chemistry to measure normal biochemical processes and to provide information on the effect of drug exposure on specific molecular targets.

  8. Sense of agency in the human brain

    OpenAIRE

    Haggard, P.

    2017-01-01

    In adult life, people normally know what they are doing. This experience of controlling one's own actions and, through them, the course of events in the outside world is called 'sense of agency'. It forms a central feature of human experience; however, the brain mechanisms that produce the sense of agency have only recently begun to be investigated systematically. This recent progress has been driven by the development of better measures of the experience of agency, improved design of cogniti...

  9. Sex beyond the genitalia: The human brain mosaic

    OpenAIRE

    Joel, Daphna; Berman, Zohar; Tavor, Ido; Wexler, Nadav; Gaber, Olga; Stein, Yaniv; Shefi, Nisan; Pool, Jared; Urchs, Sebastian; Margulies, Daniel S.; Liem, Franziskus; Hänggi, Jürgen; Jäncke, Lutz; Assaf, Yaniv

    2015-01-01

    Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features ...

  10. Borna disease virus infection perturbs energy metabolites and amino acids in cultured human oligodendroglia cells.

    Directory of Open Access Journals (Sweden)

    Rongzhong Huang

    Full Text Available BACKGROUND: Borna disease virus is a neurotropic, non-cytolytic virus that has been widely employed in neuroscientific research. Previous studies have revealed that metabolic perturbations are associated with Borna disease viral infection. However, the pathophysiological mechanism underlying its mode of action remains unclear. METHODOLOGY: Human oligodendroglia cells infected with the human strain Borna disease virus Hu-H1 and non-infected matched control cells were cultured in vitro. At day 14 post-infection, a proton nuclear magnetic resonance-based metabonomic approach was used to differentiate the metabonomic profiles of 28 independent intracellular samples from Borna disease virus-infected cells (n = 14 and matched control cells (n = 14. Partial least squares discriminant analysis was performed to demonstrate that the whole metabonomic patterns enabled discrimination between the two groups, and further statistical testing was applied to determine which individual metabolites displayed significant differences between the two groups. FINDINGS: Metabonomic profiling revealed perturbations in 23 metabolites, 19 of which were deemed individually significant: nine energy metabolites (α-glucose, acetate, choline, creatine, formate, myo-inositol, nicotinamide adenine dinucleotide, pyruvate, succinate and ten amino acids (aspartate, glutamate, glutamine, glycine, histidine, isoleucine, phenylalanine, threonine, tyrosine, valine. Partial least squares discriminant analysis demonstrated that the whole metabolic patterns enabled statistical discrimination between the two groups. CONCLUSION: Borna disease viral infection perturbs the metabonomic profiles of several metabolites in human oligodendroglia cells cultured in vitro. The findings suggest that Borna disease virus manipulates the host cell's metabolic network to support viral replication and proliferation.

  11. Nitrogen Metabolite Repression of Metabolism and Virulence in the Human Fungal Pathogen Cryptococcus neoformans

    Science.gov (United States)

    Lee, I. Russel; Chow, Eve W. L.; Morrow, Carl A.; Djordjevic, Julianne T.; Fraser, James A.

    2011-01-01

    Proper regulation of metabolism is essential to maximizing fitness of organisms in their chosen environmental niche. Nitrogen metabolite repression is an example of a regulatory mechanism in fungi that enables preferential utilization of easily assimilated nitrogen sources, such as ammonium, to conserve resources. Here we provide genetic, transcriptional, and phenotypic evidence of nitrogen metabolite repression in the human pathogen Cryptococcus neoformans. In addition to loss of transcriptional activation of catabolic enzyme-encoding genes of the uric acid and proline assimilation pathways in the presence of ammonium, nitrogen metabolite repression also regulates the production of the virulence determinants capsule and melanin. Since GATA transcription factors are known to play a key role in nitrogen metabolite repression, bioinformatic analyses of the C. neoformans genome were undertaken and seven predicted GATA-type genes were identified. A screen of these deletion mutants revealed GAT1, encoding the only global transcription factor essential for utilization of a wide range of nitrogen sources, including uric acid, urea, and creatinine—three predominant nitrogen constituents found in the C. neoformans ecological niche. In addition to its evolutionarily conserved role in mediating nitrogen metabolite repression and controlling the expression of catabolic enzyme and permease-encoding genes, Gat1 also negatively regulates virulence traits, including infectious basidiospore production, melanin formation, and growth at high body temperature (39°–40°). Conversely, Gat1 positively regulates capsule production. A murine inhalation model of cryptococcosis revealed that the gat1Δ mutant is slightly more virulent than wild type, indicating that Gat1 plays a complex regulatory role during infection. PMID:21441208

  12. Towards Developmental Connectomics of the Human Brain

    Directory of Open Access Journals (Sweden)

    Miao eCao

    2016-03-01

    Full Text Available Imaging connectomics based on graph theory has become an effective and unique methodological framework for studying structural and functional connectivity patterns of the developing brain. Normal brain development is characterized by continuous and significant network evolution throughout infancy, childhood and adolescence, following specific maturational patterns. Disruption of these normal changes is associated with neuropsychiatric developmental disorders, such as autism spectrum disorders or attention-deficit hyperactivity disorder. In this review, we focused on the recent progresses regarding typical and atypical development of human brain networks from birth to early adulthood, using a connectomic approach. Specifically, by the time of birth, structural networks already exhibit adult-like organization, with global efficient small-world and modular structures, as well as hub regions and rich-clubs acting as communication backbones. During development, the structure networks are fine-tuned, with increased global integration and robustness and decreased local segregation, as well as the strengthening of the hubs. In parallel, functional networks undergo more dramatic changes during maturation, with both increased integration and segregation during development, as brain hubs shift from primary regions to high order functioning regions, and the organization of modules transitions from a local anatomical emphasis to a more distributed architecture. These findings suggest that structural networks develop earlier than functional networks; meanwhile functional networks demonstrate more dramatic maturational changes with the evolution of structural networks serving as the anatomical backbone. In this review, we also highlighted topologically disorganized characteristics in structural and functional brain networks in several major developmental neuropsychiatric disorders (e.g., autism spectrum disorders, attention-deficit hyperactivity disorder and

  13. Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

    Science.gov (United States)

    Zhang, Kanyin E.; Wu, Ellen; Patick, Amy K.; Kerr, Bradley; Zorbas, Mark; Lankford, Angela; Kobayashi, Takuo; Maeda, Yuki; Shetty, Bhasker; Webber, Stephanie

    2001-01-01

    Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (Ki = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3′-methoxy-4′-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 μM and the M8 concentrations ranged from 0.55 to 1.96 μM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 μM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for

  14. Brain structures in the sciences and humanities.

    Science.gov (United States)

    Takeuchi, Hikaru; Taki, Yasuyuki; Sekiguchi, Atsushi; Nouchi, Rui; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos Makoto; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Sassa, Yuko; Kawashima, Ryuta

    2015-11-01

    The areas of academic interest (sciences or humanities) and area of study have been known to be associated with a number of factors associated with autistic traits. However, despite the vast amount of literature on the psychological and physiological characteristics associated with faculty membership, brain structural characteristics associated with faculty membership have never been investigated directly. In this study, we used voxel-based morphometry to investigate differences in regional gray matter volume (rGMV)/regional white matter volume (rWMV) between science and humanities students to test our hypotheses that brain structures previously robustly shown to be altered in autistic subjects are related to differences in faculty membership. We examined 312 science students (225 males and 87 females) and 179 humanities students (105 males and 74 females). Whole-brain analyses of covariance revealed that after controlling for age, sex, and total intracranial volume, the science students had significantly larger rGMV in an anatomical cluster around the medial prefrontal cortex and the frontopolar area, whereas the humanities students had significantly larger rWMV in an anatomical cluster mainly concentrated around the right hippocampus. These anatomical structures have been linked to autism in previous studies and may mediate cognitive functions that characterize differences in faculty membership. The present results may support the ideas that autistic traits and characteristics of the science students compared with the humanities students share certain characteristics from neuroimaging perspectives. This study improves our understanding of differences in faculty membership which is the link among cognition, biological factors, disorders, and education (academia).

  15. Metabolic fate of dietary carnitine in human adults: Identification and quantification of urinary and fecal metabolites

    Energy Technology Data Exchange (ETDEWEB)

    Rebouche, C.J.; Chenard, C.A. (Univ. of Iowa College of Medicine, Iowa City (USA))

    1991-04-01

    Results of kinetic and pharmacokinetic studies have suggested that dietary carnitine is not totally absorbed and is in part degraded in the gastrointestinal tract of humans. To determine the metabolic fate of dietary carnitine in humans, we administered orally a tracer dose of methyl-{sup 3}H L-carnitine with a meal to subjects who had been adapted to a low-carnitine diet or a high-carnitine diet. Urinary and fecal excretion of radiolabeled carnitine and metabolites was monitored for 5 to 11 d following administration of the test dose. Total radioactive metabolites excreted ranged from 13 to 34% (low carnitine diet) and 27 to 46% (high carnitine diet) of the ingested tracer. Major metabolites found were ({sup 3}H)trimethylamine N-oxide (8 to 39% of the administered dose; excreted primarily in urine) and ({sup 3}H)gamma-butyrobetaine (0.09 to 8% of the administered dose; excreted primarily in feces). Urinary excretion of total carnitine was 42 to 95% (high carnitine diet) and 190 to 364% (low carnitine diet) of intake. These results indicate that oral carnitine is 54 to 87% bioavailable from normal Western diets; the percentage of intake absorbed is related to the quantity ingested.

  16. Segmentation and Visualisation of Human Brain Structures

    Energy Technology Data Exchange (ETDEWEB)

    Hult, Roger

    2003-10-01

    In this thesis the focus is mainly on the development of segmentation techniques for human brain structures and of the visualisation of such structures. The images of the brain are both anatomical images (magnet resonance imaging (MRI) and autoradiography) and functional images that show blood flow (functional magnetic imaging (fMRI), positron emission tomography (PET), and single photon emission tomography (SPECT)). When working with anatomical images, the structures segmented are visible as different parts of the brain, e.g. the brain cortex, the hippocampus, or the amygdala. In functional images, the activity or the blood flow that be seen. Grey-level morphology methods are used in the segmentations to make tissue types in the images more homogenous and minimise difficulties with connections to outside tissue. A method for automatic histogram thresholding is also used. Furthermore, there are binary operations such as logic operation between masks and binary morphology operations. The visualisation of the segmented structures uses either surface rendering or volume rendering. For the visualisation of thin structures, surface rendering is the better choice since otherwise some voxels might be missed. It is possible to display activation from a functional image on the surface of a segmented cortex. A new method for autoradiographic images has been developed, which integrates registration, background compensation, and automatic thresholding to get faster and more reliable results than the standard techniques give.

  17. [Increase of brain serotonin and its metabolite in rats caused by meclofenoxate].

    Science.gov (United States)

    Koga, T

    1976-05-01

    Influence of meclofenoxate (MF) on the 5-HT and 5-HIAA contents in the cortex, diencephalon and brain stem of the rat was studied with the following results. MF caused a dose-dependent elevation of 5-HIAA level in the three different brain regions and particularly in the brain stem. An increase of 5-HT was also noted in the brain stem, whereas 5-HT in the diencephalon tended to decrease. The increase of 5-HT after pargyline was accelerated and the pargyline-induced decrease of 5-HIAA was equally inhibited by MF and probenecid, which suggests that MF blocks the efflux of 5-HIAA from the brain. The effects of MF on the brain 5-HT and 5-HIAA contents were identical with those of its hydrolysate, p-chlorophenoxyacetic acid.

  18. Identification of fipronil metabolites by time-of-flight mass spectrometry for application in a human exposure study

    OpenAIRE

    McMahen, Rebecca L.; Strynar, Mark J.; Dagnino, Sonia; Herr, David W.; Moser, Virginia C.; Garantziotis, Stavros; Andersen, Erik M.; Freeborn, Danielle L.; McMillan, Larry; Lindstrom, Andrew B.

    2015-01-01

    Fipronil is a phenylpyrazole insecticide commonly used in residential and agricultural applications. To understand more about the potential risks for human exposure associated with fipronil, urine and serum from dosed Long Evans adult rats (5 and 10 mg/kg bw) were analyzed to identify metabolites as potential biomarkers for use in human biomonitoring studies. Urine from treated rats was found to contain seven unique metabolites, two of which had not been previously reported—M4 and M7 which we...

  19. Inhibition of aromatase activity by methyl sulfonyl PCB metabolites in primary culture of human mammary fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Berg, M. van den; Heneweer, M.; Geest, M. de; Sanderson, T. [Inst. for Risk Assessment Sciences and Utrecht Univ. (Netherlands); Jong, P. de [St. Antonius Hospital, Nieuwegein (Netherlands); Bergman, A. [Stockholm Univ., Stockholm (Sweden)

    2004-09-15

    Methyl sulfonyl PCB metabolites (MeSO2-PCBs) are persistent contaminants and are ubiquitously present in humans and the environment. Lipophilicity of MeSO2- PCB metabolites is similar to the parent compounds and they have been detected in human milk, adipose, liver and lung tissue. 4- MeSO2-PCB-149 is the most abundant PCB metabolite in human adipose tissue and milk at a level of 1.5 ng/g lipids. Human blood concentration of 4-MeSO2-PCB-149 is approximately 0.03 nM. 3- MeSO2-PCB-101 is the predominant PCB metabolite in muscle and blubber in wildlife, such as otter, mink and grey seal. In the environment, they have been linked to chronic and reproductive toxicity in exposed mink. Additionaly, some MeSO{sub 2}-PCBs have been shown to be glucocorticoid receptor (GR) antagonists. Since approximately 60% of all breast tumors are estrogen responsive, exposure to compounds that are able to alter estrogen synthesis through interference with the aromatase enzyme, can lead to changes in estrogen levels and possibly to accelerated or inhibit breast tumor growth. Therefore, it is important to identify exogenous compounds that can alter aromatase activity in addition to those compounds which have direct interaction with the estrogen receptor (ER). Aromatase (CYP19) comprises the ubiquitous flavoprotein, NADPH-cytochrome P450 reductase, and a unique cytochrome P450 that is exclusively expressed in estrogen producing cells. Previous studies have revealed that expression of the aromatase gene is regulated in a species- and tissue specific manner. In healthy breast tissue, the predominantly active aromatase promoter region I.4 is regulated by glucocorticoids and class I cytokines. Therefore, it is important to investigate possible aromatase inhibiting properties of MeSO{sub 2}-PCBs (as anti glucocorticoids?) in relevant human tissues. We used primary human mammary fibroblasts because of their role in breast cancer development. We compared the results in primary fibroblasts with

  20. Hydroxy and methylsulfone metabolites of polychlorinated biphenyls in the human blood and tissues

    Energy Technology Data Exchange (ETDEWEB)

    Masuda, Yoshito; Haraguchi, Koichi [Daiichi College of Pharmaceutical Sciences, Fukuoka (Japan)

    2004-09-15

    Polychlorinated biphenyls (PCBs) are a group of chlorinated compounds which have polluted the global environment, persistently retained in wildlife and humans, and eventually affected the human health. PCBs are biotransformed to mainly hydroxy (HO-) and methylsulfone (MeSO{sub 2}-) metabolites in the animal and human tissues. About ten thousands of chemical and biological researches on PCBs, HOPCBs and MeSO{sub 2}-PCBs have been reported and reviewed so far. Letcher et al. cleverly reviewed the HO-PCBs and MeSO2-PCBs in 2000. We review the contamination of HO-PCBs and MeSO{sub 2}-PCBs in human tissues and their possible effects to human health. Different positional numberings of Cl-, HO- and MeSO{sub 2}- on biphenyl rings were used by different authors. Then, nomenclature of PCB metabolite was assessed by Maervoet et al. and they suggested to use the IUPAC chemical name and number of parent PCB congener with the subsequent assignment of the phenyl ring position number of the HO- or MeSO{sub 2}- substituent number afterward.

  1. Structural brain correlates of human sleep oscillations.

    Science.gov (United States)

    Saletin, Jared M; van der Helm, Els; Walker, Matthew P

    2013-12-01

    Sleep is strongly conserved within species, yet marked and perplexing inter-individual differences in sleep physiology are observed. Combining EEG sleep recordings and high-resolution structural brain imaging, here we demonstrate that the morphology of the human brain offers one explanatory factor of such inter-individual variability. Gray matter volume in interoceptive and exteroceptive cortices correlated with the expression of slower NREM sleep spindle frequencies, supporting their proposed role in sleep protection against conscious perception. Conversely, and consistent with an involvement in declarative memory processing, gray matter volume in bilateral hippocampus was associated with faster NREM sleep spindle frequencies. In contrast to spindles, gray matter volume in the homeostatic sleep-regulating center of the basal forebrain/hypothalamus, together with the medial prefrontal cortex, accounted for individual differences in NREM slow wave oscillations. Together, such findings indicate that the qualitative and quantitative expression of human sleep physiology is significantly related to anatomically specific differences in macroscopic brain structure. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Deconstructing Anger in the Human Brain.

    Science.gov (United States)

    Gilam, Gadi; Hendler, Talma

    2017-01-01

    Anger may be caused by a wide variety of triggers, and though it has negative consequences on health and well-being, it is also crucial in motivating to take action and approach rather than avoid a confrontation. While anger is considered a survival response inherent in all living creatures, humans are endowed with the mental flexibility that enables them to control and regulate their anger, and adapt it to socially accepted norms. Indeed, a profound interpersonal nature is apparent in most events which evoke anger among humans. Since anger consists of physiological, cognitive, subjective, and behavioral components, it is a contextualized multidimensional construct that poses theoretical and operational difficulties in defining it as a single psychobiological phenomenon. Although most neuroimaging studies have neglected the multidimensionality of anger and thus resulted in brain activations dispersed across the entire brain, there seems to be several reoccurring neural circuits subserving the subjective experience of human anger. Nevertheless, to capture the large variety in the forms and fashions in which anger is experienced, expressed, and regulated, and thus to better portray the related underlying neural substrates, neurobehavioral investigations of human anger should aim to further embed realistic social interactions within their anger induction paradigms.

  3. Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

    OpenAIRE

    Zhang, Kanyin E.; Wu, Ellen; Amy K Patick; Kerr,Bradley; Zorbas, Mark; Lankford, Angela; Kobayashi, Takuo; Maeda, Yuki; Shetty, Bhasker; Webber, Stephanie

    2001-01-01

    Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (Ki = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma...

  4. Identification of fipronil metabolites by time-of-flight mass spectrometry for application in a human exposure study.

    Science.gov (United States)

    McMahen, Rebecca L; Strynar, Mark J; Dagnino, Sonia; Herr, David W; Moser, Virginia C; Garantziotis, Stavros; Andersen, Erik M; Freeborn, Danielle L; McMillan, Larry; Lindstrom, Andrew B

    2015-05-01

    Fipronil is a phenylpyrazole insecticide commonly used in residential and agricultural applications. To understand more about the potential risks for human exposure associated with fipronil, urine and serum from dosed Long Evans adult rats (5 and 10mg/kg bw) were analyzed to identify metabolites as potential biomarkers for use in human biomonitoring studies. Urine from treated rats was found to contain seven unique metabolites, two of which had not been previously reported-M4 and M7 which were putatively identified as a nitroso compound and an imine, respectively. Fipronil sulfone was confirmed to be the primary metabolite in rat serum. The fipronil metabolites identified in the respective matrices were then evaluated in matched human urine (n=84) and serum (n=96) samples from volunteers with no known pesticide exposures. Although no fipronil or metabolites were detected in human urine, fipronil sulfone was present in the serum of approximately 25% of the individuals at concentrations ranging from 0.1 to 4ng/mL. These results indicate that many fipronil metabolites are produced following exposures in rats and that fipronil sulfone is a useful biomarker in human serum. Furthermore, human exposure to fipronil may occur regularly and require more extensive characterization. Published by Elsevier Ltd.

  5. Visualization of monoamine oxidase in human brain

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, J.S.; Volkow, N.D.; Wang, G.J.; Pappas, N.; Shea, C.; MacGregor, R.R.; Logan, J.

    1996-12-31

    Monoamine oxidase is a flavin enzyme which exists in two subtypes, MAO A and MAO B. In human brain MAO B predominates and is largely compartmentalized in cell bodies of serotonergic neurons and glia. Regional distribution of MAO B was determined by positron computed tomography with volunteers after the administration of deuterium substituted [11C]L-deprenyl. The basal ganglia and thalamus exhibited the greatest concentrations of MAO B with intermediate levels in the frontal cortex and cingulate gyrus while lowest levels were observed in the parietal and temporal cortices and cerebellum. We observed that brain MAO B increases with are in health normal subjects, however the increases were generally smaller than those revealed with post-mortem studies.

  6. Inferring human intentions from the brain data

    DEFF Research Database (Denmark)

    Stanek, Konrad

    The human brain is a massively complex organ composed of approximately a hundred billion densely interconnected, interacting neural cells. The neurons are not wired randomly - instead, they are organized in local functional assemblies. It is believed that the complex patterns of dynamic electric...... discharges across the neural tissue are responsible for emergence of high cognitive function, conscious perception and voluntary action. The brain’s capacity to exercise free will, or internally generated free choice, has long been investigated by philosophers, psychologists and neuroscientists. Rather than...... assuming a causal power of conscious will, the neuroscience of volition is based on the premise that "mental states rest on brain processes”, and hence by measuring spatial and temporal correlates of volition in carefully controlled experiments we can infer about their underlying mind processes, including...

  7. Human brain lesion-deficit inference remapped.

    Science.gov (United States)

    Mah, Yee-Haur; Husain, Masud; Rees, Geraint; Nachev, Parashkev

    2014-09-01

    Our knowledge of the anatomical organization of the human brain in health and disease draws heavily on the study of patients with focal brain lesions. Historically the first method of mapping brain function, it is still potentially the most powerful, establishing the necessity of any putative neural substrate for a given function or deficit. Great inferential power, however, carries a crucial vulnerability: without stronger alternatives any consistent error cannot be easily detected. A hitherto unexamined source of such error is the structure of the high-dimensional distribution of patterns of focal damage, especially in ischaemic injury-the commonest aetiology in lesion-deficit studies-where the anatomy is naturally shaped by the architecture of the vascular tree. This distribution is so complex that analysis of lesion data sets of conventional size cannot illuminate its structure, leaving us in the dark about the presence or absence of such error. To examine this crucial question we assembled the largest known set of focal brain lesions (n = 581), derived from unselected patients with acute ischaemic injury (mean age = 62.3 years, standard deviation = 17.8, male:female ratio = 0.547), visualized with diffusion-weighted magnetic resonance imaging, and processed with validated automated lesion segmentation routines. High-dimensional analysis of this data revealed a hidden bias within the multivariate patterns of damage that will consistently distort lesion-deficit maps, displacing inferred critical regions from their true locations, in a manner opaque to replication. Quantifying the size of this mislocalization demonstrates that past lesion-deficit relationships estimated with conventional inferential methodology are likely to be significantly displaced, by a magnitude dependent on the unknown underlying lesion-deficit relationship itself. Past studies therefore cannot be retrospectively corrected, except by new knowledge that would render them redundant

  8. The interference of ethanol with heroin-stimulated psychomotor activation in mice is not related to changed brain concentrations of the active metabolites 6MAM or morphine.

    Science.gov (United States)

    Andersen, Jannike M; Haugen, Karianne S; Ripel, Ase; Mørland, Jørg

    2014-02-01

    It has been suggested that the potentiating effect observed in human beings when combining alcohol and heroin may be due to an interference of ethanol with the pharmacokinetics of heroin, leading to accumulation of the biologically active metabolites, 6-monoacetylmorphine (6MAM) and morphine. However, experimental evidence for this hypothesis is lacking. In this study, we used mice and examined the effect of ethanol on the metabolism of heroin by combining a locomotor activity test, which is a behaviour model representative of psychomotor stimulation, with pharmacokinetic studies in blood and brain tissue. Pre-treatment with ethanol (1 and 2.5 g/kg, po) affected heroin-stimulated (2.5 and 15 μmol/kg, sc) locomotor activation significantly, resulting in a dose-dependent reduction in run distance. However, the change in the activity profiles did not indicate any increase in the concentration of active metabolites. Pharmacokinetic studies in blood and brain supported the behavioural findings, showing no change in the time-versus-concentration curves of either 6MAM or morphine after administration of heroin (15 μmol/kg, sc) to mice pre-treated with ethanol (2.5 g/kg, po). The concentration of heroin itself was elevated, but is probably of minor importance because heroin has low biological activity by itself. The in vivo pharmacokinetic findings were supported by experiments in vitro. In conclusion, studies in mice do not support the hypothesis from epidemiological studies of a pharmacokinetic interaction between alcohol and heroin. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

  9. Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain.

    Directory of Open Access Journals (Sweden)

    David A Barrière

    Full Text Available The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404 and that this metabolite contributes to paracetamol's antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA, both of which may undergo a fatty acid amide hydrolase (FAAH-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl-9Z-octadecenamide (HPODA and arvanil plus olvanil in the mouse brain, respectively. The order of potency of these lipid metabolites as TRPV1 activators was arvanil = olvanil>>AM404> HPODA. Both 4-aminophenol and HMBA displayed antinociceptive activity in various rodent pain tests. The formation of AM404, arvanil and olvanil, but not HPODA, and the antinociceptive effects of 4-aminophenol and HMBA were substantially reduced or disappeared in FAAH null mice. The activity of 4-aminophenol in the mouse formalin, von Frey and tail immersion tests was also lost in TRPV1 null mice. Intracerebroventricular injection of the TRPV1 blocker capsazepine eliminated the antinociceptive effects of 4-aminophenol and HMBA in the mouse formalin test. In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol's analgesic activity via

  10. Positive selection on gene expression in the human brain

    DEFF Research Database (Denmark)

    Khaitovich, Philipp; Tang, Kun; Franz, Henriette

    2006-01-01

    Recent work has shown that the expression levels of genes transcribed in the brains of humans and chimpanzees have changed less than those of genes transcribed in other tissues [1] . However, when gene expression changes are mapped onto the evolutionary lineage in which they occurred, the brain...... shows more changes than other tissues in the human lineage compared to the chimpanzee lineage [1] , [2] and [3] . There are two possible explanations for this: either positive selection drove more gene expression changes to fixation in the human brain than in the chimpanzee brain, or genes expressed...... in the brain experienced less purifying selection in humans than in chimpanzees, i.e. gene expression in the human brain is functionally less constrained. The first scenario would be supported if genes that changed their expression in the brain in the human lineage showed more selective sweeps than other genes...

  11. Physical biology of human brain development

    Directory of Open Access Journals (Sweden)

    Silvia eBudday

    2015-07-01

    Full Text Available Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view towards surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales-from phenomena on the cellular level towards form and function on the organ level-to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.

  12. GMP-compliant radiosynthesis of [{sup 18}F]altanserin and human plasma metabolite studies

    Energy Technology Data Exchange (ETDEWEB)

    Hasler, F. [University Hospital of Psychiatry, Heffter Research Center, Zurich (Switzerland)], E-mail: fehasler@bli.uzh.ch; Kuznetsova, O.F.; Krasikova, R.N. [Institute of the Human Brain, Russian Academy of Science, St. Petersburg (Russian Federation); Cservenyak, T. [Center for Radiopharmaceutical Sciences of ETH, PSI and University Hospital Zurich (Switzerland); Quednow, B.B.; Vollenweider, F.X. [University Hospital of Psychiatry, Heffter Research Center, Zurich (Switzerland); Ametamey, S.M.; Westera, G. [Center for Radiopharmaceutical Sciences of ETH, PSI and University Hospital Zurich (Switzerland)

    2009-04-15

    [{sup 18}F]altanserin is the preferred radiotracer for in-vivo labeling of serotonin 2A receptors by positron emission tomography (PET). We report a modified synthesis procedure suited for reliable production of multi-GBq amounts of [{sup 18}F]altanserin useful for application in humans. We introduced thermal heating for drying of [{sup 18}F]fluoride as well as for the reaction instead of microwave heating. We furthermore describe solid phase extraction and HPLC procedures for quantitative determination of [{sup 18}F]altanserin and metabolites in plasma. The time course of arterial plasma activity with and without metabolite correction was determined. 90 min after bolus injection, 38.4% of total plasma activity derived from unchanged [{sup 18}F]altanserin. Statistical comparison of kinetic profiles of [{sup 18}F]altanserin metabolism in plasma samples collected in the course of two ongoing studies employing placebo, the serotonin releaser dexfenfluramine and the hallucinogen psilocybin, revealed the same tracer metabolism. We conclude that metabolite analysis for correction of individual plasma input functions used in tracer modeling is not necessary for [{sup 18}F]altanserin studies involving psilocybin or dexfenfluramine treatment.

  13. Decrease of plasma and urinary oxidative metabolites of acetaminophen after consumption of watercress by human volunteers.

    Science.gov (United States)

    Chen, L; Mohr, S N; Yang, C S

    1996-12-01

    To investigate the effect of the consumption of watercress (Nasturtium officinale R. Br.), a cruciferous vegetable, on acetaminophen metabolism, the pharmacokinetics of acetaminophen and its metabolites were studied in a crossover trial of human volunteers. A single oral dose of acetaminophen (1 gm) was given 10 hours after ingestion of watercress homogenates (50 gm). In comparison with acetaminophen only, the ingestion of watercress resulted in a significant reduction in the area under the plasma cysteine acetaminophen (Cys-acetaminophen) concentration-time curve and in the peak plasma Cys-acetaminophen concentration by 28% +/- 3% and by 21% +/- 4% (mean +/- SE; n = 7; p < 0.005), respectively. Correspondingly, the Cys-acetaminophen formation rate constant and Cys-acetaminophen formation fraction were decreased by 55% +/- 9% and 52% +/- 7% (p < 0.01), respectively. Consistent with the results obtained from the plasma, the total urinary excretion of Cys-acetaminophen in 24 hours was also reduced. A decrease of mercapturate acetaminophen, a Cys-acetaminophen metabolite, was also shown in the plasma and urine samples. However, the plasma pharmacokinetic processes and the urinary excretions of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were not altered significantly by the watercress treatment. These results suggest that the consumption of watercress causes a decrease in the levels of oxidative metabolites of acetaminophen, probably due to inhibition of oxidative metabolism of this drug.

  14. Evolvability of Amyloidogenic Proteins in Human Brain

    Science.gov (United States)

    Hashimoto, Makoto; Ho, Gilbert; Sugama, Shuei; Takamatsu, Yoshiki; Shimizu, Yuka; Takenouchi, Takato; Waragai, Masaaki; Masliah, Eliezer

    2018-01-01

     Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-β and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of APs in aging-associated neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin’s ‘gemmules’, imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis. PMID:29439348

  15. Molecular biology of the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Jones, E.G.

    1988-01-01

    This book examines new methods of molecular biology that are providing valuable insights into the human brain, the genes that govern its assembly and function, and the many genetic defects that cause neurological diseases such as Alzheimer's, Cri du Chat syndrome, Huntington's disease, and bipolar depression disorder. In addition, the book reviews techniques in molecular neurobiological research, including the use of affinity reagents, chimeric receptors, and site-directed mutagenesis in localizing the ion channel and cholinergic binding site, and the application of somatic cell genetics in isolating specific chromosomes or chromosomal segments.

  16. Transformation products and human metabolites of triclocarban and tricllosan in sewage sludge across the United States

    Science.gov (United States)

    Pycke, Benny F.G.; Roll, Isaac B.; Brownawell, Bruce J.; Kinney, Chad A.; Furlong, Edward T.; Kolpin, Dana W.; Halden, Rolf U.

    2014-01-01

    Removal of triclocarban (TCC) and triclosan (TCS) from wastewater is a function of adsorption, abiotic degradation, and microbial mineralization or transformation, reactions that are not currently controlled or optimized in the pollution control infrastructure of standard wastewater treatment. Here, we report on the levels of eight transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in raw and treated sewage sludge. Two sample sets were studied: samples collected once from 14 wastewater treatment plants (WWTPs) representing nine states, and multiple samples collected from one WWTP monitored for 12 months. Time-course analysis of significant mass fluxes (α = 0.01) indicate that transformation of TCC (dechlorination) and TCS (methylation) occurred during sewage conveyance and treatment. Strong linear correlations were found between TCC and the human metabolite 2′-hydroxy-TCC (r = 0.84), and between the TCC-dechlorination products dichlorocarbanilide (DCC) and monochlorocarbanilide (r = 0.99). Mass ratios of DCC-to-TCC and of methyl-triclosan (MeTCS)-to-TCS, serving as indicators of transformation activity, revealed that transformation was widespread under different treatment regimes across the WWTPs sampled, though the degree of transformation varied significantly among study sites (α = 0.01). The analysis of sludge sampled before and after different unit operation steps (i.e., anaerobic digestion, sludge heat treatment, and sludge drying) yielded insights into the extent and location of TCC and TCS transformation. Results showed anaerobic digestion to be important for MeTCS transformation (37–74%), whereas its contribution to partial TCC dechlorination was limited (0.4–2.1%). This longitudinal and nationwide survey is the first to report the occurrence of transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in sewage sludge.

  17. Transformation Products and Human Metabolites of Triclocarban and Triclosan in Sewage Sludge Across the United States

    Science.gov (United States)

    2015-01-01

    Removal of triclocarban (TCC) and triclosan (TCS) from wastewater is a function of adsorption, abiotic degradation, and microbial mineralization or transformation, reactions that are not currently controlled or optimized in the pollution control infrastructure of standard wastewater treatment. Here, we report on the levels of eight transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in raw and treated sewage sludge. Two sample sets were studied: samples collected once from 14 wastewater treatment plants (WWTPs) representing nine states, and multiple samples collected from one WWTP monitored for 12 months. Time-course analysis of significant mass fluxes (α = 0.01) indicate that transformation of TCC (dechlorination) and TCS (methylation) occurred during sewage conveyance and treatment. Strong linear correlations were found between TCC and the human metabolite 2′-hydroxy-TCC (r = 0.84), and between the TCC-dechlorination products dichlorocarbanilide (DCC) and monochlorocarbanilide (r = 0.99). Mass ratios of DCC-to-TCC and of methyl-triclosan (MeTCS)-to-TCS, serving as indicators of transformation activity, revealed that transformation was widespread under different treatment regimes across the WWTPs sampled, though the degree of transformation varied significantly among study sites (α = 0.01). The analysis of sludge sampled before and after different unit operation steps (i.e., anaerobic digestion, sludge heat treatment, and sludge drying) yielded insights into the extent and location of TCC and TCS transformation. Results showed anaerobic digestion to be important for MeTCS transformation (37–74%), whereas its contribution to partial TCC dechlorination was limited (0.4–2.1%). This longitudinal and nationwide survey is the first to report the occurrence of transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in sewage sludge. PMID:24932693

  18. Mouse Genetic Models of Human Brain Disorders

    Directory of Open Access Journals (Sweden)

    Celeste eLeung

    2016-03-01

    Full Text Available Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioural phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases.

  19. Analysis of PCB and PCB metabolites in humans from Eastern Slovakia

    Energy Technology Data Exchange (ETDEWEB)

    Hovander, L.; Linderholm, L.; Athanasiadou, M.; Athanassiadis, I.; Bergman, Aa. [Stockholm Univ. (Sweden). Dept. of Environmental Chemistry; Trnovec, T.; Kocan, A.; Petrik, J. [Institute of Preventive and Clinical Medicine (Sweden). Dept. of Toxic Organic Pollutants

    2004-09-15

    Polychlorinated biphenyls (PCBs) are still major environmental contaminants threatening human health. A chemical plant in Eastern Slovakia manufactured 22,000 tonnes of PCBs between 1959 and 1984. The water in the effluent canal drained into a nearby river and contaminated the adjacent area. Over the past decade, PCB contamination in part of the district has been well documented. In 1997 and 1998, samples of soil, air, water, sediments and wildlife were collected and PCBs were analysed. Since PCBs form hydroxylated metabolites (OH-PCBs) that may show endocrine modulating properties and are, depending on their structures, retained in the blood, it is of interest to determine the OH-PCBs levels. PCB also form methylsulfonyl substituted metabolites (MeSO{sub 2}-PCBs) that may be retained in the body. In human plasma samples, the level of CB-153 show a good correlation with the total PCB level (around 25%) and could be used as a marker for total PCB. The aim of the present study was to determine the levels of OH-PCBs and MeSO{sub 2}-PCBs and also CB-153 in plasma from humans living in the contaminated area and in background areas.

  20. Identification of a novel human deoxynivalenol metabolite enhancing proliferation of intestinal and urinary bladder cells

    Science.gov (United States)

    Warth, Benedikt; Del Favero, Giorgia; Wiesenberger, Gerlinde; Puntscher, Hannes; Woelflingseder, Lydia; Fruhmann, Philipp; Sarkanj, Bojan; Krska, Rudolf; Schuhmacher, Rainer; Adam, Gerhard; Marko, Doris

    2016-09-01

    The mycotoxin deoxynivalenol (DON) is an abundant contaminant of cereal based food and a severe issue for global food safety. We report the discovery of DON-3-sulfate as a novel human metabolite and potential new biomarker of DON exposure. The conjugate was detectable in 70% of urine samples obtained from pregnant women in Croatia. For the measurement of urinary metabolites, a highly sensitive and selective LC-MS/MS method was developed and validated. The method was also used to investigate samples from a duplicate diet survey for studying the toxicokinetics of DON-3-sulfate. To get a preliminary insight into the biological relevance of the newly discovered DON-sulfates, in vitroexperiments were performed. In contrast to DON, sulfate conjugates lacked potency to suppress protein translation. However, surprisingly we found that DON-sulfates enhanced proliferation of human HT-29 colon carcinoma cells, primary human colon epithelial cells (HCEC-1CT) and, to some extent, also T24 bladder cancer cells. A proliferative stimulus, especially in tumorigenic cells raises concern on the potential impact of DON-sulfates on consumer health. Thus, a further characterization of their toxicological relevance should be of high priority.

  1. Neocortical glial cell numbers in human brains

    DEFF Research Database (Denmark)

    Pelvig, D.P.; Pakkenberg, H.; Stark, A.K.

    2008-01-01

    Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia...... while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males......, a difference of 24% with a high biological variance. These numbers can serve as reference values in quantitative studies of the human neocortex. (C) 2007 Elsevier Inc. All rights reserved Udgivelsesdato: 2008/11...

  2. Metabolite profiling of RCS-4, a novel synthetic cannabinoid designer drug, using human hepatocyte metabolism and TOF-MS

    Science.gov (United States)

    Gandhi, Adarsh S; Zhu, Mingshe; Pang, Shaokun; Wohlfarth, Ariane; Scheidweiler, Karl B; Huestis, Marilyn A

    2014-01-01

    Background Since 2009, scheduling legislation of synthetic cannabinoids prompted new compound emergence to circumvent legal restrictions. 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4) is a potent cannabinoid receptor agonist sold in herbal smoking blends. Absence of parent synthetic cannabinoids in urine suggests the importance of metabolite identification for detecting RCS-4 consumption in clinical and forensic investigations. Materials & methods & Results With 1 h human hepatocyte incubation and TOF high-resolution MS, we identified 18 RCS-4 metabolites, many not yet reported. Most metabolites were hydroxylated with or without demethylation, carboxylation and dealkylation followed by glucuronidation. One additional sulfated metabolite was also observed. O-demethylation was the most common biotransformation and generated the major metabolite. Conclusion For the first time, we present a metabolic scheme of RCS-4 obtained from human hepatocytes, including Phase I and II metabolites. Metabolite structural information and associated high-resolution mass spectra can be employed for developing clinical and forensic laboratory RCS-4 urine screening methods. PMID:25046048

  3. Transient Changes in Brain Metabolites after Transcranial Direct Current Stimulation in Spastic Cerebral Palsy: A Pilot Study.

    Science.gov (United States)

    Auvichayapat, Paradee; Aree-Uea, Benchaporn; Auvichayapat, Narong; Phuttharak, Warinthorn; Janyacharoen, Taweesak; Tunkamnerdthai, Orathai; Boonphongsathian, Wuttisak; Ngernyam, Niran; Keeratitanont, Keattichai

    2017-01-01

    Muscle spasticity is a disability caused by damage to the pyramidal system. Standard treatments for spasticity include muscle stretching, antispastic medications, and tendon release surgeries, but treatment outcomes remain unsatisfactory. Anodal transcranial direct current stimulation (tDCS) in patients with muscle spasticity is known to result in significant improvement in spastic tone (p spasticity remains unclear. This pilot study aimed to investigate the effect of anodal tDCS upon brain metabolites in the left basal ganglia and ipsilateral primary motor cortex (M1) in children with spastic cerebral palsy (CP). This study consisted of three steps: a baseline evaluation, a treatment period, and a follow-up period. During the treatment period, patients were given 20 min of 1 mA anodal tDCS over the left M1 for five consecutive days. Outcomes were compared between pre- and immediate posttreatment in terms of brain metabolites, Tardieu scales, and the quality of upper extremity skills test. Ten patients with spastic CP were enrolled. Following tDCS, there were significant increases in the ratio of N-acetylaspartate (NAA)/creatine (Cr) (p = 0.030), choline (Cho)/Cr (p = 0.043), and myoinositol (mI)/Cr (p = 0.035) in the basal ganglia. Moreover, increased glutamine-glutamate (Glx)/Cr ratio in the left M1 (p = 0.008) was found. In addition, we also observed improvements in the extent of spasticity and hand function (p = 0.028). Five consecutive days of anodal tDCS over the left M1 appeared statistically to reduce the degree of spasticity and increase NAA, Cho, mI, and Glx. Future research studies, involving a larger sample size of spastic CP patients undergoing tDCS is now warranted.

  4. Brain metabolite changes on proton magnetic resonance spectroscopy in children with poorly controlled type 1 diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Sarac, K.; Alkan, A.; Baysal, T. [Inonu University School of Medicine, Department of Radiology, Malatya (Turkey); Akinci, A.; Aslan, M. [Inonu University School of Medicine, Department of Paediatric Endocrinology, Malatya (Turkey); Oezcan, C. [Inonu University School of Medicine, Department of Neurology, Malatya (Turkey)

    2005-07-01

    The metabolite changes in the brains of children with poorly controlled type 1 diabetes mellitus (DM) were investigated by proton magnetic resonance spectroscopy (MRS). A total of 30 subjects and 14 age-matched healthy volunteers underwent single-voxel MRS (TE: 136). The duration of disease, medication, presence of hypoglycaemia episodes and the level of haemoglobin A1C (HbA1C) in the patients were noted. Voxels were placed in the pons, left basal ganglion (LBG) and left posterior parietal white matter (PPWM). N-acetylaspartate (NAA)/creatinine (Cr) and choline (Cho)/Cr ratios were calculated. The average HbA1c level was 11.9{+-}3.4 (8.2-19.4). The average number of keto-acidosis episodes was 1.9{+-}2.2 (0-9) and the average number of daily insulin injections was 2.8{+-}0.97 (2-4). MRS revealed lower NAA/Cr and Cho/Cr ratios in the pons and lower NAA/Cr ratio in the PPWM of patients with DM than in control subjects. No significant correlation was observed between the number of hypoglycaemia episodes and metabolite ratios. Metabolic abnormalities have been observed by MRS in the brain of poorly controlled type 1 DM children. These metabolic changes, in particular in the pons region, include a decrease in NAA, indicating neuronal loss or functional impairment, and likely explanations for a decrease in Cho may be dynamic changes in membrane lipids and/or decreased membrane turnover. (orig.)

  5. Evolution of the human brain: changing brain size and the fossil record.

    Science.gov (United States)

    Park, Min S; Nguyen, Andrew D; Aryan, Henry E; U, Hoi Sang; Levy, Michael L; Semendeferi, Katerina

    2007-03-01

    Although the study of the human brain is a rapidly developing and expanding science, we must take pause to examine the historical and evolutionary events that helped shape the brain of Homo sapiens. From an examination of the human lineage to a discussion of evolutionary principles, we describe the basic principles and theories behind the evolution of the human brain. Specifically, we examine several theories concerning changes in overall brain size during hominid evolution and relate them to the fossil record. This overview is intended to provide a broad understanding of some of the controversial issues that are currently being debated in the multidisciplinary field of brain evolution research.

  6. In vivo 1H spectroscopy of the human brain at 1.5 tesla. Preliminary experience at a clinical installation

    DEFF Research Database (Denmark)

    Henriksen, O; Larsson, H; Jensen, K M

    1990-01-01

    technique. Our preliminary results indicate that it is possible to detect a number of metabolites in the brain within a total measurement time of one hour. The dominant peaks in the spectra from healthy volunteers are N-acetyl aspartate, choline and creatine/phosphocreatine. The spectra obtained from......In vivo localized water suppressed proton spectroscopy of human brain was carried out on 15 healthy volunteers and 2 patients suffering from a brain tumour and an infarction, respectively. The measurements were performed on a whole body MR system, operating at 1.5 tesla using the stimulated echo...... the brain tumour and the infarct, respectively, differed very much from those obtained in healthy brain tissue. Our preliminary results indicate that localized proton spectroscopy may contribute to non-invasive brain tumour classification and possibly also to the differentiation between tumours and infarcts...

  7. Olfactory Dysfunctions and Decreased Nitric Oxide Production in the Brain of Human P301L Tau Transgenic Mice.

    Science.gov (United States)

    Hu, Yang; Ding, Wenting; Zhu, Xiaonan; Chen, Ruzhu; Wang, Xuelan

    2016-04-01

    Different patterns of olfactory dysfunction have been found in both patients and mouse models of Alzheimer's Disease. However, the underlying mechanism of the dysfunction remained unknown. Deficits of nitric oxide production in brain can cause olfactory dysfunction by preventing the formation of olfactory memory. The aim of this study was to investigate the behavioral changes in olfaction and alterations in metabolites of nitric oxide, nitrate/nitrite concentration, in the brain of human P301L tau transgenic mice. The tau mice showed impairments in olfaction and increased abnormal phosphorylation of Tau protein at AT8 in different brain areas, especially in olfactory bulb. We now report that these olfactory deficits and Tau pathological changes were accompanied by decreased nitrate/nitrite concentration in the brain, especially in the olfactory bulb, and reduced expression of nNOS in the brain of tau mice. These findings provided evidence of olfactory dysfunctions correlated with decreased nitric oxide production in the brain of tau mice.

  8. Isolation of Human Intestinal Bacteria Capable of Producing the Bioactive Metabolite Isourolithin A from Ellagic Acid

    Directory of Open Access Journals (Sweden)

    María V. Selma

    2017-08-01

    Full Text Available Urolithins are intestinal microbial metabolites produced from ellagitannin- and ellagic acid-containing foods such as walnuts, strawberries, and pomegranates. These metabolites, better absorbed than their precursors, can contribute significantly to the beneficial properties attributed to the polyphenols ellagitannins and ellagic acid (EA. However, both the ability of producing the final metabolites in this catabolism (urolithins A, B and isourolithin A and the health benefits associated with ellagitannin consumption differ considerably among individuals depending on their gut microbiota composition. Three human urolithin metabotypes have been previously described, i.e., metabotype 0 (urolithin non-producers, metabotype A (production of urolithin A as unique final urolithin and metabotype B (urolithin B and/or isourolithin A are produced besides urolithin A. Although production of some intermediary urolithins has been recently attributed to intestinal species from Eggerthellaceae family named Gordonibacter urolithinfaciens and Gordonibacter pamelaeae, the identification of the microorganisms responsible for the complete transformation of EA into the final urolithins, especially those related to metabotype B, are still unknown. In the present research we illustrate the isolation of urolithin-producing strains from human feces of a healthy adult and their ability to transform EA into different urolithin metabolites, including isourolithin A. The isolates belong to a new genus from Eggerthellaceae family. EA transformation and urolithin production arisen during the stationary phase of the growth of the bacteria under anaerobic conditions. The HPLC-DAD-MS analyses demonstrated the sequential appearance of 3,8,9,10-tetrahydroxy-urolithin (urolithin M6, 3,8,9-trihydroxy-urolithin (urolithin C and 3,9-dihydroxy-urolithin (isourolithin A while 3,8-dihydroxy-urolithin (urolithin A and 3-hydroxy-urolithin (urolithin B were not detected. For the first time

  9. Identification of the metabolites of episesamin in rat bile and human liver microsomes.

    Science.gov (United States)

    Tomimori, Namino; Nakai, Masaaki; Ono, Yoshiko; Kitagawa, Yoshinori; Kiso, Yoshinobu; Shibata, Hiroshi

    2012-01-01

    Episesamin is an isomer of sesamin, resulting from the refining process of non-roasted sesame seed oil. Episesamin has two methylendioxyphenyl groups on exo and endo faces of the bicyclic skeleton. The side methylendioxyphenyl group was metabolized by cytochrome-P450. Seven metabolites of episesamin were found in rat bile after treatment with glucuronidase/arylsulfatase and were identified using NMR and MS. The seven metabolites were (7α,7'β,8α,8'α)-3,4-dihydroxy-3',4'-methylenedioxy-7,9':7',9-diepoxylignane (EC-1-1), (7α,7'β,8α,8'α)-3,4-methylenedioxy-3',4'-dihydroxy-7,9':7',9-diepoxylignane (EC-1-2) and (7α,7'β,8α,8'α)-3,4:3',4'-bis(dihydroxy)-7,9':7',9-diepoxylignane (EC-2), (7α,7'β,8α,8'α)-3-methoxy-4-hydroxy-3',4'-methylenedioxy-7,9':7',9-diepoxylignane (EC-1m-1), (7α,7'β,8α,8'α)-3,4-methylenedioxy-3'-methoxy-4'-hydroxy-7,9':7',9-diepoxylignane (EC-1m-2), (7α,7'β,8α,8'α)-3-methoxy-4-hydroxy-3',4'-dihydroxy-7,9':7',9-diepoxylignane (EC-2m-1) and (7α,7'β,8α,8'α)-3,4-dihydroxy-3'-methoxy-4'-hydroxy-7,9':7',9-diepoxylignane (EC-2m-2). EC-1-1, EC-1-2 and EC-2 were also identified as metabolites of episesamin in human liver microsomes. These results suggested that similar metabolic pathways of episesamin could be proposed in rats and humans.

  10. Understanding the protective effects of wine components and their metabolites in the brain function

    Directory of Open Access Journals (Sweden)

    Esteban-Fernández A.

    2016-01-01

    Full Text Available Moderate wine consumption has been suggested to exert a positive effect in prevention of neurodegenerative process and cognitive impairment. With the ultimate aim of achieving a better understanding of the molecular mechanisms behind this benefit, we have investigated the role of certain wine- derived phenolic metabolites and aroma compounds in the MAPK cascade (including ERK1/2, p38, one of the routes directly related to inflammation in neuronal cells. Some of the tested phenolic compounds, especially in the case of 3,4-dihydroxyphenylacetic acid, showed a significant neuroprotective effect against SIN-1-induced neuronal death. Regarding their effect over MAPK phosphorylation, inmunoblotting technique revealed a beneficial and significant decrease on the phosphorylation of p38 and ERK1/2 kinases after incubation with wine constituents. In addition, activity of caspase3-like protease, an executor of neuronal apoptosis and a downstream signal of MAPK, was significantly diminished by 3-(3-hydroxyphenyl propionic acid and linalool, counterbalancing the increase produced by SIN-1. Altogether, these results suggest that wine aroma, phenolic compounds and their gut metabolites could exert neuroprotective actions by modulating MAPK signalling and caspase-3 proteases activation, which are known to play a key role in oxidative/ nitrosative stress-induced response.

  11. Syntheses and properties of the major hydroxy metabolites in humans of blonanserin AD-5423, a novel antipsychotic agent.

    Science.gov (United States)

    Ochi, Takeshi; Sakamoto, Masato; Minamida, Akira; Suzuki, Kenji; Ueda, Tomohiko; Une, Teruaki; Toda, Hiroshi; Matsumoto, Kazuya; Terauchi, Yoshiaki

    2005-02-15

    Two major metabolites in humans of blonanserin, 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta-[b]pyridine (code name AD-5423), were synthesized. The first, 7-hydroxylated AD-5423, was synthesized through a four-step process starting from 4-fluorobenzoylacetonitrile (1), and the second, 8-hydroxylated AD-5423, a nine-step process also from 1. The optical resolution, structures, and receptor binding properties of the metabolites were documented.

  12. Qualitative profiling and quantification of neonicotinoid metabolites in human urine by liquid chromatography coupled with mass spectrometry.

    Science.gov (United States)

    Taira, Kumiko; Fujioka, Kazutoshi; Aoyama, Yoshiko

    2013-01-01

    Neonicotinoid pesticides have been widely applied for the production of fruits and vegetables, and occasionally detected in conventionally grown produce. Thus oral exposure to neonicotinoid pesticides may exist in the general population; however, neonicotinoid metabolites in human body fluids have not been investigated comprehensively. The purpose of this study is the qualitative profiling and quantitative analysis of neonicotinoid metabolites in the human spot urine by liquid chromatography coupled with mass spectrometry (LC/MS). Human urine samples were collected from three patients suspected of subacute exposure to neonicotinoid pesticides. A qualitative profiling of urinary metabolites was performed using liquid chromatography/time-of-flight mass spectrometry (LC/TOFMS) with a database of nominal molecular weights of 57 known metabolites of three neonicotinoid pesticides (acetamiprid, Imidacloprid, and clothianidin), as well as the parent compounds. Then a quantitative analysis of selected urinary metabolites was performed using liquid chromatography/tandem mass spectrometry (LC/MS/MS) with a standard pesticide and metabolite, which were detected by the qualitative profiling. The result of qualitative profiling showed that seven metabolites, i.e. an acetamiprid metabolite, N-desmethyl-acetamiprid; three Imidacloprid metabolites, 5-hydroxy-Imidacloprid, 4,5-dihydroxy-imidacloprid, 4,5-dehydro-Imidacloprid; a common metabolite of acetamiprid and Imidacloprid, N-(6-chloronicotinoyl)-glycine; and two clothianidin metabolites, N-desmethyl-clothianidin, N-(2-(methylsulfanyl)thiazole-5-carboxyl)-glycine, as well as acetamiprid, were detected in the urine of three cases. The result of the quantitative analysis showed N-desmethyl-acetamiprid was determined in the urine of one case, which had been collected on the first visit, at a concentration of 3.2 ng/mL. This is the first report on the qualitative and quantitative detection of N-desmethyl-acetamiprid in the human

  13. Qualitative profiling and quantification of neonicotinoid metabolites in human urine by liquid chromatography coupled with mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Kumiko Taira

    Full Text Available Neonicotinoid pesticides have been widely applied for the production of fruits and vegetables, and occasionally detected in conventionally grown produce. Thus oral exposure to neonicotinoid pesticides may exist in the general population; however, neonicotinoid metabolites in human body fluids have not been investigated comprehensively. The purpose of this study is the qualitative profiling and quantitative analysis of neonicotinoid metabolites in the human spot urine by liquid chromatography coupled with mass spectrometry (LC/MS. Human urine samples were collected from three patients suspected of subacute exposure to neonicotinoid pesticides. A qualitative profiling of urinary metabolites was performed using liquid chromatography/time-of-flight mass spectrometry (LC/TOFMS with a database of nominal molecular weights of 57 known metabolites of three neonicotinoid pesticides (acetamiprid, Imidacloprid, and clothianidin, as well as the parent compounds. Then a quantitative analysis of selected urinary metabolites was performed using liquid chromatography/tandem mass spectrometry (LC/MS/MS with a standard pesticide and metabolite, which were detected by the qualitative profiling. The result of qualitative profiling showed that seven metabolites, i.e. an acetamiprid metabolite, N-desmethyl-acetamiprid; three Imidacloprid metabolites, 5-hydroxy-Imidacloprid, 4,5-dihydroxy-imidacloprid, 4,5-dehydro-Imidacloprid; a common metabolite of acetamiprid and Imidacloprid, N-(6-chloronicotinoyl-glycine; and two clothianidin metabolites, N-desmethyl-clothianidin, N-(2-(methylsulfanylthiazole-5-carboxyl-glycine, as well as acetamiprid, were detected in the urine of three cases. The result of the quantitative analysis showed N-desmethyl-acetamiprid was determined in the urine of one case, which had been collected on the first visit, at a concentration of 3.2 ng/mL. This is the first report on the qualitative and quantitative detection of N-desmethyl-acetamiprid in

  14. Comparative primate neuroimaging: insights into human brain evolution.

    Science.gov (United States)

    Rilling, James K

    2014-01-01

    Comparative neuroimaging can identify unique features of the human brain and teach us about human brain evolution. Comparisons with chimpanzees, our closest living primate relative, are critical in this endeavor. Structural magnetic resonance imaging (MRI) has been used to compare brain size development, brain structure proportions and brain aging. Positron emission tomography (PET) imaging has been used to compare resting brain glucose metabolism. Functional MRI (fMRI) has been used to compare auditory and visual system pathways, as well as resting-state networks of connectivity. Finally, diffusion-weighted imaging (DWI) has been used to compare structural connectivity. Collectively, these methods have revealed human brain specializations with respect to development, cortical organization, connectivity, and aging. These findings inform our knowledge of the evolutionary changes responsible for the special features of the modern human mind.

  15. Automated solid phase extraction and quantitative analysis of human milk for 13 phthalate metabolites.

    Science.gov (United States)

    Calafat, Antonia M; Slakman, A Ryan; Silva, Manori J; Herbert, Arnetra R; Needham, Larry L

    2004-06-05

    While the demonstrated benefits associated with breastfeeding are well recognized, breast milk is one possible route of exposure to environmental chemicals, including phthalates, by breastfeeding infants. Because of the potential health impact of phthalates to nursing children, determining whether phthalates are present in breast milk is important. We developed a sensitive method for measuring 13 phthalate metabolites in breast milk using automated solid phase extraction (SPE) coupled to isotope dilution-high-performance liquid chromatography (HPLC)-negative ion electrospray ionization-tandem mass spectrometry. We used D(4)-phthalate diesters to unequivocally establish the presence in human breast milk of enzymes capable of hydrolyzing the ubiquitous phthalate diesters to their respective monoesters. The analytical method involves acid-denaturation of the enzymes after collection of the milk to avoid hydrolysis of contaminant phthalate diesters introduced during sampling, storage, and analysis. The method shows good reproducibility (average coefficient of variations range between 4 and 27%) and accuracy (spiked recoveries are approximately 100%). The detection limits are in the low ng/ml range in 1ml of breast milk. We detected several phthalate metabolites in pooled human breast milk samples, suggesting that phthalates can be incorporated into breast milk and transferred to the nursing child.

  16. Corallocins A-C, Nerve Growth and Brain-Derived Neurotrophic Factor Inducing Metabolites from the Mushroom Hericium coralloides.

    Science.gov (United States)

    Wittstein, Kathrin; Rascher, Monique; Rupcic, Zeljka; Löwen, Eduard; Winter, Barbara; Köster, Reinhard W; Stadler, Marc

    2016-09-23

    Three new natural products, corallocins A-C (1-3), along with two known compounds were isolated from the mushroom Hericium coralloides. Their benzofuranone and isoindolinone structures were elucidated by spectral methods. All corallocins induced nerve growth factor and/or brain-derived neurotrophic factor expression in human 1321N1 astrocytes. Furthermore, corallocin B showed antiproliferative activity against HUVEC and human cancer cell lines MCF-7 and KB-3-1.

  17. The human brain in numbers: a linearly scaled-up primate brain

    Directory of Open Access Journals (Sweden)

    Suzana Herculano-Houzel

    2009-11-01

    Full Text Available The human brain has often been viewed as outstanding among mammalian brains: the most cognitively able, the largest-than-expected from body size, endowed with an overdeveloped cerebral cortex that represents over 80% of brain mass, and purportedly containing 100 billion neurons and 10x more glial cells. Such uniqueness was seemingly necessary to justify the superior cognitive abilities of humans over larger-brained mammals such as elephants and whales. However, our recent studies using a novel method to determine the cellular composition of the brain of humans and other primates as well as of rodents and insectivores show that, since different cellular scaling rules apply to the brains within these orders, brain size can no longer be considered a proxy for the number of neurons in the brain. These studies also showed that the human brain is not exceptional in its cellular composition, as it was found to contain as many neuronal and nonneuronal cells as would be expected of a primate brain of its size. Additionally, the so-called overdeveloped human cerebral cortex holds only 19% of all brain neurons, a fraction that is similar to that found in other mammals. In what regards absolute numbers of neurons, however, the human brain does have two advantages compared to other mammalian brains: compared to rodents, and probably to whales and elephants as well, it is built according to the very economical, space-saving scaling rules that apply to other primates; and, among economically-built primate brains, it is the largest, hence containing the most neurons. These findings argue in favor of a view of cognitive abilities that is centered on absolute numbers of neurons, rather than on body size or encephalization, and call for a re-examination of several concepts related to the exceptionality of the human brain.

  18. The Human Brain in Numbers: A Linearly Scaled-up Primate Brain

    Science.gov (United States)

    Herculano-Houzel, Suzana

    2009-01-01

    The human brain has often been viewed as outstanding among mammalian brains: the most cognitively able, the largest-than-expected from body size, endowed with an overdeveloped cerebral cortex that represents over 80% of brain mass, and purportedly containing 100 billion neurons and 10× more glial cells. Such uniqueness was seemingly necessary to justify the superior cognitive abilities of humans over larger-brained mammals such as elephants and whales. However, our recent studies using a novel method to determine the cellular composition of the brain of humans and other primates as well as of rodents and insectivores show that, since different cellular scaling rules apply to the brains within these orders, brain size can no longer be considered a proxy for the number of neurons in the brain. These studies also showed that the human brain is not exceptional in its cellular composition, as it was found to contain as many neuronal and non-neuronal cells as would be expected of a primate brain of its size. Additionally, the so-called overdeveloped human cerebral cortex holds only 19% of all brain neurons, a fraction that is similar to that found in other mammals. In what regards absolute numbers of neurons, however, the human brain does have two advantages compared to other mammalian brains: compared to rodents, and probably to whales and elephants as well, it is built according to the very economical, space-saving scaling rules that apply to other primates; and, among economically built primate brains, it is the largest, hence containing the most neurons. These findings argue in favor of a view of cognitive abilities that is centered on absolute numbers of neurons, rather than on body size or encephalization, and call for a re-examination of several concepts related to the exceptionality of the human brain. PMID:19915731

  19. Left Brain to Right Brain: Notes from the Human Laboratory.

    Science.gov (United States)

    Baumli, Francis

    1982-01-01

    Examines the implications of the left brain-right brain theory on communications styles in male-female relationships. The author contends that women tend to use the vagueness of their emotional responses manipulatively. Men need to apply rational approaches to increase clarity in communication. (AM)

  20. Brain metabolites in definite amyotrophic lateral sclerosis. A longitudinal proton magnetic resonance spectroscopy study.

    Science.gov (United States)

    Unrath, Alexander; Ludolph, Albert C; Kassubek, Jan

    2007-08-01

    Biomarkers beyond clinical assessment are needed in patients who suffer from amyotrophic lateral sclerosis (ALS). Here, single-voxel proton magnetic resonance spectroscopy ((1)H MRS) of the gray matter of the motor cortex and the white matter including the pyramidal tracts was used to investigate concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, glutamate, and glutamine in patients with definite ALS in a longitudinal design (three measurements at study inclusion, after 3 and 6 months). A volume-corrected analysis of gray and white matter fractions within the volumes of interest (VOI) was performed for the identification of the absolute metabolite concentrations. The patient group showed a significant decline of the compound NAA over time in the motor cortex areas both of the clinically more and less affected hemisphere between first measurement and month 6 and for the less affected side additionally between first measurement and month 3. For the NAA/(Cr + Cho) ratio, significant decline in the less affected hemisphere was observed from the first measurement to month 3 and to month 6 as well as from month 3 to month 6. In contrast, neither NAA nor the NAA/(Cr + Cho) ratios in the white matter areas showed any significant alterations. All other compounds showed no significant changes over time. In summary, the longitudinal changes of cortical metabolite concentrations in the course of ALS could be assessed by optimized (1)H MRS techniques at group level, so that (1)H MRS parameters, in particular volume-corrected values of NAA in the clinically less affected hemisphere, seem to have the potential to serve as a surrogate marker for monitoring ALS disease progression.

  1. Listeriolysin O mediates cytotoxicity against human brain microvascular

    Science.gov (United States)

    Penetration of the brain microvascular endothelial layer is one of the routes L. monocytogenes use to breach the blood-brain barrier. Because host factors in the blood severely limit direct invasion of human brain microvascular endothelial cells (HBMECs) by L. monocytogenes, alternative mechanisms m...

  2. Brain-Computer Interfaces and Human-Computer Interaction

    NARCIS (Netherlands)

    Tan, Desney; Tan, Desney S.; Nijholt, Antinus

    2010-01-01

    Advances in cognitive neuroscience and brain imaging technologies have started to provide us with the ability to interface directly with the human brain. This ability is made possible through the use of sensors that can monitor some of the physical processes that occur within the brain that

  3. Dynamic analysis of the human brain with complex cerebral sulci.

    Science.gov (United States)

    Tseng, Jung-Ge; Huang, Bo-Wun; Ou, Yi-Wen; Yen, Ke-Tien; Wu, Yi-Te

    2016-07-03

    The brain is one of the most vulnerable organs inside the human body. Head accidents often appear in daily life and are easy to cause different level of brain damage inside the skull. Once the brain suffered intense locomotive impact, external injuries, falls, or other accidents, it will result in different degrees of concussion. This study employs finite element analysis to compare the dynamic characteristics between the geometric models of an assumed simple brain tissue and a brain tissue with complex cerebral sulci. It is aimed to understand the free vibration of the internal brain tissue and then to protect the brain from injury caused by external influences. Reverse engineering method is used for a Classic 5-Part Brain (C18) model produced by 3B Scientific Corporation. 3D optical scanner is employed to scan the human brain structure model with complex cerebral sulci and imported into 3D graphics software to construct a solid brain model to simulate the real complex brain tissue. Obtaining the normal mode analysis by inputting the material properties of the true human brain into finite element analysis software, and then to compare the simplified and the complex of brain models.

  4. Insights into human brain: Vitamin A in neuropsychiatry and ophtalmology

    OpenAIRE

    Dragan M. Pavlović; Pavlović, Aleksandra; Totić-Poznanović, Sanja; Božić, Marija M.; Đorđević, Jelena R.

    2013-01-01

    Vitamin A is a liposoluble vitamin essential for brain function and vision, and is obtained only through food as retinol or as carotenoids. The active metabolite is retinoic acid (RA), which participates in cognitive processes in the hippocampus, particularly in learning and spatial functions as well as in neurogenesis. Retinoic acid is essential for the vision and the maintenance of the cornea, biological rhythms, mucosa defense against infections and regulation of many genes (one sixth of t...

  5. Advances in electronic-nose technologies for the detection of volatile biomarker metabolites in the human breath

    Science.gov (United States)

    Alphus D. Wilson

    2015-01-01

    Recent advancements in the use of electronic-nose (e-nose) devices to analyze human breath profiles for the presence of specific volatile metabolites, known as biomarkers or chemical bio-indicators of specific human diseases, metabolic disorders and the overall health status of individuals, are providing the potential for new noninvasive tools and techniques useful to...

  6. Identification and quantification of metabolites of the fungicide tebuconazole in human urine.

    Science.gov (United States)

    Mercadante, R; Polledri, E; Scurati, S; Moretto, A; Fustinoni, S

    2014-11-17

    Tebuconazole (TEB) is a fungicide used in agriculture; the objective of this work was to identify and quantify TEB metabolites in human urine. Samples from seven vineyard workers exposed to TEB were submitted to liquid chromatography interfaced with a triple quadrupole mass spectrometer, equipped with an electron spray source, and a linear ion trap to gain a profile of candidate metabolites. Based on the presence of the ion m/z 70 in the MS/MS spectra, which corresponds to protonated triazole (a specific moiety of TEB), and the isotopic pattern of the molecular ions, typical of molecules with one chlorine atom, hydroxyl and carboxyl derivatives of TEB, that is, TEB-OH and TEB-COOH, were identified as major metabolites, both as free molecules and as glucuronide (Glc) conjugates. The mean molar fractions were 0.67, 0.13, 0.13, and 0.07 for TEB-O-Glc, TEB-OH, TEB-COO-Glc, and TEB-COOH. Urine samples were submitted to hydrolysis with β-glucuronidase, and the free compounds were quantified in the presence of deuterated TEB (TEB-d6) as the internal standard (IS), by multiple reaction monitoring (MRM) mode. The assay was linear in the ranges of 0.2-600 μg/L and 0.1-240 μg/L for TEB-OH and TEB-COOH, respectively; precision, accuracy, and the limit of quantification (LOQ) were <3.1%, 98-103%, and 0.3 μg/L for both analytes. An evaluation of matrix effects showed that the use of TEB-d6 controlled these sources of bias. The urinary levels of TEB-OH and TEB-COOH in specimens collected from farmers exposed to TEB ranged from 10 to 473 and from 3 to 159 μg/L, respectively.

  7. Cristobalite and Hematite Particles in Human Brain.

    Science.gov (United States)

    Kopani, Martin; Kopaniova, A; Trnka, M; Caplovicova, M; Rychly, B; Jakubovsky, J

    2016-11-01

    Foreign substances get into the internal environment of living bodies and accumulate in various organs. Cristobalite and hematite particles in the glial cells of pons cerebri of human brain with diagnosis of Behhet disease with scanning electron microscopy (SEM), energy-dispersive microanalysis (EDX), and transmission electron microscopy (TEM) with diffraction were identified. SEM with EDX revealed the matter of irregular micrometer-sized particles sometimes forming polyhedrons with fibrilar or stratified structure. It was found in some particles Ti, Fe, and Zn. Some particles contained Cu. TEM and electron diffraction showed particles of cristobalite and hematite. The presence of the particles can be a result of environmental effect, disruption of normal metabolism, and transformation of physiologically iron-ferrihydrite into more stable form-hematite. From the size of particles can be drawn the long-term accumulation of elements in glial cells.

  8. Changes in cognitive state alter human functional brain networks

    Directory of Open Access Journals (Sweden)

    Malaak Nasser Moussa

    2011-08-01

    Full Text Available The study of the brain as a whole system can be accomplished using network theory principles. Research has shown that human functional brain networks during a resting state exhibit small-world properties and high degree nodes, or hubs, localized to brain areas consistent with the default mode network (DMN. However, the study of brain networks across different tasks and or cognitive states has been inconclusive. Research in this field is important because the underpinnings of behavioral output are inherently dependent on whether or not brain networks are dynamic. This is the first comprehensive study to evaluate multiple network metrics at a voxel-wise resolution in the human brain at both the whole brain and regional level under various conditions: resting state, visual stimulation, and multisensory (auditory and visual stimulation. Our results show that despite global network stability, functional brain networks exhibit considerable task-induced changes in connectivity, efficiency, and community structure at the regional level.

  9. Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain.

    Science.gov (United States)

    Luo, Chongyuan; Lancaster, Madeline A; Castanon, Rosa; Nery, Joseph R; Knoblich, Juergen A; Ecker, Joseph R

    2016-12-20

    Organoids derived from human pluripotent stem cells recapitulate the early three-dimensional organization of the human brain, but whether they establish the epigenomic and transcriptional programs essential for brain development is unknown. We compared epigenomic and regulatory features in cerebral organoids and human fetal brain, using genome-wide, base resolution DNA methylome and transcriptome sequencing. Transcriptomic dynamics in organoids faithfully modeled gene expression trajectories in early-to-mid human fetal brains. We found that early non-CG methylation accumulation at super-enhancers in both fetal brain and organoids marks forthcoming transcriptional repression in the fully developed brain. Demethylated regions (74% of 35,627) identified during organoid differentiation overlapped with fetal brain regulatory elements. Interestingly, pericentromeric repeats showed widespread demethylation in multiple types of in vitro human neural differentiation models but not in fetal brain. Our study reveals that organoids recapitulate many epigenomic features of mid-fetal human brain and also identified novel non-CG methylation signatures of brain development. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain

    Directory of Open Access Journals (Sweden)

    Chongyuan Luo

    2016-12-01

    Full Text Available Organoids derived from human pluripotent stem cells recapitulate the early three-dimensional organization of the human brain, but whether they establish the epigenomic and transcriptional programs essential for brain development is unknown. We compared epigenomic and regulatory features in cerebral organoids and human fetal brain, using genome-wide, base resolution DNA methylome and transcriptome sequencing. Transcriptomic dynamics in organoids faithfully modeled gene expression trajectories in early-to-mid human fetal brains. We found that early non-CG methylation accumulation at super-enhancers in both fetal brain and organoids marks forthcoming transcriptional repression in the fully developed brain. Demethylated regions (74% of 35,627 identified during organoid differentiation overlapped with fetal brain regulatory elements. Interestingly, pericentromeric repeats showed widespread demethylation in multiple types of in vitro human neural differentiation models but not in fetal brain. Our study reveals that organoids recapitulate many epigenomic features of mid-fetal human brain and also identified novel non-CG methylation signatures of brain development.

  11. "Messing with the Mind: Evolutionary Challenges to Human Brain Augmentation

    Directory of Open Access Journals (Sweden)

    ARTHUR eSANIOTIS

    2014-09-01

    Full Text Available The issue of brain augmentation has received considerable scientific attention over the last two decades. A key factor to brain augmentation that has been widely overlooked are the complex evolutionary processes which have taken place in evolving the human brain to its current state of functioning. Like other bodily organs, the human brain has been subject to the forces of biological adaptation. The structure and function of the brain, is very complex and only now we are beginning to understand some of the basic concepts of cognition. Therefore, this article proposes that brain-machine interfacing and nootropics are not going to produce augmented brains because we do not understand enough about how evolutionary pressures have informed the neural networks which support human cognitive faculties.

  12. Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

    Energy Technology Data Exchange (ETDEWEB)

    Ferramosca, Alessandra, E-mail: alessandra.ferramosca@unisalento.it [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Conte, Annalea; Guerra, Flora; Felline, Serena [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Rimoli, Maria Grazia [Dipartimento di Farmacia, Università di Napoli Federico II, Napoli (Italy); Mollo, Ernesto [Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli (Italy); Zara, Vincenzo [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Terlizzi, Antonio [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Stazione Zoologica Anton Dohrn, Napoli (Italy)

    2016-05-13

    The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic and spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.

  13. Citrus fruits as a treasure trove of active natural metabolites that potentially provide benefits for human health.

    Science.gov (United States)

    Lv, Xinmiao; Zhao, Siyu; Ning, Zhangchi; Zeng, Honglian; Shu, Yisong; Tao, Ou; Xiao, Cheng; Lu, Cheng; Liu, Yuanyan

    2015-01-01

    Citrus fruits, which are cultivated worldwide, have been recognized as some of the most high-consumption fruits in terms of energy, nutrients and health supplements. What is more, a number of these fruits have been used as traditional medicinal herbs to cure diseases in several Asian countries. Numerous studies have focused on Citrus secondary metabolites as well as bioactivities and have been intended to develop new chemotherapeutic or complementary medicine in recent decades. Citrus-derived secondary metabolites, including flavonoids, alkaloids, limonoids, coumarins, carotenoids, phenolic acids and essential oils, are of vital importance to human health due to their active properties. These characteristics include anti-oxidative, anti-inflammatory, anti-cancer, as well as cardiovascular protective effects, neuroprotective effects, etc. This review summarizes the global distribution and taxonomy, numerous secondary metabolites and bioactivities of Citrus fruits to provide a reference for further study. Flavonoids as characteristic bioactive metabolites in Citrus fruits are mainly introduced.

  14. Analysis of metabolites of organophosphate and pyrethroid pesticides in human urine from urban and agricultural populations (Catalonia and Galicia).

    Science.gov (United States)

    Garí, Mercè; González-Quinteiro, Yolanda; Bravo, Natalia; Grimalt, Joan O

    2018-05-01

    Isotope dilution solid phase extraction UPLC-MS/MS has been used to develop a robust and rapid methodology for the determination of eight specific metabolites of organophosphate and pyrethroid pesticides in human urine. The use of methanol:acetone (25:75v/v) affords an improvement in extraction efficiency in comparison to these individual solvents. The use of synthetic urine improves selectivity and limits of detection for the calibration straight lines. The method provides detection limits of 14-69pg/ml and 18-19pg/ml for the organophosphate and pyrethroid metabolites, respectively. Urine analyses of these metabolites in urban non-occupationally exposed individuals and farm workers shows that ingestion of these pesticides occurred in both populations. The concentrations of organophosphate pesticide metabolites in the latter were twofold than those from non-exposed populations. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA.

    Science.gov (United States)

    Wei, Yin; Lin, Yuan; Zhang, Ai-Qian; Guo, Liang-Hong; Cao, Jie

    2010-11-15

    The binding of reactive polycyclic aromatic hydrocarbon (PAH) metabolites, formed enzymatically, to DNA is a crucial step in PAH carcinogenesis in vivo. We investigated the noncovalent binding interactions between 11 PAH metabolites and human p53 complementary DNA (p53 cDNA) using the fluorescence displacement method and molecular docking analysis. All of the examined metabolites predominantly interacted with p53 cDNA by intercalation instead of groove binding. The dissociation constants ranged from 0.02 to 12.34μM. Of the metabolites tested, 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene showed the strongest binding affinities to DNA, while 2-naphthol was the weakest DNA intercalator. The intercalation of the metabolites was stabilized by stacking the PAH phenyl rings with the DNA base pairs and the formation of hydrogen bonds between the oxide or hydroxyl groups on the metabolites, and DNA bases or backbones. The binding of the metabolites to DNA showed some sequence selectivity. The binding affinities and hydrogen bonds for 3-hydroxybenzo[a]pyrene, benzo[a]pyrene-4,5-dihydroepoxide (BPE) and benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) differed. It seems that the functional groups on the periphery of the PAH aromatic ring play crucial roles in regulating its binding affinity with DNA. Although it was difficult to determine the correlation between DNA noncovalent binding affinity and carcinogenicity for some of the PAH metabolites, the present study improved our understanding of the formation of PAH metabolite-DNA adducts. Copyright © 2010 Elsevier B.V. All rights reserved.

  16. From reverse transcription to human brain tumors

    Directory of Open Access Journals (Sweden)

    Dmitrenko V. V.

    2013-05-01

    Full Text Available Reverse transcriptase from avian myeloblastosis virus (AMV was the subject of the study, from which the investi- gations of the Department of biosynthesis of nucleic acids were started. Production of AMV in grams quantities and isolation of AMV reverse transcriptase were established in the laboratory during the seventies of the past cen- tury and this initiated research on the cDNA synthesis, cloning and investigation of the structure and functions of the eukaryotic genes. Structures of salmon insulin and insulin-like growth factor (IGF family genes and their transcripts were determined during long-term investigations. Results of two modern techniques, microarray-ba- sed hybridization and SAGE, were used for the identification of the genes differentially expressed in astrocytic gliomas and human normal brain. Comparison of SAGE results on the genes overexpressed in glioblastoma with the results of microarray analysis revealed a limited number of common genes. 105 differentially expressed genes, common to both methods, can be included in the list of candidates for the molecular typing of glioblastoma. The first experiments on the classification of glioblastomas based on the data of the 20 genes expression were conducted by using of artificial neural network analysis. The results of these experiments showed that the expression profiles of these genes in 224 glioblastoma samples and 74 normal brain samples could be according to the Koho- nen’s maps. The CHI3L1 and CHI3L2 genes of chitinase-like cartilage protein were revealed among the most overexpressed genes in glioblastoma, which could have prognostic and diagnostic potential. Results of in vitro experiments demonstrated that both proteins, CHI3L1 and CHI3L2, may initiate the phosphorylation of ERK1/ ERK2 and AKT kinases leading to the activation of MAPK/ERK1/2 and PI3K/AKT signaling cascades in human embryonic kidney 293 cells, human glioblastoma U87MG, and U373 cells. The new human cell line

  17. Multifaceted impact of trichothecene metabolites on plant-microbe interactions and human health.

    Science.gov (United States)

    Kumari, Indu; Ahmed, Mushtaq; Akhter, Yusuf

    2016-07-01

    Fungi present in rhizosphere produce trichothecene metabolites which are small in size and amphipathic in nature and some of them may cross cell membranes passively. Hypocreaceae family of rhizosphere fungi produce trichothecene molecules, however it is not a mandatory characteristic of all genera. Some of these molecules are also reported as growth adjuvant, while others are reported as deleterious for the plant growth. In this review, we are exploring the roles of these compounds during plant-microbe interactions. The three-way interaction among the plants, symbiotic microbial agents (fungi and bacteria), and the pathogenic microbes (bacteria, fungi) or multicellular pathogens like nematodes involving these compounds may only help us to understand better the complex processes happening in the microcosm of rhizosphere. These metabolites may further modulate the activity of different proteins involved in the cell signalling events of defence-related response in plants. That may induce the defence system against pathogens and growth promoting gene expression in plants, while in animal cells, these molecules have reported biochemical and pharmacological effects such as inducing oxidative stress, cell-cycle arrest and apoptosis, and may be involved in maintenance of membrane integrity. The biochemistry, chemical structures and specific functional group-mediated activity of these compounds have not been studied in details yet. Few of these molecules are also recently reported as novel anti-cancer agent against human chondrosarcoma cells.

  18. Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution.

    Science.gov (United States)

    Cunnane, Stephen C; Crawford, Michael A

    2014-12-01

    The human brain confronts two major challenges during its development: (i) meeting a very high energy requirement, and (ii) reliably accessing an adequate dietary source of specific brain selective nutrients needed for its structure and function. Implicitly, these energetic and nutritional constraints to normal brain development today would also have been constraints on human brain evolution. The energetic constraint was solved in large measure by the evolution in hominins of a unique and significant layer of body fat on the fetus starting during the third trimester of gestation. By providing fatty acids for ketone production that are needed as brain fuel, this fat layer supports the brain's high energy needs well into childhood. This fat layer also contains an important reserve of the brain selective omega-3 fatty acid, docosahexaenoic acid (DHA), not available in other primates. Foremost amongst the brain selective minerals are iodine and iron, with zinc, copper and selenium also being important. A shore-based diet, i.e., fish, molluscs, crustaceans, frogs, bird's eggs and aquatic plants, provides the richest known dietary sources of brain selective nutrients. Regular access to these foods by the early hominin lineage that evolved into humans would therefore have helped free the nutritional constraint on primate brain development and function. Inadequate dietary supply of brain selective nutrients still has a deleterious impact on human brain development on a global scale today, demonstrating the brain's ongoing vulnerability. The core of the shore-based paradigm of human brain evolution proposes that sustained access by certain groups of early Homo to freshwater and marine food resources would have helped surmount both the nutritional as well as the energetic constraints on mammalian brain development. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Lipidomics of human brain aging and Alzheimer's disease pathology.

    Science.gov (United States)

    Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

    2015-01-01

    Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

  20. Quantitative multivoxel proton MR spectroscopy study of brain metabolites in patients with amnestic mild cognitive impairment: a pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Zhong-Xian; Cheng, Xiao-Fang; Xu, Zhi-Feng; Cao, Zhen; Xiao, Ye-Yu; You, Ke-Zeng; Liu, Yan-Yan [Medical College of Shantou University, Department of Medical Imaging, The Second Affiliated Hospital, Shantou (China); Huo, Shan-Shan [Science College of Shantou University, Department of Physics, Shantou (China); Zeng, Jie-Xia; Chen, Wei [Medical College of Shantou University, Department of Neurology, The Second Affiliated Hospital, Shantou (China); Wu, Ren-Hua [Medical College of Shantou University, Department of Medical Imaging, The Second Affiliated Hospital, Shantou (China); Medical College of Shantou University, Provincial Key Laboratory of Medical Molecular Imaging, Guangdong, Shantou (China)

    2012-05-15

    The purpose of this study is to investigate brain metabolic changes in patients with amnestic mild cognitive impairment (aMCI) using multivoxel proton MR spectroscopy ({sup 1}H-MVS). Fourteen aMCI patients and fifteen healthy control subjects participated in this experiment. All MR measurements were acquired using a 1.5-T GE scanner. {sup 1}H-MVS point resolved spectroscopy (2D PROBE-CSI PRESS) pulse sequence (TE = 35 ms; TR = 1,500 ms; phase x frequency, 18 x 18) was used for acquiring MRS data. All data were post-processed using Spectroscopy Analysis by General Electric software and linear combination of model (LCModel). The absolute concentrations of N-acetylaspartate (NAA), choline (Cho), myoinositol (MI), creatine (Cr), and the metabolite ratios of NAA/Cr, Cho/Cr, MI/Cr, and NAA/MI were measured bilaterally in the posterior cingulate gyrus (PCG), inferior precuneus (Pr), paratrigonal white matter (PWM), dorsal thalamus (DT), and lentiform nucleus (LN). Patients with aMCI displayed significantly lower NAA levels in the bilateral PCG (p < 0.01), PWM (p < 0.05), and left inferior Pr (p < 0.05). The metabolite ratio of NAA/MI was decreased in the bilateral PCG (p < 0.01) and PWM (p < 0.05) and in the left DT (p < 0.01). NAA/Cr was decreased in the left PCG (p < 0.01), DT (p < 0.05), right PWM (p < 0.05), and LN (p < 0.05). However, MI/Cr was elevated in the right PCG (p < 0.01) and left PWM (p < 0.05). Significantly increased Cho level was also evident in the left PWM (p < 0.05). Our observations of decreased NAA, NAA/Cr, and NAA/MI, in parallel with increased Cho and MI/Cr might be characteristic of aMCI patients. (orig.)

  1. Evolutionary origins of human brain and spirituality.

    Science.gov (United States)

    Henneberg, Maciej; Saniotis, Arthur

    2009-12-01

    Evolving brains produce minds. Minds operate on imaginary entities. Thus they can create what does not exist in the physical world. Spirits can be deified. Perception of spiritual entities is emotional--organic. Spirituality is a part of culture while culture is an adaptive mechanism of human groups as it allows for technology and social organization to support survival and reproduction. Humans are not rational, they are emotional. Most of explanations of the world, offered by various cultures, involve an element of "fiat", a will of a higher spiritual being, or a reference to some ideal. From this the rules of behaviour are deduced. These rules are necessary to maintain social peace and allow a complex unit consisting of individuals of both sexes and all ages to function in a way ensuring their reproductive success and thus survival. There is thus a direct biological benefit of complex ideological superstructure of culture. This complex superstructure most often takes a form of religion in which logic is mixed with appeals to emotions based on images of spiritual beings. God is a consequence of natural evolution. Whether a deity is a cause of this evolution is difficult to discover, but existence of a deity cannot be questioned.

  2. Brain metabolite changes in alcoholism: Localized proton magnetic resonance spectroscopy study of the occipital lobe

    Energy Technology Data Exchange (ETDEWEB)

    Modi, Shilpi; Bhattacharya, Manisha; Kumar, Pawan [NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (DRDO), Lucknow Road, Timarpur, Delhi 110054 (India); Deshpande, Smita N. [Department of Psychiatry, Dr. Ram Manohar Lohia Hospital, New Delhi (India); Tripathi, Rajendra Prasad [NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (DRDO), Lucknow Road, Timarpur, Delhi 110054 (India); Khushu, Subash, E-mail: skhushu@yahoo.com [NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (DRDO), Lucknow Road, Timarpur, Delhi 110054 (India)

    2011-07-15

    Chronic alcoholism is associated with altered brain metabolism, morphology and cognitive abilities. Besides deficits in higher order cognitive functions, alcoholics also show a deficit in the processing of basic sensory information viz. visual stimulation. To assess the metabolic changes associated with this deficit, {sup 1}H MRS was carried out in the occipital lobe of alcohol dependents. A significant increase in Cho/Cr ratio (p < 0.015) was observed in occipital lobe in the alcoholic group indicating altered cell membrane metabolism, which may probably be associated with the alterations in the cognitive abilities associated with vision.

  3. Macroscopic networks in the human brain: mapping connectivity in healthy and damaged brains

    NARCIS (Netherlands)

    Nijhuis, E.H.J.

    2013-01-01

    The human brain contains a network of interconnected neurons. Recent advances in functional and structural in-vivo magnetic resonance neuroimaging (MRI) techniques have provided opportunities to model the networks of the human brain on a macroscopic scale. This dissertation investigates the

  4. Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain.

    Science.gov (United States)

    Brzezinski, M R; Boutelet-Bochan, H; Person, R E; Fantel, A G; Juchau, M R

    1999-06-01

    Cytochrome P-450 2E1 (CYP2E1) is a readily inducible hemoprotein that catalyzes the oxidation of endogenous compounds and many low molecular weight xenobiotics. As the major component of the microsomal ethanol oxidizing system, it contributes significantly to ethanol metabolism and the formation of the highly reactive metabolite acetaldehyde. The leaky property of this enzyme results in the generation of reactive oxygen species that can induce oxidative stress and cytotoxic conditions deleterious to development. To further investigate the proposed role of CYP2E1 in the etiology of alcohol teratogenesis, the current study focused on the quantification of CYP2E1 in prenatal human brain, a tissue that is highly vulnerable to the damaging effects of ethanol throughout gestation. In microsomal samples prepared from pools of brain tissues, immunoreactive protein was detected by Western blot analysis using enhanced chemiluminescence, whereas functional protein was estimated with an enzymatic assay using p-nitrophenol and an electrochemical detection system. CYP2E1 transcript was consistently detected in RNA samples prepared from individual brain tissues using the ribonuclease protection assay. Quantitative data were collected by scanning densitometry and phosphorimaging technology. There was a dramatic increase in human brain CYP2E1 content around gestational day 50 and a fairly constant level was maintained throughout the early fetal period, until at least day 113. The relatively low levels of the P-450 isoform present in conceptal brain may be sufficient to generate reactive intermediates that elicit neuroembryotoxicity following maternal alcohol consumption.

  5. Characterisation of the Metabolites of 1,8-Cineole Transferred into Human Milk: Concentrations and Ratio of Enantiomers

    Science.gov (United States)

    Kirsch, Frauke; Buettner, Andrea

    2013-01-01

    1,8-Cineole is a widely distributed odorant that also shows physiological effects, but whose human metabolism has hitherto not been extensively investigated. The aim of the present study was, thus, to characterise the metabolites of 1,8-cineole, identified previously in human milk, after the oral intake of 100 mg of this substance. Special emphasis was placed on the enantiomeric composition of the metabolites since these data may provide important insights into potential biotransformation pathways, as well as potential biological activities of these substances, for example on the breastfed child. The volatile fraction of the human milk samples was therefore isolated via Solvent Assisted Flavour Evaporation (SAFE) and subjected to gas chromatography-mass spectrometry (GC-MS). The absolute concentrations of each metabolite were determined by matrix calibration with an internal standard, and the ratios of enantiomers were analysed on chiral capillaries. The concentrations varied over a broad range, from traces in the upper ng/kg region up to 40 µg/kg milk, with the exception of the main metabolite α2-hydroxy-1,8-cineole that showed concentrations of 100–250 µg/kg. Also, large inter- and intra-individual variations were recorded for the enantiomers, with nearly enantiomerically pure α2-hydroxy- and 3-oxo-1,8-cineole, while all other metabolites showed ratios of ~30:70 to 80:20. PMID:24957890

  6. MR spectroscopy-based brain metabolite profiling in propionic acidaemia: metabolic changes in the basal ganglia during acute decompensation and effect of liver transplantation

    Directory of Open Access Journals (Sweden)

    McKiernan Patrick J

    2011-05-01

    Full Text Available Abstract Background Propionic acidaemia (PA results from deficiency of Propionyl CoA carboxylase, the commonest form presenting in the neonatal period. Despite best current management, PA is associated with severe neurological sequelae, in particular movement disorders resulting from basal ganglia infarction, although the pathogenesis remains poorly understood. The role of liver transplantation remains controversial but may confer some neuro-protection. The present study utilises quantitative magnetic resonance spectroscopy (MRS to investigate brain metabolite alterations in propionic acidaemia during metabolic stability and acute encephalopathic episodes. Methods Quantitative MRS was used to evaluate brain metabolites in eight children with neonatal onset propionic acidaemia, with six elective studies acquired during metabolic stability and five studies during acute encephalopathic episodes. MRS studies were acquired concurrently with clinically indicated MR imaging studies at 1.5 Tesla. LCModel software was used to provide metabolite quantification. Comparison was made with a dataset of MRS metabolite concentrations from a cohort of children with normal appearing MR imaging. Results MRI findings confirm the vulnerability of basal ganglia to infarction during acute encephalopathy. We identified statistically significant decreases in basal ganglia glutamate+glutamine and N-Acetylaspartate, and increase in lactate, during encephalopathic episodes. In white matter lactate was significantly elevated but other metabolites not significantly altered. Metabolite data from two children who had received liver transplantation were not significantly different from the comparator group. Conclusions The metabolite alterations seen in propionic acidaemia in the basal ganglia during acute encephalopathy reflect loss of viable neurons, and a switch to anaerobic respiration. The decrease in glutamine + glutamate supports the hypothesis that they are consumed to

  7. Characterization of the radiolabeled metabolite of tau PET tracer {sup 18}F-THK5351

    Energy Technology Data Exchange (ETDEWEB)

    Harada, Ryuichi [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Furumoto, Shozo; Tago, Tetsuro; Iwata, Ren; Tashiro, Manabu [Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Katsutoshi, Furukawa; Ishiki, Aiko; Tomita, Naoki; Arai, Hiroyuki [Tohoku University, Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Sendai (Japan); Yanai, Kazuhiko [Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Okamura, Nobuyuki [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University, Cyclotron and Radioisotope Center, Sendai (Japan); Tohoku Medical and Pharmaceutical University, Division of Pharmacology, Faculty of Medicine, Sendai (Japan)

    2016-11-15

    {sup 18}F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of {sup 18}F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties. Venous blood samples were collected from three human subjects after injection of {sup 18}F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood-brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples. About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of {sup 18}F-THK5351. The isolated radiometabolite of {sup 18}F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood-brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples. These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images. (orig.)

  8. Transient Changes in Brain Metabolites after Transcranial Direct Current Stimulation in Spastic Cerebral Palsy: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Paradee Auvichayapat

    2017-07-01

    Full Text Available BackgroundMuscle spasticity is a disability caused by damage to the pyramidal system. Standard treatments for spasticity include muscle stretching, antispastic medications, and tendon release surgeries, but treatment outcomes remain unsatisfactory. Anodal transcranial direct current stimulation (tDCS in patients with muscle spasticity is known to result in significant improvement in spastic tone (p < 0.001. However, the mechanism of action by which tDCS treatment affects spasticity remains unclear. This pilot study aimed to investigate the effect of anodal tDCS upon brain metabolites in the left basal ganglia and ipsilateral primary motor cortex (M1 in children with spastic cerebral palsy (CP.Materials and methodsThis study consisted of three steps: a baseline evaluation, a treatment period, and a follow-up period. During the treatment period, patients were given 20 min of 1 mA anodal tDCS over the left M1 for five consecutive days. Outcomes were compared between pre- and immediate posttreatment in terms of brain metabolites, Tardieu scales, and the quality of upper extremity skills test.ResultsTen patients with spastic CP were enrolled. Following tDCS, there were significant increases in the ratio of N-acetylaspartate (NAA/creatine (Cr (p = 0.030, choline (Cho/Cr (p = 0.043, and myoinositol (mI/Cr (p = 0.035 in the basal ganglia. Moreover, increased glutamine–glutamate (Glx/Cr ratio in the left M1 (p = 0.008 was found. In addition, we also observed improvements in the extent of spasticity and hand function (p = 0.028.ConclusionFive consecutive days of anodal tDCS over the left M1 appeared statistically to reduce the degree of spasticity and increase NAA, Cho, mI, and Glx. Future research studies, involving a larger sample size of spastic CP patients undergoing tDCS is now warranted.

  9. Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans

    Science.gov (United States)

    Orrú, Marco; Guitart, Xavier; Karcz-Kubicha, Marzena; Solinas, Marcello; Justinova, Zuzana; Barodia, Sandeep Kumar; Zanoveli, Janaina; Cortes, Antoni; Lluis, Carme; Casado, Vicent; Moeller, F. Gerard; Ferré, Sergi

    2013-01-01

    Caffeine induces locomotor activation by its ability to block adenosine receptors. Caffeine is metabolized to several methylxanthines, with paraxanthine being the main metabolite in humans. In this study we show that in rats paraxanthine has a stronger locomotor activating effect than caffeine or the two other main metabolites of caffeine, theophylline and theobromine. As previously described for caffeine, the locomotor activating doses of paraxanthine more efficiently counteract the locomotor depressant effects of an adenosine A1 than an adenosine A2A receptor agonist. In drug discrimination experiments in rats trained to discriminate a maximal locomotor activating dose of caffeine, paraxanthine, unlike theophylline, generalized poorly to caffeine suggesting the existence of additional mechanisms other than adenosine antagonism in the behavioral effects of paraxanthine. Pretreatment with the nitric oxide inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) reduced the locomotor activating effects of paraxanthine, but not caffeine. On the other hand, pretreatment with the selective cGMP-preferring phosphodiesterase PDE9 inhibitor BAY 73-6691, increased locomotor activity induced by caffeine, but not paraxanthine. Ex vivo experiments demonstrated that paraxanthine, but not caffeine, can induce cGMP accumulation in the rat striatum. Finally, in vivo microdialysis experiments showed that paraxanthine, but not caffeine, significantly increases extracellular levels of dopamine in the dorsolateral striatum, which was blocked by L-NAME. These findings indicate that inhibition of cGMP-preferring PDE is involved in the locomotor activating effects of the acute administration of paraxanthine. The present results demonstrate a unique psychostimulant profile of paraxanthine, which might contribute to the reinforcing effects of caffeine in humans. PMID:23261866

  10. A Culture-Behavior-Brain Loop Model of Human Development.

    Science.gov (United States)

    Han, Shihui; Ma, Yina

    2015-11-01

    Increasing evidence suggests that cultural influences on brain activity are associated with multiple cognitive and affective processes. These findings prompt an integrative framework to account for dynamic interactions between culture, behavior, and the brain. We put forward a culture-behavior-brain (CBB) loop model of human development that proposes that culture shapes the brain by contextualizing behavior, and the brain fits and modifies culture via behavioral influences. Genes provide a fundamental basis for, and interact with, the CBB loop at both individual and population levels. The CBB loop model advances our understanding of the dynamic relationships between culture, behavior, and the brain, which are crucial for human phylogeny and ontogeny. Future brain changes due to cultural influences are discussed based on the CBB loop model. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Region-specific effects on brain metabolites of hypoxia and hyperoxia overlaid on cerebral ischemia in young and old rats: a quantitative proton magnetic resonance spectroscopy study

    Directory of Open Access Journals (Sweden)

    Giuliani Patricia

    2010-02-01

    Full Text Available Abstract Background Both hypoxia and hyperoxia, deregulating the oxidative balance, may play a role in the pathology of neurodegenerative disorders underlain by cerebral ischemia. In the present study, quantitative proton magnetic resonance spectroscopy was used to evaluate regional metabolic alterations, following a 24-hour hypoxic or hyperoxic exposure on the background of ischemic brain insult, in two contrasting age-groups of rats: young - 3 months old and aged - 24 months old. Methods Cerebral ischemia was induced by ligation of the right common carotid artery. Concentrations of eight metabolites (alanine, choline-containing compounds, total creatine, γ-aminobutyric acid, glutamate, lactate, myo-inositol and N-acetylaspartate were quantified from extracts in three different brain regions (fronto-parietal and occipital cortices and the hippocampus from both hemispheres. Results In the control normoxic condition, there were significant increases in lactate and myo-inositol concentrations in the hippocampus of the aged rats, compared with the respective values in the young ones. In the ischemia-hypoxia condition, the most prevalent changes in the brain metabolites were found in the hippocampal regions of both young and aged rats; but the effects were more evident in the aged animals. The ischemia-hyperoxia procedure caused less dedicated changes in the brain metabolites, which may reflect more limited tissue damage. Conclusions We conclude that the hippocampus turns out to be particularly susceptible to hypoxia overlaid on cerebral ischemia and that old age further increases this susceptibility.

  12. The prognostic value of multivoxel magnetic resonance spectroscopy determined metabolite levels in white and grey matter brain tissue for adverse outcome in term newborns following perinatal asphyxia

    Energy Technology Data Exchange (ETDEWEB)

    Doormaal, Pieter Jan van [University Medical Center Groningen and University of Groningen, Department of Pediatrics, Division of Neonatology, Groningen (Netherlands); Meander Medical Center Amersfoort, Department of Radiology, PO Box 1502, Amersfoort (Netherlands); Meiners, Linda C.; Sijens, Paul E. [University Medical Center Groningen and University of Groningen, Department of Radiology, Groningen (Netherlands); Horst, Hendrik J. ter; Veere, Christa N. van der [University Medical Center Groningen and University of Groningen, Department of Pediatrics, Division of Neonatology, Groningen (Netherlands)

    2012-04-15

    Magnetic resonance spectroscopy can identify brain metabolic changes in perinatal asphyxia by providing ratios of metabolites, such as choline (Cho), creatine (Cr), N-acetyl aspartate (NAA) and lactate (Lact) [Cho/Cr, Lact/NAA, etc.]. The purpose of this study was to quantify the separate white and grey matter metabolites in a slab cranial to the ventricles and relate these to the outcome. A standard 2D-chemical shift imaging protocol was used for measuring a transverse volume of interest located cranial to the ventricles allowing for direct comparison of the metabolites in white and grey matter brain tissue in 24 term asphyxiated newborns aged 3 to 16 days. Cho, NAA and Lact showed significant differences between four subgroups of asphyxiated infants with more and less favourable outcomes. High levels of Cho and Lact in the grey matter differentiated non-survivors from survivors (P = 0.003 and P = 0.017, respectively). In perinatal asphyxia the levels of Cho, NAA and Lact in both white and grey matter brain tissue are affected. The levels of Cho and Lact measured in the grey matter are the most indicative of survival. It is therefore advised to include grey matter brain tissue in the region of interest examined by multivoxel MR spectroscopy. (orig.)

  13. Measurement of caffeine and its three primary metabolites in human plasma by HPLC-ESI-MS/MS and clinical application.

    Science.gov (United States)

    Chen, Feng; Hu, Zhe-Yi; Parker, Robert B; Laizure, S Casey

    2017-06-01

    Caffeine is a mild stimulant with significant potential for abuse, being consumed in larger doses with the widespread availability of energy drinks and by novel routes of administration such as inspired powder, oral sprays and electronic cigarettes. How these recent changes in caffeine consumption affecting caffeine disposition and abuse potential is of growing concern. In the study of caffeine disposition in humans, it is common to only measure the caffeine concentration; however, caffeine's three major metabolites (paraxanthine, theobromine and theophylline) retain central nervous system stimulant activity that may contribute to the overall pharmacological activity and toxicity. Therefore, it would be scientifically more rigorous to measure caffeine and its major metabolites in the evaluation of caffeine disposition in human subjects. Herein, we report a method for the simultaneous quantification of caffeine and its three major metabolites in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). Human plasma samples were treated by simple protein precipitation and the analytes were separated using a 6 min gradient program. Precision and accuracy were well within in the 15% acceptance range. The simple sample preparation, short runtime, sensitivity and the inclusion of caffeine's major metabolites make this assay methodology optimal for the study of caffeine's pharmacokinetics and pharmacodynamics in human subjects. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Metabolic costs and evolutionary implications of human brain development.

    Science.gov (United States)

    Kuzawa, Christopher W; Chugani, Harry T; Grossman, Lawrence I; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R; Wildman, Derek E; Sherwood, Chet C; Leonard, William R; Lange, Nicholas

    2014-09-09

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

  15. Determination of fluoxetine and its metabolite norfluoxetine in serum and brain areas using high-performance liquid chromatography with ultraviolet detection.

    Science.gov (United States)

    Alvarez, J C; Bothua, D; Collignon, I; Advenier, C; Spreux-Varoquaux, O

    1998-04-10

    A high-performance liquid chromatography (HPLC) method using only 0.1 ml of serum or homogenate from brain areas has been developed for the determination of fluoxetine (FLU) and its metabolite, norfluoxetine (N-FLU), with ultraviolet detection at 227 nm. The small volume of sample required in this method allows studies in small animals, such as mouse. The method provides recoveries of up to 90% for both compounds. Acceptable coefficients of variation were found for both within-run and day-to-day assays. The limit of detection was 5.0 ng/ml. No interferences were found with tricyclic antidepressant drugs and benzodiazepines, which allows this method to be used in clinical studies, Pharmacokinetic parameters for the two compounds are reported in mouse serum, frontal cortex and caudate nucleus. We also report the values of FLU and N-FLU in serum from humans who were treated once daily with 20 mg of FLU, obtained after 1, 14 and 28 days of treatment.

  16. Human brain networks function in connectome-specific harmonic waves.

    Science.gov (United States)

    Atasoy, Selen; Donnelly, Isaac; Pearson, Joel

    2016-01-21

    A key characteristic of human brain activity is coherent, spatially distributed oscillations forming behaviour-dependent brain networks. However, a fundamental principle underlying these networks remains unknown. Here we report that functional networks of the human brain are predicted by harmonic patterns, ubiquitous throughout nature, steered by the anatomy of the human cerebral cortex, the human connectome. We introduce a new technique extending the Fourier basis to the human connectome. In this new frequency-specific representation of cortical activity, that we call 'connectome harmonics', oscillatory networks of the human brain at rest match harmonic wave patterns of certain frequencies. We demonstrate a neural mechanism behind the self-organization of connectome harmonics with a continuous neural field model of excitatory-inhibitory interactions on the connectome. Remarkably, the critical relation between the neural field patterns and the delicate excitation-inhibition balance fits the neurophysiological changes observed during the loss and recovery of consciousness.

  17. The immune response of the human brain to abdominal surgery

    DEFF Research Database (Denmark)

    Forsberg, Anton; Cervenka, Simon; Jonsson Fagerlund, Malin

    2017-01-01

    OBJECTIVE: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans....... This study examines the short- and long-term impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. METHODS: Eight males undergoing prostatectomy under general...... to change in [(11) C]PBR28 binding (p = 0.027). INTERPRETATION: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may...

  18. Mapping human whole-brain structural networks with diffusion MRI.

    Directory of Open Access Journals (Sweden)

    Patric Hagmann

    Full Text Available Understanding the large-scale structural network formed by neurons is a major challenge in system neuroscience. A detailed connectivity map covering the entire brain would therefore be of great value. Based on diffusion MRI, we propose an efficient methodology to generate large, comprehensive and individual white matter connectional datasets of the living or dead, human or animal brain. This non-invasive tool enables us to study the basic and potentially complex network properties of the entire brain. For two human subjects we find that their individual brain networks have an exponential node degree distribution and that their global organization is in the form of a small world.

  19. From Brain-Environment Connections to Temporal Dynamics and Social Interaction: Principles of Human Brain Function.

    Science.gov (United States)

    Hari, Riitta

    2017-06-07

    Experimental data about brain function accumulate faster than does our understanding of how the brain works. To tackle some general principles at the grain level of behavior, I start from the omnipresent brain-environment connection that forces regularities of the physical world to shape the brain. Based on top-down processing, added by sparse sensory information, people are able to form individual "caricature worlds," which are similar enough to be shared among other people and which allow quick and purposeful reactions to abrupt changes. Temporal dynamics and social interaction in natural environments serve as further essential organizing principles of human brain function. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Sex beyond the genitalia: The human brain mosaic.

    Science.gov (United States)

    Joel, Daphna; Berman, Zohar; Tavor, Ido; Wexler, Nadav; Gaber, Olga; Stein, Yaniv; Shefi, Nisan; Pool, Jared; Urchs, Sebastian; Margulies, Daniel S; Liem, Franziskus; Hänggi, Jürgen; Jäncke, Lutz; Assaf, Yaniv

    2015-12-15

    Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only "male" or only "female" features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the "maleness-femaleness" continuum are rare. Rather, most brains are comprised of unique "mosaics" of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain.

  1. Brain-Computer Interface Controlled Cyborg: Establishing a Functional Information Transfer Pathway from Human Brain to Cockroach Brain.

    Science.gov (United States)

    Li, Guangye; Zhang, Dingguo

    2016-01-01

    An all-chain-wireless brain-to-brain system (BTBS), which enabled motion control of a cyborg cockroach via human brain, was developed in this work. Steady-state visual evoked potential (SSVEP) based brain-computer interface (BCI) was used in this system for recognizing human motion intention and an optimization algorithm was proposed in SSVEP to improve online performance of the BCI. The cyborg cockroach was developed by surgically integrating a portable microstimulator that could generate invasive electrical nerve stimulation. Through Bluetooth communication, specific electrical pulse trains could be triggered from the microstimulator by BCI commands and were sent through the antenna nerve to stimulate the brain of cockroach. Serial experiments were designed and conducted to test overall performance of the BTBS with six human subjects and three cockroaches. The experimental results showed that the online classification accuracy of three-mode BCI increased from 72.86% to 78.56% by 5.70% using the optimization algorithm and the mean response accuracy of the cyborgs using this system reached 89.5%. Moreover, the results also showed that the cyborg could be navigated by the human brain to complete walking along an S-shape track with the success rate of about 20%, suggesting the proposed BTBS established a feasible functional information transfer pathway from the human brain to the cockroach brain.

  2. Toward discovery science of human brain function

    DEFF Research Database (Denmark)

    Biswal, Bharat B; Mennes, Maarten; Zuo, Xi-Nian

    2010-01-01

    Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints...... individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships...... in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/....

  3. Early-life exercise may promote lasting brain and metabolic health through gut bacterial metabolites.

    Science.gov (United States)

    Mika, Agnieszka; Fleshner, Monika

    2016-02-01

    The 100 trillion microorganisms residing within our intestines contribute roughly 5 million additional genes to our genetic gestalt, thus posing the potential to influence many aspects of our physiology. Microbial colonization of the gut shortly after birth is vital for the proper development of immune, neural and metabolic systems, while sustaining a balanced, diverse gut flora populated with beneficial bacteria is necessary for maintaining optimal function of these systems. Although symbiotic host-microbial interactions are important throughout the lifespan, these interactions can have greater and longer lasting impacts during certain critical developmental periods. A better understanding of these sensitive periods is necessary to improve the impact and effectiveness of health-promoting interventions that target the microbial ecosystem. We have recently reported that exercise initiated in early life increases gut bacterial species involved in promoting psychological and metabolic health. In this review, we emphasize the ability of exercise during this developmentally receptive time to promote optimal brain and metabolic function across the lifespan through microbial signals.

  4. Identification of fipronil metabolites in rodents by time-of-flight mass spectrometry for application in a human exposure study

    Science.gov (United States)

    Fipronil is a phenylpyrazole insecticide commonly used in residential and agricultural applications. To understand more about the potential risks associated with fipronil, dosed Long Evans rats were evaluated for metabolites to develop a set of biomarkers for use in human exposur...

  5. In vivo measurements of T1 relaxation times of 31P-metabolites in human skeletal muscle

    DEFF Research Database (Denmark)

    Thomsen, C; Jensen, K E; Henriksen, O

    1989-01-01

    The T1 relaxation times were estimated for 31P-metabolites in human skeletal muscle. Five healthy volunteers were examined in a 1.5 Tesla wholebody imaging system using an inversion recovery pulse sequence. The calculated T1 relaxation times ranged from 5.517 sec for phosphocreatine to 3.603 sec...

  6. [Survival of the fattest: the key to human brain evolution].

    Science.gov (United States)

    Cunnane, Stephen C

    2006-01-01

    The circumstances of human brain evolution are of central importance to accounting for human origins, yet are still poorly understood. Human evolution is usually portrayed as having occurred in a hot, dry climate in East Africa where the earliest human ancestors became bipedal and evolved tool-making skills and language while struggling to survive in a wooded or savannah environment. At least three points need to be recognised when constructing concepts of human brain evolution : (1) The human brain cannot develop normally without a reliable supply of several nutrients, notably docosahexaenoic acid, iodine and iron. (2) At term, the human fetus has about 13 % of body weight as fat, a key form of energy insurance supporting brain development that is not found in other primates. (3) The genome of humans and chimpanzees is human brain become so much larger, and how was its present-day nutritional vulnerability circumvented during 5-6 million years of hominid evolution ? The abundant presence of fish bones and shellfish remains in many African hominid fossil sites dating to 2 million years ago implies human ancestors commonly inhabited the shores, but this point is usually overlooked in conceptualizing how the human brain evolved. Shellfish, fish and shore-based animals and plants are the richest dietary sources of the key nutrients needed by the brain. Whether on the shores of lakes, marshes, rivers or the sea, the consumption of most shore-based foods requires no specialized skills or tools. The presence of key brain nutrients and a rich energy supply in shore-based foods would have provided the essential metabolic and nutritional support needed to gradually expand the hominid brain. Abundant availability of these foods also provided the time needed to develop and refine proto-human attributes that subsequently formed the basis of language, culture, tool making and hunting. The presence of body fat in human babies appears to be the product of a long period of

  7. Further evaluation of [11C]MP-10 as a radiotracer for phosphodiesterase 10A (PDE10A): PET imaging study in rhesus monkeys and brain tissue metabolite analysis

    Science.gov (United States)

    Lin, Shu-fei; Labaree, David; Chen, Ming-Kai; Holden, Daniel; Gallezot, Jean-Dominique; Kapinos, Michael; Teng, Jo-Ku; Najafzadeh, Soheila; Plisson, Christophe; Rabiner, Eugenii A.; Gunn, Roger N.; Carson, Richard E.; Huang, Yiyun

    2014-01-01

    [11C]MP-10 is a potent and specific PET tracer previously shown to be suitable for imaging the PDE10A in baboons with reversible kinetics and high specific binding. However, another report indicated that [11C]MP-10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood-brain-barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re-evaluating [11C]MP-10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self-blocking scans with unlabeled MP-10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague-Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [11C]MP-10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP-10 reduced the binding of [11C]MP-10 in a dose-dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution (VT) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible (< 2.7%) amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [11C]MP-10 as a radiotracer for PET imaging and quantification of PDE10A in non-human primates. PMID:25450608

  8. NMR-based metabolite profiling of human milk: A pilot study of methods for investigating compositional changes during lactation

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Junfang [Department of Chemistry, Umeå University (Sweden); Domellöf, Magnus [Department of Clinical Sciences, Pediatrics, Umeå University (Sweden); Zivkovic, Angela M. [Foods for Health Institute, University of California, Davis, CA (United States); Department of Nutrition, University of California, Davis, CA (United States); Larsson, Göran [Department of Medical Biochemistry and Biophysics, Unit of Research, Education and Development-Östersund, Umeå University (Sweden); Öhman, Anders, E-mail: anders.ohman01@umu.se [Department of Pharmacology and Clinical Neuroscience, Umeå University (Sweden); Nording, Malin L., E-mail: malin.nording@umu.se [Department of Chemistry, Umeå University (Sweden)

    2016-01-15

    Low-molecular-weight metabolites in human milk are gaining increasing interest in studies of infant nutrition. In the present study, the milk metabolome from a single mother was explored at different stages of lactation. Metabolites were extracted from sample aliquots using either methanol/water (MeOH/H{sub 2}O) extraction or ultrafiltration. Nuclear magnetic resonance (NMR) spectroscopy was used for metabolite identification and quantification, and multi- and univariate statistical data analyses were used to detect changes over time of lactation. Compared to MeOH/H{sub 2}O extraction, ultrafiltration more efficiently reduced the interference from lipid and protein resonances, thereby enabling the identification and quantification of 36 metabolites. The human milk metabolomes at the early (9–24 days after delivery) and late (31–87 days after delivery) stages of lactation were distinctly different according to multi- and univariate statistics. The late lactation stage was characterized by significantly elevated concentrations of lactose, choline, alanine, glutamate, and glutamine, as well as by reduced levels of citrate, phosphocholine, glycerophosphocholine, and N-acetylglucosamine. Our results indicate that there are significant compositional changes of the human milk metabolome also in different phases of the matured lactation stage. These findings complement temporal studies on the colostrum and transitional metabolome in providing a better understanding of the nutritional variations received by an infant. - Highlights: • 36 metabolites were simultaneously quantified in human milk by NMR. • Ultrafiltration more efficiently reduces interferences than MeOH/H{sub 2}O extraction. • Compositional changes of the human milk exist during the matured lactation stage.

  9. Determination of miloxacin and metabolites in human serum and urine by high-pressure liquid chromatography.

    Science.gov (United States)

    Yoshitake, A; Kawahara, K; Shono, F; Umeda, I; Izawa, A; Komatsu, T

    1980-01-01

    A sensitive and reliable high-pressure liquid chromatography (HPLC) assay for miloxacin and its two principal metabolites, 5,8-dihydro-8-oxo-2H-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid (M-1) and 1,4-dihydro-1,6-dimethoxy-7-hydroxy-4-oxoquinoline-3-carboxylic acid (M-2), in human serum and urine was developed. A strong anion-exchange Zipax SAX column using a mobile phase of 0.01 M citric acid solution containing 0.03 M sodium nitrate with pH 5.0 was used to achieve separation of the three compounds. The retention times of miloxacin, M-1, and M-2 were 3.8, 9.3, and 5.9 min, respectively. Serum and urine concentrations of these compounds as low as 10 ng/ml were measured. When results from the HPLC assay were compared with those from the microbiological assay of serum and urine samples from human subjects receiving miloxacin orally, the correlation coefficients were 0.94 for the serum and 0.99 for the urine. The HPLC assay method presents an alternative to the microbiological assay and permits future pharmacokinetic investigations of miloxacin. PMID:7416751

  10. Acquisition-weighted chemical shift imaging improves SLOOP quantification of human cardiac phosphorus metabolites

    Energy Technology Data Exchange (ETDEWEB)

    Geier, Oliver [Oslo University Hospital (Norway). The Intervention Centre; Weng, Andreas Max; Toepell, Andreas; Hahn, Dietbert [Wuerzburg Univ. (Germany). Inst. of Radiology; Spindler, Matthias [Wuerzburg Univ. (Germany). Dept. of Internal Medicine; Beer, Meinrad [Wuerzburg Univ. (Germany). Inst. of Radiology; Medical Univ. Graz (Austria). Dept. of Pediatric Radiology; Koestler, Herbert [Wuerzburg Univ. (Germany). Inst. of Radiology; Wuerzburg Univ. (Germany). Comprehensive Heart Failure Center

    2014-03-01

    Purpose: Phosphorous metabolite ratios in human myocardium were determined by a combination of acquisition weighted CSI and a SLOOP evaluation and the results were compared to corresponding SLOOP experiments using standard CSI. Materials and Methods: 10 healthy subjects were examined at 1.5 T using both standard CSI and acquisition weighted CSI. Both experiments were performed with a similar acquisition time and the same spatial resolution. The PCr/ATP ratio was determined and the localization properties of both experiments were compared. Results: The PCr/ATP ratio of 2.2 ± 0.4 found for the experiment using acquisition weighted CSI was almost identical to the value of 2.0 ± 0.4 for standard CSI. The sensitivity and the localization properties improved in all subjects using SLOOP evaluation of the acquisition weighted sampling in comparison to the standard CSI acquisition with an average of 3% and 18%, respectively. Conclusion: The employment of acquisition weighting allows for a further improvement of the {sup 31}P SLOOP spectroscopy of the human heart. (orig.)

  11. Formation of the Thiol Conjugates and Active Metabolite of Clopidogrel by Human Liver Microsomes

    Science.gov (United States)

    Lau, Wei C.; Hollenberg, Paul F.

    2012-01-01

    We reported previously the formation of a glutathionyl conjugate of the active metabolite (AM) of clopidogrel and the covalent modification of a cysteinyl residue of human cytochrome P450 2B6 in a reconstituted system (Mol Pharmacol 80:839–847, 2011). In this work, we extended our studies of the metabolism of clopidogrel to human liver microsomes in the presence of four reductants, namely, GSH, l-Cys, N-acetyl-l-cysteine (NAC), and ascorbic acid. Our results demonstrated that formation of the AM was greatly affected by the reductant used and the relative amounts of the AM formed were increased in the following order: NAC (17%) clopidogrel. It was observed that the AM was slowly converted to the thiol conjugate, with a half-life of ∼10 h. Addition of dithiothreitol to the reaction mixture reversed the conversion, which resulted in a decrease in AM-thiol conjugate levels and a concomitant increase in AM levels, whereas addition of NAC led to the formation of AM-NAC and a concomitant decrease in AM-GSH levels. These results not only confirm that the AM is formed through oxidative opening of the thiolactone ring but also suggest the existence of an equilibrium between the AM, the thiol conjugates, and the reductants. These factors may affect the effective concentrations of the AM in vivo. PMID:22584220

  12. Common genetic variants influence human subcortical brain structures

    OpenAIRE

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magn...

  13. Alcohol’s Effects on the Brain: Neuroimaging Results in Humans and Animal Models

    Science.gov (United States)

    Zahr, Natalie M.; Pfefferbaum, Adolf

    2017-01-01

    Brain imaging technology has allowed researchers to conduct rigorous studies of the dynamic course of alcoholism through periods of drinking, sobriety, and relapse and to gain insights into the effects of chronic alcoholism on the human brain. Magnetic resonance imaging (MRI) studies have distinguished alcohol-related brain effects that are permanent from those that are reversible with abstinence. In support of postmortem neuropathological studies showing degeneration of white matter, MRI studies have shown a specific vulnerability of white matter to chronic alcohol exposure. Such studies have demonstrated white-matter volume deficits as well as damage to selective gray-matter structures. Diffusion tensor imaging (DTI), by permitting microstructural characterization of white matter, has extended MRI findings in alcoholics. MR spectroscopy (MRS) allows quantification of several metabolites that shed light on brain biochemical alterations caused by alcoholism. This article focuses on MRI, DTI, and MRS findings in neurological disorders that commonly co-occur with alcoholism, including Wernicke’s encephalopathy, Korsakoff’s syndrome, and hepatic encephalopathy. Also reviewed are neuroimaging findings in animal models of alcoholism and related neurological disorders. This report also suggests that the dynamic course of alcoholism presents a unique opportunity to examine brain structural and functional repair and recovery. PMID:28988573

  14. Bioavailability of hydroxycinnamates in an instant green/roasted coffee blend in humans. Identification of novel colonic metabolites.

    Science.gov (United States)

    Gómez-Juaristi, Miren; Martínez-López, Sara; Sarria, Beatriz; Bravo, Laura; Mateos, Raquel

    2017-11-27

    Roasting greatly reduces the phenolic content in green coffee beans. Considering the beneficial effects of coffee polyphenols, blends containing green coffee beans are being consumed as a healthier alternative to roasted coffee. This study was aimed at assessing the absorption and metabolism of hydroxycinnamates in an instant green/roasted (35/65) coffee blend in healthy humans. Twelve fasting men and women consumed a cup of coffee containing 269.5 mg (760.6 μmol) of chlorogenic acids. Blood and urine samples were taken before and after coffee consumption at different times and analyzed by LC-MS-QToF. Up to 25 and 42 metabolites were identified in plasma and urine, respectively, mainly in the form of sulfate and methyl derivatives, and to a lower extent as glucuronides. Un-metabolized hydroxycinnamate esters (caffeoyl-, feruloyl-, and coumaroylquinic acids), hydroxycinnamic acids (caffeic, ferulic and coumaric acids) and their phase II metabolites, in addition to phase II derivatives of lactones, represented a minor group of metabolites (16.3% of the metabolites excreted in urine) with kinetics compatible with small intestine absorption. Dihydrohydroxycinnamic acids and their phase II derivatives, in addition to feruloylglycine, showed delayed kinetics due to their colonic origin and represented the most abundant group of metabolites (75.7% of total urinary metabolites). Dihydrohydroxycinnamate esters (dihydroferuloyl-, dihydrocaffeoyl- and dihydrocoumaroylquinic acids) have been identified for the first time in both plasma and urine, with microbial origin (excreted 8-12 h after coffee intake) amounting to 8% of total urinary metabolites. In conclusion, coffee polyphenols are partially bioavailable and extensively metabolized, mainly by the colonic microbiota.

  15. Cell diversity and network dynamics in photosensitive human brain organoids

    Science.gov (United States)

    Quadrato, Giorgia; Nguyen, Tuan; Macosko, Evan Z.; Sherwood, John L.; Yang, Sung Min; Berger, Daniel; Maria, Natalie; Scholvin, Jorg; Goldman, Melissa; Kinney, Justin; Boyden, Edward S.; Lichtman, Jeff; Williams, Ziv M.; McCarroll, Steven A.; Arlotta, Paola

    2017-01-01

    In vitro models of the developing brain such as 3D brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, it remains undefined what cells are generated within organoids and to what extent they recapitulate the regional complexity, cellular diversity, and circuit functionality of the brain. Here, we analyzed gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (over 9 months) enabling unprecedented levels of maturity including the formation of dendritic spines and of spontaneously-active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photoreceptor-like cells, which may offer ways to probe the functionality of human neuronal circuits using physiological sensory stimuli. PMID:28445462

  16. Impact of Human like Cues on Human Trust in Machines: Brain Imaging and Modeling Studies for Human-Machine Interactions

    Science.gov (United States)

    2018-01-05

    AFRL-AFOSR-JP-TR-2018-0006 Impact of Human like Cues on Human Trust in Machines: Brain Imaging and Modeling Studies for Human -Machine Interactions...AND SUBTITLE Impact of Human like Cues on Human Trust in Machines: Brain Imaging and Modeling Studies for Human -Machine Interactions 5a.  CONTRACT...DISTRIBUTION UNLIMITED: PB Public Release 13. SUPPLEMENTARY NOTES 14. ABSTRACT When a human and an intelligent machine work together as a team, human

  17. Is enzymatic hydrolysis a reliable analytical strategy to quantify glucuronidated and sulfated polyphenol metabolites in human fluids?

    Science.gov (United States)

    Quifer-Rada, Paola; Martínez-Huélamo, Miriam; Lamuela-Raventos, Rosa M

    2017-07-19

    Phenolic compounds are present in human fluids (plasma and urine) mainly as glucuronidated and sulfated metabolites. Up to now, due to the unavailability of standards, enzymatic hydrolysis has been the method of choice in analytical chemistry to quantify these phase II phenolic metabolites. Enzymatic hydrolysis procedures vary in enzyme concentration, pH and temperature; however, there is a lack of knowledge about the stability of polyphenols in their free form during the process. In this study, we evaluated the stability of 7 phenolic acids, 2 flavonoids and 3 prenylflavanoids in urine during enzymatic hydrolysis to assess the suitability of this analytical procedure, using three different concentrations of β-glucuronidase/sulfatase enzymes from Helix pomatia. The results indicate that enzymatic hydrolysis negatively affected the recovery of the precursor and free-form polyphenols present in the sample. Thus, enzymatic hydrolysis does not seem an ideal analytical strategy to quantify glucuronidated and sulfated polyphenol metabolites.

  18. NMR-based metabolite profiling of human milk: A pilot study of methods for investigating compositional changes during lactation.

    Science.gov (United States)

    Wu, Junfang; Domellöf, Magnus; Zivkovic, Angela M; Larsson, Göran; Öhman, Anders; Nording, Malin L

    2016-01-15

    Low-molecular-weight metabolites in human milk are gaining increasing interest in studies of infant nutrition. In the present study, the milk metabolome from a single mother was explored at different stages of lactation. Metabolites were extracted from sample aliquots using either methanol/water (MeOH/H2O) extraction or ultrafiltration. Nuclear magnetic resonance (NMR) spectroscopy was used for metabolite identification and quantification, and multi- and univariate statistical data analyses were used to detect changes over time of lactation. Compared to MeOH/H2O extraction, ultrafiltration more efficiently reduced the interference from lipid and protein resonances, thereby enabling the identification and quantification of 36 metabolites. The human milk metabolomes at the early (9-24 days after delivery) and late (31-87 days after delivery) stages of lactation were distinctly different according to multi- and univariate statistics. The late lactation stage was characterized by significantly elevated concentrations of lactose, choline, alanine, glutamate, and glutamine, as well as by reduced levels of citrate, phosphocholine, glycerophosphocholine, and N-acetylglucosamine. Our results indicate that there are significant compositional changes of the human milk metabolome also in different phases of the matured lactation stage. These findings complement temporal studies on the colostrum and transitional metabolome in providing a better understanding of the nutritional variations received by an infant. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Metabolic costs and evolutionary implications of human brain development

    Science.gov (United States)

    Kuzawa, Christopher W.; Chugani, Harry T.; Grossman, Lawrence I.; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R.; Wildman, Derek E.; Sherwood, Chet C.; Leonard, William R.; Lange, Nicholas

    2014-01-01

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain’s glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain–body metabolic trade-offs using the ratios of brain glucose uptake to the body’s resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate. PMID:25157149

  20. Automated tissue segmentation and blind recovery of (1)H MRS imaging spectral patterns of normal and diseased human brain.

    Science.gov (United States)

    Du, Shuyan; Mao, Xiangling; Sajda, Paul; Shungu, Dikoma C

    2008-01-01

    Constrained non-negative matrix factorization (cNMF) with iterative data selection is described and demonstrated as a data analysis method for fast and automatic recovery of biochemically meaningful and diagnostically specific spectral patterns of the human brain from (1)H MRS imaging ((1)H MRSI) data. To achieve this goal, cNMF decomposes in vivo multidimensional (1)H MRSI data into two non-negative matrices representing (a) the underlying tissue-specific spectral patterns and (b) the spatial distribution of the corresponding metabolite concentrations. Central to the proposed approach is automatic iterative data selection which uses prior knowledge about the spatial distribution of the spectra to remove voxels that are due to artifacts and undesired metabolites/tissues such as the strong lipid and water components. The automatic recovery of diagnostic spectral patterns is demonstrated for long-TE (1)H MRSI data on normal human brain, multiple sclerosis, and serial brain tumor. The results show the ability of cNMF with iterative data selection to automatically and simultaneously recover tissue-specific spectral patterns and achieve segmentation of normal and diseased human brain tissue, concomitant with simplification of information content. These features of cNMF, which permit rapid recovery, reduction and interpretation of the complex diagnostic information content of large multi-dimensional spectroscopic imaging data sets, have the potential to enhance the clinical utility of in vivo(1)H MRSI.

  1. An anatomically comprehensive atlas of the adult human brain transcriptome

    NARCIS (Netherlands)

    Hawrylycz, M.J.; Beckmann, Christian

    2012-01-01

    Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising

  2. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivieres, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Loohuis, Loes M. Olde; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santianez, Roberto; Rose, Emma J.; Salami, Alireza; Saemann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Puetz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Goering, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzah, Eva; Melle, Ingrid; Mahnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Muehleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Noethen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdes Hernandez, Maria C.; van't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffman, Wolfgang; Hosten, Norbert; Kahn, Rene S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Mueller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Voelzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernandez, Guillen; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Pol, Hilleke E. Hulshoff; Joensson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To

  3. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    D.P. Hibar (Derrek); J.L. Stein; M.E. Rentería (Miguel); A. Arias-Vásquez (Alejandro); S. Desrivières (Sylvane); N. Jahanshad (Neda); R. Toro (Roberto); K. Wittfeld (Katharina); L. Abramovic (Lucija); M. Andersson (Micael); B. Aribisala (Benjamin); N.J. Armstrong (Nicola J.); M. Bernard (Manon); M.M. Bohlken (Marc M.); M.P.M. Boks (Marco); L.B.C. Bralten (Linda); A.A. Brown (Andrew); M.M. Chakravarty (M. Mallar); Q. Chen (Qiang); C.R.K. Ching (Christopher); G. Cuellar-Partida (Gabriel); A. den Braber (Anouk); S. Giddaluru (Sudheer); A.L. Goldman (Aaron L.); O. Grimm (Oliver); T. Guadalupe (Tulio); J. Hass (Johanna); G. Woldehawariat (Girma); A.J. Holmes (Avram); M. Hoogman (Martine); D. Janowitz (Deborah); T. Jia (Tianye); S. Kim (Shinseog); M. Klein (Marieke); B. Kraemer (Bernd); P.H. Lee (Phil H.); L.M. Olde Loohuis (Loes M.); M. Luciano (Michelle); C. MacAre (Christine); R. Mather; M. Mattheisen (Manuel); Y. Milaneschi (Yuri); K. Nho (Kwangsik); M. Papmeyer (Martina); A. Ramasamy (Adaikalavan); S.L. Risacher (Shannon); R. Roiz-Santiañez (Roberto); E.J. Rose (Emma); A. Salami (Alireza); P.G. Sämann (Philipp); L. Schmaal (Lianne); N.J. Schork (Nicholas); J. Shin (Jean); V.M. Strike (Vanessa); A. Teumer (Alexander); M.M.J. Van Donkelaar (Marjolein M. J.); K.R. van Eijk (Kristel); R.K. Walters (Raymond); L.T. Westlye (Lars); C.D. Whelan (Christopher); A.M. Winkler (Anderson); M.P. Zwiers (Marcel); S. Alhusaini (Saud); L. Athanasiu (Lavinia); S.M. Ehrlich (Stefan); M. Hakobjan (Marina); C.B. Hartberg (Cecilie B.); U.K. Haukvik (Unn); A.J.G.A.M. Heister (Angelien J. G. A. M.); D. Hoehn (David); D. Kasperaviciute (Dalia); D.C. Liewald (David C.); L.M. Lopez (Lorna); R.R.R. Makkinje (Remco R. R.); M. Matarin (Mar); M.A.M. Naber (Marlies A. M.); D. Reese McKay; M. Needham (Margaret); A.C. Nugent (Allison); B. Pütz (Benno); N.A. Royle (Natalie); L. Shen (Li); R. Sprooten (Roy); D. Trabzuni (Danyah); S.S.L. Van Der Marel (Saskia S. L.); K.J.E. Van Hulzen (Kimm J. E.); E. Walton (Esther); A. Björnsson (Asgeir); L. Almasy (Laura); D.J. Ames (David); S. Arepalli (Sampath); A.A. Assareh; M.E. Bastin (Mark); H. Brodaty (Henry); K. Bulayeva (Kazima); M.A. Carless (Melanie); S. Cichon (Sven); A. Corvin (Aiden); J.E. Curran (Joanne); M. Czisch (Michael); G.I. de Zubicaray (Greig); A. Dillman (Allissa); A. Duggirala (Aparna); M.D. Dyer (Matthew); S. Erk; I. Fedko (Iryna); L. Ferrucci (Luigi); T. Foroud (Tatiana); P.T. Fox (Peter); M. Fukunaga (Masaki); J. Raphael Gibbs; H.H.H. Göring (Harald H.); R.C. Green (Robert C.); S. Guelfi (Sebastian); N.K. Hansell (Narelle); C.A. Hartman (Catharina); K. Hegenscheid (Katrin); J. Heinz (Judith); D.G. Hernandez (Dena); D.J. Heslenfeld (Dirk); P.J. Hoekstra (Pieter); F. Holsboer; G. Homuth (Georg); J.J. Hottenga (Jouke Jan); M. Ikeda (Masashi); C.R. Jack Jr. (Clifford); S. Jenkinson (Sarah); R. Johnson (Robert); R. Kanai (Ryota); M. Keil (Maria); J.W. Kent (Jack W.); P. Kochunov (Peter); J.B. Kwok (John B.); S. Lawrie (Stephen); X. Liu (Xinmin); D.L. Longo (Dan L.); K.L. Mcmahon (Katie); E. Meisenzahl (Eva); I. Melle (Ingrid); S. Mohnke (Sebastian); G.W. Montgomery (Grant); J.C. Mostert (Jeanette C.); T.W. Mühleisen (Thomas); M.A. Nalls (Michael); T.E. Nichols (Thomas); L.G. Nilsson; M.M. Nöthen (Markus); K. Ohi (Kazutaka); R.L. Olvera (Rene); R. Perez-Iglesias (Rocio); G. Bruce Pike; S.G. Potkin (Steven); I. Reinvang (Ivar); S. Reppermund; M. Rietschel (Marcella); N. Seiferth (Nina); G.D. Rosen (Glenn D.); D. Rujescu (Dan); K. Schnell (Kerry); C.J. Schofield (Christopher); C. Smith (Colin); V.M. Steen (Vidar); J. Sussmann (Jessika); A. Thalamuthu (Anbupalam); A.W. Toga (Arthur W.); B. Traynor (Bryan); J.C. Troncoso (Juan); J. Turner (Jessica); M.C. Valdés Hernández (Maria); D. van 't Ent (Dennis); M.P. van der Brug (Marcel); N.J. van der Wee (Nic); M.J.D. van Tol (Marie-José); D.J. Veltman (Dick); A.M.J. Wassink (Annemarie); E. Westman (Eric); R.H. Zielke (Ronald H.); A.B. Zonderman (Alan B.); D.G. Ashbrook (David G.); R. Hager (Reinmar); L. Lu (Lu); F.J. Mcmahon (Francis J); D.W. Morris (Derek W); R.W. Williams (Robert W.); H.G. Brunner; M. Buckner; J.K. Buitelaar (Jan K.); W. Cahn (Wiepke); V.D. Calhoun Vince D. (V.); G. Cavalleri (Gianpiero); B. Crespo-Facorro (Benedicto); A.M. Dale (Anders); G.E. Davies (Gareth); N. Delanty; C. Depondt (Chantal); S. Djurovic (Srdjan); D.A. Drevets (Douglas); T. Espeseth (Thomas); R.L. Gollub (Randy); B.C. Ho (Beng ); W. Hoffmann (Wolfgang); N. Hosten (Norbert); R. Kahn (René); S. Le Hellard (Stephanie); A. Meyer-Lindenberg; B. Müller-Myhsok (B.); M. Nauck (Matthias); L. Nyberg (Lars); M. Pandolfo (Massimo); B.W.J.H. Penninx (Brenda); J.L. Roffman (Joshua); S.M. Sisodiya (Sanjay); J.W. Smoller; H. van Bokhoven (Hans); N.E.M. van Haren (Neeltje E.); H. Völzke (Henry); H.J. Walter (Henrik); M.W. Weiner (Michael); W. Wen (Wei); T.J.H. White (Tonya); I. Agartz (Ingrid); O.A. Andreassen (Ole); J. Blangero (John); D.I. Boomsma (Dorret); R.M. Brouwer (Rachel); D.M. Cannon (Dara); M.R. Cookson (Mark); E.J.C. de Geus (Eco); I.J. Deary (Ian J.); D.J. Donohoe (Dennis); G. Fernandez (Guillén); S.E. Fisher (Simon); C. Francks (Clyde); D.C. Glahn (David); H.J. Grabe (Hans Jörgen); O. Gruber (Oliver); J. Hardy (John); R. Hashimoto (Ryota); H.E. Hulshoff Pol (Hilleke); E.G. Jönsson (Erik); I. Kloszewska (Iwona); S. Lovestone (Simon); V.S. Mattay (Venkata S.); P. Mecocci (Patrizia); C. McDonald (Colm); A.M. McIntosh (Andrew); R.A. Ophoff (Roel); T. Paus (Tomas); Z. Pausova (Zdenka); M. Ryten (Mina); P.S. Sachdev (Perminder); A.J. Saykin (Andrew); A. Simmons (Andrew); A. Singleton (Andrew); H. Soininen (H.); J.M. Wardlaw (J.); M.E. Weale (Michael); D.R. Weinberger (Daniel); H.H.H. Adams (Hieab); L.J. Launer (Lenore); S. Seiler (Stephan); R. Schmidt (Reinhold); G. Chauhan (Ganesh); C.L. Satizabal (Claudia L.); J.T. Becker (James); L.R. Yanek (Lisa); S.J. van der Lee (Sven); M. Ebling (Maritza); B. Fischl (Bruce); W.T. Longstreth Jr; D. Greve (Douglas); R. Schmidt (Reinhold); P. Nyquist (Paul); L.N. Vinke (Louis N.); C.M. van Duijn (Cornelia); L. Xue (Luting); B. Mazoyer (Bernard); J.C. Bis (Joshua); V. Gudnason (Vilmundur); S. Seshadri (Sudha); M.A. Ikram (Arfan); N.G. Martin (Nicholas); M.J. Wright (Margaret); G. Schumann (Gunter); B. Franke (Barbara); P.M. Thompson (Paul); S.E. Medland (Sarah Elizabeth)

    2015-01-01

    textabstractThe highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate

  4. Genetic contributions to human brain morphology and intelligence

    NARCIS (Netherlands)

    Hulshoff Pol, H.E.; Schnack, H.G.; Posthuma, D.; Mandl, R.C.W.; Baaré, W.F.; van Oel, C.J.; van Haren, N.E.M.; Colins, D.L.; Evans, A.C.; Amunts, K.; Bürgel, U.; Zilles, K.; de Geus, E.J.C.; Boomsma, D.I.; Kahn, R.S.

    2006-01-01

    Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, although genetic effects on morphology of

  5. Genetic contributions to human brain morphology and intelligence

    DEFF Research Database (Denmark)

    Hulshoff Pol, HE; Schnack, HG; Posthuma, D

    2006-01-01

    Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, although genetic effects on morphology of spec...

  6. Simultaneous Determination of Ticagrelor and Its Metabolites in Human Plasma and Urine Using Liquid Chromatography-Tandem Mass Spectrometry.

    Science.gov (United States)

    Zhong, Wanping; Wang, Xipei; Tang, Lan; Mai, Liping; Chen, Xiao-Ping; He, Guodong; Zheng, Zhijie; Zhong, Shilong

    2016-07-01

    We have developed and validated a rapid, selective and sensitive method using high-performance liquid chromatography-tandem mass spectrometry (MS) for the quantification of ticagrelor and all of its as-yet-identified metabolites in human plasma and urine. For the analysis of ticagrelor, its metabolites and the internal standard (IS) plasma samples were processed by liquid-liquid extraction using ethyl acetate and urine was processed by protein precipitation. Separations were performed on an Ultimate XB-C18 column (2.1 mm × 150 mm, 3 μm), using aqueous ammonium acetate (0.025 mM)/acetonitrile (35 : 65, v:v) as the mobile phase. Ticagrelor and all 11 metabolites were eluted within 4.5 min. Quantification was performed using electrospray ionization, operating in negative ion mode. The ticagrelor and metabolite M8 (AR-C124910XX) responses were optimized at the m/z 521.2 → 361.2 and m/z 477.2 → 361.1 transitions, respectively. The assay was validated over the linear range of 0.5-2,000 ng/mL for ticagrelor and M8. The intra- and inter-assay precisions were ≤14.6% for ticagrelor and ≤14.7% for M8, respectively. The matrix effects of plasma and urine were in the range of 98.3-110.7% for ticagrelor and 102.1-112.3% for M8. The relative quantification of other metabolites was performed by assessing the ratio of metabolite to IS peaks. The newly developed method was successfully used in a pharmacokinetic study characterizing ticagrelor metabolism in human volunteers. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Central activation, metabolites, and calcium handling during fatigue with repeated maximal isometric contractions in human muscle.

    Science.gov (United States)

    Cairns, Simeon P; Inman, Luke A G; MacManus, Caroline P; van de Port, Ingrid G L; Ruell, Patricia A; Thom, Jeanette M; Thompson, Martin W

    2017-08-01

    To determine the roles of calcium (Ca 2+ ) handling by sarcoplasmic reticulum (SR) and central activation impairment (i.e., central fatigue) during fatigue with repeated maximal voluntary isometric contractions (MVC) in human muscles. Contractile performance was assessed during 3 min of repeated MVCs (7-s contraction, 3-s rest, n = 17). In ten participants, in vitro SR Ca 2+ -handling, metabolites, and fibre-type composition were quantified in biopsy samples from quadriceps muscle, along with plasma venous [K + ]. In 11 participants, central fatigue was compared using tetanic stimulation superimposed on MVC in quadriceps and adductor pollicis muscles. The decline of peak MVC force with fatigue was similar for both muscles. Fatigue resistance correlated directly with % type I fibre area in quadriceps (r = 0.77, P = 0.009). The maximal rate of ryanodine-induced Ca 2+ -release and Ca 2+ -uptake fell by 31 ± 26 and 28 ± 13%, respectively. The tetanic force depression was correlated with the combined reduction of ATP and PCr, and increase of lactate (r = 0.77, P = 0.009). Plasma venous [K + ] increased from 4.0 ± 0.3 to 5.4 ± 0.8 mM over 1-3-min exercise. Central fatigue occurred during the early contractions in the quadriceps in 7 out of 17 participants (central activation ratio fell from 0.98 ± 0.05 to 0.86 ± 0.11 at 1 min), but dwindled at exercise cessation. Central fatigue was seldom apparent in adductor pollicis. Fatigue with repeated MVC in human limb muscles mainly involves peripheral aspects which include impaired SR Ca 2+ -handling and we speculate that anaerobic metabolite changes are involved. A faster early force loss in quadriceps muscle with some participants is attributed to central fatigue.

  8. Toward discovery science of human brain function.

    Science.gov (United States)

    Biswal, Bharat B; Mennes, Maarten; Zuo, Xi-Nian; Gohel, Suril; Kelly, Clare; Smith, Steve M; Beckmann, Christian F; Adelstein, Jonathan S; Buckner, Randy L; Colcombe, Stan; Dogonowski, Anne-Marie; Ernst, Monique; Fair, Damien; Hampson, Michelle; Hoptman, Matthew J; Hyde, James S; Kiviniemi, Vesa J; Kötter, Rolf; Li, Shi-Jiang; Lin, Ching-Po; Lowe, Mark J; Mackay, Clare; Madden, David J; Madsen, Kristoffer H; Margulies, Daniel S; Mayberg, Helen S; McMahon, Katie; Monk, Christopher S; Mostofsky, Stewart H; Nagel, Bonnie J; Pekar, James J; Peltier, Scott J; Petersen, Steven E; Riedl, Valentin; Rombouts, Serge A R B; Rypma, Bart; Schlaggar, Bradley L; Schmidt, Sein; Seidler, Rachael D; Siegle, Greg J; Sorg, Christian; Teng, Gao-Jun; Veijola, Juha; Villringer, Arno; Walter, Martin; Wang, Lihong; Weng, Xu-Chu; Whitfield-Gabrieli, Susan; Williamson, Peter; Windischberger, Christian; Zang, Yu-Feng; Zhang, Hong-Ying; Castellanos, F Xavier; Milham, Michael P

    2010-03-09

    Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.

  9. Isolation of Borna Disease Virus from Human Brain Tissue

    Science.gov (United States)

    Nakamura, Yurie; Takahashi, Hirokazu; Shoya, Yuko; Nakaya, Takaaki; Watanabe, Makiko; Tomonaga, Keizo; Iwahashi, Kazuhiko; Ameno, Kiyoshi; Momiyama, Noriko; Taniyama, Hiroyuka; Sata, Tetsutaro; Kurata, Takeshi; de la Torre, Juan Carlos; Ikuta, Kazuyoshi

    2000-01-01

    Serological and molecular epidemiological studies indicate that Borna disease virus (BDV) can infect humans and is possibly associated with certain neuropsychiatric disorders. We examined brain tissue collected at autopsy from four schizophrenic patients and two healthy controls for the presence of BDV markers in 12 different brain regions. BDV RNA and antigen was detected in four brain regions of a BDV-seropositive schizophrenic patient (P2) with a very recent (2 years) onset of disease. BDV markers exhibited a regionally localized distribution. BDV RNA was found in newborn Mongolian gerbils intracranially inoculated with homogenates from BDV-positive brain regions of P2. Human oligodendroglia (OL) cells inoculated with brain homogenates from BDV-positive gerbils allowed propagation and isolation of BDVHuP2br, a human brain-derived BDV. Virus isolation was also possible by transfection of Vero cells with ribonucleoprotein complexes prepared from BDV-positive human and gerbil brain tissues. BDVHuP2br was genetically closely related to but distinct from previously reported human- and animal-derived BDV sequences. PMID:10775596

  10. Sex beyond the genitalia: The human brain mosaic

    Science.gov (United States)

    Joel, Daphna; Berman, Zohar; Tavor, Ido; Wexler, Nadav; Gaber, Olga; Stein, Yaniv; Shefi, Nisan; Pool, Jared; Urchs, Sebastian; Margulies, Daniel S.; Liem, Franziskus; Hänggi, Jürgen; Jäncke, Lutz; Assaf, Yaniv

    2015-01-01

    Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains (“female brain” or “male brain”). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only “male” or only “female” features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the “maleness-femaleness” continuum are rare. Rather, most brains are comprised of unique “mosaics” of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain. PMID:26621705

  11. PCB 28 metabolites elimination kinetics in human plasma on a real case scenario: Study of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites of PCB 28 in a highly exposed German Cohort.

    Science.gov (United States)

    Quinete, Natalia; Esser, André; Kraus, Thomas; Schettgen, Thomas

    2017-07-05

    Polychlorinated biphenyls (PCBs) are suspected of carcinogenic, neurotoxic and immunotoxic effects in animals and humans. Although background levels of PCBs have been slowly decreased after their ban, they are still among the most persistent and ubiquitous pollutants in the environment, remaining the subject of great concern. PCB 28 is a trichlorinated PCB found in high concentrations not only in human plasma but also in indoor air in Europe, yet little is known about its metabolic pathway and potential metabolites in humans. The present study aims to elucidate the kinetics of metabolite formation and elimination by analyzing four hydroxylated PCBs (OH-PCBs) in human plasma as potential metabolites of the PCB 28 congener. For this purpose, the study was conducted in plasma samples of highly PCB-exposed individuals (N=268), collected from 2010 to 2014 as a representation of a real case scenario with longitudinal data. OH-PCBs have been predicted, synthesized in the course of this study and further identified and quantitated in human plasma. This is the first time that previously unknown PCB 28 metabolites have been measured in human plasma and half-lives have been estimated for PCB metabolites, which could then provide further understanding in the toxicological consequences of exposure to PCBs in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Long-term multi-species Lactobacillus and Bifidobacterium dietary supplement enhances memory and changes regional brain metabolites in middle-aged rats.

    Science.gov (United States)

    O'Hagan, Caroline; Li, Jia V; Marchesi, Julian R; Plummer, Sue; Garaiova, Iveta; Good, Mark A

    2017-10-01

    Ageing is associated with changes in the gut microbiome that may contribute to age-related changes in cognition. Previous work has shown that dietary supplements with multi-species live microorganisms can influence brain function, including induction of hippocampal synaptic plasticity and production of brain derived neurotrophic factor, in both young and aged rodents. However, the effect of such dietary supplements on memory processes has been less well documented, particularly in the context of aging. The main aim of the present study was to examine the impact of a long-term dietary supplement with a multi-species live Lactobacillus and Bifidobacteria mixture (Lactobacillus acidophilus CUL60, L. acidophilus CUL21, Bifidobacterium bifidum CUL20 and B. lactis CUL34) on tests of memory and behavioural flexibility in 15-17-month-old male rats. Following behavioural testing, the hippocampus and prefrontal cortex was extracted and analysed ex vivo using (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy to examine brain metabolites. The results showed a small beneficial effect of the dietary supplement on watermaze spatial navigation and robust improvements in long-term object recognition memory and short-term memory for object-in-place associations. Short-term object novelty and object temporal order memory was not influenced by the dietary supplement in aging rats. (1)H NMR analysis revealed diet-related regional-specific changes in brain metabolites; which indicated changes in several pathways contributing to modulation of neural signaling. These data suggest that chronic dietary supplement with multi-species live microorganisms can alter brain metabolites in aging rats and have beneficial effects on memory. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Database Extraction of Metabolite Information of Drug Candidates: Analysis of 27 AstraZeneca Compounds with Human Absorption, Distribution, Metabolism, and Excretion Data.

    Science.gov (United States)

    Iegre, Jessica; Hayes, Martin A; Thompson, Richard A; Weidolf, Lars; Isin, Emre M

    2016-05-01

    As part of the drug discovery and development process, it is important to understand the human metabolism of a candidate drug prior to clinical studies. Preclinical in vitro and in vivo experiments across species are conducted to build knowledge concerning human circulating metabolites in preparation for clinical studies; therefore, the quality of these experiments is critical. Within AstraZeneca, all metabolite identification (Met-ID) information is stored in a global database using ACDLabs software. In this study, the Met-ID information derived from in vitro and in vivo studies for 27 AstraZeneca drug candidates that underwent human absorption, distribution, metabolism, and excretion studies was extracted from the database. The retrospective analysis showed that 81% of human circulating metabolites were previously observed in preclinical in vitro and/or in vivo experiments. A detailed analysis was carried out to understand which human circulating metabolites were not captured in the preclinical experiments. Metabolites observed in human hepatocytes and rat plasma but not seen in circulation in humans (extraneous metabolites) were also investigated. The majority of human specific circulating metabolites derive from multistep biotransformation reactions that may not be observed in in vitro studies within the limited time frame in which cryopreserved hepatocytes are active. Factors leading to the formation of extraneous metabolites in preclinical studies seemed to be related to species differences with respect to transporter activity, secondary metabolism, and enzyme kinetics. This retrospective analysis assesses the predictive value of Met-ID experiments and improves our ability to discriminate between metabolites expected to circulate in humans and irrelevant metabolites seen in preclinical studies. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Quantitation of glial fibrillary acidic protein in human brain tumours

    DEFF Research Database (Denmark)

    Rasmussen, S; Bock, E; Warecka, K

    1980-01-01

    The glial fibrillary acidic protein (GFA) content of 58 human brain tumours was determined by quantitative immunoelectrophoresis, using monospecific antibody against GFA. Astrocytomas, glioblastomas, oligodendrogliomas, spongioblastomas, ependymomas and medulloblastomas contained relatively high...... amounts of GFA, up to 85 times the concentration in parietal grey substance of normal human brain. GFA was not found in neurinomas, meningiomas, adenomas of the hypophysis, or in a single case of metastasis of adenocarcinoma. Non-glial tumours of craniopharyngioma and haemangioblastoma were infiltrated...

  15. Optogenetic control of human neurons in organotypic brain cultures

    DEFF Research Database (Denmark)

    Andersson, My; Avaliani, Natalia; Svensson, Andreas

    2016-01-01

    Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof......-of-concept for the use of optogenetics in neuromodulation of human cortical and hippocampal neurons as a possible tool to explore network mechanisms and develop future therapeutic strategies....

  16. Centrality of Social Interaction in Human Brain Function.

    Science.gov (United States)

    Hari, Riitta; Henriksson, Linda; Malinen, Sanna; Parkkonen, Lauri

    2015-10-07

    People are embedded in social interaction that shapes their brains throughout lifetime. Instead of emerging from lower-level cognitive functions, social interaction could be the default mode via which humans communicate with their environment. Should this hypothesis be true, it would have profound implications on how we think about brain functions and how we dissect and simulate them. We suggest that the research on the brain basis of social cognition and interaction should move from passive spectator science to studies including engaged participants and simultaneous recordings from the brains of the interacting persons. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Outer brain barriers in rat and human development

    DEFF Research Database (Denmark)

    Brøchner, Christian B; Holst, Camilla Bjørnbak; Møllgård, Kjeld

    2015-01-01

    Complex barriers at the brain's surface, particularly in development, are poorly defined. In the adult, arachnoid blood-cerebrospinal fluid (CSF) barrier separates the fenestrated dural vessels from the CSF by means of a cell layer joined by tight junctions. Outer CSF-brain barrier provides...... diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6-21st weeks post...

  18. Influence of Sulforaphane Metabolites on Activities of Human Drug-Metabolizing Cytochrome P450 and Determination of Sulforaphane in Human Liver Cells.

    Science.gov (United States)

    Vanduchova, Alena; Tomankova, Veronika; Anzenbacher, Pavel; Anzenbacherova, Eva

    2016-12-01

    The influence of metabolites of sulforaphane, natural compounds present in broccoli (Brassica oleracea var. botrytis italica) and in other cruciferous vegetables, on drug-metabolizing cytochrome P450 (CYP) enzymes in human liver microsomes and possible entry of sulforaphane into human hepatic cells were investigated. Metabolites studied are compounds derived from sulforaphane by the mercapturic acid pathway (conjugation with glutathione and by following reactions), namely sulforaphane glutathione and sulforaphane cysteine conjugates and sulforaphane-N-acetylcysteine. Their possible effect on four drug-metabolizing CYP enzymes, CYP3A4 (midazolam 1'-hydroxylation), CYP2D6 (bufuralol 1'-hydroxylation), CYP1A2 (7-ethoxyresorufin O-deethylation), and CYP2B6 (7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation), was tested. Inhibition of four prototypical CYP activities by sulforaphane metabolites was studied in pooled human liver microsomes. Sulforaphane metabolites did not considerably affect biological function of drug-metabolizing CYPs in human liver microsomes except for CYP2D6, which was found to be inhibited down to 73-78% of the original activity. Analysis of the entry of sulforaphane into human hepatocytes was done by cell disruption by sonication, methylene chloride extraction, and modified high-performance liquid chromatography method. The results have shown penetration of sulforaphane into the human hepatic cells.

  19. UPLC/MS MS data of testosterone metabolites in human and zebrafish liver microsomes and whole zebrafish larval microsomes

    Directory of Open Access Journals (Sweden)

    Moayad Saad

    2018-02-01

    Full Text Available This article represents data regarding a study published in Toxicology in vitro entitled “ in vitro CYP-mediated drug metabolism in the zebrafish (embryo using human reference compounds” (Saad et al., 2017 [1]. Data were acquired with ultra-performance liquid chromatography – accurate mass mass spectrometry (UPLC-amMS. A full spectrum scan was conducted for the testosterone (TST metabolites from the microsomal stability assay in zebrafish and humans. The microsomal proteins were extracted from adult zebrafish male (MLM and female (FLM livers, whole body homogenates of 96 h post fertilization larvae (EM and a pool of human liver microsomes from 50 donors (HLM. Data are expressed as the abundance from the extracted ion chromatogram of the metabolites.

  20. Extended findings of Brain Metabolite Normalization in MA-Dependent Subjects Across Sustained Abstinence: A Proton MRS Study

    Science.gov (United States)

    Salo, Ruth; Buonocore, Michael H.; Leamon, Martin; Natsuaki, Yutaka; Waters, Christy; Moore, Charles D.; Galloway, Gantt P.; Nordahl, Thomas E.

    2010-01-01

    Objective The goal of the present study was to extend our previous findings on long-term methamphetamine (MA) use and drug abstinence on brain metabolite levels in an expanded group of MA-dependent individuals. Methods Seventeen MA abusers with sustained drug abstinence (1 year to 5 years), 30 MA abusers with short-term drug abstinence (1 month to 6 months) and 24 non-substance using controls were studied using MR spectroscopy (MRS). MRS measures of NAA/Cr, Cho/Cr and Cho/NAA were obtained in the anterior cingulate cortex (ACC) and in the primary visual cortex (PVC). Results ACC-Cho/NAA values were abnormally high in the short-term abstinent group compared to controls [F(1,52)=18.76, p<0.0001]. No differences were observed between controls and the long-term abstinent group [F(1,39)=0.97, p=0.97]. New evidence of lower ACC-NAA/Cr levels were observed in the short-term abstinent MA abusers compared to controls [F(1,52)=23.05, p<0.0001] and long-term abstinent MA abusers [F(1,45)=7.06, p=0.01]. No differences were observed between long-term abstinent MA abusers and controls [F(1,39)=0.48, p=0.49]. Conclusions The new findings of relative NAA/Cr normalization across periods of abstinence suggest that adaptive changes following cessation of MA abuse may be broader than initially thought. These changes may contribute to some degree of normalization of neuronal function in the ACC. PMID:20739127

  1. Evaluation of mycotoxins and their metabolites in human breast milk using liquid chromatography coupled to high resolution mass spectrometry.

    Science.gov (United States)

    Rubert, Josep; León, Nuria; Sáez, Carmen; Martins, Claudia P B; Godula, Michal; Yusà, Vicent; Mañes, Jordi; Soriano, José Miguel; Soler, Carla

    2014-04-11

    Humans can be exposed to mycotoxins through the food chain. Mycotoxins are mainly found as contaminants in food and could be subsequently excreted via biological fluids such as urine or human breast milk in native or metabolised form. Since breast milk is usually supposed as the only food for new-borns, the occurrence of mycotoxins in thirty-five human milk samples was evaluated by a newly developed method based on QuEChERS extraction and UHPLC-HRMS detection. The method described here allows the detection of target mycotoxins in order to determine the quality of this initial feeding. The method has been fully validated, with recoveries ranging from 64% to 93% and relative standard deviations (RSD, %) being lower than 20%. Using the method described, non-metabolised mycotoxins such as ZEA, NEO, NIV, ENA, ENA1, ENB, ENB1 and metabolites, such as ZEA metabolites, HT-2, DOM and T-2 triol were detected in human milk samples. Results obtained help to estimate the exposure of mothers and infants to mycotoxins. Moreover, to the best of our knowledge, this is the first work describing the simultaneous detection, quantification and screening of mycotoxins and their metabolites in human mature milk. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Modern human brain growth and development. Contribution to brain evolution in hominids

    OpenAIRE

    Ventrice, F

    2011-01-01

    Human phylogenetic history is directly related to brain evolution. But many biologic processes related to the appearance of this complex organ are unknown, mainly due to the fact that it is an organ composed of soft tissue, which is not sensitive to the fossilization processes. Hence, to infer human brain evolution it is essential to study the indirect evidences it leaves in the cranial bones, such as the endocranial size (cranial capacity) and shape. In this sense, the hominid fossil record ...

  3. Estimating Neural Signal Dynamics in the Human Brain

    Directory of Open Access Journals (Sweden)

    Christopher W Tyler

    2011-06-01

    Full Text Available Although brain imaging methods are highly effective for localizing the effects of neural activation throughout the human brain in terms of the blood oxygenation level dependent (BOLD response, there is currently no way to estimate the underlying neural signal dynamics in generating the BOLD response in each local activation region (except for processes slower than the BOLD time course. Knowledge of the neural signal is critical information if spatial mapping is to progress to the analysis of dynamic information flow through the cortical networks as the brain performs its tasks. We introduce an analytic approach that provides a new level of conceptualization and specificity in the study of brain processing by noninvasive methods. This technique allows us to use brain imaging methods to determine the dynamics of local neural population responses to their native temporal resolution throughout the human brain, with relatively narrow confidence intervals on many response properties. The ability to characterize local neural dynamics in the human brain represents a significant enhancement of brain imaging capabilities, with potential application from general cognitive studies to assessment of neuropathologies.

  4. Quantitative determination of selenium metabolites in human urine by LC-DRC-ICP-MS

    DEFF Research Database (Denmark)

    Gammelgaard, Bente; Bendahl, L.; Jacobsen, N.W.

    2005-01-01

    Two selenium metabolites, Se-methylseleno-N-acetylgalactosamine (SeGal-N-Ac) and Se-methyl-selenogalactosamine (SeGal-NH2), were quantified in human urine by LC-DRC-ICP-MS. Urine samples were analysed after 1+1 dilution in a reversed phase chromatographic system using an eluent consisting of 200 m......M ammonium acetate and 5% methanol with a pH of 9.25 and quantified by standard addition. Samples were collected from 8 volunteers before and after 5 days ingestion of 100 mu g Se day(-1) in form of selenized yeast. The average concentration of (SeGal-NH2) before and after selenium intake was 1.4 and 1.9 mu...... g Se L-1, respectively, while the average concentration of Se-Gal-N-Ac increased from 2.6 to 11.6 mu g Se L-1 before and after selenium consumption. Detection limits calculated on basis of three times the standard deviation on peak areas of 2 mu g Se L-1 solutions were 0.1 mu g Se L-1 for SeGal-NH2...

  5. The cyanobacterial metabolite nocuolin a is a natural oxadiazine that triggers apoptosis in human cancer cells.

    Directory of Open Access Journals (Sweden)

    Kateřina Voráčová

    Full Text Available Oxadiazines are heterocyclic compounds containing N-N-O or N-N-C-O system within a six membered ring. These structures have been up to now exclusively prepared via organic synthesis. Here, we report the discovery of a natural oxadiazine nocuolin A (NoA that has a unique structure based on 1,2,3-oxadiazine. We have identified this compound in three independent cyanobacterial strains of genera Nostoc, Nodularia, and Anabaena and recognized the putative gene clusters for NoA biosynthesis in their genomes. Its structure was characterized using a combination of NMR, HRMS and FTIR methods. The compound was first isolated as a positive hit during screening for apoptotic inducers in crude cyanobacterial extracts. We demonstrated that NoA-induced cell death has attributes of caspase-dependent apoptosis. Moreover, NoA exhibits a potent anti-proliferative activity (0.7-4.5 μM against several human cancer lines, with p53-mutated cell lines being even more sensitive. Since cancers bearing p53 mutations are resistant to several conventional anti-cancer drugs, NoA may offer a new scaffold for the development of drugs that have the potential to target tumor cells independent of their p53 status. As no analogous type of compound was previously described in the nature, NoA establishes a novel class of bioactive secondary metabolites.

  6. Identification of metabolites of meisoindigo in rat, pig and human liver microsomes by UFLC-MS/MS.

    Science.gov (United States)

    Huang, Meng; Ho, Paul C

    2009-04-15

    3-(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)-1,3-dihydro-1-methyl-2H-indol-2-one, abbreviated as meisoindigo, has been a routine therapeutic agent in the clinical treatment of chronic myelogenous leukemia in China since the 1980s. To gain an understanding of the interspecies differences in the metabolism of meisoindigo, the relevant metabolism studies were carried out for the first time in rat, pig and human liver microsomes of different genders by ultra fast liquid chromatography/tandem mass spectrometry (UFLC-MS/MS). The qualitative metabolite identification was accomplished by multiple reaction monitoring (MRM) in combination with Enhanced Product Ion (EPI). The semi-quantitative metabolic stability and metabolite formation were simultaneously measured by MRM. The in vitro metabolic pathways of meisoindigo in three species were proposed as 3,3' double bond reduction, followed by N-demethylation, and reduction followed by phenyl mono-oxidation. Two novel metabolic pathways involving direct phenyl mono-oxidation without reduction in the three species, and direct N-demethylation without reduction in only pig and human, were also proposed. It may be noted that the two metabolites formed after reduction followed by phenyl mono-oxidation at positions 4, 5, 6 or 7, as well as one metabolite formed from direct phenyl mono-oxidation at either of the two phenyl rings without reduction were found to be uniquely present in human. The in vitro t(1/2) and in vitro CL(int) values of meisoindigo were calculated. Statistical analysis showed there were no significant differences in the metabolic stability profiles of meisoindigo among three species, and gender effect on the metabolic stability of meisoindigo was negligible. Formation profiles of the most significant reductive metabolites were obtained in the three species.

  7. Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6.

    Science.gov (United States)

    Denton, Travis T; Zhang, Xiaodong; Cashman, John R

    2004-02-15

    S-(-)-Nicotine and 13 of the most prevalent nicotine-related alkaloids and metabolites (i.e., S-(-)-nornicotine, myosmine, beta-nicotyrine, S-cotinine, S-norcotinine, S-(-)-nicotine N-1'-oxide, S-(-)-nicotine Delta1'-5'-iminium ion, S-(-)-anabasine, S-(-)-N-methylanabasine, anabaseine, S-(-)-anatabine, nicotelline, and 2,3'-bipyridyl) were evaluated as inhibitors of human cDNA-expressed cytochrome P-450 2A6 (CYP2A6) mediated coumarin 7-hydroxylation. Tobacco alkaloids myosmine, S-(-)-nornicotine, S-cotinine, S-norcotinine, S-(-)-nicotine N-1'-oxide, S-(-)-nicotine Delta1'-5'-iminium ion, S-(-)-N-methylanabasine, anabaseine, and nicotelline had Ki values for inhibition of coumarin 7-hydroxylation ranging from 20 microM to more than 300 microM whereas nicotine and S-(-)-anatabine were much more potent (i.e. 4.4 and 3.8 microM, respectively). The tobacco alkaloids 2,3'-bipyridyl (7.7 microM) and S-(-)-anabasine (5.4 microM), were somewhat less potent compared with S-(-)-nicotine or S-(-)-anatabine in inhibition of human CYP2A6. beta-Nicotyrine, in which the N-methylpyrrolidino moiety of nicotine was replaced by the aromatic N-methylpyrrole ring, was shown to inhibit human CYP2A6 with much greater potency (Ki=0.37 microM) compared with S-(-)-nicotine. Among the compounds examined, only nicotine and beta-nicotyrine were mechanism-based inhibitors of human CYP2A6. The potency of the mechanism-based CYP2A6 inhibitors suggests that, for smokers, modulation of CYP2A6 may be greater than that predicted on the basis of serum concentration of these alkaloids. Our results indicate that the prominent nicotine-related alkaloid beta-nicotyrine present after smoking potently inhibits human CYP2A6.

  8. Do glutathione levels decline in aging human brain?

    Science.gov (United States)

    Tong, Junchao; Fitzmaurice, Paul S; Moszczynska, Anna; Mattina, Katie; Ang, Lee-Cyn; Boileau, Isabelle; Furukawa, Yoshiaki; Sailasuta, Napapon; Kish, Stephen J

    2016-04-01

    For the past 60 years a major theory of "aging" is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23-99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for "replication" investigations employing the new (1)H MRS imaging procedures in living human brain. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Plastination of dissected brain specimens and Mulligan-stained sections of the human brain.

    Science.gov (United States)

    Baeres, F M; Møller, M

    2001-12-01

    The difficulties in obtaining human brain material for teaching neuroanatomy have increased the demand for more durable brain specimens. In this paper, we describe results obtained by preparing large, plastinated, dissected human brain specimens and Mulligan-stained sections of the human brain. The brains were fixed in formalin, washed and dissected in order to visualize the fibre tracts and larger nuclei in the central nervous system. This was followed by dehydration at -20 degrees C in acetone. The specimens were then impregnated with silicone, Biodur S10, in vacuo and hardened in Biodur S6 vapour. The grey and white substance in the central nervous system as well as the larger fibre tracts and nuclei were clearly visible in the dissected, plastinated specimens. Coronal and sagittal sections of the human brain were stained according to Tompsett's modification of the Mulligan method. The sections were then dehydrated in cold acetone followed by forced impregnation with Biodur S10 and hardening. The plastinated sections stained distinctly and strongly and the nuclei in the forebrain, cerebellum and brain stem could be identified easily. The sections did not fade when exposed to light and could be easily handled in the classroom without damage. Therefore, the distinct visualization of neuroanatomical structures, the improved durability of the specimens, as well as the lack of odour make plastinated specimens and stained sections of the central nervous system a valuable tool for teaching neuroanatomy that compliments the use of wet preparations.

  10. Conscious brain-to-brain communication in humans using non-invasive technologies.

    Science.gov (United States)

    Grau, Carles; Ginhoux, Romuald; Riera, Alejandro; Nguyen, Thanh Lam; Chauvat, Hubert; Berg, Michel; Amengual, Julià L; Pascual-Leone, Alvaro; Ruffini, Giulio

    2014-01-01

    Human sensory and motor systems provide the natural means for the exchange of information between individuals, and, hence, the basis for human civilization. The recent development of brain-computer interfaces (BCI) has provided an important element for the creation of brain-to-brain communication systems, and precise brain stimulation techniques are now available for the realization of non-invasive computer-brain interfaces (CBI). These technologies, BCI and CBI, can be combined to realize the vision of non-invasive, computer-mediated brain-to-brain (B2B) communication between subjects (hyperinteraction). Here we demonstrate the conscious transmission of information between human brains through the intact scalp and without intervention of motor or peripheral sensory systems. Pseudo-random binary streams encoding words were transmitted between the minds of emitter and receiver subjects separated by great distances, representing the realization of the first human brain-to-brain interface. In a series of experiments, we established internet-mediated B2B communication by combining a BCI based on voluntary motor imagery-controlled electroencephalographic (EEG) changes with a CBI inducing the conscious perception of phosphenes (light flashes) through neuronavigated, robotized transcranial magnetic stimulation (TMS), with special care taken to block sensory (tactile, visual or auditory) cues. Our results provide a critical proof-of-principle demonstration for the development of conscious B2B communication technologies. More fully developed, related implementations will open new research venues in cognitive, social and clinical neuroscience and the scientific study of consciousness. We envision that hyperinteraction technologies will eventually have a profound impact on the social structure of our civilization and raise important ethical issues.

  11. Conscious brain-to-brain communication in humans using non-invasive technologies.

    Directory of Open Access Journals (Sweden)

    Carles Grau

    Full Text Available Human sensory and motor systems provide the natural means for the exchange of information between individuals, and, hence, the basis for human civilization. The recent development of brain-computer interfaces (BCI has provided an important element for the creation of brain-to-brain communication systems, and precise brain stimulation techniques are now available for the realization of non-invasive computer-brain interfaces (CBI. These technologies, BCI and CBI, can be combined to realize the vision of non-invasive, computer-mediated brain-to-brain (B2B communication between subjects (hyperinteraction. Here we demonstrate the conscious transmission of information between human brains through the intact scalp and without intervention of motor or peripheral sensory systems. Pseudo-random binary streams encoding words were transmitted between the minds of emitter and receiver subjects separated by great distances, representing the realization of the first human brain-to-brain interface. In a series of experiments, we established internet-mediated B2B communication by combining a BCI based on voluntary motor imagery-controlled electroencephalographic (EEG changes with a CBI inducing the conscious perception of phosphenes (light flashes through neuronavigated, robotized transcranial magnetic stimulation (TMS, with special care taken to block sensory (tactile, visual or auditory cues. Our results provide a critical proof-of-principle demonstration for the development of conscious B2B communication technologies. More fully developed, related implementations will open new research venues in cognitive, social and clinical neuroscience and the scientific study of consciousness. We envision that hyperinteraction technologies will eventually have a profound impact on the social structure of our civilization and raise important ethical issues.

  12. Optogenetic control of human neurons in organotypic brain cultures

    DEFF Research Database (Denmark)

    Andersson, My; Avaliani, Natalia; Svensson, Andreas

    2016-01-01

    Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof-of-c......-of-concept for the use of optogenetics in neuromodulation of human cortical and hippocampal neurons as a possible tool to explore network mechanisms and develop future therapeutic strategies.......Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof...

  13. Metabolite profiling and enzyme reaction phenotyping of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in humans.

    Science.gov (United States)

    Miyata, Atsunori; Hasegawa, Masatoshi; Hachiuma, Kenji; Mori, Haruyuki; Horiuchi, Nobuko; Mizuno-Yasuhira, Akiko; Chino, Yukihiro; Jingu, Shigeji; Sakai, Soichi; Samukawa, Yoshishige; Nakai, Yasuhiro; Yamaguchi, Jun-Ichi

    2017-04-01

    1. To understand the clearance mechanism of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, we investigated its human metabolite profile and metabolic enzymes responsible for the primary metabolic pathways in human using reaction phenotyping. 2. Sixteen metabolites of luseogliflozin were found in human plasma and/or urine and their structural information indicated that the drug was metabolized via multiple metabolic pathways. The primary metabolic pathways involve (1) O-deethylation to form M2 and subsequent glucuronidation to form M12, (2) ω-hydroxylation at ethoxy group to form M3 followed by oxidation to form the corresponding carboxylic acid metabolite (M17) and (3) direct glucuronidation to form M8. 3. The reaction phenotyping studies indicated that the formation of M2 was mainly mediated by cytochrome P450 (CYP) 3A4/5, and subsequently M12 formation was catalyzed by UGT1A1, UGT1A8 and UGT1A9. The formation of M3 was mediated by CYP4A11, CYP4F2 and CYP4F3B, and the further oxidation of M3 to M17 was mediated by alcohol dehydrogenase and aldehyde dehydrogenase. The formation of M8 was catalyzed by UGT1A1. 4. These results demonstrate that luseogliflozin is metabolized through multiple pathways, including CYP-mediated oxidation and glucuronidation, in human.

  14. Chimeric cytochromes P450 engineered by domain swapping and random mutagenesis for producing human metabolites of drugs.

    Science.gov (United States)

    Kang, Ji-Yeon; Ryu, Sang Hoon; Park, Sun-Ha; Cha, Gun Su; Kim, Dong-Hyun; Kim, Keon-Hee; Hong, Austin W; Ahn, Taeho; Pan, Jae-Gu; Joung, Young Hee; Kang, Hyung-Sik; Yun, Chul-Ho

    2014-07-01

    Human drug metabolites produced by cytochrome P450 enzymes are critical for safety testing and may themselves act as drugs or leads in the drug discovery and development process. Here, highly active chimeric fusion proteins (chimeras) were obtained by reductase domain swapping of mutants at key catalytic residues of the heme domain with that of a natural variant (CYP102A1.2) of P450 BM3 (CYP102A1.1) from Bacillus megaterium. Random mutagenesis at the heme domain of the chimera was also used to generate chimeric mutants that were more active and diverse than the chimeras themselves. To determine whether the chimeras and several mutants of the highly active chimera displayed enhanced catalytic activity and, more importantly, whether they acquired activities of biotechnological importance, we measured the oxidation activities of the chimeras and chimeric mutants toward human P450 substrates, mainly drugs. Some of the chimeric mutants showed high activity toward typical human P450 substrates including drugs. Statin leads, especially chiral products, with inhibitory effects toward HMG-CoA reductase could be obtained from metabolites of statin drugs generated using these chimeric mutants. This study reveals the critical role of the reductase domain for the activity of P450 BM3 and shows that chimeras generated by domain swapping can be used to develop industrial enzymes for the synthesis of human metabolites from drugs and drug leads. © 2014 Wiley Periodicals, Inc.

  15. Lactate fuels the human brain during exercise

    DEFF Research Database (Denmark)

    Quistorff, Bjørn; Secher, Niels H; Van Lieshout, Johannes J

    2008-01-01

    lactate in proportion to the arterial concentration. Cerebral lactate uptake, together with glucose uptake, is larger than the uptake accounted for by the concomitant O(2) uptake, as reflected by the decrease in cerebral metabolic ratio (CMR) [the cerebral molar uptake ratio O(2)/(glucose+(1/2) lactate...... blockade but not with beta(1)-adrenergic blockade alone. Also, CMR decreases in response to epinephrine, suggesting that a beta(2)-adrenergic receptor mechanism enhances glucose and perhaps lactate transport across the blood-brain barrier. The pattern of CMR decrease under various forms of brain activation...

  16. Comparison of 1.5T and 3T 1H MR Spectroscopy for Human Brain Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ji hoon; Chang, Kee Hyun; Na, Dong Gyu; Song, In Chan; Kim, Seung Ja; Kwon, Bae Ju; Han, Moon Hee [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2006-09-15

    We wanted to estimate the practical improvements of 3T proton MR spectroscopy (1H MRS) as compared with 1.5T 1H MRS for the evaluation of human brain tumors. Single voxel 1H MRS was performed at both 1.5T and 3T in 13 patients suffering with brain tumors. Using the same data acquisition parameters at both field strengths, the 1H MRS spectra were obtained with a short echo time (TE) (35 msec) and an intermediate TE (144 msec) with the voxel size ranging from 2.0 cm{sup 3} to 8.7 cm{sup 3}. The signal to noise ratios (SNRs) of the metabolites (myoinositol [MI], choline compounds [Cho], creatine /phosphocreatine [Cr], N-acetyl-aspartate [NAA], lipid and lactate [LL]) and the metabolite ratios of MI/Cr, Cho/Cr, Cho/NAA and LL/Cr were compared at both TEs between the two field strengths in each brain tumor. The degrees 70f spectral resolution between the Cho and Cr peaks were qualitatively compared between the two field strengths in each brain tumor. The SNRs of the metabolites at 3T demonstrated 49-73% increase at a short TE (p< 0.01) and only 2-12% increase at an intermediate TE (p> 0.05) compared with those of 1.5T. The SNR of inverted lactate at an intermediate TE decreased down to 49% with poorer inversion at 3T (p< 0.05). There was no significant difference in the metabolite ratios between the two field strengths. The degrees of the spectral resolution at 3T were slightly superior to those of 1.5T at a short TE. As compared with 1.5T, 3T {sup 1}H MRS demonstrated 49-73% SNR increase in the cerebral metabolites and slightly superior spectral resolution only at a short TE, but little at an intermediate TE, in the brain tumors. There was no significant difference in the metabolite ratios between the two field strengths.

  17. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells.

    Science.gov (United States)

    Gober, Hans-Jürgen; Kistowska, Magdalena; Angman, Lena; Jenö, Paul; Mori, Lucia; De Libero, Gennaro

    2003-01-20

    T lymphocytes expressing the T cell receptor (TCR)-gammadelta recognize unknown antigens on tumor cells. Here we identify metabolites of the mevalonate pathway as the tumor ligands that activate TCR-gammadelta cells. In tumor cells, blockade of hydroxy-methylglutaryl-CoA reductase (HMGR), the rate limiting enzyme of the mevalonate pathway, prevents both accumulation of mevalonate metabolites and recognition by TCR-gammadelta cells. When metabolite accumulation is induced by overexpressing HMGR or by treatment with nitrogen-containing bisphosphonate drugs, tumor cells derived from many tissues acquire the capacity to stimulate the same TCR-gammadelta population. Accumulation of mevalonate metabolites in tumor cells is a powerful danger signal that activates the immune response and may represent a novel target of tumor immunotherapy.

  18. Human Development XII: A Theory for the Structure and Function of the Human Brain

    OpenAIRE

    Søren Ventegodt; Tyge Dahl Hermansen; Isack Kandel; Joav Merrick

    2008-01-01

    The human brain is probably the most complicated single structure in the biological universe. The cerebral cortex that is traditionally connected with consciousness is extremely complex. The brain contains approximately 1,000,000 km of nerve fibers, indicating its enormous complexity and which makes it difficult for scientists to reveal the function of the brain. In this paper, we propose a new model for brain functions, i.e., information-guided self-organization of neural patterns, where inf...

  19. Evaluation and metabolite studies of {sup 125}I- and {sup 123}I-labelled E-(R,R)-IQNP: potential radioligands for visualization of M{sub 1} muscarinic acetylcholine receptors in brain

    Energy Technology Data Exchange (ETDEWEB)

    Bergstroem, Kim A.; Halldin, Christer; Hiltunen, Jukka; Swahn, Carl-Gunnar; Ito, Hiroshi; Ginovart, Nathalie; Hall, Haakan; McPherson, Daniel W.; Knapp, F. F. (Russ); Larsson, Stig; Schnell, Per-Olof; Farde, Lars

    1998-04-01

    A new ligand for the M{sub 1} muscarinic receptor subtype, E-(R,R)-1-azabicyclo[2.2.2]oct-3-yl {alpha}-hydroxy-{alpha}-(1-iodo-1-propen-3-yl)-{alpha}-phenylacetate (E-IQNP), was labelled with {sup 125}I and {sup 123}I for autoradiographic studies on human whole-brain cryosections and SPET studies, respectively, in Cynomolgus monkey. Autoradiography demonstrated E-[{sup 125}I]IQNP binding in M{sub 1} receptor-rich regions such as the neocortex and the striatum. The binding was displaceable by the selective M{sub 1} antagonist biperiden. In vivo single photon emission tomography (SPET) studies with E-[{sup 123}I]IQNP demonstrated a high accumulation of radioactivity in the monkey neocortex. Rapid hydrolysis of the quinuclidinyl ester to the free acid was found to be a major biotransformation route for E-[{sup 123}I]IQNP. The free acid of E-[{sup 123}I]IQNP does not pass the blood-brain barrier, but the plasma concentration was high as compared to the total radioactivity in brain. It is thus necessary to correct for the high concentration of radioactive metabolites in parenchymal blood (CBV) to obtain accurate values for E-[{sup 123}I]IQNP binding in brain.

  20. Green tea catechins and their metabolites in human skin before and after exposure to ultraviolet radiation.

    Science.gov (United States)

    Clarke, Kayleigh A; Dew, Tristan P; Watson, Rachel E B; Farrar, Mark D; Osman, Joanne E; Nicolaou, Anna; Rhodes, Lesley E; Williamson, Gary

    2016-01-01

    Dietary flavonoids may protect against sunburn inflammation in skin. Preliminary reports using less complete analysis suggest that certain catechins and their metabolites are found in skin biopsies and blister fluid after consumption of green tea; however, it is not known if they are affected by solar-simulated ultraviolet radiation (UVR) or whether conjugated forms, with consequently altered bioactivity, are present. The present study tested the hypothesis that UVR affects the catechin levels in the skin of healthy volunteers after consumption of green tea and how catechins in the plasma are related to their presence in skin tissue samples. In an open oral intervention study, 11 subjects consumed green tea and vitamin C supplements daily for 3months. Presupplementation and postsupplementation plasma samples, suction blister fluid and skin biopsies were collected; the latter two samples were collected both before and after UVR. A sensitive high-performance liquid chromatography/mass spectrometric assay was used to measure the intact catechin metabolites, conjugates and free forms. Seven green tea catechins and their corresponding metabolites were identified postsupplementation in skin biopsies, 20 in blister fluid and 26 in plasma, with 15 green tea catechin metabolites present in both blister fluid and plasma. The valerolactone, O-methyl-M4-O-sulfate, a gut microbiota metabolite of catechins, was significantly increased 1.6-fold by UVR in blister fluid samples. In conclusion, there were some common catechin metabolites in the plasma and blister fluid, and the concentration was always higher in plasma. The results suggest that green tea catechins and metabolites are bioavailable in skin and provide a novel link between catechin metabolites derived from the skin and gut microbiota. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Toward discovery science of human brain function.

    NARCIS (Netherlands)

    Biswal, B.B.; Mennes, M.J.J.; Zuo, X.N.; Gohel, S.; Kelly, C.; Smith, S.M.; Beckmann, C.F.; Adelstein, J.S.; Buckner, R.L.; Colcombe, S.; Dogonowski, A.M.; Ernst, M.; Fair, D.; Hampson, M.; Hoptman, M.J.; Hyde, J.S.; Kiviniemi, V.J.; Kotter, R.; Li, S.J.; Lin, C.P.; Lowe, M.J.; Mackay, C.; Madden, D.J.; Madsen, K.H.; Margulies, D.S.; Mayberg, H.S.; McMahon, K.; Monk, C.S.; Mostofsky, S.H.; Nagel, B.J.; Pekar, J.J.; Peltier, S.J.; Petersen, S.E.; Riedl, V.; Rombouts, S.A.R.B.; Rypma, B.; Schlaggar, B.L.; Schmidt, S.; Seidler, R.D.; Siegle, G.J.; Sorg, C.; Teng, G.J.; Veijola, J.; Villringer, A.; Walter, M.; Wang, L.; Weng, X.C.; Whitfield-Gabrieli, S.; Williamson, P.; Windischberger, C.; Zang, Y.F.; Zhang, H.Y.; Castellanos, F.X.; Milham, M.P.

    2010-01-01

    Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a

  2. Weight lifting in the human brain

    NARCIS (Netherlands)

    Lange, F.P. de

    2006-01-01

    The world, just like us, is constantly changing. Making predictions about what will happen to you when you do something (and correcting these predictions based on what is actually happening) is therefore of vital importance. An influential theory states that the brain solves this challenge by using

  3. TV, Brain Waves and Human Behavior

    Science.gov (United States)

    Science News, 1978

    1978-01-01

    Describes the procedure to test the hypothesis that subjects' brain waves in response to a television flicker (distraction) would be smaller in amplitude during television programs of high, in contrast to low, interest. Results from 12 viewers support the hypothesis. (CP)

  4. On Expression Patterns and Developmental Origin of Human Brain Regions.

    Science.gov (United States)

    Kirsch, Lior; Chechik, Gal

    2016-08-01

    Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92%) exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions.

  5. On Expression Patterns and Developmental Origin of Human Brain Regions.

    Directory of Open Access Journals (Sweden)

    Lior Kirsch

    2016-08-01

    Full Text Available Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92% exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions.

  6. Human Stem Cell?Derived Endothelial?Hepatic Platform for Efficacy Testing of Vascular?Protective Metabolites from Nutraceuticals

    OpenAIRE

    Narmada, Balakrishnan Chakrapani; Goh, Yeek Teck; Li, Huan; Sinha, Sanjay; Yu, Hanry; Cheung, Christine

    2016-01-01

    Abstract Atherosclerosis underlies many cardiovascular and cerebrovascular diseases. Nutraceuticals are emerging as a therapeutic moiety for restoring vascular health. Unlike small?molecule drugs, the complexity of ingredients in nutraceuticals often confounds evaluation of their efficacy in preclinical evaluation. It is recognized that the liver is a vital organ in processing complex compounds into bioactive metabolites. In this work, we developed a coculture system of human pluripotent stem...

  7. Methodology for and the determination of the major constituents and metabolites of the Amazonian botanical medicine ayahuasca in human urine.

    Science.gov (United States)

    McIlhenny, Ethan H; Riba, Jordi; Barbanoj, Manel J; Strassman, Rick; Barker, Steven A

    2011-09-01

    Ayahuasca, also known as caapi or yage among various South American groups, holds a highly esteemed and millennia-old position in these cultures' medical and religious pharmacopeia. There is now an increasing interest in the potential for modern medical applications of ayahuasca, as well as concerns regarding its increasing potential for abuse. Toxicological and clinical research to address these issues will require information regarding its metabolism and clearance. Thus, a rapid, sensitive and specific method for characterization and quantitation of the major constituents and of the metabolites of ayahuasca in urine is needed. The present research provides a protocol for conducting such analyses. The characteristics of the method, conducted by sample dilution and using HPLC-electrospray ionization (ESI)-selected reaction monitoring (SRM)-tandem mass spectrometry, are presented. The application of the analytical protocol to urine samples collected from three individuals that were administered ayahuasca has also been demonstrated. The data show that the major metabolite of the hallucinogenic component of ayahuasca, N,N-dimethyltryptamine (DMT), is the corresponding N-oxide, the first time this metabolite has been described in in vivo studies in humans. Further, very little DMT was detected in urine, despite the inhibition of monoamine oxidase afforded by the presence of the harmala alkaloids in ayahuasca. The major harmala alkaloid excreted was tetrahydroharmine. Other excretion products and metabolites were also identified and quantified. The method described would be suitable for use in further toxicological and clinical research on ayahuasca. Copyright © 2010 John Wiley & Sons, Ltd.

  8. BrainNet Viewer: a network visualization tool for human brain connectomics.

    Science.gov (United States)

    Xia, Mingrui; Wang, Jinhui; He, Yong

    2013-01-01

    The human brain is a complex system whose topological organization can be represented using connectomics. Recent studies have shown that human connectomes can be constructed using various neuroimaging technologies and further characterized using sophisticated analytic strategies, such as graph theory. These methods reveal the intriguing topological architectures of human brain networks in healthy populations and explore the changes throughout normal development and aging and under various pathological conditions. However, given the huge complexity of this methodology, toolboxes for graph-based network visualization are still lacking. Here, using MATLAB with a graphical user interface (GUI), we developed a graph-theoretical network visualization toolbox, called BrainNet Viewer, to illustrate human connectomes as ball-and-stick models. Within this toolbox, several combinations of defined files with connectome information can be loaded to display different combinations of brain surface, nodes and edges. In addition, display properties, such as the color and size of network elements or the layout of the figure, can be adjusted within a comprehensive but easy-to-use settings panel. Moreover, BrainNet Viewer draws the brain surface, nodes and edges in sequence and displays brain networks in multiple views, as required by the user. The figure can be manipulated with certain interaction functions to display more detailed information. Furthermore, the figures can be exported as commonly used image file formats or demonstration video for further use. BrainNet Viewer helps researchers to visualize brain networks in an easy, flexible and quick manner, and this software is freely available on the NITRC website (www.nitrc.org/projects/bnv/).

  9. BrainNet Viewer: a network visualization tool for human brain connectomics.

    Directory of Open Access Journals (Sweden)

    Mingrui Xia

    Full Text Available The human brain is a complex system whose topological organization can be represented using connectomics. Recent studies have shown that human connectomes can be constructed using various neuroimaging technologies and further characterized using sophisticated analytic strategies, such as graph theory. These methods reveal the intriguing topological architectures of human brain networks in healthy populations and explore the changes throughout normal development and aging and under various pathological conditions. However, given the huge complexity of this methodology, toolboxes for graph-based network visualization are still lacking. Here, using MATLAB with a graphical user interface (GUI, we developed a graph-theoretical network visualization toolbox, called BrainNet Viewer, to illustrate human connectomes as ball-and-stick models. Within this toolbox, several combinations of defined files with connectome information can be loaded to display different combinations of brain surface, nodes and edges. In addition, display properties, such as the color and size of network elements or the layout of the figure, can be adjusted within a comprehensive but easy-to-use settings panel. Moreover, BrainNet Viewer draws the brain surface, nodes and edges in sequence and displays brain networks in multiple views, as required by the user. The figure can be manipulated with certain interaction functions to display more detailed information. Furthermore, the figures can be exported as commonly used image file formats or demonstration video for further use. BrainNet Viewer helps researchers to visualize brain networks in an easy, flexible and quick manner, and this software is freely available on the NITRC website (www.nitrc.org/projects/bnv/.

  10. Conservation of regional gene expression in mouse and human brain.

    Directory of Open Access Journals (Sweden)

    Andrew D Strand

    2007-04-01

    Full Text Available Many neurodegenerative diseases have a hallmark regional and cellular pathology. Gene expression analysis of healthy tissues may provide clues to the differences that distinguish resistant and sensitive tissues and cell types. Comparative analysis of gene expression in healthy mouse and human brain provides a framework to explore the ability of mice to model diseases of the human brain. It may also aid in understanding brain evolution and the basis for higher order cognitive abilities. Here we compare gene expression profiles of human motor cortex, caudate nucleus, and cerebellum to one another and identify genes that are more highly expressed in one region relative to another. We separately perform identical analysis on corresponding brain regions from mice. Within each species, we find that the different brain regions have distinctly different expression profiles. Contrasting between the two species shows that regionally enriched genes in one species are generally regionally enriched genes in the other species. Thus, even when considering thousands of genes, the expression ratios in two regions from one species are significantly correlated with expression ratios in the other species. Finally, genes whose expression is higher in one area of the brain relative to the other areas, in other words genes with patterned expression, tend to have greater conservation of nucleotide sequence than more widely expressed genes. Together these observations suggest that region-specific genes have been conserved in the mammalian brain at both the sequence and gene expression levels. Given the general similarity between patterns of gene expression in healthy human and mouse brains, we believe it is reasonable to expect a high degree of concordance between microarray phenotypes of human neurodegenerative diseases and their mouse models. Finally, these data on very divergent species provide context for studies in more closely related species that address

  11. Shortcomings of the Human Brain and Remedial Action by Religion

    Science.gov (United States)

    Reich, K. Helmut

    2010-01-01

    There is no consensus as to whether, and if so, in which regard and to what extent science and religion is needed for human survival. Here a circumscribed domain is taken up: the sovereignty and sufficiency of the human brain in this context. Several of its shortcomings are pointed out. Religion and other aspects of culture are needed for remedial…

  12. Anandamide hydrolysis by human cells in culture and brain

    NARCIS (Netherlands)

    Vliegenthart, J.F.G.; Maccarrone, M.; Stelt, M. van der; Rossi, A.; Veldink, G.A.; Finazzi Agrò, A.

    1998-01-01

    Anandamide (arachidonylethanolamide; AnNH) has important neuromodulatory and immunomodulatory activities. This lipid is rapidly taken up and hydrolyzed to arachidonate and ethanolamine in many organisms. As yet, AnNH inactivation has not been studied in humans. Here, a human brain fatty-acid amide

  13. The Evolution of Human Intelligence and the Coefficient of Additive Genetic Variance in Human Brain Size

    Science.gov (United States)

    Miller, Geoffrey F.; Penke, Lars

    2007-01-01

    Most theories of human mental evolution assume that selection favored higher intelligence and larger brains, which should have reduced genetic variance in both. However, adult human intelligence remains highly heritable, and is genetically correlated with brain size. This conflict might be resolved by estimating the coefficient of additive genetic…

  14. Expression of iron-related genes in human brain and brain tumors

    Directory of Open Access Journals (Sweden)

    Britton Robert S

    2009-04-01

    Full Text Available Abstract Background Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (HAMP, HFE, neogenin (NEO1, transferrin receptor 1 (TFRC, transferrin receptor 2 (TFR2, and hemojuvelin (HFE2 in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines. Results Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions, low expression of HFE in normal brain with elevated HFE expression in meningiomas, and absence of hepcidin mRNA in astrocytoma cell lines despite expression in normal brain and tumor specimens. Conclusion These results indicate that several iron-related genes are expressed in normal brain, and that their expression may be dysregulated in brain tumors.

  15. Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice.

    Science.gov (United States)

    Yuan, Zhi-Xin; Rapoport, Stanley I

    2015-10-01

    Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd.

  16. Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Larsen Simon

    2012-03-01

    Full Text Available Abstract Background Various by-products of the cellular metabolism, such as reactive carbonyl species (RCS are potentially harmful to cells and tissues, and play a role in many physiological and pathological processes. Among various RCS is the highly reactive dicarbonyl glyoxal (GO, which is a natural physiological metabolite produced by the auto-oxidation of glucose, and can form covalent adducts known as advanced glycation endproducts (AGE. We have previously reported that GO accelerates ageing and causes premature senescence in normal human skin fibroblasts. Results Using a bone marrow-derived telomerase-immortalised mesenchymal stem cell line hMSC-TERT we have observed that an exposure of cells to 0.75 mM and 1 mM GO induces irreversible cellular senescence within 3 days. Induction of senescence in hMSC-TERT was demonstrated by a variety of markers, including characteristic cell morphology and enlargement, vacuolisation, multinucleation, induction of senescence associated β-galactosidase, cell cycle arrest, and increased levels of a cell cycle inhibitor p16. These changes were accompanied by increased extent of DNA breaks as measured by the comet assay, and increased levels of the AGE product, carboxymethyl-lysine (CML. Furthermore, the in vitro differentiation potential of hMSC-TERT to become functional osteoblasts was highly reduced in GO-treated stem cells, as determined by alkaline phosphatase (ALP activity and mineralized matrix (MM formation. Conclusions The results of our study imply that an imbalanced glucose metabolism can reduce the functioning ability of stem cells in vivo both during ageing and during stem cell-based therapeutic interventions.

  17. Season of sampling and season of birth influence serotonin metabolite levels in human cerebrospinal fluid.

    Directory of Open Access Journals (Sweden)

    Jurjen J Luykx

    Full Text Available BACKGROUND: Animal studies have revealed seasonal patterns in cerebrospinal fluid (CSF monoamine (MA turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large set of healthy adults. METHODOLOGY/PRINCIPAL FINDINGS: Standardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA, dopamine (homovanillic acid, HVA and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG were measured using high performance liquid chromatography (HPLC. Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75. The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050, with predicted maximum (PC(max and minimum (PC(min concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PC(max = 172 and PC(min = 126. The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations. CONCLUSION: In subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall.

  18. Simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell cultures and in sub-regions of guinea pig brain.

    Science.gov (United States)

    Schou-Pedersen, Anne Marie V; Hansen, Stine N; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2016-08-15

    In the present paper, we describe a validated chromatographic method for the simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell culture and in sub-regions of the guinea pig brain. Electrochemical detection provided limits of quantifications (LOQs) between 3.6 and 12nM. Within the linear range, obtained recoveries were from 90.9±9.9 to 120±14% and intra-day and inter-day precisions found to be less than 5.5% and 12%, respectively. The analytical method was applicable for quantification of intracellular and extracellular amounts of monoamine neurotransmitters and their metabolites in guinea pig frontal cortex and hippocampal primary neuronal cell cultures. Noradrenaline, dopamine and serotonin were found to be in a range from 0.31 to 1.7pmol per 2 million cells intracellularly, but only the biogenic metabolites could be detected extracellularly. Distinct differences in monoamine concentrations were observed when comparing concentrations in guinea pig frontal cortex and cerebellum tissue with higher amounts of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid in frontal cortex, as compared to cerebellum. The chemical turnover in frontal cortex tissue of guinea pig was for serotonin successfully predicted from the turnover observed in the frontal cortex cell culture. In conclusion, the present analytical method shows high precision, accuracy and sensitivity and is broadly applicable to monoamine measurements in cell cultures as well as brain biopsies from animal models used in preclinical neurochemistry. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. The bilingual brain: Flexibility and control in the human cortex

    Science.gov (United States)

    Buchweitz, Augusto; Prat, Chantel

    2013-12-01

    The goal of the present review is to discuss recent cognitive neuroscientific findings concerning bilingualism. Three interrelated questions about the bilingual brain are addressed: How are multiple languages represented in the brain? how are languages controlled in the brain? and what are the real-world implications of experience with multiple languages? The review is based on neuroimaging research findings about the nature of bilingual processing, namely, how the brain adapts to accommodate multiple languages in the bilingual brain and to control which language should be used, and when. We also address how this adaptation results in differences observed in the general cognition of bilingual individuals. General implications for models of human learning, plasticity, and cognitive control are discussed.

  20. Electrical Guidance of Human Stem Cells in the Rat Brain

    Directory of Open Access Journals (Sweden)

    Jun-Feng Feng

    2017-07-01

    Full Text Available Limited migration of neural stem cells in adult brain is a roadblock for the use of stem cell therapies to treat brain diseases and injuries. Here, we report a strategy that mobilizes and guides migration of stem cells in the brain in vivo. We developed a safe stimulation paradigm to deliver directional currents in the brain. Tracking cells expressing GFP demonstrated electrical mobilization and guidance of migration of human neural stem cells, even against co-existing intrinsic cues in the rostral migration stream. Transplanted cells were observed at 3 weeks and 4 months after stimulation in areas guided by the stimulation currents, and with indications of differentiation. Electrical stimulation thus may provide a potential approach to facilitate brain stem cell therapies.

  1. The maternal brain and its plasticity in humans

    Science.gov (United States)

    Kim, Pilyoung; Strathearn, Lane; Swain, James E.

    2015-01-01

    Early mother-infant relationships play important roles in infants’ optimal development. New mothers undergo neurobiological changes that support developing mother-infant relationships regardless of great individual differences in those relationships. In this article, we review the neural plasticity in human mothers’ brains based on functional magnetic resonance imaging (fMRI) studies. First, we review the neural circuits that are involved in establishing and maintaining mother-infant relationships. Second, we discuss early postpartum factors (e.g., birth and feeding methods, hormones, and parental sensitivity) that are associated with individual differences in maternal brain neuroplasticity. Third, we discuss abnormal changes in the maternal brain related to psychopathology (i.e., postpartum depression, posttraumatic stress disorder, substance abuse) and potential brain remodeling associated with interventions. Last, we highlight potentially important future research directions to better understand normative changes in the maternal brain and risks for abnormal changes that may disrupt early mother-infant relationships. PMID:26268151

  2. Brain and Social Networks: Fundamental Building Blocks of Human Experience.

    Science.gov (United States)

    Falk, Emily B; Bassett, Danielle S

    2017-09-01

    How do brains shape social networks, and how do social ties shape the brain? Social networks are complex webs by which ideas spread among people. Brains comprise webs by which information is processed and transmitted among neural units. While brain activity and structure offer biological mechanisms for human behaviors, social networks offer external inducers or modulators of those behaviors. Together, these two axes represent fundamental contributors to human experience. Integrating foundational knowledge from social and developmental psychology and sociology on how individuals function within dyads, groups, and societies with recent advances in network neuroscience can offer new insights into both domains. Here, we use the example of how ideas and behaviors spread to illustrate the potential of multilayer network models. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. A family of hyperelastic models for human brain tissue

    Science.gov (United States)

    Mihai, L. Angela; Budday, Silvia; Holzapfel, Gerhard A.; Kuhl, Ellen; Goriely, Alain

    2017-09-01

    Experiments on brain samples under multiaxial loading have shown that human brain tissue is both extremely soft when compared to other biological tissues and characterized by a peculiar elastic response under combined shear and compression/tension: there is a significant increase in shear stress with increasing axial compression compared to a moderate increase with increasing axial tension. Recent studies have revealed that many widely used constitutive models for soft biological tissues fail to capture this characteristic response. Here, guided by experiments of human brain tissue, we develop a family of modeling approaches that capture the elasticity of brain tissue under varying simple shear superposed on varying axial stretch by exploiting key observations about the behavior of the nonlinear shear modulus, which can be obtained directly from the experimental data.

  4. Decade of the Brain 1990--2000: Maximizing human potential

    Energy Technology Data Exchange (ETDEWEB)

    1991-04-01

    The US Decade of the Brain offers scientists throughout the Federal Government a unique opportunity to advance and apply scientific knowledge about the brain and nervous system. During the next 10 years, scientists hope to maximize human potential through studies of human behavior, senses and communication, learning and memory, genetic/chemical alterations, and environmental interactions. Progress in these areas should lead to reductions in mortality from brain and nervous system disorders and to improvements in the quality of life. This report identifies nine research areas that could form the basis of an integrated program in the brain and behavioral sciences. A chart summarizing the Federal activities in these nine areas may be found at the back of the report. In addition, three areas that span the nine research areas -- basic research, technology and international activities -- are considered.

  5. Fundamental Dynamical Modes Underlying Human Brain Synchronization

    Directory of Open Access Journals (Sweden)

    Catalina Alvarado-Rojas

    2012-01-01

    Full Text Available Little is known about the long-term dynamics of widely interacting cortical and subcortical networks during the wake-sleep cycle. Using large-scale intracranial recordings of epileptic patients during seizure-free periods, we investigated local- and long-range synchronization between multiple brain regions over several days. For such high-dimensional data, summary information is required for understanding and modelling the underlying dynamics. Here, we suggest that a compact yet useful representation is given by a state space based on the first principal components. Using this representation, we report, with a remarkable similarity across the patients with different locations of electrode placement, that the seemingly complex patterns of brain synchrony during the wake-sleep cycle can be represented by a small number of characteristic dynamic modes. In this space, transitions between behavioral states occur through specific trajectories from one mode to another. These findings suggest that, at a coarse level of temporal resolution, the different brain states are correlated with several dominant synchrony patterns which are successively activated across wake-sleep states.

  6. Small-world human brain networks: Perspectives and challenges.

    Science.gov (United States)

    Liao, Xuhong; Vasilakos, Athanasios V; He, Yong

    2017-06-01

    Modelling the human brain as a complex network has provided a powerful mathematical framework to characterize the structural and functional architectures of the brain. In the past decade, the combination of non-invasive neuroimaging techniques and graph theoretical approaches enable us to map human structural and functional connectivity patterns (i.e., connectome) at the macroscopic level. One of the most influential findings is that human brain networks exhibit prominent small-world organization. Such a network architecture in the human brain facilitates efficient information segregation and integration at low wiring and energy costs, which presumably results from natural selection under the pressure of a cost-efficiency balance. Moreover, the small-world organization undergoes continuous changes during normal development and ageing and exhibits dramatic alterations in neurological and psychiatric disorders. In this review, we survey recent advances regarding the small-world architecture in human brain networks and highlight the potential implications and applications in multidisciplinary fields, including cognitive neuroscience, medicine and engineering. Finally, we highlight several challenging issues and areas for future research in this rapidly growing field. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Three-dimensional microtomographic imaging of human brain cortex

    CERN Document Server

    Mizutania, Ryuta; Uesugi, Kentaro; Ohyama, Masami; Takekoshi, Susumu; Osamura, R Yoshiyuki; Suzuki, Yoshio

    2016-01-01

    This paper describes an x-ray microtomographic technique for imaging the three-dimensional structure of the human cerebral cortex. Neurons in the brain constitute a neural circuit as a three-dimensional network. The brain tissue is composed of light elements that give little contrast in a hard x-ray transmission image. The contrast was enhanced by staining neural cells with metal compounds. The obtained structure revealed the microarchitecture of the gray and white matter regions of the frontal cortex, which is responsible for the higher brain functions.

  8. Pharmacokinetics of 6-, 8-, 10-Gingerols and 6-Shogaol and Conjugate Metabolites in Healthy Human Subjects

    Science.gov (United States)

    Zick, Suzanna M.; Djuric, Zora; Ruffin, Mack T.; Litzinger, Amie J.; Normolle, Daniel P.; Feng, Meihua Rose; Brenner, Dean E.

    2009-01-01

    Background Ginger demonstrates promising anticancer properties. No research has examined the pharmacokinetics of the ginger constituents 6-, 8-, 10-gingerol and 6-shogaol in humans. We conducted a clinical trial with 6-, 8-, 10-gingerol and 6-shogaol examining the pharmacokinetics and tolerability of these analytes and their conjugate metabolites Methods Human volunteers were given ginger at doses from 100 mg, to 2.0 g (N=27), and blood samples were obtained at 15 minutes to 72 hours after a single oral dose. Participants were allocated in a dose-escalation manner starting with 100 mg. There was a total of three participants at each dose except for 1.0 g (N=6) and 2.0 g (N=9). Results No participant had detectable free 6-, 8-, 10-gingerol or 6-shogaol, but 6-, 8-, 10-gingerol and 6-shogaol glucuronides were detected. The 6-gingerol sulfate conjugate was detected above the 1.0 g dose but there were no detectable 10-gingerol or 6-shogaol sulfates except for one participant with detectable 8-gingerol sulfate. The Cmax and AUC values (Mean±SE) estimated for the 2.0 g dose are 0.85±0.43, 0.23±0.16, 0.53±0.40, and 0.15±0.12 μg/mL ; and 65.6.33±44.4, 18.1±20.3, 50.1±49.3, and 10.9±13.0 μg·hr/mL for 6-, 8-, 10-gingerol, and 6-shogaol. The corresponding tmax values are 65.6±44.4, 73.1±29.4, 75.0±27.8, and 65.6±22.6 minutes and the analytes had elimination half-lives gingerol and 6-shogaol conjugates were present as either glucuronide or sulfate conjugates, not as mixed conjugates, although 6-, 10-gingerol were an exception. Conclusion Six-, 8-, 10-gingerol and 6-shogaol is absorbed after oral dosing and can be detected as glucuronide and sulfate conjugates. PMID:18708382

  9. Human-like brain hemispheric dominance in birdsong learning

    OpenAIRE

    Moorman, Sanne; Gobes, Sharon M. H.; Kuijpers, Maaike; Kerkhofs, Amber; Zandbergen, Matthijs A.; Bolhuis, Johan J.

    2012-01-01

    Unlike nonhuman primates, songbirds learn to vocalize very much like human infants acquire spoken language. In humans, Broca’s area in the frontal lobe and Wernicke’s area in the temporal lobe are crucially involved in speech production and perception, respectively. Songbirds have analogous brain regions that show a similar neural dissociation between vocal production and auditory perception and memory. In both humans and songbirds, there is evidence for lateralization of neural responsivenes...

  10. Distribution of vesicular glutamate transporters in the human brain

    Directory of Open Access Journals (Sweden)

    Erika eVigneault

    2015-03-01

    Full Text Available Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3 are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains.

  11. Several methods to determine heavy metals in the human brain

    Science.gov (United States)

    Andrási, Erzsébet; Igaz, Sarolta; Szoboszlai, Norbert; Farkas, Éva; Ajtony, Zsolt

    1999-05-01

    The determination of naturally occurring heavy metals in various parts of the human brain is discussed. The patients had no diseases in their central nervous systems (five individuals, mean age 70 years). Twenty brain parts were selected from both hemispheres. The analysis was carried out by graphite furnace atomic absorption spectrometry, inductively coupled plasma atomic emission spectrometry and instrumental neutron activation analysis methods. Accuracy and precision of the applied techniques were tested by using standard reference materials. Two digestion methods were used to dissolve the brain samples for ICP-AES and GF-AAS. One was performed in a Parr-bomb and the second in a microwave oven. The present results show a non-homogeneous distribution of the essential elements (Cu, Fe, Mn, Zn) in normal human brain. Corresponding regions in both hemispheres showed an almost identical concentration of these elements. In the case of toxic elements (Pb, Cd) an average value in different brain regions can not be established because of the high variability of individual data. This study indicates that beside differences in Pb and Cd intake with foods or cigarette smoke inhalation, the main factors of the high inter-individual variability of these element concentrations in human brain parts may be a marked difference in individual elimination or accumulation capabilities.

  12. A psychology of the human brain-gut-microbiome axis.

    Science.gov (United States)

    Allen, Andrew P; Dinan, Timothy G; Clarke, Gerard; Cryan, John F

    2017-04-01

    In recent years, we have seen increasing research within neuroscience and biopsychology on the interactions between the brain, the gastrointestinal tract, the bacteria within the gastrointestinal tract, and the bidirectional relationship between these systems: the brain-gut-microbiome axis. Although research has demonstrated that the gut microbiota can impact upon cognition and a variety of stress-related behaviours, including those relevant to anxiety and depression, we still do not know how this occurs. A deeper understanding of how psychological development as well as social and cultural factors impact upon the brain-gut-microbiome axis will contextualise the role of the axis in humans and inform psychological interventions that improve health within the brain-gut-microbiome axis. Interventions ostensibly aimed at ameliorating disorders in one part of the brain-gut-microbiome axis (e.g., psychotherapy for depression) may nonetheless impact upon other parts of the axis (e.g., microbiome composition and function), and functional gastrointestinal disorders such as irritable bowel syndrome represent a disorder of the axis, rather than an isolated problem either of psychology or of gastrointestinal function. The discipline of psychology needs to be cognisant of these interactions and can help to inform the future research agenda in this emerging field of research. In this review, we outline the role psychology has to play in understanding the brain-gut-microbiome axis, with a focus on human psychology and the use of research in laboratory animals to model human psychology.

  13. Purification and characterization of a human brain galectin-1 ligand.

    Science.gov (United States)

    Chadli, A; LeCaer, J P; Bladier, D; Joubert-Caron, R; Caron, M

    1997-04-01

    Our previous studies have characterized an endogenous lectin from human brain identified as galectin-1. A soluble ligand of galectin-1 was purified from human brain by affinity chromatography and preparative electrophoresis. The purified ligand (termed HBGp82, for human brain galectin-1-binding polypeptide of 82,000 daltons) has an apparent molecular mass of 82 kDa and is glycosylated by N-linked biantennary complex structures. HBGp82 was partially characterized by microsequencing of peptide fragments. Similar peptides were found in a heat shock of protein of 90,000 daltons, hsp90. However, comparison of apparent molecular weights and matrix-assisted laser desorption mass spectrometry clearly showed that HBGp82 differs to some degree from hsp90.

  14. Oat avenanthramide-C (2c) is biotransformed by mice and the human microbiota into bioactive metabolites.

    Science.gov (United States)

    Wang, Pei; Chen, Huadong; Zhu, Yingdong; McBride, Jennifer; Fu, Junsheng; Sang, Shengmin

    2015-02-01

    Avenanthramides (AVAs), which are found exclusively in oats, may play an important role in anti-inflammation and antiatherogenesis. Although the bioavailability of AVAs has been investigated previously, little is known about their metabolism. The aim of the present study was to investigate the metabolism of avenanthramide-C (2c), one of the major AVAs, in mice and by the human microbiota, as well as to elucidate the bioactivity of its major metabolites with the goal of finding new exposure markers to precisely reflect oat consumption. For the mouse study, 10 CF-1 female mice were divided into control (vehicle-treated) and 2c intragastrically treated (200 mg/kg) groups (5 mice/group). Twenty-four-hour urine and fecal samples were collected with use of metabolic cages. For the batch culture incubations, 2c was cultured with fecal slurries obtained from 6 human donors. Incubated samples were collected at various time points (0, 12, 24, 48, 72, 96, and 120 h). Metabolites were identified via HPLC with electrochemical detection and LC with electrospray ionization/mass spectrometry. To investigate whether 2c metabolites retain the biological effects of 2c, we compared their effects on the growth of and induction of apoptosis in HCT-116 human colon cancer cells. Eight metabolites were detected from the 2c-treated mouse urine samples. They were identified as 5-hydroxyanthranilic acid (M1), dihydrocaffeic acid (M2), caffeic acid (M3), dihydroferulic acid (M4), ferulic acid (M5), dihydroavenanthramide-C (M6), dihydroavenanthramide-B (M7), and avenanthramide-B (M8) via analysis of their MS(n) (n = 1-3) spectra. We found that the reduction of 2c's C7'-C8' double bond and the cleavage of its amide bond were the major metabolic routes. In the human microbiota study, 2c was converted into M1-M3 and M6. Moreover, interindividual differences in 2c metabolism were observed among the 6 human subjects. Subjects B, C, E, and F could rapidly metabolize 2c to M6, whereas subject D

  15. Phosphorylethanolamine content of human brain tumors.

    Science.gov (United States)

    Kinoshita, Y; Yokota, A; Koga, Y

    1994-12-01

    Phosphorylethanolamine (PEA) is the major component of the phosphomonoester peak detected by phosphorus-31 magnetic resonance spectroscopy, but the absolute concentration has not been determined. This study measured the PEA concentration in biopsy specimens of brain tumors and lobectomized cerebral cortex using high-performance liquid chromatography. The concentration of PEA was 118.5 +/- 10.0 mumol/100 g wet wt in cortex, and was significantly higher in malignant gliomas, metastatic pulmonary adenocarcinoma, and neurinoma. The concentration of PEA was especially high in pituitary adenoma, malignant lymphoma, and medulloblastoma.

  16. Human cadaver brain infusion skull model for neurosurgical training.

    Science.gov (United States)

    Olabe, Jon; Olabe, Javier; Roda, Jose Maria; Sancho, Vidal

    2011-01-01

    Microsurgical technique and anatomical knowledge require extensive laboratory training. Human cadaver models are especially valuable as they supply a good microsurgical training environment simultaneously providing authentic brain anatomy. We developed the "skull infusion model" as an extension of our previous "brain infusion model" taking it a step further maintaining simplicity but enhancing realism. Four human cadaveric brains donated for educational purposes were explanted at autopsy. The specimens were prepared cannulating carotid and vertebral arteries with plastic tubings, flushed with abundant water and fixed for 1 month in formaldehyde. They were then enclosed with white silk clothing (emulating the dura mater) and inserted into human skulls cut previously into two pieces. Tap water at a flow rate of 10 L/h was infused through the arterial tubings. Diverse microsurgical procedures were performed by two trainees, including craniotomies with microsurgical approaches and techniques such as sylvian fissure exposure, extra-intracranial and intra-intracranial bypass, approaches to the ventricles and choroidal fissure opening. The water infusion fills the arterial system, leaking into the interstitial and cisternal space and finally moistening the whole specimen. This makes vascular microsurgical techniques become extremely realistic, increasing its compliance making manipulations easier and more authentic. Standard microsurgical laboratories frequently have difficulties to work with decapitated human cadaver heads but could have human brains readily available. Using the infusion model and inserting it in a human skull makes the environment much more realistic. Its simplicity and inexpensiveness make it a good alternative for developing microsurgical techniques.

  17. NMR metabolomics profiling of blood plasma mimics shows that medium- and long-chain fatty acids differently release metabolites from human serum albumin

    Science.gov (United States)

    Jupin, M.; Michiels, P. J.; Girard, F. C.; Spraul, M.; Wijmenga, S. S.

    2014-02-01

    Metabolite profiling by NMR of body fluids is increasingly used to successfully differentiate patients from healthy individuals. Metabolites and their concentrations are direct reporters of body biochemistry. However, in blood plasma the NMR-detected free-metabolite concentrations are also strongly affected by interactions with the abundant plasma proteins, which have as of yet not been considered much in metabolic profiling. We previously reported that many of the common NMR-detected metabolites in blood plasma bind to human serum albumin (HSA) and many are released by fatty acids present in fatted HSA. HSA is the most abundant plasma protein and main transporter of endogenous and exogenous metabolites. Here, we show by NMR how the two most common fatty acids (FAs) in blood plasma - the long-chain FA, stearate (C18:0) and medium-chain FA, myristate (C14:0) - affect metabolite-HSA interaction. Of the set of 18 common NMR-detected metabolites, many are released by stearate and/or myristate, lactate appearing the most strongly affected. Myristate, but not stearate, reduces HSA-binding of phenylalanine and pyruvate. Citrate signals were NMR invisible in the presence of HSA. Only at high myristate-HSA mole ratios 11:1, is citrate sufficiently released to be detected. Finally, we find that limited dilution of blood-plasma mimics releases HSA-bound metabolites, a finding confirmed in real blood plasma samples. Based on these findings, we provide recommendations for NMR experiments for quantitative metabolite profiling.

  18. Characterization and identification of eight designer benzodiazepine metabolites by incubation with human liver microsomes and analysis by a triple quadrupole mass spectrometer.

    Science.gov (United States)

    El Balkhi, Souleiman; Chaslot, Maxime; Picard, Nicolas; Dulaurent, Sylvain; Delage, Martine; Mathieu, Olivier; Saint-Marcoux, Franck

    2017-07-01

    Designer benzodiazepines (DBZDs) have become of particular importance in the past few years. The metabolite monitoring of DBZD in biological fluids could be of great interest in clinical and forensic toxicology. However, DBZD metabolites are not known or not commercially available. The identification of some DBZD metabolites has been mostly explored by self-administration studies or by in vitro studies followed by high-resolution mass spectrometry. The question arose whether a unit resolution instrument could be efficient enough to allow the identification of DBZD metabolites. In this study, we used an in vitro experiment where eight DBZDs (diclazepam, flubromazepam, etizolam, deschloroetizolam, flubromazolam, nifoxipam, meclonazepam and clonazolam) were incubated with human liver microsomes (HLMs) and metabolite identification was carried out by using a UHPLC coupled to a QTRAP triple quadrupole linear iontrap tandem mass spectrometer system. Post-mortem samples obtained from a real poisoning case, involving deschloroetizolam and diclazepam, were also analysed and discussed. Our study using HLM allowed the identification of 26 metabolites of the 8 DBZDs. These were denitro-, mono- or di-hydroxylated and desmethyl metabolites. In the forensic case, diclazepam was not detected whereas its metabolites (lormetazepam and lorazepam) were present at high concentrations in urine. We also identified hydroxy-deschloroetizolam in urine, while the parent compound was not detected in this matrix. This supports the approach that LC coupled to a simple QTRAP could be used by laboratories to identify other not-known/not-commercialized new psychoactive substance (NPS) metabolites.

  19. Human-like brain hemispheric dominance in birdsong learning.

    Science.gov (United States)

    Moorman, Sanne; Gobes, Sharon M H; Kuijpers, Maaike; Kerkhofs, Amber; Zandbergen, Matthijs A; Bolhuis, Johan J

    2012-07-31

    Unlike nonhuman primates, songbirds learn to vocalize very much like human infants acquire spoken language. In humans, Broca's area in the frontal lobe and Wernicke's area in the temporal lobe are crucially involved in speech production and perception, respectively. Songbirds have analogous brain regions that show a similar neural dissociation between vocal production and auditory perception and memory. In both humans and songbirds, there is evidence for lateralization of neural responsiveness in these brain regions. Human infants already show left-sided dominance in their brain activation when exposed to speech. Moreover, a memory-specific left-sided dominance in Wernicke's area for speech perception has been demonstrated in 2.5-mo-old babies. It is possible that auditory-vocal learning is associated with hemispheric dominance and that this association arose in songbirds and humans through convergent evolution. Therefore, we investigated whether there is similar song memory-related lateralization in the songbird brain. We exposed male zebra finches to tutor or unfamiliar song. We found left-sided dominance of neuronal activation in a Broca-like brain region (HVC, a letter-based name) of juvenile and adult zebra finch males, independent of the song stimulus presented. In addition, juvenile males showed left-sided dominance for tutor song but not for unfamiliar song in a Wernicke-like brain region (the caudomedial nidopallium). Thus, left-sided dominance in the caudomedial nidopallium was specific for the song-learning phase and was memory-related. These findings demonstrate a remarkable neural parallel between birdsong and human spoken language, and they have important consequences for our understanding of the evolution of auditory-vocal learning and its neural mechanisms.

  20. Measuring dopamine release in the human brain with PET

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York at Stony Brook, Stony Brook, NY (United States). Dept. of Psychiatry; Fowler, J.S.; Logan, J.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)

    1995-12-01

    The dopamine system is involved in the regulation of brain regions that subserve motor, cognitive and motivational behaviors. Disruptions of dopamine (DA) function have ben implicated in neurological and psychiatric illnesses including substance abuse as well as on some of the deficits associated with aging of the human brain. This has made the DA system an important topic in research in the neurosciences and neuroimaging as well as an important molecular target for drug development. Positron Emission Tomography (PET), was the first technology that enabled direct measurement of components of the DA system in the living human brain. Imaging studies of DA in the living brain have been indirect, relying on the development of radiotracers to label DA receptors, DA transporters, compounds which have specificity for the enzymes which degrade synaptic DA. Additionally, through the use of tracers that provide information on regional brain activity (ie brain glucose metabolism and cerebral blood flow) and of appropriate pharmacological interventions, it has been possible to assess the functional consequences of changes in brain DA activity. DA specific ligands have been useful in the evaluation of patients with neuropsychiatric illnesses as well as to investigate receptor blockade by antipsychotic drugs. A limitation of strategies that rely on the use of DA specific ligands is that the measures do not necessarily reflect the functional state of the dopaminergic system and that there use to study the effects of drugs is limited to the investigation of receptor or transporter occupancy. Newer strategies have been developed in an attempt to provide with information on dopamine release and on the functional responsivity of the DA system in the human brain. This in turn allows to investigate the effects of pharmacological agent in an analogous way to what is done with microdialysis techniques.

  1. Fetal microchimerism in human brain tumors.

    Science.gov (United States)

    Broestl, Lauren; Rubin, Joshua B; Dahiya, Sonika

    2017-09-18

    Sex differences in cancer incidence and survival, including central nervous system tumors, are well documented. Multiple mechanisms contribute to sex differences in health and disease. Recently, the presence of fetal-in-maternal microchimeric cells has been shown to have prognostic significance in breast and colorectal cancers. The frequency and potential role of these cells has not been investigated in brain tumors. We therefore selected two common primary adult brain tumors for this purpose: meningioma, which is sex hormone responsive and has a higher incidence in women, and glioblastoma, which is sex hormone independent and occurs more commonly in men. Quantitative PCR was used to detect the presence of male DNA in tumor samples from women with a positive history of male pregnancy and a diagnosis of either glioblastoma or meningioma. Fluorescence in situ hybridization for the X and Y chromosomes was used to verify the existence of intact male cells within tumor tissue. Fetal microchimerism was found in approximately 80% of glioblastoma cases and 50% of meningioma cases. No correlations were identified between the presence of microchimerism and commonly used clinical or molecular diagnostic features of disease. The impact of fetal microchimeric cells should be evaluated prospectively. © 2017 International Society of Neuropathology.

  2. Advances in Electronic-Nose Technologies for the Detection of Volatile Biomarker Metabolites in the Human Breath

    Directory of Open Access Journals (Sweden)

    Alphus D. Wilson

    2015-03-01

    Full Text Available Recent advancements in the use of electronic-nose (e-nose devices to analyze human breath profiles for the presence of specific volatile metabolites, known as biomarkers or chemical bio-indicators of specific human diseases, metabolic disorders and the overall health status of individuals, are providing the potential for new noninvasive tools and techniques useful to point-of-care clinical disease diagnoses. This exciting new area of electronic disease detection and diagnosis promises to yield much faster and earlier detection of human diseases and disorders, allowing earlier, more effective treatments, resulting in more rapid patient recovery from various afflictions. E-nose devices are particularly suited for the field of disease diagnostics, because they are sensitive to a wide range of volatile organic compounds (VOCs and can effectively distinguish between different complex gaseous mixtures via analysis of electronic aroma sensor-array output profiles of volatile metabolites present in the human breath. This review provides a summary of some recent developments of electronic-nose technologies, particularly involving breath analysis, with the potential for providing many new diagnostic applications for the detection of specific human diseases associated with different organs in the body, detectable from e-nose analyses of aberrant disease-associated VOCs present in air expired from the lungs.

  3. Short parietal lobe connections of the human and monkey brain

    DEFF Research Database (Denmark)

    Catani, Marco; Robertsson, Naianna; Beyh, Ahmad

    2017-01-01

    The parietal lobe has a unique place in the human brain. Anatomically, it is at the crossroad between the frontal, occipital, and temporal lobes, thus providing a middle ground for multimodal sensory integration. Functionally, it supports higher cognitive functions that are characteristic...... in the medial and lateral aspects of the parietal lobe were identified in both species. A tract connecting the medial parietal cortex to the lateral inferior parietal cortex was observed in the monkey brain only. Our findings suggest a consistent pattern of intralobar parietal connections between humans...

  4. A novel toxicokinetic modeling of cypermethrin and permethrin and their metabolites in humans for dose reconstruction from biomarker data.

    Directory of Open Access Journals (Sweden)

    Jonathan Côté

    Full Text Available To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data.

  5. A novel toxicokinetic modeling of cypermethrin and permethrin and their metabolites in humans for dose reconstruction from biomarker data.

    Science.gov (United States)

    Côté, Jonathan; Bonvalot, Yvette; Carrier, Gaétan; Lapointe, Caroline; Fuhr, Uwe; Tomalik-Scharte, Dorota; Wachall, Bertil; Bouchard, Michèle

    2014-01-01

    To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA) in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor) along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data.

  6. A Novel Toxicokinetic Modeling of Cypermethrin and Permethrin and Their Metabolites in Humans for Dose Reconstruction from Biomarker Data

    Science.gov (United States)

    Côté, Jonathan; Bonvalot, Yvette; Carrier, Gaétan; Lapointe, Caroline; Fuhr, Uwe; Tomalik-Scharte, Dorota; Wachall, Bertil; Bouchard, Michèle

    2014-01-01

    To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA) in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor) along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data. PMID:24586336

  7. PET evaluation of the dopamine system of the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Fowler, J.S.; Gatley, S. [Brookhaven National Laboratory, Upton, NY (United States)]|[SUNY-Stony Brook, NY (United States)] [and others

    1996-07-01

    Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson`s disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of change in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson`s disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochemical parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. This paper summarizes the different tracers and experimental strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clinical research. 254 refs., 7 figs., 3 tabs.

  8. Gender development and the human brain.

    Science.gov (United States)

    Hines, Melissa

    2011-01-01

    Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.

  9. A Recombinant Humanized Anti-Cocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Rats

    Science.gov (United States)

    Gooden, Felicia C. T.; Tabet, Michael R.; Ball, William J.

    2014-01-01

    The monoclonal antibody (mAb), h2E2, is a humanized version of the chimeric human/murine anti-cocaine mAb 2E2. The recombinant h2E2 protein was produced in vitro from a transfected mammalian cell line and retained high affinity (4 nM Kd) and specificity for cocaine over its inactive metabolites benzoylecgonine (BE) and ecgonine methyl ester. In rats, pharmacokinetic studies of h2E2 (120 mg/kg i.v.) showed a long terminal elimination half-life of 9.0 days and a low volume of distribution at steady state (Vdss) of 0.3 l/kg. Pretreatment with h2E2 produced a dramatic 8.8-fold increase in the area under the plasma cocaine concentration-time curve (AUC) and in brain a concomitant decrease of 68% of cocaine’s AUC following an i.v. injection of an equimolar cocaine dose. Sequestration of cocaine in plasma by h2E2, shown via reduction of cocaine’s Vdss, indicates potential clinical efficacy. Although the binding of cocaine to h2E2 in plasma should inhibit distribution and metabolism, the elimination of cocaine remained multicompartmental and was still rapidly eliminated from plasma despite the presence of h2E2. BE was the major cocaine metabolite, and brain BE concentrations were sixfold higher than in plasma, indicating that cocaine is normally metabolized in the brain. In the presence of h2E2, brain BE concentrations were decreased and plasma BE was increased, consistent with the observed h2E2-induced changes in cocaine disposition. The inhibition of cocaine distribution to the brain confirms the humanized mAb, h2E2, as a lead candidate for development as an immunotherapy for cocaine abuse. PMID:24733787

  10. Toward an in Vivo Neurochemical Profile: Quantification of 18 Metabolites in Short-Echo-Time 1H NMR Spectra of the Rat Brain

    Science.gov (United States)

    Pfeuffer, Josef; Tkáč , Ivan; Provencher, Stephen W.; Gruetter, Rolf

    1999-11-01

    Localized in vivo1H NMR spectroscopy was performed with 2-ms echo time in the rat brain at 9.4 T. Frequency domain analysis with LCModel showed that the in vivo spectra can be explained by 18 metabolite model solution spectra and a highly structured background, which was attributed to resonances with fivefold shorter in vivo T1 than metabolites. The high spectral resolution (full width at half maximum approximately 0.025 ppm) and sensitivity (signal-to-noise ratio approximately 45 from a 63-μL volume, 512 scans) was used for the simultaneous measurement of the concentrations of metabolites previously difficult to quantify in 1H spectra. The strongly represented signals of N-acetylaspartate, glutamate, taurine, myo-inositol, creatine, phosphocreatine, glutamine, and lactate were quantified with Cramér-Rao lower bounds below 4%. Choline groups, phosphorylethanolamine, glucose, glutathione, γ-aminobutyric acid, N-acetylaspartylglutamate, and alanine were below 13%, whereas aspartate and scyllo-inositol were below 22%. Intra-assay variation was assessed from a time series of 3-min spectra, and the coefficient of variation was similar to the calculated Cramér-Rao lower bounds. Interassay variation was determined from 31 pooled spectra, and the coefficient of variation for total creatine was 7%. Tissue concentrations were found to be in very good agreement with neurochemical data from the literature.

  11. Effects of a high-caloric diet and physical exercise on brain metabolite levels: a combined proton MRS and histologic study.

    Science.gov (United States)

    Auer, Matthias K; Sack, Markus; Lenz, Jenny N; Jakovcevski, Mira; Biedermann, Sarah V; Falfán-Melgoza, Claudia; Deussing, Jan; Steinle, Jörg; Bielohuby, Maximilian; Bidlingmaier, Martin; Pfister, Frederik; Stalla, Günter K; Ende, Gabriele; Weber-Fahr, Wolfgang; Fuss, Johannes; Gass, Peter

    2015-03-31

    Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS). It has been suggested that one mechanism in this context is the promotion of neuroinflammation. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating the effects of physical exercise in a cafeteria-diet mouse model on CNS metabolites by means of in vivo proton magnetic resonance spectroscopy ((1)HMRS). In addition postmortem histologic and real-time (RT)-PCR analyses for inflammatory markers were performed. Cafeteria diet induced obesity and hyperglycemia, which was only partially moderated by exercise. It also induced several changes in CNS metabolites such as reduced hippocampal glutamate (Glu), choline-containing compounds (tCho) and N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamic acid (NAAG) (tNAA) levels, whereas opposite effects were seen for running. No association of these effects with markers of central inflammation could be observed. These findings suggest that while voluntary wheel running alone is insufficient to prevent the unfavorable peripheral sequelae of the diet, it counteracted many changes in brain metabolites. The observed effects seem to be independent of neuroinflammation.

  12. Interplay between gut microbiota, its metabolites and human metabolism: Dissecting cause from consequence

    NARCIS (Netherlands)

    Hartstra, A. V.; Nieuwdorp, M.; Herrema, H.

    2016-01-01

    Background: Alterations in gut microbiota composition and bacterial metabolites have been increasingly recognized to affect host metabolism and are at the basis of metabolic diseases such as obesity and type 2 diabetes (DM2). Intestinal enteroendocrine cells (EEC's) sense gut luminal content and

  13. Synthetic methods for the preparation of ARQ 501 (beta-Lapachone) human blood metabolites.

    Science.gov (United States)

    Yang, Rui-Yang; Kizer, Darin; Wu, Hui; Volckova, Erika; Miao, Xiu-Sheng; Ali, Syed M; Tandon, Manish; Savage, Ronald E; Chan, Thomas C K; Ashwell, Mark A

    2008-05-15

    ARQ 501 (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b] pyran-5,6-dione), a synthetic version of beta-Lapachone, is a promising anti-cancer agent currently in multiple Phase II clinical trials. Promising anti-cancer activity was observed in Phase I and Phase II trials. Metabolism by red blood cells of drugs is an understudied area of research and the metabolites arising from oxidative ring opening (M2 and M3), decarbonylation/ring contraction (M5), and decarbonylation/oxidation (M4 and M6) of ARQ 501 offer a unique opportunity to provide insight into these metabolic processes. Since these metabolites were not detected in in vitro incubations of ARQ 501 with liver microsomes and were structurally diverse, confirmation by chemical synthesis was considered essential. In this report, we disclose the synthetic routes employed and the characterization of the reference standards for these blood metabolites as well as additional postulated structures, which were not confirmed as metabolites.

  14. Comprehensive cellular‐resolution atlas of the adult human brain

    Science.gov (United States)

    Royall, Joshua J.; Sunkin, Susan M.; Ng, Lydia; Facer, Benjamin A.C.; Lesnar, Phil; Guillozet‐Bongaarts, Angie; McMurray, Bergen; Szafer, Aaron; Dolbeare, Tim A.; Stevens, Allison; Tirrell, Lee; Benner, Thomas; Caldejon, Shiella; Dalley, Rachel A.; Dee, Nick; Lau, Christopher; Nyhus, Julie; Reding, Melissa; Riley, Zackery L.; Sandman, David; Shen, Elaine; van der Kouwe, Andre; Varjabedian, Ani; Write, Michelle; Zollei, Lilla; Dang, Chinh; Knowles, James A.; Koch, Christof; Phillips, John W.; Sestan, Nenad; Wohnoutka, Paul; Zielke, H. Ronald; Hohmann, John G.; Jones, Allan R.; Bernard, Amy; Hawrylycz, Michael J.; Hof, Patrick R.; Fischl, Bruce

    2016-01-01

    ABSTRACT Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations such as lack of whole‐brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high‐resolution histology, and chemoarchitecture across a complete adult female brain, consisting of magnetic resonance imaging (MRI), diffusion‐weighted imaging (DWI), and 1,356 large‐format cellular resolution (1 µm/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto‐ and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. J. Comp. Neurol. 524:3127–3481, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:27418273

  15. Human brain functional MRI and DTI visualization with virtual reality.

    Science.gov (United States)

    Chen, Bin; Moreland, John; Zhang, Jingyu

    2011-12-01

    Magnetic resonance diffusion tensor imaging (DTI) and functional MRI (fMRI) are two active research areas in neuroimaging. DTI is sensitive to the anisotropic diffusion of water exerted by its macromolecular environment and has been shown useful in characterizing structures of ordered tissues such as the brain white matter, myocardium, and cartilage. The diffusion tensor provides two new types of information of water diffusion: the magnitude and the spatial orientation of water diffusivity inside the tissue. This information has been used for white matter fiber tracking to review physical neuronal pathways inside the brain. Functional MRI measures brain activations using the hemodynamic response. The statistically derived activation map corresponds to human brain functional activities caused by neuronal activities. The combination of these two methods provides a new way to understand human brain from the anatomical neuronal fiber connectivity to functional activities between different brain regions. In this study, virtual reality (VR) based MR DTI and fMRI visualization with high resolution anatomical image segmentation and registration, ROI definition and neuronal white matter fiber tractography visualization and fMRI activation map integration is proposed. Rationale and methods for producing and distributing stereoscopic videos are also discussed.

  16. Neurospin Seminar: From the Proton to the Human Brain

    CERN Multimedia

    CERN. Geneva

    2016-01-01

    From the Proton to the Human Brain Speaker: Prof Denis Le Bihan Abstract: The understanding of the human brain is one of the main scientific challenges of the 21st century. In the early 2000s the French Atomic Energy Commission (CEA) launched a program to conceive and build a “human brain explorer”, the first human MRI scanner operating at 11.7T. This scanner was envisioned to be part of the ambitious Iseult project, bridging together industrial and academic partners to push the limits of molecular neuroimaging, from mouse to man, using Ultra-High Field (UHF) MRI. In this seminar a summary of the main features of this magnet, and the neuroscience and medical targets of NeuroSpin where this outstanding instrument will be installed in 2017 will be surveyed. The unprecedented resolution and the new contrasts allowed by such UHF magnets, in combination with innovative concepts in physics and neurobiology, will allow to explore the human brain at a mesoscale at which everything remains to d...

  17. Addiction circuitry in the human brain (*).

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.

    2011-09-27

    A major challenge in understanding substance-use disorders lies in uncovering why some individuals become addicted when exposed to drugs, whereas others do not. Although genetic, developmental, and environmental factors are recognized as major contributors to a person's risk of becoming addicted, the neurobiological processes that underlie this vulnerability are still poorly understood. Imaging studies suggest that individual variations in key dopamine-modulated brain circuits, including circuits involved in reward, memory, executive function, and motivation, contribute to some of the differences in addiction vulnerability. A better understanding of the main circuits affected by chronic drug use and the influence of social stressors, developmental trajectories, and genetic background on these circuits is bound to lead to a better understanding of addiction and to more effective strategies for the prevention and treatment of substance-use disorders.

  18. The sleep-deprived human brain.

    Science.gov (United States)

    Krause, Adam J; Simon, Eti Ben; Mander, Bryce A; Greer, Stephanie M; Saletin, Jared M; Goldstein-Piekarski, Andrea N; Walker, Matthew P

    2017-07-01

    How does a lack of sleep affect our brains? In contrast to the benefits of sleep, frameworks exploring the impact of sleep loss are relatively lacking. Importantly, the effects of sleep deprivation (SD) do not simply reflect the absence of sleep and the benefits attributed to it; rather, they reflect the consequences of several additional factors, including extended wakefulness. With a focus on neuroimaging studies, we review the consequences of SD on attention and working memory, positive and negative emotion, and hippocampal learning. We explore how this evidence informs our mechanistic understanding of the known changes in cognition and emotion associated with SD, and the insights it provides regarding clinical conditions associated with sleep disruption.

  19. ``the Human BRAIN & Fractal quantum mechanics''

    Science.gov (United States)

    Rosary-Oyong, Se, Glory

    In mtDNA ever retrieved from Iman Tuassoly, et.al:Multifractal analysis of chaos game representation images of mtDNA''.Enhances the price & valuetales of HE. Prof. Dr-Ing. B.J. HABIBIE's N-219, in J. Bacteriology, Nov 1973 sought:'' 219 exist as separate plasmidDNA species in E.coli & Salmonella panama'' related to ``the brain 2 distinct molecular forms of the (Na,K)-ATPase..'' & ``neuron maintains different concentration of ions(charged atoms'' thorough Rabi & Heisenber Hamiltonian. Further, after ``fractal space time are geometric analogue of relativistic quantum mechanics''[Ord], sought L.Marek Crnjac: ``Chaotic fractals at the root of relativistic quantum physics''& from famous Nottale: ``Scale relativity & fractal space-time:''Application to Quantum Physics , Cosmology & Chaotic systems'',1995. Acknowledgements to HE. Mr. H. TUK SETYOHADI, Jl. Sriwijaya Raya 3, South-Jakarta, INDONESIA.

  20. Mathematical logic in the human brain: syntax.

    Directory of Open Access Journals (Sweden)

    Roland Friedrich

    Full Text Available Theory predicts a close structural relation of formal languages with natural languages. Both share the aspect of an underlying grammar which either generates (hierarchically structured expressions or allows us to decide whether a sentence is syntactically correct or not. The advantage of rule-based communication is commonly believed to be its efficiency and effectiveness. A particularly important class of formal languages are those underlying the mathematical syntax. Here we provide brain-imaging evidence that the syntactic processing of abstract mathematical formulae, written in a first order language, is, indeed efficient and effective as a rule-based generation and decision process. However, it is remarkable, that the neural network involved, consisting of intraparietal and prefrontal regions, only involves Broca's area in a surprisingly selective way. This seems to imply that despite structural analogies of common and current formal languages, at the neural level, mathematics and natural language are processed differently, in principal.

  1. Automated data processing of { 1H-decoupled} 13C MR spectra acquired from human brain in vivo

    Science.gov (United States)

    Shic, Frederick; Ross, Brian

    2003-06-01

    In clinical 13C infusion studies, broadband excitation of 200 ppm of the human brain yields 13C MR spectra with a time resolution of 2-5 min and generates up to 2000 metabolite peaks over 2 h. We describe a fast, automated, observer-independent technique for processing { 1H-decoupled} 13C spectra. Quantified 13C spectroscopic signals, before and after the administration of [1- 13C]glucose and/or [1- 13C]acetate in human subjects are determined. Stepwise improvements of data processing are illustrated by examples of normal and pathological results. Variation in analysis of individual 13C resonances ranged between 2 and 14%. Using this method it is possible to reliably identify subtle metabolic effects of brain disease including Alzheimer's disease and epilepsy.

  2. Abnormal brain iron homeostasis in human and animal prion disorders.

    Directory of Open Access Journals (Sweden)

    Ajay Singh

    2009-03-01

    Full Text Available Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrP(Sc, a beta-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrP(C. Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease-affected human, hamster, and mouse brains show increased total and redox-active Fe (II iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf and transferrin receptor (TfR at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD-affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrP(Sc as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrP(Sc-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrP(Sc-ferritin complexes induces a state of iron bio-insufficiency in prion disease-affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These

  3. The modular and integrative functional architecture of the human brain.

    Science.gov (United States)

    Bertolero, Maxwell A; Yeo, B T Thomas; D'Esposito, Mark

    2015-12-08

    Network-based analyses of brain imaging data consistently reveal distinct modules and connector nodes with diverse global connectivity across the modules. How discrete the functions of modules are, how dependent the computational load of each module is to the other modules' processing, and what the precise role of connector nodes is for between-module communication remains underspecified. Here, we use a network model of the brain derived from resting-state functional MRI (rs-fMRI) data and investigate the modular functional architecture of the human brain by analyzing activity at different types of nodes in the network across 9,208 experiments of 77 cognitive tasks in the BrainMap database. Using an author-topic model of cognitive functions, we find a strong spatial correspondence between the cognitive functions and the network's modules, suggesting that each module performs a discrete cognitive function. Crucially, activity at local nodes within the modules does not increase in tasks that require more cognitive functions, demonstrating the autonomy of modules' functions. However, connector nodes do exhibit increased activity when more cognitive functions are engaged in a task. Moreover, connector nodes are located where brain activity is associated with many different cognitive functions. Connector nodes potentially play a role in between-module communication that maintains the modular function of the brain. Together, these findings provide a network account of the brain's modular yet integrated implementation of cognitive functions.

  4. Unveiling the mystery of visual information processing in human brain.

    Science.gov (United States)

    Diamant, Emanuel

    2008-08-15

    It is generally accepted that human vision is an extremely powerful information processing system that facilitates our interaction with the surrounding world. However, despite extended and extensive research efforts, which encompass many exploration fields, the underlying fundamentals and operational principles of visual information processing in human brain remain unknown. We still are unable to figure out where and how along the path from eyes to the cortex the sensory input perceived by the retina is converted into a meaningful object representation, which can be consciously manipulated by the brain. Studying the vast literature considering the various aspects of brain information processing, I was surprised to learn that the respected scholarly discussion is totally indifferent to the basic keynote question: "What is information?" in general or "What is visual information?" in particular. In the old days, it was assumed that any scientific research approach has first to define its basic departure points. Why was it overlooked in brain information processing research remains a conundrum. In this paper, I am trying to find a remedy for this bizarre situation. I propose an uncommon definition of "information", which can be derived from Kolmogorov's Complexity Theory and Chaitin's notion of Algorithmic Information. Embracing this new definition leads to an inevitable revision of traditional dogmas that shape the state of the art of brain information processing research. I hope this revision would better serve the challenging goal of human visual information processing modeling.

  5. Human-specific transcriptional networks in the brain

    Science.gov (United States)

    Konopka, Genevieve; Friedrich, Tara; Davis-Turak, Jeremy; Winden, Kellen; Oldham, Michael C.; Gao, Fuying; Chen, Leslie; Wang, Guang-Zhong; Luo, Rui; Preuss, Todd M.; Geschwind, Daniel H.

    2013-01-01

    Summary Understanding human-specific patterns of brain gene expression and regulation can provide key insights into human brain evolution and speciation. Here, we use next generation sequencing, and Illumina and Affymetrix microarray platforms, to compare the transcriptome of human, chimpanzee, and macaque telencephalon. Our analysis reveals a predominance of genes differentially expressed within human frontal lobe and a striking increase in transcriptional complexity specific to the human lineage in the frontal lobe. In contrast, caudate nucleus gene expression is highly conserved. We also identify gene co-expression signatures related to either neuronal processes or neuropsychiatric diseases, including a human-specific module with CLOCK as its hub gene and another module enriched for neuronal morphological processes and genes co-expressed with FOXP2, a gene important for language evolution. These data demonstrate that transcriptional networks have undergone evolutionary remodeling even within a given brain region, providing a new window through which to view the foundation of uniquely human cognitive capacities. PMID:22920253

  6. Rock magnetism linked to human brain magnetite

    Science.gov (United States)

    Kirschvink, Joseph L.

    Magnetite has a long and distinguished career as one of the most important minerals in geophysics, as it is responsible for most of the remanent magnetization in marine sediments and the oceanic crust. It may come as a surprise to discover that it also ranks as the third or fourth most diverse mineral product formed biochemically by living organisms, and forms naturally in a variety of human tissues [Kirschvink et al., 1992].Magnetite was discovered in teeth of the Polyplacophora mollusks over 30 years ago, in magnetotactic bacteria nearly 20 years ago, in honey bees and homing pigeons nearly 15 years ago, but only recently in human tissue.

  7. New Metabolites of Coumarin Detected in Human Urine Using Ultra Performance Liquid Chromatography/Quadrupole-Time-of-Flight Tandem Mass Spectrometry

    Directory of Open Access Journals (Sweden)

    Letícia Paula Leonart

    2017-11-01

    Full Text Available Coumarin (1,2-benzopyrone is a natural compound whose metabolism in humans was established in the 1970s. However, a new metabolite was recently identified in human plasma, indicating that the metabolism of coumarin has not been completely elucidated. To complement the knowledge of its metabolism, a rapid and sensitive method using UPLC-QTOF-MS was developed. A total of 12 metabolites was identified using MetaboLynxTM software, including eight metabolites not previously reported in human urine. The identified biotransformation included hydroxylation, glucuronidation, sulfation, methylation, and conjugation with N-acetylcysteine. The present work demonstrates that the metabolism study of coumarin was incomplete, possibly due to limitations of old techniques. The identification of eight inedited metabolites of such a simple molecule suggests that the information regarding the metabolism of other drugs may also be incomplete, and therefore, new investigations are necessary.

  8. Uncovering intrinsic modular organization of spontaneous brain activity in humans.

    Directory of Open Access Journals (Sweden)

    Yong He

    Full Text Available The characterization of topological architecture of complex brain networks is one of the most challenging issues in neuroscience. Slow (<0.1 Hz, spontaneous fluctuations of the blood oxygen level dependent (BOLD signal in functional magnetic resonance imaging are thought to be potentially important for the reflection of spontaneous neuronal activity. Many studies have shown that these fluctuations are highly coherent within anatomically or functionally linked areas of the brain. However, the underlying topological mechanisms responsible for these coherent intrinsic or spontaneous fluctuations are still poorly understood. Here, we apply modern network analysis techniques to investigate how spontaneous neuronal activities in the human brain derived from the resting-state BOLD signals are topologically organized at both the temporal and spatial scales. We first show that the spontaneous brain functional networks have an intrinsically cohesive modular structure in which the connections between regions are much denser within modules than between them. These identified modules are found to be closely associated with several well known functionally interconnected subsystems such as the somatosensory/motor, auditory, attention, visual, subcortical, and the "default" system. Specifically, we demonstrate that the module-specific topological features can not be captured by means of computing the corresponding global network parameters, suggesting a unique organization within each module. Finally, we identify several pivotal network connectors and paths (predominantly associated with the association and limbic/paralimbic cortex regions that are vital for the global coordination of information flow over the whole network, and we find that their lesions (deletions critically affect the stability and robustness of the brain functional system. Together, our results demonstrate the highly organized modular architecture and associated topological properties in

  9. Simultaneous LC-MS/MS analysis of eicosanoids and related metabolites in human serum, sputum and BALF.

    Science.gov (United States)

    Thakare, Rhishikesh; Chhonker, Yashpal S; Gautam, Nagsen; Nelson, Amy; Casaburi, Richard; Criner, Gerard; Dransfield, Mark T; Make, Barry; Schmid, Kendra K; Rennard, Stephen I; Alnouti, Yazen

    2017-10-04

    The differences among individual eicosanoids in eliciting different physiological and pathological responses are largely unknown because of the lack of valid and simple analytical methods for the quantification of individual eicosanoids and their metabolites in serum, sputum and bronchial alveolar lavage fluid (BALF). Therefore, a simple and sensitive LC-MS/MS method for the simultaneous quantification of 34 eicosanoids in human serum, sputum and BALF was developed and validated. This method is valid and sensitive with a limit of quantification ranging from 0.2 to 3 ng/mL for the various analytes, and has a large dynamic range (500 ng/mL) and a short run time (25 min). The intra- and inter-day accuracy and precision values met the acceptance criteria according to US Food and Drug Administration guidelines. Using this method, detailed eicosanoid profiles were quantified in serum, sputum and BALF from a pilot human study. In summary, a reliable and simple LC-MS/MS method to quantify major eicosanoids and their metabolites was developed and applied to quantify eicosanoids in human various fluids, demonstrating its suitability to assess eicosanoid biomarkers in human clinical trials. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Visual dictionaries as intermediate features in the human brain

    Directory of Open Access Journals (Sweden)

    Kandan eRamakrishnan

    2015-01-01

    Full Text Available The human visual system is assumed to transform low level visual features to object and scene representations via features of intermediate complexity. How the brain computationally represents intermediate features is still unclear. To further elucidate this, we compared the biologically plausible HMAX model and Bag of Words (BoW model from computer vision. Both these computational models use visual dictionaries, candidate features of intermediate complexity, to represent visual scenes, and the models have been proven effective in automatic object and scene recognition. These models however differ in the computation of visual dictionaries and pooling techniques. We investigated where in the brain and to what extent human fMRI responses to short video can be accounted for by multiple hierarchical levels of the HMAX and BoW models. Brain activity of 20 subjects obtained while viewing a short video clip was analyzed voxel-wise using a distance-based variation partitioning method. Results revealed that both HMAX and BoW explain a significant amount of brain activity in early visual regions V1, V2 and V3. However BoW exhibits more consistency across subjects in accounting for brain activity compared to HMAX. Furthermore, visual dictionary representations by HMAX and BoW explain significantly some brain activity in higher areas which are believed to process intermediate features. Overall our results indicate that, although both HMAX and BoW account for activity in the human visual system, the BoW seems to more faithfully represent neural responses in low and intermediate level visual areas of the brain.

  11. Data supporting the rat brain sample preparation and validation assays for simultaneous determination of 8 neurotransmitters and their metabolites using liquid chromatography–tandem mass spectrometry

    Directory of Open Access Journals (Sweden)

    Aneta Wojnicz

    2016-06-01

    Full Text Available The data presented in this article supports the rat brain sample preparation procedure previous to its injection into the liquid chromatography–tandem mass spectrometry (LC–MS/MS system to monitor levels of adrenaline, noradrenaline, glutamic acid, γ-aminobutyric acid, dopamine, 5-hydroxytryptamine, 5-hydroxyindole acetic acid, and 3-methoxy-4-hydroxyphenylglycol. In addition, we describe the method validation assays (such as calibration curve, lower limit of quantification, precision and accuracy intra- and inter-day, selectivity, extraction recovery and matrix effect, stability, and carry-over effect according to the United States Food and Drug Administration and European Medicine Agency to measure in one step different neurotransmitters and their metabolites. The data supplied in this article is related to the research study entitled: “Simultaneous determination of 8 neurotransmitters and their metabolite levels in rat brain using liquid chromatography in tandem with mass spectrometry: application to the murine Nrf2 model of depression” (Wojnicz et al. 2016 [1].

  12. Chemical Probes for Visualizing Intact Animal and Human Brain Tissue.

    Science.gov (United States)

    Lai, Hei Ming; Ng, Wai-Lung; Gentleman, Steve M; Wu, Wutian

    2017-06-22

    Newly developed tissue clearing techniques can be used to render intact tissues transparent. When combined with fluorescent labeling technologies and optical sectioning microscopy, this allows visualization of fine structure in three dimensions. Gene-transfection techniques have proved very useful in visualizing cellular structures in animal models, but they are not applicable to human brain tissue. Here, we discuss the characteristics of an ideal chemical fluorescent probe for use in brain and other cleared tissues, and offer a comprehensive overview of currently available chemical probes. We describe their working principles and compare their performance with the goal of simplifying probe selection for neuropathologists and stimulating probe development by chemists. We propose several approaches for the development of innovative chemical labeling methods which, when combined with tissue clearing, have the potential to revolutionize how we study the structure and function of the human brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Comparison between Short and Long Echo Time Magnetic Resonance Spectroscopic Imaging at 3T and 7T for Evaluating Brain Metabolites in Patients with Glioma.

    Science.gov (United States)

    Li, Yan; Lafontaine, Marisa; Chang, Susan; Nelson, Sarah J

    2018-01-17

    Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) is a powerful non-invasive tool for characterizing spatial variations in metabolic profiles for patients with glioma. Metabolic parameters obtained using this technique have been shown to predict treatment response, disease progression, and transformation to a more malignant phenotype. The availability of ultra-high-field MR systems has the potential to improve the characterization of metabolites. The purpose of this study was to compare the metabolite profiles acquired with conventional long echo time (TE) MRSI at 3T with those obtained with short TE MRSI at 3T and 7T in patients with glioma. The data acquisition parameters were optimized separately for each echo time and field strength to obtain volumetric coverage within clinically feasible data acquisition times of 5-10 min. While a higher field strength did provide better detection of metabolites with overlapping peaks, spatial coverage was reduced and the use of inversion recovery to reduce lipid precluded the detection of lipid in regions of necrosis. For serial evaluation of large, heterogeneous lesions, the use of 3T short TE MRSI may thus be preferred. Despite the limited number of metabolites that it is able to detect, the use of 3T long TE MRSI gives the best contrast in choline/N-acetyl aspartate between normal appearing brain and tumor and also allows the separate detection of lactate and lipid. It may therefore be preferred for serial evaluation of patients with high-grade glioma and for detection of malignant transformation in patients with low-grade glioma.

  14. In vivo quantification of brain metabolites by 1H-MRS using water as an internal standard

    DEFF Research Database (Denmark)

    Christiansen, P; Henriksen, O; Stubgaard, M

    1993-01-01

    in quantification of N-acetyl aspartate (NAA) concentration was about 1-2 mM (6-12%). Also in vivo a good linearity between water signal and selected voxel size was seen. The same was true for the studied metabolites, N-acetyl aspartate (NAA), creatine/phosphocreatine (Cr/PCr), and choline (Cho). Calculated average...

  15. Utilizing relative potency factors (RPF) and threshold of toxicological concern (TTC) concepts to assess hazard and human risk assessment profiles of environmental metabolites: a case study.

    Science.gov (United States)

    Terry, C; Rasoulpour, R J; Knowles, S; Billington, R

    2015-03-01

    There is currently no standard paradigm for hazard and human risk assessment of environmental metabolites for agrochemicals. Using an actual case study, solutions to challenges faced are described and used to propose a generic concept to address risk posed by metabolites to human safety. A novel approach - built on the foundation of predicted human exposures to metabolites in various compartments (such as food and water), the threshold of toxicological concern (TTC) and the concept of comparative toxicity - was developed for environmental metabolites of a new chemical, sulfoxaflor (X11422208). The ultimate aim was to address the human safety of the metabolites with the minimum number of in vivo studies, while at the same time, ensuring that human safety would be considered addressed on a global regulatory scale. The third component, comparative toxicity, was primarily designed to determine whether the metabolites had the same or similar toxicity profiles to their parent molecule, and also to one another. The ultimate goal was to establish whether the metabolites had the potential to cause key effects - such as cancer and developmental toxicity, based on mode-of-action (MoA) studies - and to develop a relative potency factor (RPF) compared to the parent molecule. Collectively, the work presented here describes the toxicology programme developed for sulfoxaflor and its metabolites, and how it might be used to address similar future challenges aimed at determining the relevance of the metabolites from a human hazard and risk perspective. Sulfoxaflor produced eight environmental metabolites at varying concentrations in various compartments - soil, water, crops and livestock. The MoA for the primary effects of the parent molecule were elucidated in detail and a series of in silico, in vitro, and/or in vivo experiments were conducted on the environmental metabolites to assess relative potency of their toxicity profiles when compared to the parent. The primary metabolite

  16. Human serum determination and in vitro anti-inflammatory activity of the vitamin E metabolite α-(13'-hydroxy)-6-hydroxychroman.

    Science.gov (United States)

    Ciffolilli, Silvia; Wallert, Maria; Bartolini, Desirée; Krauth, Verena; Werz, Oliver; Piroddi, Marta; Sebastiani, Bartolomeo; Torquato, Pierangelo; Lorkowski, Stefan; Birringer, Marc; Galli, Francesco

    2015-12-01

    Cytochrome P450-derived long-chain metabolites are gaining increasing interest as bioactive intermediates of vitamin E. In this study we first report on the HPLC-ECD and GC-MS analysis in human serum of the earliest metabolite of this vitamin, namely α-(13'-hydroxy)-6-hydroxychroman (α-13'-OH). The two chromatographic procedure are sensitive enough (LOQ of 10nM) to measure α-13'-OH after hexane extraction of 1 ml of sample obtained from healthy volunteers supplemented for 1-week with 1000 IU/d (671 mg/d) RRR-α-tocopherol. The observed concentrations ranged between 15 and 50 nM, with minor differences between fasting and 4-hr post-meal state. Baseline (non-supplemented state) levels of 7.2 ± 1.6 nM were observed extracting higher volumes of serum. Biological effects of α-13'-OH investigated for the first time in RAW264.7 murine macrophages involved transcriptional control of inflammatory cytokines, and transcriptional and functional regulation of COX2 and iNOS enzymes in response to lipopolysaccharides. In conclusion, here we present the first quantitative evaluation of serum α-13'-OH also providing early evidence of the anti-inflammatory potential of this metabolite that is worth of further investigation in the area of functional and nutraceutical implications of vitamin E metabolism. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Integration of letters and speech sounds in the human brain

    NARCIS (Netherlands)

    van Atteveldt, Nienke; Formisano, Elia; Goebel, Rainer; Blomert, Leo

    2004-01-01

    Most people acquire literacy skills with remarkable ease, even though the human brain is not evolutionarily adapted to this relatively new cultural phenomenon. Associations between letters and speech sounds form the basis of reading in alphabetic scripts. We investigated the functional neuroanatomy

  18. Quantitative MRI of the human brain at 7 tesla

    NARCIS (Netherlands)

    Polders, D.L.

    2012-01-01

    This thesis describes the implementation of quantitative MR methods in the human brain at 7 T. By highlighting the drawbacks and advantages of the increased field strength, the use of 7 T MRI for quantitative measurements in clinical research was demonstrated. Inhomogeneities in the transmitted RF

  19. Human brain evolution, theories of innovation, and lessons from the ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Biosciences; Volume 29; Issue 3. Human brain evolution, theories of innovation, and lessons from the history of technology. Alfred Gierer. Perspectives Volume 29 Issue 3 September 2004 pp 235-244. Fulltext. Click here to view fulltext PDF. Permanent link:

  20. Simultaneous analysis of regorafenib and sorafenib and three of their metabolites in human plasma using LC-MS/MS.

    Science.gov (United States)

    Allard, Marie; Khoudour, Nihel; Rousseau, Benoît; Joly, Charlotte; Costentin, Charlotte; Blanchet, Benoît; Tournigand, Christophe; Hulin, Anne

    2017-08-05

    A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold® column using a gradient elution of 10mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000ng/mL for REGO and its metabolites and 80 to 5 000ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Studies on the Biotransformation of Veratric Acid, a Human Metabolite of Mebeverine, by Using the Incubated Hen's Egg.

    Science.gov (United States)

    Kiep, L; Göhl, M; Schmidt, J; Seifert, K

    2015-09-01

    Metabolism studies with selected test substances have shown that a model on the basis of the incubated hen's egg is suitable as a supplement to animal experimentation. Because of its 3,4-dimethoxyphenyl structure veratric acid (3,4-dimethoxybenzoic acid), a known human metabolite of mebeverine, was chosen as model substance for the present investigations and the parent compound as well as 4-hydroxy-3-methoxybenzoic acid were identified as main metabolites. The absence of 3-hydroxy-4-methoxybenzoic acid lets conclude that the O-demethylation takes place exclusively at the p-methoxyl function. In addition, 3,3',4,4'-tetramethoxy-l-ornithuric acid (2,5-bis-(3,4-dimethoxybenzoylamino)pentanoic acid) and its O-desmethyl derivative could be characterized as further metabolites. So far an amino acid conjugate has not been described after veratric acid administration in a vertebrate. There were no indications for the appearance of 3,4-dihydroxybenzoic acid in the veratric acid metabolism. This was confirmed by corresponding studies having the isomeric guaiacol acids as precursor. Furthermore, it could be proved that in ovo the O-methylation of 3,4-dihydroxybenzoic acid occurs regioselective at the m-hydroxyl group. The results which broaden the knowledge on the metabolic fate of veratric acid are discussed in comparison with those in mammals. The metabolites were identified by GC-MS, ESI-HRMS and LC/ESI-MS/MS. The structure of the synthesized reference substance was confirmed by MS, (1)H and (13)C NMR spectral data. © Georg Thieme Verlag KG Stuttgart · New York.

  2. Tilting Plant Metabolism for Improved Metabolite Biosynthesis and Enhanced Human Benefit

    Directory of Open Access Journals (Sweden)

    Bhekumthetho Ncube

    2015-07-01

    Full Text Available The immense chemical diversity of plant-derived secondary metabolites coupled with their vast array of biological functions has seen this group of compounds attract considerable research interest across a range of research disciplines. Medicinal and aromatic plants, in particular, have been exploited for this biogenic pool of phytochemicals for products such as pharmaceuticals, fragrances, dyes, and insecticides, among others. With consumers showing increasing interests in these products, innovative biotechnological techniques are being developed and employed to alter plant secondary metabolism in efforts to improve on the quality and quantity of specific metabolites of interest. This review provides an overview of the biosynthesis for phytochemical compounds with medicinal and other related properties and their associated biological activities. It also provides an insight into how their biosynthesis/biosynthetic pathways have been modified/altered to enhance production.

  3. Identifying topological motif patterns of human brain functional networks.

    Science.gov (United States)

    Wei, Yongbin; Liao, Xuhong; Yan, Chaogan; He, Yong; Xia, Mingrui

    2017-05-01

    Recent imaging connectome studies demonstrated that the human functional brain network follows an efficient small-world topology with cohesive functional modules and highly connected hubs. However, the functional motif patterns that represent the underlying information flow remain largely unknown. Here, we investigated motif patterns within directed human functional brain networks, which were derived from resting-state functional magnetic resonance imaging data with controlled confounding hemodynamic latencies. We found several significantly recurring motifs within the network, including the two-node reciprocal motif and five classes of three-node motifs. These recurring motifs were distributed in distinct patterns to support intra- and inter-module functional connectivity, which also promoted integration and segregation in network organization. Moreover, the significant participation of several functional hubs in the recurring motifs exhibited their critical role in global integration. Collectively, our findings highlight the basic architecture governing brain network organization and provide insight into the information flow mechanism underlying intrinsic brain activities. Hum Brain Mapp 38:2734-2750, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. Zika Virus Infects Human Fetal Brain Microglia and Induces Inflammation.

    Science.gov (United States)

    Lum, Fok-Moon; Low, Donovan K S; Fan, Yiping; Tan, Jeslin J L; Lee, Bernett; Chan, Jerry K Y; Rénia, Laurent; Ginhoux, Florent; Ng, Lisa F P

    2017-04-01

    The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive. Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus-infected fetal brain cells were measured simultaneously in microbead-based immunoassays. We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1). Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis.

  5. Ex-vivo MR Volumetry of Human Brain Hemispheres

    Science.gov (United States)

    Kotrotsou, Aikaterini; Bennett, David A.; Schneider, Julie A.; Dawe, Robert J.; Golak, Tom; Leurgans, Sue E.; Yu, Lei; Arfanakis, Konstantinos

    2013-01-01

    Purpose The aims of this work were to: a) develop an approach for ex-vivo MR volumetry of human brain hemispheres that does not contaminate the results of histopathological examination, b) longitudinally assess regional brain volumes postmortem, and c) investigate the relationship between MR volumetric measurements performed in-vivo and ex-vivo. Methods An approach for ex-vivo MR volumetry of human brain hemispheres was developed. Five hemispheres from elderly subjects were imaged ex-vivo longitudinally. All datasets were segmented. The longitudinal behavior of volumes measured ex-vivo was assessed. The relationship between in-vivo and ex-vivo volumetric measurements was investigated in seven elderly subjects imaged both ante-mortem and postmortem. Results The presented approach for ex-vivo MR volumetry did not contaminate the results of histopathological examination. For a period of 6 months postmortem, within-subject volume variation across time points was substantially smaller than inter-subject volume variation. A close linear correspondence was detected between in-vivo and ex-vivo volumetric measurements. Conclusion Regional brain volumes measured with the presented approach for ex-vivo MR volumetry remain relatively unchanged for a period of 6 months postmortem. Furthermore, the linear relationship between in-vivo and ex-vivo MR volumetric measurements suggests that the presented approach captures information linked to ante-mortem macrostructural brain characteristics. PMID:23440751

  6. Detection, quantification, and total synthesis of novel 3-hydroxykynurenine glucoside-derived metabolites present in human lenses.

    Science.gov (United States)

    Gad, Nicholas A; Mizdrak, Jasminka; Pattison, David I; Davies, Michael J; Truscott, Roger J W; Jamie, Joanne F

    2014-02-10

    3-Hydroxykynurenine O-β-D-glucoside (3OHKG) protects the lens from UV damage, and novel related species may act analogously. The aim of this study was to detect, quantify, and elucidate the structures of novel 3-hydroxykynurenine glucoside-derived metabolites present in the human lens. Compounds were detected and quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 24 human lenses of different ages, of which 22 were normal and two had cataract. Structures of these were confirmed through total synthesis. 3OHKG concentrations decreased with age in the lens nuclei, whereas the levels of three novel species, 4-(2-amino-3-hydroxyphenyl)-2-hydroxy-4-oxobutanoic acid O-β-D-glucoside (3OHKG-W), 3-hydroxykynurenine O-β-D-glucoside yellow (3OHKG-Y), and 2-amino-3-hydroxyacetophenone O-β-D-glucoside (AHAG), increased, though to different extents. In contrast, the concentrations present in the cortex of the lens remained constant with age. Three novel 3OHKG-derived metabolites have been detected in extracts from human lenses.

  7. Common genetic variants influence human subcortical brain structures

    Science.gov (United States)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  8. Topological isomorphisms of human brain and financial market networks.

    Science.gov (United States)

    Vértes, Petra E; Nicol, Ruth M; Chapman, Sandra C; Watkins, Nicholas W; Robertson, Duncan A; Bullmore, Edward T

    2011-01-01

    Although metaphorical and conceptual connections between the human brain and the financial markets have often been drawn, rigorous physical or mathematical underpinnings of this analogy remain largely unexplored. Here, we apply a statistical and graph theoretic approach to the study of two datasets - the time series of 90 stocks from the New York stock exchange over a 3-year period, and the fMRI-derived time series acquired from 90 brain regions over the course of a 10-min-long functional MRI scan of resting brain function in healthy volunteers. Despite the many obvious substantive differences between these two datasets, graphical analysis demonstrated striking commonalities in terms of global network topological properties. Both the human brain and the market networks were non-random, small-world, modular, hierarchical systems with fat-tailed degree distributions indicating the presence of highly connected hubs. These properties could not be trivially explained by the univariate time series statistics of stock price returns. This degree of topological isomorphism suggests that brains and markets can be regarded broadly as members of the same family of networks. The two systems, however, were not topologically identical. The financial market was more efficient and more modular - more highly optimized for information processing - than the brain networks; but also less robust to systemic disintegration as a result of hub deletion. We conclude that the conceptual connections between brains and markets are not merely metaphorical; rather these two information processing systems can be rigorously compared in the same mathematical language and turn out often to share important topological properties in common to some degree. There will be interesting scientific arbitrage opportunities in further work at the graph-theoretically mediated interface between systems neuroscience and the statistical physics of financial markets.

  9. The song system of the human brain.

    Science.gov (United States)

    Brown, Steven; Martinez, Michael J; Hodges, Donald A; Fox, Peter T; Parsons, Lawrence M

    2004-08-01

    Although sophisticated insights have been gained into the neurobiology of singing in songbirds, little comparable knowledge exists for humans, the most complex singers in nature. Human song complexity is evidenced by the capacity to generate both richly structured melodies and coordinated multi-part harmonizations. The present study aimed to elucidate this multi-faceted vocal system by using 15O-water positron emission tomography to scan "listen and respond" performances of amateur musicians either singing repetitions of novel melodies, singing harmonizations with novel melodies, or vocalizing monotonically. Overall, major blood flow increases were seen in the primary and secondary auditory cortices, primary motor cortex, frontal operculum, supplementary motor area, insula, posterior cerebellum, and basal ganglia. Melody repetition and harmonization produced highly similar patterns of activation. However, whereas all three tasks activated secondary auditory cortex (posterior Brodmann Area 22), only melody repetition and harmonization activated the planum polare (BA 38). This result implies that BA 38 is responsible for an even higher level of musical processing than BA 22. Finally, all three of these "listen and respond" tasks activated the frontal operculum (Broca's area), a region involved in cognitive/motor sequence production and imitation, thereby implicating it in musical imitation and vocal learning.

  10. Regional mechanical properties of human brain tissue for computational models of traumatic brain injury.

    Science.gov (United States)

    Finan, John D; Sundaresh, Sowmya N; Elkin, Benjamin S; McKhann, Guy M; Morrison, Barclay

    2017-06-01

    To determine viscoelastic shear moduli, stress relaxation indentation tests were performed on samples of human brain tissue resected in the course of epilepsy surgery. Through the use of a 500µm diameter indenter, regional mechanical properties were measured in cortical grey and white matter and subregions of the hippocampus. All regions were highly viscoelastic. Cortical grey matter was significantly more compliant than the white matter or hippocampus which were similar in modulus. Although shear modulus was not correlated with the age of the donor, cortex from male donors was significantly stiffer than from female donors. The presented material properties will help to populate finite element models of the brain as they become more anatomically detailed. We present the first mechanical characterization of fresh, post-operative human brain tissue using an indentation loading mode. Indentation generates highly localized data, allowing structure-specific mechanical properties to be determined from small tissue samples resected during surgery. It also avoids pitfalls of cadaveric tissue and allows data to be collected before degenerative processes alter mechanical properties. To correctly predict traumatic brain injury, finite element models must calculate intracranial deformation during head impact. The functional consequences of injury depend on the anatomical structures injured. Therefore, morbidity depends on the distribution of deformation across structures. Accurate prediction of structure-specific deformation requires structure-specific mechanical properties. This data will facilitate deeper understanding of the physical mechanisms that lead to traumatic brain injury. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  11. Brain lactate metabolism in humans with subarachnoid hemorrhage.

    Science.gov (United States)

    Oddo, Mauro; Levine, Joshua M; Frangos, Suzanne; Maloney-Wilensky, Eileen; Carrera, Emmanuel; Daniel, Roy T; Levivier, Marc; Magistretti, Pierre J; LeRoux, Peter D

    2012-05-01

    Lactate is central for the regulation of brain metabolism and is an alternative substrate to glucose after injury. Brain lactate metabolism in patients with subarachnoid hemorrhage has not been fully elucidated. Thirty-one subarachnoid hemorrhage patients monitored with cerebral microdialysis (CMD) and brain oxygen (PbtO(2)) were studied. Samples with elevated CMD lactate (>4 mmol/L) were matched to PbtO(2) and CMD pyruvate and categorized as hypoxic (PbtO(2) 119 μmol/L) versus nonhyperglycolytic. Median per patient samples with elevated CMD lactate was 54% (interquartile range, 11%-80%). Lactate elevations were more often attributable to cerebral hyperglycolysis (78%; interquartile range, 5%-98%) than brain hypoxia (11%; interquartile range, 4%-75%). Mortality was associated with increased percentage of samples with elevated lactate and brain hypoxia (28% [interquartile range 9%-95%] in nonsurvivors versus 9% [interquartile range 3%-17%] in survivors; P=0.02) and lower percentage of elevated lactate and cerebral hyperglycolysis (13% [interquartile range, 1%-87%] versus 88% [interquartile range, 27%-99%]; P=0.07). Cerebral hyperglycolytic lactate production predicted good 6-month outcome (odds ratio for modified Rankin Scale score, 0-3 1.49; CI, 1.08-2.05; P=0.016), whereas increased lactate with brain hypoxia was associated with a reduced likelihood of good outcome (OR, 0.78; CI, 0.59-1.03; P=0.08). Brain lactate is frequently elevated in subarachnoid hemorrhage patients, predominantly because of hyperglycolysis rather than hypoxia. A pattern of increased cerebral hyperglycolytic lactate was associated with good long-term recovery. Our data suggest that lactate may be used as an aerobic substrate by the injured human brain.

  12. Xanthine oxidase activity regulates human embryonic brain cells growth

    Directory of Open Access Journals (Sweden)

    Kevorkian G. A.

    2011-10-01

    Full Text Available Aim. Involvement of Xanthine Oxidase (XO; EC1.1.3.22 in cellular proliferation and differentiation has been suggested by the numerous investigations. We have proposed that XO might have undoubtedly important role during the development, maturation as well as the death of human embryos brain cells. Methods. Human abortion material was utilized for the cultivation of brain cells (E90. XO activity was measured by the formation of uric acid in tissue. Cell death was detected by the utility of Trypan Blue dye. Results. Allopurinol suppressed the XO activity in the brain tissue (0.12 ± 0.02; 0.20 ± 0.03 resp., p < 0.05. On day 12th the number of cells in the culture treated with the Allopurinol at the early stage of development was higher in comparison with the Control (2350.1 ± 199.0 vs 2123 ± 96 and higher in comparison with the late period of treatment (1479.6 ± 103.8, p < < 0.05. In all groups, the number of the dead cells was less than in Control, indicating the protective nature of Allopurinol as an inhibitor of XO. Conclusions. Allopurinol initiates cells proliferation in case of the early treatment of the human brain derived cell culture whereas at the late stages it has an opposite effect.

  13. The nicotinic cholinergic system function in the human brain.

    Science.gov (United States)

    Nees, Frauke

    2015-09-01

    Research on the nicotinic cholinergic system function in the brain was previously mainly derived from animal studies, yet, research in humans is growing. Up to date, findings allow significant advances on the understanding of nicotinic cholinergic effects on human cognition, emotion and behavior using a range of functional brain imaging approaches such as pharmacological functional magnetic resonance imaging or positron emission tomography. Studies provided insights across various mechanistic psychological domains using different tasks as well as at rest in both healthy individuals and patient populations, with so far partly mixed results reporting both enhancements and decrements of neural activity related to the nicotinic cholinergic system. Moreover, studies on the relation between brain structure and the nicotinic cholinergic system add important information in this context. The present review summarizes the current status of human brain imaging studies and presents the findings within a theoretical and clinical perspective as they may be useful not only for an advancement of the understanding of basic nicotinic cholinergic-related mechanisms, but also for the development and integration of psychological and pharmacological treatment approaches. Patterns of functional neuroanatomy and neural circuitry across various cognitive and emotional domains may be used as neuropsychological markers of mental disorders such as addiction, Alzheimer's disease, Parkinson disease or schizophrenia, where nicotinic cholinergic system changes are characteristic. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Mapping the calcitonin receptor in human brain stem

    DEFF Research Database (Denmark)

    Bower, Rebekah L; Eftekhari, Sajedeh; Waldvogel, Henry J

    2016-01-01

    understanding of these hormone systems by mapping CTR expression in the human brain stem, specifically the medulla oblongata. Widespread CTR-like immunoreactivity was observed throughout the medulla. Dense CTR staining was noted in several discrete nuclei, including the nucleus of the solitary tract...... receptors (AMY) are a heterodimer formed by the coexpression of CTR with receptor activity-modifying proteins (RAMPs). CTR with RAMP1 responds potently to both amylin and CGRP. The brain stem is a major site of action for circulating amylin and is a rich site of CGRP binding. This study aimed to enhance our...

  15. Characterization of ornidazole metabolites in human bile after intraveneous doses by ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry

    Directory of Open Access Journals (Sweden)

    Jiangbo Du

    2012-04-01

    Full Text Available Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS was used to characterize ornidazole metabolites in human bile after intravenous doses. A liquid chromatography tandem mass spectrometry (LC–MS/MS assay was developed for the determination of the bile level of ornidazole. Bile samples, collected from four patients with T-tube drainage after biliary tract surgery, were prepared by protein precipitation with acetonitrile before analysis. A total of 12 metabolites, including 10 novel metabolites, were detected and characterized. The metabolites of ornidazole in human bile were the products of hydrochloride (HCl elimination, oxidative dechlorination, hydroxylation, sulfation, diastereoisomeric glucuronation, and substitution of NO2 or Cl atom by cysteine or N-acetylcysteine, and oxidative dechlorination followed by further carboxylation. The bile levels of ornidazole at 12 h after multiple intravenous infusions were well above its minimal inhibitory concentration for common strains of anaerobic bacteria.

  16. Human cadaver brain infusion model for neurosurgical training.

    Science.gov (United States)

    Olabe, Jon; Olabe, Javier; Sancho, Vidal

    2009-12-01

    Microneurosurgical technique and anatomical knowledge require extensive laboratory training before mastering these skills. There are diverse training models based on synthetic materials, anesthetized animals, cadaver animals, or human cadaver. Human cadaver models are especially beneficial because they are the closest to live surgery with the greatest disadvantage of lacking hemodynamic factors. We developed the "brain infusion model" to provide a simple but realistic training method minimizing animal use or needs for special facilities. Four human cadaveric brains donated for educational purposes were explanted at autopsy. Carotids and vertebral arteries were cannulated with plastic tubes and fixed with suture. Water was flushed through the tubings until the whole arterial vasculature was observed as clean. The cannulated specimens were fixed with formaldehyde. Tap water infusion at a flow rate of 10 L/h was infused through the arterial tubings controlled with a drip regulator filling the arterial tree and leaking into the interstitial and cisternal space. Multiple microneurosurgical procedures were performed by 4 trainees. Cisternal and vascular dissection was executed in a very realistic fashion. Bypass anastomosis was created as well as aneurysm simulation with venous pouches. Vessel and aneurysm clipping and rupture situations were emulated and solution techniques were trained. Standard microsurgical laboratories regularly have scarce opportunities for working with decapitated human cadaver heads but could have human brains readily available. The human brain infusion model presents a realistic microneurosurgical training method. It is inexpensive and easy to set up. Such simplicity provides the adequate environment for developing microsurgical techniques. Copyright 2009 Elsevier Inc. All rights reserved.

  17. Electrokinetic supercharging in nonaqueous capillary electrophoresis for online preconcentration and determination of tamoxifen and its metabolites in human plasma.

    Science.gov (United States)

    Thang, Lee Yien; Breadmore, Michael C; See, Hong Heng

    2016-08-26

    An online preconcentration method, namely electrokinetic supercharging (EKS), was evaluated for the determination of tamoxifen and its metabolites in human plasma in nonaqueous capillary electrophoresis with ultraviolet detection (NACE-UV). This method was comprehensively optimized in terms of the leading electrolyte (LE) and terminating electrolyte (TE) injection lengths, as well as electrokinetic sample injection time. The optimized EKS conditions employed were as follows: hydrodynamic injection (HI) of 10mM potassium chloride as LE at 150mbar for 36s (4% of total capillary volume). The sample was injected at 10kV for 300s, followed by HI of 10mM pimozide as TE at 150mbar for 36s (4% of total capillary volume). Separation was performed in 7.5mM deoxycholic acid sodium salt, 15mM acetic acid and 1mM 18-crown-6 in 100% methanol at +25kV with UV detection at 205nm. Under optimized conditions, the sensitivity was enhanced between 160- and 600-fold when compared with our previously developed method based on HI at 150mbar for 12s. The detection limit of the method for tamoxifen and its metabolites were 0.05-0.25ng/mL, with RSDs between 2.1% and 3.5%. Recoveries in spiked human plasma were 95.6%-99.7%. A comparison was also made between the proposed EKS approach and the standard field-amplified sample injection (FASI) technique. EKS proved to be 3-5 times more sensitive than the FASI. The new EKS method was applied to the analysis of tamoxifen and its metabolites in plasma samples from breast cancer patients after liquid-liquid extraction. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Human Stem Cell-Derived Endothelial-Hepatic Platform for Efficacy Testing of Vascular-Protective Metabolites from Nutraceuticals.

    Science.gov (United States)

    Narmada, Balakrishnan Chakrapani; Goh, Yeek Teck; Li, Huan; Sinha, Sanjay; Yu, Hanry; Cheung, Christine

    2017-03-01

    Atherosclerosis underlies many cardiovascular and cerebrovascular diseases. Nutraceuticals are emerging as a therapeutic moiety for restoring vascular health. Unlike small-molecule drugs, the complexity of ingredients in nutraceuticals often confounds evaluation of their efficacy in preclinical evaluation. It is recognized that the liver is a vital organ in processing complex compounds into bioactive metabolites. In this work, we developed a coculture system of human pluripotent stem cell-derived endothelial cells (hPSC-ECs) and human pluripotent stem cell-derived hepatocytes (hPSC-HEPs) for predicting vascular-protective effects of nutraceuticals. To validate our model, two compounds (quercetin and genistein), known to have anti-inflammatory effects on vasculatures, were selected. We found that both quercetin and genistein were ineffective at suppressing inflammatory activation by interleukin-1β owing to limited metabolic activity of hPSC-ECs. Conversely, hPSC-HEPs demonstrated metabolic capacity to break down both nutraceuticals into primary and secondary metabolites. When hPSC-HEPs were cocultured with hPSC-ECs to permit paracrine interactions, the continuous turnover of metabolites mitigated interleukin-1β stimulation on hPSC-ECs. We observed significant reductions in inflammatory gene expressions, nuclear translocation of nuclear factor κB, and interleukin-8 production. Thus, integration of hPSC-HEPs could accurately reproduce systemic effects involved in drug metabolism in vivo to unravel beneficial constituents in nutraceuticals. This physiologically relevant endothelial-hepatic platform would be a great resource in predicting the efficacy of complex nutraceuticals and mechanistic interrogation of vascular-targeting candidate compounds. Stem Cells Translational Medicine 2017;6:851-863. © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  19. Characterization of thiol-conjugated metabolites of ginger components shogaols in mouse and human rrine and modulation of the glutathione levels in cancer cells by [6]-shogaol

    Science.gov (United States)

    Chen, Huadong; Soroka, Dominique N.; Hu, Yuhui; Chen, Xiaoxin; Sang, Shengmin

    2013-01-01

    Scope Shogaols, a series of major constituents in dried ginger with the most abundant being [6]-, [8]-, and [10]-shogaols, show much higher anti-cancer potencies than gingerols. Previously, we reported the mercapturic acid pathway as a major metabolic route for [6]-shogaol in mice. However, it is still unclear how the side chain length affects the metabolism of shogaols and how shogaols are metabolized in humans. Methods and results We first investigate the metabolism of [10]-shogaol in mouse urine, and then investigate the biotransformation of shogaols in human urine. Our results show that eight major thiol-conjugated metabolites of [10]-shogaol were detected in mouse urine, while six major thiol-conjugated metabolites of [6]-shogaol, two thiol-conjugated metabolites of [8]-shogaol, and two thiol-conjugated metabolites of [10]-shogaol were detected in urine collected from human after drinking ginger tea, using liquid chromatography/electrospray ionization tandem mass spectrometry. Our results clearly indicate the mercapturic acid pathway is a major metabolic route for [10]-shogaol in mice and for shogaols in human. Furthermore, we also investigated the regulation of glutathione (GSH) by [6]-shogaol in human colon cancer cells HCT-116. Our results show [6]-shogaol, after initially depleting glutathione levels, can subsequently restore and increase GSH levels over time. Conclusion Shogaols are metabolized extensively in mouse and human to form thiol-conjugated metabolites and GSH might play an important role in the cancer preventative activity of ginger. PMID:23322393

  20. A human-specific de novo protein-coding gene associated with human brain functions.

    Directory of Open Access Journals (Sweden)

    Chuan-Yun Li

    2010-03-01

    Full Text Available To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203. Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions.

  1. Responses of the Human Brain to Mild Dehydration and Rehydration Explored In Vivo by 1H-MR Imaging and Spectroscopy.

    Science.gov (United States)

    Biller, A; Reuter, M; Patenaude, B; Homola, G A; Breuer, F; Bendszus, M; Bartsch, A J

    2015-12-01

    As yet, there are no in vivo data on tissue water changes and associated morphometric changes involved in the osmo-adaptation of normal brains. Our aim was to evaluate osmoadaptive responses of the healthy human brain to osmotic challenges of de- and rehydration by serial measurements of brain volume, tissue fluid, and metabolites. Serial T1-weighted and (1)H-MR spectroscopy data were acquired in 15 healthy individuals at normohydration, on 12 hours of dehydration, and during 1 hour of oral rehydration. Osmotic challenges were monitored by serum measures, including osmolality and hematocrit. MR imaging data were analyzed by using FreeSurfer and LCModel. On dehydration, serum osmolality increased by 0.67% and brain tissue fluid decreased by 1.63%, on average. MR imaging morphometry demonstrated corresponding decreases of cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus. These changes reversed during rehydration. Continuous fluid ingestion of 1 L of water for 1 hour within the scanner lowered serum osmolality by 0.96% and increased brain tissue fluid by 0.43%, on average. Concomitantly, cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus increased. Changes in brain tissue fluid were related to volume changes of the whole brain, the white matter, and hypothalamus/thalamus. Only volume changes of the hypothalamus/thalamus significantly correlated with serum osmolality. This is the first study simultaneously evaluating changes in brain tissue fluid, metabolites, volume, and cortical thickness. Our results reflect cellular volume regulatory mechanisms at a macroscopic level and emphasize that it is essential to control for hydration levels in studies on brain morphometry and metabolism in order to avoid confounding the findings. © 2015 by American Journal of Neuroradiology.

  2. Brain-Computer Interfaces Revolutionizing Human-Computer Interaction

    CERN Document Server

    Graimann, Bernhard; Allison, Brendan

    2010-01-01

    A brain-computer interface (BCI) establishes a direct output channel between the human brain and external devices. BCIs infer user intent via direct measures of brain activity and thus enable communication and control without movement. This book, authored by experts in the field, provides an accessible introduction to the neurophysiological and signal-processing background required for BCI, presents state-of-the-art non-invasive and invasive approaches, gives an overview of current hardware and software solutions, and reviews the most interesting as well as new, emerging BCI applications. The book is intended not only for students and young researchers, but also for newcomers and other readers from diverse backgrounds keen to learn about this vital scientific endeavour.

  3. Is the Social Brain Theory Applicable to Human Individual Differences? Relationship between Sociability Personality Dimension and Brain Size

    Directory of Open Access Journals (Sweden)

    Klára Horváth

    2011-04-01

    Full Text Available Our study intends to examine whether the social brain theory is applicable to human individual differences. According to the social brain theory primates have larger brains as it could be expected from their body sizes due to the adaptation to a more complex social life. Regarding humans there were few studies about the relationship between theory of mind and frontal and temporal brain lobes. We hypothesized that these brain lobes, as well as the whole cerebrum and neocortex are in connection with the Sociability personality dimension that is associated with individuals' social lives. Our findings support this hypothesis as Sociability correlated positively with the examined brain structures if we control the effects of body size differences and age. These results suggest that the social brain theory can be extended to human interindividual differences and they have some implications to personality psychology too.

  4. Is the social brain theory applicable to human individual differences? Relationship between sociability personality dimension and brain size.

    Science.gov (United States)

    Horváth, Klára; Martos, János; Mihalik, Béla; Bódizs, Róbert

    2011-06-17

    Our study intends to examine whether the social brain theory is applicable to human individual differences. According to the social brain theory primates have larger brains as it could be expected from their body sizes due to the adaptation to a more complex social life. Regarding humans there were few studies about the relationship between theory of mind and frontal and temporal brain lobes. We hypothesized that these brain lobes, as well as the whole cerebrum and neocortex are in connection with the Sociability personality dimension that is associated with individuals' social lives. Our findings support this hypothesis as Sociability correlated positively with the examined brain structures if we control the effects of body size differences and age. These results suggest that the social brain theory can be extended to human interindividual differences and they have some implications to personality psychology too.

  5. Tracing cytotoxic effects of small organic Se species in human liver cells back to total cellular Se and Se metabolites.

    Science.gov (United States)

    Marschall, T A; Kroepfl, N; Jensen, K B; Bornhorst, J; Meermann, B; Kuehnelt, D; Schwerdtle, T

    2017-03-22

    Small selenium (Se) species play a major role in the metabolism, excretion and dietary supply of the essential trace element selenium. Human cells provide a valuable tool for investigating currently unresolved issues on the cellular mechanisms of Se toxicity and metabolism. In this study, we developed two isotope dilution inductively coupled plasma tandem-mass spectrometry based methods and applied them to human hepatoma cells (HepG2) in order to quantitatively elucidate total cellular Se concentrations and cellular Se species transformations in relation to the cytotoxic effects of four small organic Se species. Species- and incubation time-dependent results were obtained: the two major urinary excretion metabolites trimethylselenonium (TMSe) and methyl-2-acetamido-2-deoxy-1-seleno-β-d-galactopyranoside (SeSugar 1) were taken up by the HepG2 cells in an unmodified manner and did not considerably contribute to the Se pool. In contrast, Se-methylselenocysteine (MeSeCys) and selenomethionine (SeMet) were taken up in higher amounts, they were largely incorporated by the cells (most likely into proteins) and metabolized to other small Se species. Two new metabolites of MeSeCys, namely γ-glutamyl-Se-methylselenocysteine and Se-methylselenoglutathione, were identified by means of HPLC-electrospray-ionization-Orbitrap-MS. They are certainly involved in the (de-)toxification modes of Se metabolism and require further investigation.

  6. In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice.

    Directory of Open Access Journals (Sweden)

    Jose Morales-Corraliza

    2009-09-01

    Full Text Available The metabolism of the amyloid precursor protein (APP and tau are central to the pathobiology of Alzheimer's disease (AD. We have examined the in vivo turnover of APP, secreted APP (sAPP, Abeta and tau in the wild-type and Tg2576 mouse brain using cycloheximide to block protein synthesis. In spite of overexpression of APP in the Tg2576 mouse, APP is rapidly degraded, similar to the rapid turnover of the endogenous protein in the wild-type mouse. sAPP is cleared from the brain more slowly, particularly in the Tg2576 model where the half-life of both the endogenous murine and transgene-derived human sAPP is nearly doubled compared to wild-type mice. The important Abeta degrading enzymes neprilysin and IDE were found to be highly stable in the brain, and soluble Abeta40 and Abeta42 levels in both wild-type and Tg2576 mice rapidly declined following the depletion of APP. The cytoskeletal-associated protein tau was found to be highly stable in both wild-type and Tg2576 mice. Our findings unexpectedly show that of these various AD-relevant protein metabolites, sAPP turnover in the brain is the most different when comparing a wild-type mouse and a beta-amyloid depositing, APP overexpressing transgenic model. Given the neurotrophic roles attributed to sAPP, the enhanced stability of sAPP in the beta-amyloid depositing Tg2576 mice may represent a neuroprotective response.

  7. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders

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    Thomas Raymond H

    2012-07-01

    Full Text Available Abstract Gastrointestinal symptoms and altered blood phospholipid profiles have been reported in patients with autism spectrum disorders (ASD. Most of the phospholipid analyses have been conducted on the fatty acid composition of isolated phospholipid classes following hydrolysis. A paucity of information exists on how the intact phospholipid molecular species are altered in ASD. We applied ESI/MS to determine how brain and blood intact phospholipid species were altered during the induction of ASD-like behaviors in rats following intraventricular infusions with the enteric bacterial metabolite propionic acid. Animals were infused daily for 8 days, locomotor activity assessed, and animals killed during the induced behaviors. Propionic acid infusions increased locomotor activity. Lipid analysis revealed treatment altered 21 brain and 30 blood phospholipid molecular species. Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species. These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.

  8. Deformation of the human brain induced by mild acceleration.

    Science.gov (United States)

    Bayly, P V; Cohen, T S; Leister, E P; Ajo, D; Leuthardt, E C; Genin, G M

    2005-08-01

    Rapid deformation of brain matter caused by skull acceleration is most likely the cause of concussion, as well as more severe traumatic brain injury (TBI). The inability to measure deformation directly has led to disagreement and confusion about the biomechanics of concussion and TBI. In the present study, brain deformation in human volunteers was measured directly during mild, but rapid, deceleration of the head (20-30 m/sec2 peak, approximately 40 msec duration), using an imaging technique originally developed to measure cardiac deformation. Magnetic resonance image sequences with imposed "tag" lines were obtained at high frame rates by repeating the deceleration and acquiring a subset of image data each repetition. Displacements of points on tag lines were used to estimate the Lagrangian strain tensor field. Qualitative (visual) and quantitative (strain) results illustrate clearly the deformation of brain matter due to occipital deceleration. Strains of 0.02-0.05 were typical during these events (0.05 strain corresponds roughly to a 5% change in the dimension of a local tissue element). Notably, compression in frontal regions and stretching in posterior regions were observed. The motion of the brain appears constrained by structures at the frontal base of the skull; it must pull away from such constraints before it can compress against the occipital bone. This mechanism is consistent with observations of contrecoup injury in occipital impact.

  9. Pulsatile cerebrospinal fluid dynamics in the human brain.

    Science.gov (United States)

    Linninger, Andreas A; Tsakiris, Cristian; Zhu, David C; Xenos, Michalis; Roycewicz, Peter; Danziger, Zachary; Penn, Richard

    2005-04-01

    Disturbances of the cerebrospinal fluid (CSF) flow in the brain can lead to hydrocephalus, a condition affecting thousands of people annually in the US. Considerable controversy exists about fluid and pressure dynamics, and about how the brain responds to changes in flow patterns and compression in hydrocephalus. This paper presents a new model based on the first principles of fluid mechanics. This model of fluid-structure interactions predicts flows and pressures throughout the brain's ventricular pathways consistent with both animal intracranial pressure (ICP) measurements and human CINE phase-contrast magnetic resonance imaging data. The computations provide approximations of the tissue deformations of the brain parenchyma. The model also quantifies the pulsatile CSF motion including flow reversal in the aqueduct as well as the changes in ICPs due to brain tissue compression. It does not require the existence of large transmural pressure differences as the force for ventricular expansion. Finally, the new model gives an explanation of communicating hydrocephalus and the phenomenon of asymmetric hydrocephalus.

  10. The maternal brain and its plasticity in humans.

    Science.gov (United States)

    Kim, Pilyoung; Strathearn, Lane; Swain, James E

    2016-01-01

    This article is part of a Special Issue "Parental Care". Early mother-infant relationships play important roles in infants' optimal development. New mothers undergo neurobiological changes that support developing mother-infant relationships regardless of great individual differences in those relationships. In this article, we review the neural plasticity in human mothers' brains based on functional magnetic resonance imaging (fMRI) studies. First, we review the neural circuits that are involved in establishing and maintaining mother-infant relationships. Second, we discuss early postpartum factors (e.g., birth and feeding methods, hormones, and parental sensitivity) that are associated with individual differences in maternal brain neuroplasticity. Third, we discuss abnormal changes in the maternal brain related to psychopathology (i.e., postpartum depression, posttraumatic stress disorder, substance abuse) and potential brain remodeling associated with interventions. Last, we highlight potentially important future research directions to better understand normative changes in the maternal brain and risks for abnormal changes that may disrupt early mother-infant relationships. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Mapping human brain lesions and their functional consequences.

    Science.gov (United States)

    Karnath, Hans-Otto; Sperber, Christoph; Rorden, Christopher

    2018-01-15

    Neuroscience has a long history of inferring brain function by examining the relationship between brain injury and subsequent behavioral impairments. The primary advantage of this method over correlative methods is that it can tell us if a certain brain region is necessary for a given cognitive function. In addition, lesion-based analyses provide unique insights into clinical deficits. In the last decade, statistical voxel-based lesion behavior mapping (VLBM) emerged as a powerful method for understanding the architecture of the human brain. This review illustrates how VLBM improves our knowledge of functional brain architecture, as well as how it is inherently limited by its mass-univariate approach. A wide array of recently developed methods appear to supplement traditional VLBM. This paper provides an overview of these new methods, including the use of specialized imaging modalities, the combination of structural imaging with normative connectome data, as well as multivariate analyses of structural imaging data. We see these new methods as complementing rather than replacing traditional VLBM, providing synergistic tools to answer related questions. Finally, we discuss the potential for these methods to become established in cognitive neuroscience and in clinical applications. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Human Brain Stem Structures Respond Differentially to Noxious Heat

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    Alexander eRitter

    2013-09-01

    Full Text Available Concerning the physiological correlates of pain, the brain stem is considered to be one core region that is activated by noxious input. In animal studies, different slopes of skin heating (SSH with noxious heat led to activation in different columns of the midbrain periaqueductal grey (PAG. The present study aimed at finding a method for differentiating structures in PAG and other brain stem structures, which are associated with different qualities of pain in humans according to the structures that were associated with different behavioral significances to noxious thermal stimulation in animals. Brain activity was studied by fMRI in healthy subjects in response to steep and shallow SSH with noxious heat. We found differential activation to different SSH in the PAG and the rostral ventromedial medulla (RVM. In a second experiment we demonstrate that the different SSH were associated with different pain qualities. Our experiments provide evidence that brainstem structures, i.e. the PAG and the RVM, become differentially activated by different SSH. Therefore, different SSH can be utilized when brain stem structures are investigated and when it is aimed to activate these structures differentially. Moreover, percepts of first pain were elicited by shallow SSH whereas percepts of second pain were elicited by steep SSH. The stronger activation of these brain stem structures to SSH, eliciting percepts of second vs. first pain, might be of relevance for activating different coping strategies in response to the noxious input with the two types of SSH.

  13. The Speculative Neuroscience of the Future Human Brain

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    Robert A. Dielenberg

    2013-05-01

    Full Text Available The hallmark of our species is our ability to hybridize symbolic thinking with behavioral output. We began with the symmetrical hand axe around 1.7 mya and have progressed, slowly at first, then with greater rapidity, to producing increasingly more complex hybridized products. We now live in the age where our drive to hybridize has pushed us to the brink of a neuroscientific revolution, where for the first time we are in a position to willfully alter the brain and hence, our behavior and evolution. Nootropics, transcranial direct current stimulation (tDCS, transcranial magnetic stimulation (TMS, deep brain stimulation (DBS and invasive brain mind interface (BMI technology are allowing humans to treat previously inaccessible diseases as well as open up potential vistas for cognitive enhancement. In the future, the possibility exists for humans to hybridize with BMIs and mobile architectures. The notion of self is becoming increasingly extended. All of this to say: are we in control of our brains, or are they in control of us?

  14. Peroxisomes in human health and disease: metabolic pathways, metabolite transport, interplay with other organelles and signal transduction.

    Science.gov (United States)

    Wanders, Ronald J A

    2013-01-01

    Peroxisomes play a key role in human physiology as exemplified by the devastating consequences of a defect in peroxisome biogenesis as observed in patients affected by Zellweger syndrome. The main metabolic functions of peroxisomes in humans include: (1) fatty acid beta-oxidation; (2) etherphospholipid synthesis; (3) bile acid synthesis; (4) fatty acid alpha-oxidation, and (5) glyoxylate detoxification. Since peroxisomes lack a citric acid cycle and respiratory chain like mitochondria do, metabolism in peroxisomes requires continued cross-talk with other organelles, notably mitochondria and the endoplasmic reticulum in order to allow continued metabolism of the products generated by peroxisomes. Many of the metabolites which require peroxisomes for homeostasis, are involved in signal transduction pathways. These include the primary bile acids; platelet activating factor; plasmalogens, N-acylglycines and N-acyltaurines; docosahexaenoic acid as well as multiple prostanoids. The current state of knowledge in this area will be discussed in this review.

  15. Determination of fluoxetine and its metabolite norfluoxetine in human liver microsomes by reversed-phase HPLC in vitro.

    Science.gov (United States)

    Liu, Z Q; Cheng, Z N; Wang, W; Tan, Z R; Ou-Yang, D S; Zhou, H H

    2000-11-01

    A high-performance liquid chromatography (HPLC) method was developed for the determination of fluoxetine (FLU) and its metabolite norfluoxetine (N-FLU) in human liver microsomes in vitro. An incubation buffer containing human liver microsomes, NADPH-generating system, and FLU, after termination of enzyme reaction and addition of nortriptyline (NOR) as internal standard (IS), was extracted with n-hexane/acetonitrile, and separated on a reversed-phase ODS column. Detection was achieved at 226 nm by ultraviolet detector (UV). The limit of detection was 5 micrograms/L for both FLU and N-FLU. No potential interference was found. The method provides recoveries of up to 94%-104% and acceptable coefficients of variation were found for both within-run (< 7.8%) and day to day (< 9.1%) assays. This method is rapid, sensitive, and simple for studying the metabolism of FLU and N-FLU.

  16. Simultaneous Pharmacokinetic Modeling of Alkylresorcinols and Their Main Metabolites Indicates Dual Absorption Mechanisms and Enterohepatic Elimination in Humans

    DEFF Research Database (Denmark)

    Marklund, Matti; Strömberg, Eric A,; Lærke, Helle Nygaard

    2014-01-01

    a single dose (120 g) of rye bran and validated against fasting plasma concentrations from 8 women and 7 men with controlled rye bran intake (23, 45, or 90 g/d). Alkylresorcinols in the lymph and plasma of a pig fed a single alkylresorcinol dose (1.3 mmol) were quantified to assess absorption. Human...... of absorbed alkylresorcinols was metabolized before reaching the systemic circulation. Plasma concentrations of alkylresorcinols and their metabolites depended on absorption and formation, respectively, and the mean ± SEM terminal elimination half-life of alkylresorcinols (1.9 ± 0.59 h), DHPPA (1.5 ± 0.26 h......% of the alkylresorcinol dose was recovered in the lymph. DHPPA was identified in both human ileostomal effluent and pig bile, indicating availability of DHPPA for absorption and enterohepatic circulation.Conclusion: Intact alkylresorcinols have advantages over DHBA and DHPPA as plasma biomarkers for whole-grain wheat...

  17. Human NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated inactivation of reactive quinoneimine metabolites of diclofenac and mefenamic acid.

    Science.gov (United States)

    Vredenburg, Galvin; Elias, Naura S; Venkataraman, Harini; Hendriks, Delilah F G; Vermeulen, Nico P E; Commandeur, Jan N M; Vos, J Chris

    2014-04-21

    quinone oxidoreductase 1 (NQO1) is an enzyme capable of reducing a broad range of chemically reactive quinones and quinoneimines (QIs) and can be strongly upregulated by Nrf2/Keap1-mediated stress responses. Several commonly used drugs implicated in adverse drug reactions (ADRs) are known to form reactive QI metabolites upon bioactivation by P450, such as acetaminophen (APAP), diclofenac (DF), and mefenamic acid (MFA). In the present study, the reductive activity of human NQO1 toward the QI metabolites derived from APAP and hydroxy-metabolites of DF and MFA was studied, using purified bacterial P450 BM3 (CYP102A1) mutant M11 as a bioactivation system. The NQO1-catalyzed reduction of the QI metabolites was quantified relative to spontaneous glutathione (GSH) conjugation. Addition of NQO1 to the incubations strongly reduced the formation of all corresponding GSH conjugates, and this activity could be prevented by dicoumarol, a selective NQO1 inhibitor. The GSH conjugation was strongly increased by adding human GSTP1-1 in a wide range of GSH concentrations. Still, NQO1 could effectively compete with the GST catalyzed GSH conjugation by reducing the QIs. In conclusion, we identified the QI metabolites of the 4'- and 5-hydroxy-metabolites of DF and MFA as novel substrates for human NQO1. NQO1-mediated reduction proves to be an effective pathway to detoxify these QI metabolites in addition to GSH conjugation. Genetically determined deficiency of NQO1 therefore might be a risk factor for ADRs induced by reactive QI drug metabolites.

  18. Determination of monoamine neurotransmitters and their metabolites in a mouse brain microdialysate by coupling high-performance liquid chromatography with gold nanoparticle-initiated chemiluminescence

    Energy Technology Data Exchange (ETDEWEB)

    Li Na; Guo Jizhao; Liu Bo; Yu Yuqi [Department of Chemistry, University of Science and Technology of China (USTC), JinZhai Road No: 96, 230026 Hefei, Anhui (China); Cui Hua, E-mail: hcui@ustc.edu.cn [Department of Chemistry, University of Science and Technology of China (USTC), JinZhai Road No: 96, 230026 Hefei, Anhui (China); Mao Lanqun; Lin Yuqing [Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences (CAS), 100080 Beijing (China)

    2009-07-10

    Our previous work showed that gold nanoparticles could trigger chemiluminescence (CL) between luminol and AgNO{sub 3}. In the present work, the effect of some biologically important reductive compounds, including monoamine neurotransmitters and their metabolites, reductive amino acids, ascorbic acid, uric acid, and glutathione, on the novel CL reaction were investigated for analytical purpose. It was found that all of them could inhibit the CL from the luminol-AgNO{sub 3}-Au colloid system. Among them, monoamine neurotransmitters and their metabolites exhibited strong inhibition effect. Taking dopamine as a model compound, the CL mechanism was studied by measuring absorption spectra during the CL reaction and the reaction kinetics via stopped-flow technique. The CL inhibition mechanism is proposed to be due to that these tested compounds competed with luminol for AgNO{sub 3} to inhibit the formation of luminol radicals and to accelerate deposition of Ag atoms on surface of gold nanoparticles, leading to a decrease in CL intensity. Based on the inhibited CL, a novel method for simultaneous determination of monoamine neurotransmitters and their metabolites was developed by coupling high-performance liquid chromatography with this CL reaction. The new method was successfully applied to determine the compounds in a mouse brain microdialysate. Compared with the reported HPLC-CL methods, the proposed method is simple, fast, and could determine more analytes. Moreover, the limits of linear ranges for NE, E, and DA using the proposed method were one order of magnitude lower than the luminol system without gold nanoparticles.

  19. A Novel Human Body Area Network for Brain Diseases Analysis.

    Science.gov (United States)

    Lin, Kai; Xu, Tianlang

    2016-10-01

    Development of wireless sensor and mobile communication technology provide an unprecedented opportunity for realizing smart and interactive healthcare systems. Designing such systems aims to remotely monitor the health and diagnose the diseases for users. In this paper, we design a novel human body area network for brain diseases analysis, which is named BABDA. Considering the brain is one of the most complex organs in the human body, the BABDA system provides four function modules to ensure the high quality of the analysis result, which includes initial data collection, data correction, data transmission and comprehensive data analysis. The performance evaluation conducted in a realistic environment with several criteria shows the availability and practicability of the BABDA system.

  20. Magnetic Deposits of Iron Oxides in the Human Brain

    Directory of Open Access Journals (Sweden)

    Makohusová Miroslava

    2014-06-01

    Full Text Available Deposits of iron oxides in the human brain (globus pallidus are visible under electron microscopy as object of regular and or/irregular shape but giving sharp diffraction patterns in the transmission mode. The SQUID magnetometry reveals that the magnetization curves decline form an ideal Langevin function due to the dominating diamagnetism of organic tissue. The fitting procedure yields the quantitative characteristics of the overall magnetization curves that were further processed by statistical multivariate methods

  1. Human brain arteriovenous malformations express lymphatic-associated genes

    OpenAIRE

    Shoemaker, Lorelei D.; Fuentes, Laurel F; Santiago, Shauna M; Allen, Breanna M; Cook, Douglas J.; Steinberg, Gary K.; Chang, Steven D.

    2014-01-01

    Objective Brain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may ...

  2. Dynamic Network Centrality Summarizes Learning in the Human Brain

    OpenAIRE

    Mantzaris, Alexander V.; Bassett, Danielle S.; Wymbs, Nicholas F.; Estrada, Ernesto; Porter, Mason A.; Mucha, Peter J; Grafton, Scott T.; Higham, Desmond J.

    2012-01-01

    We study functional activity in the human brain using functional Magnetic Resonance Imaging and recently developed tools from network science. The data arise from the performance of a simple behavioural motor learning task. Unsupervised clustering of subjects with respect to similarity of network activity measured over three days of practice produces significant evidence of `learning', in the sense that subjects typically move between clusters (of subjects whose dynamics are similar) as time ...

  3. A mechanistic account of value computation in the human brain

    OpenAIRE

    Philiastides, Marios G.; Biele, Guido; Heekeren, Hauke R.

    2010-01-01

    To make decisions based on the value of different options, we often have to combine different sources of probabilistic evidence. For example, when shopping for strawberries on a fruit stand, one uses their color and size to infer—with some uncertainty—which strawberries taste best. Despite much progress in understanding the neural underpinnings of value-based decision making in humans, it remains unclear how the brain represents different sources of probabilistic evidence and how they are use...

  4. A novel LC-MS/MS method for the simultaneous quantification of topiramate and its main metabolites in human plasma.

    Science.gov (United States)

    Milosheska, Daniela; Roškar, Robert

    2017-05-10

    The aim of the present report was to develop and validate simple, sensitive and reliable LC-MS/MS method for quantification of topiramate (TPM) and its main metabolites: 2,3-desisopropylidene TPM, 4,5-desisopropylidene TPM, 10-OH TPM and 9-OH TPM in human plasma samples. The most abundant metabolite 2,3-desisopropylidene TPM was isolated from patients urine, characterized and afterwards used as an authentic standard for method development and validation. Sample preparation method employs 100μL of plasma sample and liquid-liquid extraction with a mixture of ethyl acetate and diethyl ether as extraction solvent. Chromatographic separation was achieved on a 1290 Infinity UHPLC coupled to 6460 Triple Quad Mass Spectrometer operated in negative MRM mode using Kinetex C18 column (50×2.1mm, 2.6μm) by gradient elution using water and methanol as a mobile phase and stable isotope labeled TPM as internal standard. The method showed to be selective, accurate, precise and linear over the concentration ranges of 0.10-20μg/mL for TPM, 0.01-2.0μg/mL for 2,3-desisopropylidene TPM, and 0.001-0.200μg/mL for 4,5-desisopropylidene TPM, 10-OH TPM and 9-OH TPM. The described method is the first fully validated method capable of simultaneous determination of TPM and its main metabolites in plasma over the selected analytical range. The suitability of the method was successfully demonstrated by the quantification of all analytes in plasma samples of patients with epilepsy and can be considered as reliable analytical tool for future investigations of the TPM metabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites.

    Science.gov (United States)

    Liang, Si-Cheng; Ge, Guang-Bo; Xia, Yang-Liu; Pei-Pei, Dong; Ping, Wang; Qi, Xiao-Yi; Cai-Xia, Tu; Ling, Yang

    2017-06-01

    1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC). 2. Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC50 values for daphnetin (0.51∼0.53 μM) and 8-O-methyldaphnetin (22.5∼24.3 μM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (Ki) between daphnetin (competitive, 0.37 μM) and 8-O-methyldaphnetin (noncompetitive, 25.7 μM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro-in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin. 3. With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.

  6. Investigation of G72 (DAOA expression in the human brain

    Directory of Open Access Journals (Sweden)

    Hirsch Steven

    2008-12-01

    Full Text Available Abstract Background Polymorphisms at the G72/G30 locus on chromosome 13q have been associated with schizophrenia or bipolar disorder in more than ten independent studies. Even though the genetic findings are very robust, the physiological role of the predicted G72 protein has thus far not been resolved. Initial reports suggested G72 as an activator of D-amino acid oxidase (DAO, supporting the glutamate dysfunction hypothesis of schizophrenia. However, these findings have subsequently not been reproduced and reports of endogenous human G72 mRNA and protein expression are extremely limited. In order to better understand the function of this putative schizophrenia susceptibility gene, we attempted to demonstrate G72 mRNA and protein expression in relevant human brain regions. Methods The expression of G72 mRNA was studied by northern blotting and semi-quantitative SYBR-Green and Taqman RT-PCR. Protein expression in human tissue lysates was investigated by western blotting using two custom-made specific anti-G72 peptide antibodies. An in-depth in silico analysis of the G72/G30 locus was performed in order to try and identify motifs or regulatory elements that provide insight to G72 mRNA expression and transcript stability. Results Despite using highly sensitive techniques, we failed to identify significant levels of G72 mRNA in a variety of human tissues (e.g. adult brain, amygdala, caudate nucleus, fetal brain, spinal cord and testis human cell lines or schizophrenia/control post mortem BA10 samples. Furthermore, using western blotting in combination with sensitive detection methods, we were also unable to detect G72 protein in a number of human brain regions (including cerebellum and amygdala, spinal cord or testis. A detailed in silico analysis provides several lines of evidence that support the apparent low or absent expression of G72. Conclusion Our results suggest that native G72 protein is not normally present in the tissues that we analysed

  7. Imaging synaptic density in the living human brain.

    Science.gov (United States)

    Finnema, Sjoerd J; Nabulsi, Nabeel B; Eid, Tore; Detyniecki, Kamil; Lin, Shu-Fei; Chen, Ming-Kai; Dhaher, Roni; Matuskey, David; Baum, Evan; Holden, Daniel; Spencer, Dennis D; Mercier, Joël; Hannestad, Jonas; Huang, Yiyun; Carson, Richard E

    2016-07-20

    Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand [(11)C]UCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that [(11)C]UCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, [(11)C]UCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders. Copyright © 2016, American Association for the Advancement of Science.

  8. Determination of two mebeverine metabolites, mebeverine alcohol and desmethylmebeverine alcohol, in human plasma by a dual stable isotope-based gas chromatographic-mass spectrometric method.

    Science.gov (United States)

    Tulich, L J; Randall, J L; Kelm, G R; Wehmeyer, K R

    1996-07-12

    A dual stable isotope-based GC-MS method was developed for the simultaneous determination of two metabolites of mebeverine, mebeverine alcohol and desmethylmebeverine alcohol, in human plasma. Plasma samples were treated with beta-glucuronidase to cleave the glucuronide conjugates of both compounds prior to analysis. The treated plasma was prepared for analysis by solid-phase extraction using octadecylsilane cartridges. The isolated metabolites were derivatized and analyzed by GC-MS using selected-ion monitoring. Plots of peak-area ratio were linear with metabolite concentration from 2 to 200 ng/ml and the limit of detection for both metabolites was 0.5 ng/ml. The GC-MS methodology was applied to the analysis of plasma from human subjects following peroral administration of mebeverine. Pharmacokinetic parameters for both metabolites were determined and suggest that relative systemic mebeverine exposure may potentially be assessed using metabolite kinetics, if the latter subsequently are demonstrated to be linear with mebeverine dose.

  9. Comparative study of microbial-derived phenolic metabolites in human feces after intake of gin, red wine, and dealcoholized red wine.

    Science.gov (United States)

    Jiménez-Girón, Ana; Queipo-Ortuño, María Isabel; Boto-Ordóñez, Maria; Muñoz-González, Irene; Sánchez-Patán, Fernando; Monagas, Maria; Martín-Álvarez, Pedro J; Murri, Mora; Tinahones, Francisco J; Andrés-Lacueva, Cristina; Bartolomé, Begoña; Moreno-Arribas, M Victoria

    2013-04-24

    The analysis of microbial phenolic metabolites in fecal samples from in vivo studies is crucial to understanding the potential modulatory effects derived from polyphenol consumption and its overall health effects, particularly at the gut level. In this study, the composition of microbial phenolic metabolites in human feces collected after regular consumption of either red wine, dealcoholized red wine, or gin was analyzed by UPLC-ESI-MS/MS. Red wine interventions produce a change in the content of eight phenolic acids, which are probably derived from the catabolism of flavan-3-ols and anthocyanins, the main flavonoids in red wine. Moreover, alcohol seemed not to influence the formation of phenolic metabolites by the gut microbiota. A principal component analysis revealed large interindividual differences in the formation of microbial metabolites after each red wine polyphenol intervention, but not after the gin intervention, indicating differences in the gut microbial composition among subjects.

  10. Functional interactions as big data in the human brain.

    Science.gov (United States)

    Turk-Browne, Nicholas B

    2013-11-01

    Noninvasive studies of human brain function hold great potential to unlock mysteries of the human mind. The complexity of data generated by such studies, however, has prompted various simplifying assumptions during analysis. Although this has enabled considerable progress, our current understanding is partly contingent upon these assumptions. An emerging approach embraces the complexity, accounting for the fact that neural representations are widely distributed, neural processes involve interactions between regions, interactions vary by cognitive state, and the space of interactions is massive. Because what you see depends on how you look, such unbiased approaches provide the greatest flexibility for discovery.

  11. 6-gingerdiols as the major metabolites of 6-gingerol in cancer cells and in mice and their cytotoxic effects on human cancer cells.

    Science.gov (United States)

    Lv, Lishuang; Chen, Huadong; Soroka, Dominique; Chen, Xiaoxin; Leung, TinChung; Sang, Shengmin

    2012-11-14

    6-Gingerol, a major pungent component of ginger (Zingiber officinale Roscoe, Zingiberaceae), has been reported to have antitumor activities. However, the metabolic fate of 6-gingerol and the contribution of its metabolites to the observed activities are still unclear. In the present study, we investigated the biotransformation of 6-gingerol in different cancer cells and in mice, purified and identified the major metabolites from human lung cancer cells, and determined the effects of the major metabolites on the proliferation of human cancer cells. Our results show that 6-gingerol is extensively metabolized in H-1299 human lung cancer cells, CL-13 mouse lung cancer cells, HCT-116 and HT-29 human colon cancer cells, and in mice. The two major metabolites in H-1299 cells were purified and identified as (3R,5S)-6-gingerdiol (M1) and (3S,5S)-6-gingerdiol (M2) based on the analysis of their 1D and 2D NMR data. Both metabolites induced cytotoxicity in cancer cells after 24 h, with M1 having a comparable effect to 6-gingerol in H-1299 cells.

  12. Simulation of Human Plasma Concentrations of Thalidomide and Primary 5-Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice.

    Science.gov (United States)

    Nishiyama, Sayako; Suemizu, Hiroshi; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2015-11-16

    Plasma concentrations of thalidomide and primary 5-hydroxylated metabolites including 5,6-dihydroxythalidomide and glutathione (GSH) conjugate(s) were investigated in chimeric mice with highly "humanized" liver cells harboring cytochrome P450 3A5*1. Following oral administration of thalidomide (100 mg/kg), plasma concentrations of GSH conjugate(s) of 5-hydroxythalidomide were higher in humanized mice than in controls. Simulation of human plasma concentrations of thalidomide were achieved with a simplified physiologically based pharmacokinetic model in accordance with reported thalidomide concentrations. The results indicate that the pharmacokinetics in humans of GSH conjugate and/or catechol primary 5-hydroxylated thalidomide contributing in vivo activation can be estimated for the first time.

  13. Effects of psychotropic drugs on brain plasticity in humans.

    Science.gov (United States)

    Paulzen, Michael; Veselinovic, Tanja; Gründer, Gerhard

    2014-01-01

    Although neurotransmitter-based hypotheses still prevail current thinking about the mechanism of action of psychotropic drugs, recent insight into the pathophysiology of psychiatric disorders has unveiled a range of new therapeutic actions of the drugs used to treat those disorders. Especially antidepressants seem to exert at least some of their effects via restoration of synaptic/neuronal plasticity. In addition, there is increasing evidence that several of the second-generation antipsychotics and some anticonvulsants affect neuronal survival/apoptosis as well as synaptic plasticity. Most of this evidence stems from work in animals. In this review, we will focus on the evidence for neuroplastic effects of psychotropic drugs in humans being aware of the fact that most of the data are derived from animals and that volumetric studies in humans can only indicate structural plasticity and not necessarily functional plasticity. However, as the data from human studies are rather poor and inconclusive, and sometimes even conflicting, it seems impossible to draw general conclusions. Until now studies on neuroplasticity in humans can only explain small pieces of the effects of psychotropic drugs on brain plasticity in humans. Nevertheless, future prospects for the development of new drugs targeting brain plasticity will be of importance and will complete this overview.

  14. Bidirectional placental transfer of Bisphenol A and its main metabolite, Bisphenol A-Glucuronide, in the isolated perfused human placenta.

    Science.gov (United States)

    Corbel, T; Gayrard, V; Puel, S; Lacroix, M Z; Berrebi, A; Gil, S; Viguié, C; Toutain, P-L; Picard-Hagen, N

    2014-08-01

    The widespread human exposure to Bisphenol A (BPA), an endocrine disruptor interfering with developmental processes, raises the question of the risk for human health of BPA fetal exposure. In humans, highly variable BPA concentrations have been reported in the feto-placental compartment. However the human fetal exposure to BPA still remains unclear. The aim of the study was to characterize placental exchanges of BPA and its main metabolite, Bisphenol A-Glucuronide (BPA-G) using the non-recirculating dual human placental perfusion. This high placental bidirectional permeability to the lipid soluble BPA strongly suggests a transport by passive diffusion in both materno-to-fetal and feto-to-maternal direction, leading to a calculated ratio between fetal and maternal free BPA concentrations of about 1. In contrast, BPA-G has limited placental permeability, particularly in the materno-to-fetal direction. Thus the fetal exposure to BPA conjugates could be explained mainly by its limited capacity to extrude BPA-G. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics.

    Science.gov (United States)

    Riba, Jordi; Valle, Marta; Urbano, Gloria; Yritia, Mercedes; Morte, Adelaida; Barbanoj, Manel J

    2003-07-01

    The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.

  16. Amine metabolism in the human brain : evaluation of the probenecid test

    NARCIS (Netherlands)

    Korf, Jacob

    1971-01-01

    There are indirect indications, that biogenic amines in the brain are concerned with pathological states such as depression (serotonin, 5HT and noradrenaline, NA) and Parkonsonism (dopamine, DA). These indications were obtained from measurements of amines and their metabolites in pe - ripheral

  17. A Rapid and Sensitive HPLC-Fluorescence Method for Determination of Mirtazapine and Its two Major Metabolites in Human Plasma.

    Science.gov (United States)

    Lavasani, Hoda; Giorgi, Mario; Sheikholeslami, Behjat; Hedayati, Mohammadhasan; Rouini, Mohammad Reza

    2014-01-01

    A rapid and sensitive HPLC method has been developed for the quantification of mirtazapine (MRZ), a noradrenergic and specific serotonergic inhibitor antidepressant (NaSSA) and its two major metabolites N-desmethyl mirtazapine (NDM) and 8-hydroxymirtazapine (8-OHM) in human plasma. The separation was achieved using Chromolith C18 column and a mobile phase of acetonitrile: phosphate buffer (pH = 3, 20:80, v/v) in isocratic mode at a flow rate of 2 mL/min. A fluorescence detector was set at 290 and 350 nm for excitation and emission, respectively. Zolpidem was used as the internal standard. Liquid-liquid extraction was applied for sample clean up. All analytes were eluted in less than 5 minutes with LOQ of 1 ng/mL for MRZ and 2 ng/mL for both NDM and 8-OHM. The developed method was successfully applied to quantify MRZ and its metabolites in plasma of a healthy volunteer.

  18. Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom.

    Science.gov (United States)

    Le, David; Goggin, Melissa M; Janis, Gregory C

    2012-01-01

    The leaves of the South Asian plant kratom are described as having stimulating effects at low doses, and opiate-like analgesic and euphoric effects at high doses. A long history of use and abuse has led to the classification of kratom as a controlled substance in its native Thailand and other South Asian countries. However, kratom is not controlled in the United States, and the ready availability of kratom has led to its emergence as an herbal drug of abuse. With the growing popularity of kratom, efficient procedures are needed to detect kratom use. In the current study, both ultra-high-performance liquid chromatography and high-performance liquid chromatography-tandem mass spectrometry methods have been developed and validated for monitoring the major alkaloids and metabolites found in urine following kratom use. The primary unique alkaloid mitragynine is quantified in human urine from 1.00-500.00 ng/mL using mitraphylline as an internal standard. In addition, two metabolites (5-desmethylmitragynine and 17-desmethyldihydromitragynine) and the related active, alkaloid 7-hydroxy-mitragynine, are simultaneously qualitatively monitored. The presence of analytes are confirmed by an information-dependent acquisition-enhanced product ion procedure generating full fragmentation data used to positively identify detected analytes. The validated method has been utilized for clinical and forensic analyses of urine for the detection of kratom use.

  19. Long-chain metabolites of α-tocopherol occur in human serum and inhibit macrophage foam cell formation in vitro.

    Science.gov (United States)

    Wallert, Maria; Mosig, Sandy; Rennert, Knut; Funke, Harald; Ristow, Michael; Pellegrino, Roberto Maria; Cruciani, Gabriele; Galli, Francesco; Lorkowski, Stefan; Birringer, Marc

    2014-03-01

    Despite intensive research the physiological role and molecular mechanisms of action of the lipophilic antioxidant α-tocopherol (α-TOH) are still poorly understood. Hepatic α-TOH catabolism results in intermediate formation of the long-chain metabolites (α-LCMs) α-13'-hydroxy- and α-13'-carboxychromanol (α-13'-OH and α-13'-COOH). We propose that α-LCMs have biological functions that need further exploration. Here we report that α-13'-COOH, as detected by LC/MS Q-TOF, occurs in human serum, providing evidence for its systemic bioavailability. Using semisynthetically derived α-LCMs we performed flow cytometric analyses and found that α-LCMs decrease oxidized LDL (oxLDL) uptake (α-13'-OH, 24±6%, α-13'-COOH, 20±5% vs control) and oxLDL-induced lipid accumulation in human macrophages in vitro (α-13'-OH, 26±4%, α-13'-COOH, 21±9% vs oxLDL), probably owing to α-LCM-mediated reduction in phagocytosis of oxLDL (α-13'-OH, 16±6%, α-13'-COOH, 41±3% vs oxLDL). At the same time, α-LCMs induced expression of CD36, the major scavenger receptor for oxLDL, in human macrophages by about 4.5-fold. Blocking experiments provided evidence that α-LCMs influence oxLDL uptake independent of CD36. A key finding of our study is that bioactivity of the α-LCMs occurs at lower concentrations and with mechanisms distinct from those of their metabolic precursor α-TOH. Our findings shed new light on the mechanistic aspects of α-TOH function in macrophages, which seem to be complicated by circulating α-LCMs. We speculate that α-LCMs represent a new class of regulatory metabolites. Further studies are required to elucidate their physiological role and contribution to cardiovascular disease. © 2013 Elsevier Inc. All rights reserved.

  20. Oxidative metabolism of dehydroepiandrosterone (DHEA) and biologically active oxygenated metabolites of DHEA and epiandrosterone (EpiA)--recent reports.

    Science.gov (United States)

    El Kihel, Laïla

    2012-01-01

    Dehydroepiandrosterone (DHEA) is a multifunctional steroid with a broad range of biological effects in humans and animals. DHEA can be converted to multiple oxygenated metabolites in the brain and peripheral tissues. The mechanisms by which DHEA exerts its effects are not well understood. However, evidence that the effects of DHEA are mediated by its oxygenated metabolites has accumulated. This paper will review the panel of oxygenated DHEA metabolites (7, 16 and 17-hydroxylated derivatives) including a number of 5α-androstane derivatives, such as epiandrosterone (EpiA) metabolites. The most important aspects of the oxidative metabolism of DHEA in the liver, intestine and brain are described. Then, this article reviews the reported biological effects of oxygenated DHEA metabolites from recent findings with a specific focus on cancer, inflammatory and immune processes, osteoporosis, thermogenesis, adipogenesis, the cardiovascular system, the brain and the estrogen and androgen receptors. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. A new microcontroller-based human brain hypothermia system.

    Science.gov (United States)

    Kapidere, Metin; Ahiska, Raşit; Güler, Inan

    2005-10-01

    Many studies show that artificial hypothermia of brain in conditions of anesthesia with the rectal temperature lowered down to 33 degrees C produces pronounced prophylactic effect protecting the brain from anoxia. Out of the methods employed now in clinical practice for reducing the oxygen consumption by the cerebral tissue, the most efficacious is craniocerebral hypothermia (CCH). It is finding even more extensive application in cardiovascular surgery, neurosurgery, neurorenimatology and many other fields of medical practice. In this study, a microcontroller-based designed human brain hypothermia system (HBHS) is designed and constructed. The system is intended for cooling and heating the brain. HBHS consists of a thermoelectric hypothermic helmet, a control and a power unit. Helmet temperature is controlled by 8-bit PIC16F877 microcontroller which is programmed using MPLAB editor. Temperature is converted to 10-bit digital and is controlled automatically by the preset values which have been already entered in the microcontroller. Calibration is controlled and the working range is tested. Temperature of helmet is controlled between -5 and +46 degrees C by microcontroller, with the accuracy of +/-0.5 degrees C.

  2. Regional selection of the brain size regulating gene CASC5 provides new insight into human brain evolution.

    Science.gov (United States)

    Shi, Lei; Hu, Enzhi; Wang, Zhenbo; Liu, Jiewei; Li, Jin; Li, Ming; Chen, Hua; Yu, Chunshui; Jiang, Tianzi; Su, Bing

    2017-02-01

    Human evolution is marked by a continued enlargement of the brain. Previous studies on human brain evolution focused on identifying sequence divergences of brain size regulating genes between humans and nonhuman primates. However, the evolutionary pattern of the brain size regulating genes during recent human evolution is largely unknown. We conducted a comprehensive analysis of the brain size regulating gene CASC5 and found that in recent human evolution, CASC5 has accumulated many modern human specific amino acid changes, including two fixed changes and six polymorphic changes. Among human populations, 4 of the 6 amino acid polymorphic sites have high frequencies of derived alleles in East Asians, but are rare in Europeans and Africans. We proved that this between-population allelic divergence was caused by regional Darwinian positive selection in East Asians. Further analysis of brain image data of Han Chinese showed significant associations of the amino acid polymorphic sites with gray matter volume. Hence, CASC5 may contribute to the morphological and structural changes of the human brain during recent evolution. The observed between-population divergence of CASC5 variants was driven by natural selection that tends to favor a larger gray matter volume in East Asians.

  3. Serum metabolites from walnut-fed aged rats attenuate stress-induced neurotoxicity in brain cells in vitro

    Science.gov (United States)

    The shift in equilibrium towards excess reactive oxygen or nitrogen species production from innate antioxidant defense in brain is a critical factor in the declining neural functions and cognitive deficits accompanying age. In aging, there are noticeable alterations in the membrane microenvironment,...

  4. Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites

    DEFF Research Database (Denmark)

    Tuohimaa, Pentti; Wang, Jing-Huan; Khan, Sofia

    2013-01-01

    and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary...... and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic...

  5. Organizational Principles of Abstract Words in the Human Brain.

    Science.gov (United States)

    Wang, Xiaosha; Wu, Wei; Ling, Zhenhua; Xu, Yangwen; Fang, Yuxing; Wang, Xiaoying; Binder, Jeffrey R; Men, Weiwei; Gao, Jia-Hong; Bi, Yanchao

    2017-11-23

    words constitute nearly half of the human lexicon and are critically associated with human abstract thoughts, yet little is known about how they are represented in the brain. We tested the neural basis of 2 classical cognitive notions of abstract meaning representation: by linguistic contexts and by semantic features. We collected fMRI BOLD responses for 360 abstract words and built theoretical representational models from state-of-the-art corpus-based natural language processing models and behavioral ratings of semantic features. Representational similarity analyses revealed that both linguistic contextual and semantic feature similarity affected the representation of abstract concepts, but in distinct neural levels. The corpus-based similarity was coded in the high-level linguistic processing system, whereas semantic feature information was reflected in distributed brain regions and in the principal component space derived from whole-brain activation patterns. These findings highlight the multidimensional organization and the neural dissociation between linguistic contextual and featural aspects of abstract concepts. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Canonical Genetic Signatures of the Adult Human Brain

    Science.gov (United States)

    Hawrylycz, Michael; Miller, Jeremy A.; Menon, Vilas; Feng, David; Dolbeare, Tim; Guillozet-Bongaarts, Angela L.; Jegga, Anil G.; Aronow, Bruce J.; Lee, Chang-Kyu; Bernard, Amy; Glasser, Matthew F.; Dierker, Donna L.; Menche, Jörge; Szafer, Aaron; Collman, Forrest; Grange, Pascal; Berman, Kenneth A.; Mihalas, Stefan; Yao, Zizhen; Stewart, Lance; Barabási, Albert-László; Schulkin, Jay; Phillips, John; Ng, Lydia; Dang, Chinh; Haynor, David R.; Jones, Allan; Van Essen, David C.; Koch, Christof; Lein, Ed

    2015-01-01

    The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure, and function. We applied a correlation-based metric of “differential stability” (DS) to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing meso-scale genetic organization. The highest DS genes are highly biologically relevant, with enrichment for brain-related biological annotations, disease associations, drug targets, and literature citations. Using high DS genes we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components, and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely-patterned genes displayed dramatic shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry. PMID:26571460

  7. Regioselective C-H hydroxylation of omeprazole sulfide by Bacillus megaterium CYP102A1 to produce a human metabolite.

    Science.gov (United States)

    Jang, Hyun-Hee; Ryu, Sang-Hoon; Le, Thien-Kim; Doan, Tiep Thi My; Nguyen, Thi Huong Ha; Park, Ki Deok; Yim, Da-Eun; Kim, Dong-Hyun; Kang, Choong-Kyung; Ahn, Taeho; Kang, Hyung-Sik; Yun, Chul-Ho

    2017-01-01

    To find a simple enzymatic strategy for the efficient synthesis of the expensive 5'-hydroxyomeprazole sulfide, a recently identified minor human metabolite, from omeprazole sulfide, which is an inexpensive substrate. The practical synthetic strategy for the 5'-OH omeprazole sulfide was accomplished with a set of highly active CYP102A1 mutants, which were obtained by blue colony screening from CYP102A1 libraries with a high conversion yield. The mutant and even the wild-type enzyme of CYP102A1 catalyzed the high regioselective (98 %) C-H hydroxylation of omeprazole sulfide to 5'-OH omeprazole sulfide with a high conversion yield (85-90 %). A highly efficient synthesis of 5'-OH omeprazole sulfide was developed using CYP102A1 from Bacillus megaterium as a biocatalyst.

  8. CCQM-K132: low-polarity analytes in a biological matrix: vitamin D metabolites in human serum

    Science.gov (United States)

    Wise, Stephen A.; Tai, Susan S.-C.; Duewer, David L.; Bedner, Mary; Camara, Johanna E.; Lippa, Katrice A.; Qinde, Liu; Kang, Dukjin; Kim, Byungjoo; Quan, Can; Shi, Lianhua; Nammoonnoy, Jintana; Vamathevan, Veronica; Ceyhan Gören, Ahmet; Bilsel, Gökhan; Yilmaz, Hasibe

    2017-01-01

    Vitamin D is a fat-soluble vitamin that occurs primarily in two forms, vitamin D2 and vitamin D3. Vitamin D3 is produced naturally when skin is exposed to UV radiation, is naturally-occurring in foods (generally of animal origin), and is fortified in some foods and dietary supplements. Vitamin D2 occurs in food (generally plant sources) and until recently was the form most often used in dietary supplements. Vitamin D is metabolized in the body to produce several closely related, hydroxylated species (metabolites), with 25-hydroxyvitamin D3 [25(OH)D3] and 25-hydroxyvitamin D2 [25(OH)D2] as the most common metabolites measured in human serum. Concentrations of total vitamin D in human serum, calculated as the sum of 25(OH)D2 and 25(OH)D3, are typically in the 16 ng/g to 30 ng/g (40 nmol/L to 75 nmol/L) range, with 25(OH)D3 usually accounting for more than 90 % of the total. An epimer of 25(OH)D3, 3-epi-25(OH)D3, can be present at levels up to 10 % of 25(OH)D3 concentration. Seven National Metrology Institutions participated in the Track C Key Comparison CCQM-K132 low-polarity analytes in a biological matrix: vitamin D metabolites in human serum. Participants were requested to evaluate the mass fractions, expressed in ng/g, of 25(OH)D3, 25(OH)D2, and 3-epi-25(OH)D3 in two human serum materials, termed Serum Pool I and Serum Pool II. Due to the known low levels of 3-epi-25(OH)D3 in both materials and the very low level of 25(OH)D2 in Serum Pool I, the study protocol stated that key comparison reference values (KCRVs) would be assigned only to 25(OH)D3 in both materials and 25(OH)D2 in Serum Pool II. Results for 3-epi-25(OH)D3 were requested to evaluate the separation technologies employed; 3-epi-25(OH)D3 needs to be chromatographically separated from 25(OH)D3 for proper quantification of 25(OH)D3. Results for 25(OH)D2 in Serum Pool I were requested to explore measurement performance at its low level. All participants used isotope dilution liquid chromatography with

  9. Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain.

    Science.gov (United States)

    Narasimhan, Sneha; Guo, Jing L; Changolkar, Lakshmi; Stieber, Anna; McBride, Jennifer D; Silva, Luisa V; He, Zhuohao; Zhang, Bin; Gathagan, Ronald J; Trojanowski, John Q; Lee, Virginia M Y

    2017-11-22

    Pathological tau aggregates occur in Alzheimer's disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies. SIGNIFICANCE STATEMENT Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease

  10. Consequences of traumatic brain injury for human vergence dynamics.

    Science.gov (United States)

    Tyler, Christopher W; Likova, Lora T; Mineff, Kristyo N; Elsaid, Anas M; Nicholas, Spero C

    2014-01-01

    Traumatic brain injury involving loss of consciousness has focal effects in the human brainstem, suggesting that it may have particular consequences for eye movement control. This hypothesis was investigated by measurements of vergence eye movement parameters. Disparity vergence eye movements were measured for a population of 123 normally sighted individuals, 26 of whom had suffered diffuse traumatic brain injury (dTBI) in the past, while the remainder served as controls. Vergence tracking responses were measured to sinusoidal disparity modulation of a random-dot field. Disparity vergence step responses were characterized in terms of their dynamic parameters separately for the convergence and divergence directions. The control group showed notable differences between convergence and divergence dynamics. The dTBI group showed significantly abnormal vergence behavior on many of the dynamic parameters. The results support the hypothesis that occult injury to the oculomotor control system is a common residual outcome of dTBI.

  11. Memory-related brain lateralisation in birds and humans.

    Science.gov (United States)

    Moorman, Sanne; Nicol, Alister U

    2015-03-01

    Visual imprinting in chicks and song learning in songbirds are prominent model systems for the study of the neural mechanisms of memory. In both systems, neural lateralisation has been found to be involved in memory formation. Although many processes in the human brain are lateralised--spatial memory and musical processing involves mostly right hemisphere dominance, whilst language is mostly left hemisphere dominant--it is unclear what the function of lateralisation is. It might enhance brain capacity, make processing more efficient, or prevent occurrence of conflicting signals. In both avian paradigms we find memory-related lateralisation. We will discuss avian lateralisation findings and propose that birds provide a strong model for studying neural mechanisms of memory-related lateralisation. Copyright © 2014. Published by Elsevier Ltd.

  12. A Map for Social Navigation in the Human Brain.

    Science.gov (United States)

    Tavares, Rita Morais; Mendelsohn, Avi; Grossman, Yael; Williams, Christian Hamilton; Shapiro, Matthew; Trope, Yaacov; Schiller, Daniela

    2015-07-01

    Deciphering the neural mechanisms of social behavior has propelled the growth of social neuroscience. The exact computations of the social brain, however, remain elusive. Here we investigated how the human brain tracks ongoing changes in social relationships using functional neuroimaging. Participants were lead characters in a role-playing game in which they were to find a new home and a job through interactions with virtual cartoon characters. We found that a two-dimensional geometric model of social relationships, a "social space" framed by power and affiliation, predicted hippocampal activity. Moreover, participants who reported better social skills showed stronger covariance between hippocampal activity and "movement" through "social space." The results suggest that the hippocampus is crucial for social cognition, and imply that beyond framing physical locations, the hippocampus computes a more general, inclusive, abstract, and multidimensional cognitive map consistent with its role in episodic memory. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. A neonatal piglet model for investigating brain and cognitive development in small for gestational age human infants.

    Science.gov (United States)

    Radlowski, Emily C; Conrad, Matthew S; Lezmi, Stephane; Dilger, Ryan N; Sutton, Brad; Larsen, Ryan; Johnson, Rodney W

    2014-01-01

    The piglet was investigated as a potential model for studying brain and cognitive deficits associated with being born small for gestational age (SGA). Naturally farrowed SGA (0.7-1.0 kg BW) and average for gestational age (AGA, 1.3-1.6 kg BW) piglets were obtained on postnatal day (PD) 2, placed in individual cages, and provided a nutritionally adequate milk replacer diet (285 ml/kg/d). Beginning at PD14, performance in a spatial T-maze task was assessed. At PD28, piglets were anesthetized for magnetic resonance (MR) imaging to assess brain structure (voxel-based morphometry), connectivity (diffusion-tensor imaging) and metabolites in the hippocampus and corpus callosum (proton MR spectroscopy). Piglets born SGA showed compensatory growth such that BW of SGA and AGA piglets was similar (P>0.05), by PD15. Birth weight affected maze performance, with SGA piglets taking longer to reach criterion than AGA piglets (pdevelopment and connectivity. None of the metabolites measured were different between groups. Collectively, the results show that SGA piglets have spatial learning deficits and abnormal development of white matter. As learning deficits and abnormalities in white matter are common in SGA human infants, the piglet is a tractable translational model that can be used to investigate SGA-associated cognitive deficits and potential interventions.

  14. Supramodal representations of perceived emotions in the human brain.

    Science.gov (United States)

    Peelen, Marius V; Atkinson, Anthony P; Vuilleumier, Patrik

    2010-07-28

    Basic emotional states (such as anger, fear, and joy) can be similarly conveyed by the face, the body, and the voice. Are there human brain regions that represent these emotional mental states regardless of the sensory cues from which they are perceived? To address this question, in the present study participants evaluated the intensity of emotions perceived from face movements, body movements, or vocal intonations, while their brain activity was measured with functional magnetic resonance imaging (fMRI). Using multivoxel pattern analysis, we compared the similarity of response patterns across modalities to test for brain regions in which emotion-specific patterns in one modality (e.g., faces) could predict emotion-specific patterns in another modality (e.g., bodies). A whole-brain searchlight analysis revealed modality-independent but emotion category-specific activity patterns in medial prefrontal cortex (MPFC) and left superior temporal sulcus (STS). Multivoxel patterns in these regions contained information about the category of the perceived emotions (anger, disgust, fear, happiness, sadness) across all modality comparisons (face-body, face-voice, body-voice), and independently of the perceived intensity of the emotions. No systematic emotion-related differences were observed in the overall amplitude of activation in MPFC or STS. These results reveal supramodal representations of emotions in high-level brain areas previously implicated in affective processing, mental state attribution, and theory-of-mind. We suggest that MPFC and STS represent perceived emotions at an abstract, modality-independent level, and thus play a key role in the understanding and categorization of others' emotional mental states.

  15. The evolution of distributed association networks in the human brain.

    Science.gov (United States)

    Buckner, Randy L; Krienen, Fenna M

    2013-12-01

    The human cerebral cortex is vastly expanded relative to other primates and disproportionately occupied by distributed association regions. Here we offer a hypothesis about how association networks evolved their prominence and came to possess circuit properties vital to human cognition. The rapid expansion of the cortical mantle may have untethered large portions of the cortex from strong constraints of molecular gradients and early activity cascades that lead to sensory hierarchies. What fill the gaps between these hierarchies are densely interconnected networks that widely span the cortex and mature late into development. Limitations of the tethering hypothesis are discussed as well as its broad implications for understanding critical features of the human brain as a byproduct of size scaling. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Social Rewards and Social Networks in the Human Brain.

    Science.gov (United States)

    Fareri, Dominic S; Delgado, Mauricio R

    2014-08-01

    The rapid development of social media and social networking sites in human society within the past decade has brought about an increased focus on the value of social relationships and being connected with others. Research suggests that we pursue socially valued or rewarding outcomes-approval, acceptance, reciprocity-as a means toward learning about others and fulfilling social needs of forming meaningful relationships. Focusing largely on recent advances in the human neuroimaging literature, we review findings highlighting the neural circuitry and processes that underlie pursuit of valued rewarding outcomes across non-social and social domains. We additionally discuss emerging human neuroimaging evidence supporting the idea that social rewards provide a gateway to establishing relationships and forming social networks. Characterizing the link between social network, brain, and behavior can potentially identify contributing factors to maladaptive influences on decision making within social situations. © The Author(s) 2014.

  17. In Vitro Study of Nitric Oxide Metabolites Effects on Human Hydatid of Echinococcus granulosus

    Directory of Open Access Journals (Sweden)

    Razika Zeghir-Bouteldja

    2009-01-01

    Full Text Available Hydatidosis is characterized by the long-term coexistence of larva Echinococcus granulosus and its host without effective rejection. Previous studies demonstrated nitric oxide (NO production (in vivo and in vitro during hydatidosis. In this study, we investigated the direct in vitro effects of NO species: nitrite (NO2−, nitrate (NO3− and peroxynitrite (ONOO− on protoscolices (PSCs viability and hydatid cyst layers integrity for 24 hours and 48 hours. Our results showed protoscolicidal activity of NO2− and ONOO− 24 hours and 3 hours after treatment with 320 μM and 80 μM respectively. Degenerative effects were observed on germinal and laminated layers. The comparison of the in vitro effects of NO species on the PSCs viability indicated that ONOO− is more cytotoxic than NO2−. In contrast, NO3− has no effect. These results suggest possible involvement of NO2− and ONOO− in antihydatic action and point the efficacy of these metabolites as scolicidal agents.

  18. Simultaneous and sensitive LC-MS/MS determination of tetrahydrocannabinol and metabolites in human plasma.

    Science.gov (United States)

    Ferreirós, N; Labocha, S; Walter, C; Lötsch, J; Geisslinger, G

    2013-02-01

    Cannabis is not only a widely used illicit drug but also a substance which can be used in pharmacological therapy because of its analgesic, antiemetic, and antispasmodic properties. A very rapid and sensitive method for determination of ∆(9)-tetrahydrocannabinol (THC), the principal active component of cannabis, and two of its phase I metabolites in plasma has been developed and validated. After solid-phase extraction of plasma (0.2 mL), the clean extracts were analyzed by tandem mass spectrometry after a 5-min liquid chromatographic separation. The linear calibration ranges were from 0.05 to 30 ng mL(-1) for THC and 11-nor-∆(9)-carboxy-tetrahydrocannabinol (THC-COOH) and from 0.2 to 30 ng mL(-1) for ∆(9)-(11-OH)-tetrahydrocannabinol (11-OH-THC). Imprecision and inaccuracy were always below 7 and 12 % (expressed as relative standard deviation and relative error), respectively. The method has been successfully applied to determination of the three analytes in plasma obtained from healthy volunteers after oral administration of 20 mg dronabinol.

  19. Comparative Analysis of the Macroscale Structural Connectivity in the Macaque and Human Brain

    NARCIS (Netherlands)

    Goulas, A.; Bastiani, M.; Bezgin, G.; Uylings, H.B.M.; Roebroeck, A.; Stiers, P.

    2014-01-01

    The macaque brain serves as a model for the human brain, but its suitability is challenged by unique human features, including connectivity reconfigurations, which emerged during primate evolution. We perform a quantitative comparative analysis of the whole brain macroscale structural connectivity

  20. Infection and upregulation of proinflammatory cytokines in human brain vascular pericytes by human cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Alcendor Donald J

    2012-05-01

    Full Text Available Abstract Background Congenital human cytomegalovirus (HCMV infections can result in CNS abnormalities in newborn babies including vision loss, mental retardation, motor deficits, seizures, and hearing loss. Brain pericytes play an essential role in the development and function of the blood–brain barrier yet their unique role in HCMV dissemination and neuropathlogy has not been reported. Methods Primary human brain vascular pericytes were exposed to a primary clinical isolate of HCMV designated ‘SBCMV’. Infectivity was analyzed by microscopy, immunofluorescence, Western blot, and qRT-PCR. Microarrays were performed to identify proinflammatory cytokines upregulated after SBCMV exposure, and the results validated by real-time quantitative polymerase chain reaction (qPCR methodology. In situ cytokine expression of pericytes after exposure to HCMV was examined by ELISA and in vivo evidence of HCMV infection of brain pericytes was shown by dual-labeled immunohistochemistry. Results HCMV-infected human brain vascular pericytes as evidenced by several markers. Using a clinical isolate of HCMV (SBCMV, microscopy of infected pericytes showed virion production and typical cytomegalic cytopathology. This finding was confirmed by the expression of major immediate early and late virion proteins and by the presence of HCMV mRNA. Brain pericytes were fully permissive for CMV lytic replication after 72 to 96 hours in culture compared to human astrocytes or human brain microvascular endothelial cells (BMVEC. However, temporal transcriptional expression of pp65 virion protein after SBCMV infection was lower than that seen with the HCMV Towne laboratory strain. Using RT-PCR and dual-labeled immunofluorescence, proinflammatory cytokines CXCL8/IL-8, CXCL11/ITAC, and CCL5/Rantes were upregulated in SBCMV-infected cells, as were tumor necrosis factor-alpha (TNF-alpha, interleukin-1 beta (IL-1beta, and interleukin-6 (IL-6. Pericytes exposed to SBCMV elicited

  1. Infection and upregulation of proinflammatory cytokines in human brain vascular pericytes by human cytomegalovirus

    Science.gov (United States)

    2012-01-01

    Background Congenital human cytomegalovirus (HCMV) infections can result in CNS abnormalities in newborn babies including vision loss, mental retardation, motor deficits, seizures, and hearing loss. Brain pericytes play an essential role in the development and function of the blood–brain barrier yet their unique role in HCMV dissemination and neuropathlogy has not been reported. Methods Primary human brain vascular pericytes were exposed to a primary clinical isolate of HCMV designated ‘SBCMV’. Infectivity was analyzed by microscopy, immunofluorescence, Western blot, and qRT-PCR. Microarrays were performed to identify proinflammatory cytokines upregulated after SBCMV exposure, and the results validated by real-time quantitative polymerase chain reaction (qPCR) methodology. In situ cytokine expression of pericytes after exposure to HCMV was examined by ELISA and in vivo evidence of HCMV infection of brain pericytes was shown by dual-labeled immunohistochemistry. Results HCMV-infected human brain vascular pericytes as evidenced by several markers. Using a clinical isolate of HCMV (SBCMV), microscopy of infected pericytes showed virion production and typical cytomegalic cytopathology. This finding was confirmed by the expression of major immediate early and late virion proteins and by the presence of HCMV mRNA. Brain pericytes were fully permissive for CMV lytic replication after 72 to 96 hours in culture compared to human astrocytes or human brain microvascular endothelial cells (BMVEC). However, temporal transcriptional expression of pp65 virion protein after SBCMV infection was lower than that seen with the HCMV Towne laboratory strain. Using RT-PCR and dual-labeled immunofluorescence, proinflammatory cytokines CXCL8/IL-8, CXCL11/ITAC, and CCL5/Rantes were upregulated in SBCMV-infected cells, as were tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin-6 (IL-6). Pericytes exposed to SBCMV elicited higher levels of IL-6

  2. Multi-dimensional dynamics of human electromagnetic brain activity

    Directory of Open Access Journals (Sweden)

    Tetsuo eKida

    2016-01-01

    Full Text Available Magnetoencephalography (MEG and electroencephalography (EEG are invaluable neuroscientific tools for unveiling human neural dynamics in three dimensions (space, time, and frequency, which are associated with a wide variety of perceptions, cognition, and actions. MEG/EEG also provides different categories of neuronal indices including activity magnitude, connectivity, and network properties along the three dimensions. In the last 20 years, interest has increased in inter-regional connectivity and complex network properties assessed by various sophisticated scientific analyses. We herein review the definition, computation, short history, and pros and cons of connectivity and complex network (graph-theory analyses applied to MEG/EEG signals. We briefly describe recent developments in source reconstruction algorithms essential for source-space connectivity and network analyses. Furthermore, we discuss a relatively novel approach used in MEG/EEG studies to examine the complex dynamics represented by human brain activity. The correct and effective use of these neuronal metrics provides a new insight into the multi-dimensional dynamics of the neural representations of various functions in the complex human brain.

  3. Multi-Dimensional Dynamics of Human Electromagnetic Brain Activity.

    Science.gov (United States)

    Kida, Tetsuo; Tanaka, Emi; Kakigi, Ryusuke

    2015-01-01

    Magnetoencephalography (MEG) and electroencephalography (EEG) are invaluable neuroscientific tools for unveiling human neural dynamics in three dimensions (space, time, and frequency), which are associated with a wide variety of perceptions, cognition, and actions. MEG/EEG also provides different categories of neuronal indices including activity magnitude, connectivity, and network properties along the three dimensions. In the last 20 years, interest has increased in inter-regional connectivity and complex network properties assessed by various sophisticated scientific analyses. We herein review the definition, computation, short history, and pros and cons of connectivity and complex network (graph-theory) analyses applied to MEG/EEG signals. We briefly describe recent developments in source reconstruction algorithms essential for source-space connectivity and network analyses. Furthermore, we discuss a relatively novel approach used in MEG/EEG studies to examine the complex dynamics represented by human brain activity. The correct and effective use of these neuronal metrics provides a new insight into the multi-dimensional dynamics of the neural representations of various functions in the complex human brain.

  4. Why our brains cherish humanity: Mirror neurons and colamus humanitatem

    Directory of Open Access Journals (Sweden)

    John R. Skoyles

    2008-06-01

    Full Text Available Commonsense says we are isolated. After all, our bodies are physically separate. But Seneca’s colamus humanitatem, and John Donne’s observation that “no man is an island” suggests we are neither entirely isolated nor separate. A recent discovery in neuroscience—that of mirror neurons—argues that the brain and the mind is neither built nor functions remote from what happens in other individuals. What are mirror neurons? They are brain cells that process both what happens to or is done by an individual, and, as it were, its perceived “refl ection,” when that same thing happens or is done by another individual. Thus, mirror neurons are both activated when an individual does a particular action, and when that individual perceives that same action done by another. The discovery of mirror neurons suggests we need to radically revise our notions of human nature since they offer a means by which we may not be so separated as we think. Humans unlike other apes are adapted to mirror interact nonverbally when together. Notably, our faces have been evolved to display agile and nimble movements. While this is usually explained as enabling nonverbal communication, a better description would be nonverbal commune based upon mirror neurons. I argue we cherish humanity, colamus humanitatem, because mirror neurons and our adapted mirror interpersonal interface blur the physical boundaries that separate us.

  5. Studying variability in human brain aging in a population-based German cohort—rationale and design of 1000BRAINS

    OpenAIRE

    Svenja eCaspers; Susanne eMoebus; Silke eLux; Noreen ePundt; Holger eSchütz; Mühleisen, Thomas W.; Vincent eGras; Eickhoff, Simon B.; Sandro eRomanzetti; Tony eStöcker; Rüdiger eStirnberg; Kirlangic, Mehmet E.; Martina eMinnerop; Peter ePieperhoff; Ulrich eMödder

    2014-01-01

    The ongoing 1000 brains study (1000BRAINS) is an epidemiological and neuroscientific investigation of structural and functional variability in the human brain during aging. The two recruitment sources are the 10-year follow-up cohort of the German Heinz Nixdorf Recall (HNR) Study, and the HNR MultiGeneration Study cohort, which comprises spouses and offspring of HNR subjects. The HNR is a longitudinal epidemiological investigation of cardiovascular risk factors, with a comprehensive collectio...

  6. The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide.

    Science.gov (United States)

    Tilmanis, Danielle; van Baalen, Carel; Oh, Ding Yuan; Rossignol, Jean-Francois; Hurt, Aeron C

    2017-11-01

    Nitazoxanide is a thiazolide compound that was originally developed as an anti-parasitic agent, but has recently been repurposed for the treatment of influenza virus infections. Thought to exert its anti-influenza activity via the inhibition of hemagglutinin maturation and intracellular trafficking in infected cells, the effectiveness of nitazoxanide in treating patients with non-complicated influenza is currently being assessed in phase III clinical trials. Here, we describe the susceptibility of 210 seasonal influenza viruses to tizoxanide, the active circulating metabolite of nitazoxanide. An optimised cell culture-based focus reduction assay was used to determine the susceptibility of A(H1N1)pdm09, A(H3N2), and influenza B viruses circulating in the southern hemisphere from the period March 2014 to August 2016. Tizoxanide showed potent in vitro antiviral activity against all influenza viruses tested, including neuraminidase inhibitor-resistant viruses, allowing the establishment of a baseline level of susceptibility for each subtype. Median EC 50 values (±IQR) of 0.48 μM (0.33-0.71), 0.62 μM (0.56-0.75), 0.66 μM (0.62-0.69), and 0.60 μM (0.51-0.67) were obtained for A(H1N1)pdm09, A(H3N2), B(Victoria lineage), and B(Yamagata lineage) influenza viruses respectively. There was no significant difference in the median baseline tizoxanide susceptibility for each influenza subtype tested. This is the first report on the susceptibility of circulating viruses to tizoxanide. The focus reduction assay format described is sensitive, robust, and less laborious than traditional cell based antiviral assays, making it highly suitable for the surveillance of tizoxanide susceptibility in circulating seasonal influenza viruses. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  7. Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion.

    Directory of Open Access Journals (Sweden)

    Natalay Kouprina

    2004-05-01

    Full Text Available Primary microcephaly (MCPH is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume. The microcephalic brain has a volume comparable to that of early hominids, raising the possibility that some MCPH genes may have been evolutionary targets in the expansion of the cerebral cortex in mammals and especially primates. Mutations in ASPM, which encodes the human homologue of a fly protein essential for spindle function, are the most common known cause of MCPH. Here we have isolated large genomic clones containing the complete ASPM gene, including promoter regions and introns, from chimpanzee, gorilla, orangutan, and rhesus macaque by transformation-associated recombination cloning in yeast. We have sequenced these clones and show that whereas much of the sequence of ASPM is substantially conserved among primates, specific segments are subject to high Ka/Ks ratios (nonsynonymous/synonymous DNA changes consistent with strong positive selection for evolutionary change. The ASPM gene sequence shows accelerated evolution in the African hominoid clade, and this precedes hominid brain expansion by several million years. Gorilla and human lineages show particularly accelerated evolution in the IQ domain of ASPM. Moreover, ASPM regions under positive selection in primates are also the most highly diverged regions between primates and nonprimate mammals. We report the first direct application of TAR cloning technology to the study of human evolution. Our data suggest that evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size.

  8. Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion.

    Science.gov (United States)

    Kouprina, Natalay; Pavlicek, Adam; Mochida, Ganeshwaran H; Solomon, Gregory; Gersch, William; Yoon, Young-Ho; Collura, Randall; Ruvolo, Maryellen; Barrett, J Carl; Woods, C Geoffrey; Walsh, Christopher A; Jurka, Jerzy; Larionov, Vladimir

    2004-05-01

    Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume. The microcephalic brain has a volume comparable to that of early hominids, raising the possibility that some MCPH genes may have been evolutionary targets in the expansion of the cerebral cortex in mammals and especially primates. Mutations in ASPM, which encodes the human homologue of a fly protein essential for spindle function, are the most common known cause of MCPH. Here we have isolated large genomic clones containing the complete ASPM gene, including promoter regions and introns, from chimpanzee, gorilla, orangutan, and rhesus macaque by transformation-associated recombination cloning in yeast. We have sequenced these clones and show that whereas much of the sequence of ASPM is substantially conserved among primates, specific segments are subject to high Ka/Ks ratios (nonsynonymous/synonymous DNA changes) consistent with strong positive selection for evolutionary change. The ASPM gene sequence shows accelerated evolution in the African hominoid clade, and this precedes hominid brain expansion by several million years. Gorilla and human lineages show particularly accelerated evolution in the IQ domain of ASPM. Moreover, ASPM regions under positive selection in primates are also the most highly diverged regions between primates and nonprimate mammals. We report the first direct application of TAR cloning technology to the study of human evolution. Our data suggest that evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size.

  9. Conversion of the HIV protease inhibitor nelfinavir to a bioactive metabolite by human liver CYP2C19.

    Science.gov (United States)

    Hirani, Vandana N; Raucy, Judy L; Lasker, Jerome M

    2004-12-01

    Antiretroviral therapy for human immunodeficiency virus (HIV) infection includes treatment with both reverse transcriptase inhibitors and protease inhibitors, which markedly suppress viral replication and circulating HIV RNA levels. Cytochrome P450 (P450) enzymes in human liver, chiefly CYP3A4, play a pivotal role in protease inhibitor biotransformation, converting these agents to largely inactive metabolites. However, the protease inhibitor nelfinavir (Viracept) is metabolized mainly to nelfinavir hydroxy-t-butylamide (M8), which exhibits potent antiviral activity, and to other minor products (termed M1 and M3) that are inactive. Since indirect evidence suggests that CYP2C19 underlies M8 formation, we examined the role of this inducible, polymorphic P450 enzyme in nelfinavir t-butylamide hydroxylation by human liver. Rates of microsomal M8 formation were 50.6 +/- 28.3 pmol of product formed/min/nmol P450 (n = 5 subjects), whereas kinetic analysis of the reaction revealed a KM of 21.6 microM and a Vmax of 24.6 pmol/min/nmol P450. In reconstituted systems, CYP2C19 catalyzed nelfinavir t-butylamide hydroxylation at a turnover rate of 2.2 min(-1), whereas CYP2C9, CYP2C8, and CYP3A4 were inactive toward nelfinavir. Polyclonal anti-CYP2C9 (cross-reactive with CYP2C19) and monoclonal anti-CYP2C19 completely inhibited microsomal M8 production, whereas monoclonal CYP2C9 and polyclonal CYP3A4 antibodies were without effect. Similarly, the CYP2C19 substrate omeprazole strongly inhibited (75%) hepatic nelfinavir t-butylamide hydroxylation at a concentration of only 12.5 microM. Our study shows that CYP2C19 underlies formation in human liver of M8, a bioactive nelfinavir metabolite. The inducibility of CYP2C19 by agents (e.g., rifampicin) often taken concurrently with nelfinavir, together with this P450's known polymorphic nature, may thus be important determinants of nelfinavir's antiviral potency.

  10. Alcohol's Effects on the Brain: Neuroimaging Results in Humans and Animal Models

    National Research Council Canada - National Science Library

    Natalie M Zahr; Adolf Pfefferbaum

    2017-01-01

    ... into the effects of chronic alcoholism on the human brain. Magnetic resonance imaging (MRI) studies have distinguished alcohol-related brain effects that are permanent from those that are reversible with abstinence...

  11. brain-coX: investigating and visualising gene co-expression in seven human brain transcriptomic datasets.

    Science.gov (United States)

    Freytag, Saskia; Burgess, Rosemary; Oliver, Karen L; Bahlo, Melanie

    2017-06-08

    The pathogenesis of neurological and mental health disorders often involves multiple genes, complex interactions, as well as brain- and development-specific biological mechanisms. These characteristics make identification of disease genes for such disorders challenging, as conventional prioritisation tools are not specifically tailored to deal with the complexity of the human brain. Thus, we developed a novel web-application-brain-coX-that offers gene prioritisation with accompanying visualisations based on seven gene expression datasets in the post-mortem human brain, the largest such resource ever assembled. We tested whether our tool can correctly prioritise known genes from 37 brain-specific KEGG pathways and 17 psychiatric conditions. We achieved average sensitivity of nearly 50%, at the same time reaching a specificity of approximately 75%. We also compared brain-coX's performance to that of its main competitors, Endeavour and ToppGene, focusing on the ability to discover novel associations. Using a subset of the curated SFARI autism gene collection we show that brain-coX's prioritisations are most similar to SFARI's own curated gene classifications. brain-coX is the first prioritisation and visualisation web-tool targeted to the human brain and can be freely accessed via http://shiny.bioinf.wehi.edu.au/freytag.s/ .

  12. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moran, Jeffery H. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States); Prather, Paul L., E-mail: pratherpaull@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2013-06-01

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018

  13. The representation of biological classes in the human brain.

    Science.gov (United States)

    Connolly, Andrew C; Guntupalli, J Swaroop; Gors, Jason; Hanke, Michael; Halchenko, Yaroslav O; Wu, Yu-Chien; Abdi, Hervé; Haxby, James V

    2012-02-22

    Evidence of category specificity from neuroimaging in the human visual system is generally limited to a few relatively coarse categorical distinctions-e.g., faces versus bodies, or animals versus artifacts-leaving unknown the neural underpinnings of fine-grained category structure within these large domains. Here we use fMRI to explore brain activity for a set of categories within the animate domain, including six animal species-two each from three very different biological classes: primates, birds, and insects. Patterns of activity throughout ventral object vision cortex reflected the biological classes of the stimuli. Specifically, the abstract representational space-measured as dissimilarity matrices defined between species-specific multivariate patterns of brain activity-correlated strongly with behavioral judgments of biological similarity of the same stimuli. This biological class structure was uncorrelated with structure measured in retinotopic visual cortex, which correlated instead with a dissimilarity matrix defined by a model of V1 cortex for the same stimuli. Additionally, analysis of the shape of the similarity space in ventral regions provides evidence for a continuum in the abstract representational space-with primates at one end and insects at the other. Further investigation into the cortical topography of activity that contributes to this category structure reveals the partial engagement of brain systems active normally for inanimate objects in addition to animate regions.

  14. Mobile phone types and SAR characteristics of the human brain

    Science.gov (United States)

    Lee, Ae-Kyoung; Hong, Seon-Eui; Kwon, Jong-Hwa; Choi, Hyung-Do; Cardis, Elisabeth

    2017-04-01

    Mobile phones differ in terms of their operating frequency, outer shape, and form and location of the antennae, all of which affect the spatial distributions of their electromagnetic field and the level of electromagnetic absorption in the human head or brain. For this paper, the specific absorption rate (SAR) was calculated for four anatomical head models at different ages using 11 numerical phone models of different shapes and antenna configurations. The 11 models represent phone types accounting for around 86% of the approximately 1400 commercial phone models released into the Korean market since 2002. Seven of the phone models selected have an internal dual-band antenna, and the remaining four possess an external antenna. Each model was intended to generate an average absorption level equivalent to that of the same type of commercial phone model operating at the maximum available output power. The 1 g peak spatial SAR and ipsilateral and contralateral brain-averaged SARs were reported for all 11 phone models. The effects of the phone type, phone position, operating frequency, and age of head models on the brain SAR were comprehensively determined.

  15. Unmasking Language Lateralization in Human Brain Intrinsic Activity.

    Science.gov (United States)

    McAvoy, Mark; Mitra, Anish; Coalson, Rebecca S; d'Avossa, Giovanni; Keidel, James L; Petersen, Steven E; Raichle, Marcus E

    2016-04-01

    Lateralization of function is a fundamental feature of the human brain as exemplified by the left hemisphere dominance of language. Despite the prominence of lateralization in the lesion, split-brain and task-based fMRI literature, surprisingly little asymmetry has been revealed in the increasingly popular functional imaging studies of spontaneous fluctuations in the fMRI BOLD signal (so-called resting-state fMRI). Here, we show the global signal, an often discarded component of the BOLD signal in resting-state studies, reveals a leftward asymmetry that maps onto regions preferential for semantic processing in left frontal and temporal cortex and the right cerebellum and a rightward asymmetry that maps onto putative attention-related regions in right frontal, temporoparietal, and parietal cortex. Hemispheric asymmetries in the global signal resulted from amplitude modulation of the spontaneous fluctuations. To confirm these findings obtained from normal, healthy, right-handed subjects in the resting-state, we had them perform 2 semantic processing tasks: synonym and numerical magnitude judgment and sentence comprehension. In addition to establishing a new technique for studying lateralization through functional imaging of the resting-state, our findings shed new light on the physiology of the global brain signal. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Human intestinal and lung cell lines exposed to beta-carotene show a large variation in intracellular levels of beta-carotene and its metabolites

    NARCIS (Netherlands)

    Franssen-Hal, van N.L.W.; Bunschoten, J.E.; Venema, D.P.; Hollman, P.C.H.; Riss, G.; Keijer, J.

    2005-01-01

    Although in vitro models are often used in ß-carotene research, knowledge about the uptake and metabolism of ß-carotene in cell lines is lacking. We measured by HPLC the intracellular levels of ß-carotene and its metabolites in 9 human intestinal and lung cell lines after exposure to 1 ¿M ß-carotene

  17. Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.

    Science.gov (United States)

    Haage, Pernilla; Kronstrand, Robert; Carlsson, Björn; Kugelberg, Fredrik C; Josefsson, Martin

    2016-02-05

    The analgesic drug tramadol and its metabolites are chiral compounds, with the (+)- and (-)-enantiomers showing different pharmacological and toxicological effects. This novel enantioselective method, based on LC-MS/MS in reversed phase mode, enabled measurement of the parent compound and its three main metabolites O-desmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol simultaneously. Whole blood samples of 0.5g were fortified with internal standards (tramadol-(13)C-D3 and O-desmethyl-cis-tramadol-D6) and extracted under basic conditions (pH 11) by liquid-liquid extraction. Chromatography was performed on a chiral alpha-1-acid glycoprotein (AGP) column preceded by an AGP guard column. The mobile phase consisted of 0.8% acetonitrile and 99.2% ammonium acetate (20mM, pH 7.2). A post-column infusion with 0.05% formic acid in acetonitrile was used to enhance sensitivity. Quantitation as well as enantiomeric ratio measurements were covered by quality controls. Validation parameters for all eight enantiomers included selectivity (high), matrix effects (no ion suppression/enhancement), calibration model (linear, weight 1/X(2), in the range of 0.25-250ng/g), limit of quantitation (0.125-0.50ng/g), repeatability (2-6%) and intermediate precision (2-7%), accuracy (83-114%), dilution integrity (98-115%), carry over (not exceeding 0.07%) and stability (stable in blood and extract). The method was applied to blood samples from a healthy volunteer administrated a single 100mg dose and to a case sample concerning an impaired driver, which confirmed its applicability in human pharmacokinetic studies as well as in toxicological and forensic investigations. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Stable functional networks exhibit consistent timing in the human brain.

    Science.gov (United States)

    Chapeton, Julio I; Inati, Sara K; Zaghloul, Kareem A

    2017-03-01

    Despite many advances in the study of large-scale human functional networks, the question of timing, stability, and direction of communication between cortical regions has not been fully addressed. At the cellular level, neuronal communication occurs through axons and dendrites, and the time required for such communication is well defined and preserved. At larger spatial scales, however, the relationship between timing, direction, and communication between brain regions is less clear. Here, we use a measure of effective connectivity to identify connections between brain regions that exhibit communication with consistent timing. We hypothesized that if two brain regions are communicating, then knowledge of the activity in one region should allow an external observer to better predict activity in the other region, and that such communication involves a consistent time delay. We examine this question using intracranial electroencephalography captured from nine human participants with medically refractory epilepsy. We use a coupling measure based on time-lagged mutual information to identify effective connections between brain regions that exhibit a statistically significant increase in average mutual information at a consistent time delay. These identified connections result in sparse, directed functional networks that are stable over minutes, hours, and days. Notably, the time delays associated with these connections are also highly preserved over multiple time scales. We characterize the anatomic locations of these connections, and find that the propagation of activity exhibits a preferred posterior to anterior temporal lobe direction, consistent across participants. Moreover, networks constructed from connections that reliably exhibit consistent timing between anatomic regions demonstrate features of a small-world architecture, with many reliable connections between anatomically neighbouring regions and few long range connections. Together, our results demonstrate

  19. The brain's silent messenger: using selective attention to decode human thought for brain-based communication.

    Science.gov (United States)

    Naci, Lorina; Cusack, Rhodri; Jia, Vivian Z; Owen, Adrian M

    2013-05-29

    The interpretation of human thought from brain activity, without recourse to speech or action, is one of the most provoking and challenging frontiers of modern neuroscience. In particular, patients who are fully conscious and awake, yet, due to brain damage, are unable to show any behavioral responsivity, expose the limits of the neuromuscular system and the necessity for alternate forms of communication. Although it is well established that selective attention can significantly enhance the neural representation of attended sounds, it remains, thus far, untested as a response modality for brain-based communication. We asked whether its effect could be reliably used to decode answers to binary (yes/no) questions. Fifteen healthy volunteers answered questions (e.g., "Do you have brothers or sisters?") in the fMRI scanner, by selectively attending to the appropriate word ("yes" or "no"). Ninety percent of the answers were decoded correctly based on activity changes within the attention network. The majority of volunteers conveyed their answers with less than 3 min of scanning, suggesting that this technique is suited for communication in a reasonable a