Underlying sources of cognitive-anatomical variation in multi-modal neuroimaging and cognitive testing.

Healthy adults have robust individual differences in neuroanatomy and cognitive ability not captured by demographics or gross morphology (Luders, Narr, Thompson, & Toga, 2009). We used a hierarchical independent component analysis (hICA) to create novel characterizations of individual differences in our participants (N=190). These components fused data across multiple cognitive tests and neuroanatomical variables. The first level contained four independent, underlying sources of phenotypic variance that predominately modeled broad relationships within types of data (e.g., "white matter," or "subcortical gray matter"), but were not reflective of traditional individual difference measures such as sex, age, or intracranial volume. After accounting for the novel individual difference measures, a second level analysis identified two underlying sources of phenotypic variation. One of these made strong, joint contributions to both the anatomical structures associated with the core fronto-parietal "rich club" network (van den Heuvel & Sporns, 2011), and to cognitive factors. These findings suggest that a hierarchical, data-driven approach is able to identify underlying sources of individual difference that contribute to cognitive-anatomical variation in healthy young adults.

Improvement of fractional flow reserve and collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial).

BACKGROUND: Arteriogenesis (collateral artery growth) is nature's most efficient rescue mechanism to overcome the fatal consequences of arterial occlusion or stenosis. The goal of this trial was to investigate the effect of external counterpulsation (ECP) on coronary collateral artery growth. MATERIALS AND METHODS: A total of 23 patients (age 61 +/- 2.5 years) with stable coronary artery disease and at least one haemodynamic significant stenosis eligible for percutaneous coronary intervention were prospectively recruited into the two study groups in a 2 : 1 manner (ECP : control). One group (ECP group, n = 16) underwent 35 1-h sessions of ECP in 7 weeks. In the control group (n = 7), the natural course of collateral circulation over 7 weeks was evaluated. All patients underwent a cardiac catheterization at baseline and after 7 weeks, with invasive measurements of the pressure-derived collateral flow index (CFIp, primary endpoint) and fractional flow reserve (FFR). RESULTS: In the ECP group, the CFIp (from 0.08 +/- 0.01 to 0.15 +/- 0.02; P < 0.001) and FFR (from 0.68 +/- 0.03 to 0.79 +/- 0.03; P = 0.001) improved significantly, while in the control group no change was observed. Only the ECP group showed a reduction of the Canadian Cardiovascular Society (CCS, P = 0.008) and New York Heart Association (NYHA, P < 0.001) classification. CONCLUSION: In this study, we provide direct functional evidence for the stimulation of coronary arteriogenesis via ECP in patients with stable coronary artery disease. These data might open a novel noninvasive and preventive treatment avenue for patients with non-acute vascular stenotic disease.

Diethylnitrosamine enhances hepatic tumorigenic pathways in mice fed with high fat diet (Hfd).

Obesity has been implicated in the genesis of metabolic syndromes including insulin resistance and Type 2 Diabetes Mellitus (T2DM). Given the association between T2DM and the risk of hepatocellular carcinoma (HCC), our specific goal was to determine whether the liver of HFD-induced T2DM mice is more sensitive to the carcinogen diethylnitrosamine (DEN), due to a modification of the molecular pathways implicated in the early stages of HCC pathogenesis. C57BL/6 male mice (five-week-old) were divided into 4 groups: C, C + DEN, HFD and HFD + DEN. Mice were euthanized twenty-five weeks after DEN-injection. Livers of HDF-fed mice showed a higher proliferative index than Control groups. In line with this, HFD groups showed an increase of nuclear ß-catenin, and interestingly, DEN treatment led to a slight increase in the expression of this protein in HFD group. Based on these results, and to confirm this effect, we analyzed ß-catenin target genes, finding that DEN treatment in HFD group led to a significant increase of Vegf, c-myc, c-jun and cyclin D1 expression levels. According to our results, the expression of TCF4 showed to be significantly increased in HFD + DEN vs. HFD. In this regard, the ß-catenin/TCF4 complex enhanced its association with pSmads 2/3, as we observed an increase of nuclear Smads expression in HFD + DEN, suggesting a possible role of TGF-ß1/Smads signaling pathway in this phenomenon. Our results show that the liver of HFD fed model that resembles early T2DM pathology in mice, is more sensitive to DEN, by inducing both Wnt/ß-catenin and TGF ß1/Smads tumorigenic pathways.

Diethylnitrosamine Increases Proliferation in Early Stages of Hepatic Carcinogenesis in Insulin-Treated Type 1 Diabetic Mice.

Diethylnitrosamine (DEN) induces hepatocarcinogenesis, increasing mitotic hepatocytes and leading to chronic inflammation. In addition, type 1 diabetes mellitus (T1DM) is also characterized by a proinflammatory state and by requiring insulin exogenous treatment. Given the association of diabetes, insulin treatment, and cell proliferation, our specific goal was to determine whether the liver in the diabetic state presents a greater response to DEN-induced cell cycle alteration, which is essential for the malignant transformation. Male C57BL/6 mice (four-week-old) were divided into 4 groups: C, C + DEN, T1DM, and T1DM + DEN. Mice were euthanized ten weeks after DEN injection. DEN per se produced an increase in liver lipid peroxidation levels. Besides, in T1DM + DEN, we found a greater increase in the proliferation index, in comparison with C + DEN. These results are in agreement with the increased expression observed in cell cycle progression markers: cyclin D1 and E1. In addition, a proapoptotic factor, such as activated caspase-3, evidenced a decrease in T1DM + DEN, while the Vascular Endothelial Growth Factor (VEGF) and the protooncogene p53 showed a higher increase with respect to C + DEN. Overall, the results allow us to highlight a major DEN response in T1DM, which may explain in part the greater predisposition to the development of hepatocarcinoma (HCC) during the diabetic state.

Recognition characters in peptide-polyphenol complex formation.

Dietary polyphenols have received attention for their anti-oxidative, anti-carcinogenic and anti-neurodegenerative effects. Polyphenols bind to proteins leading to the formation of soluble or insoluble protein-polyphenol complexes which could significantly influence their biological activities. NMR and molecular modeling studies were performed to investigate the influence of the bulk, flexibility and hydrophobicity of polyphenols on the association with bradykinin, the peptide model. Our results show that the strength of the interactions could be positively correlated with polyphenol hydrophobicity and a comparison between pentagalloylglucose and vescalagin indicated that flexibility might play a positive role in the interaction with peptides and proteins.

Role of peptide primary sequence in polyphenol-protein recognition: an example with neurotensin.

Polyphenols are known for their impact on health and one of their major properties is the formation of complexes with proteins. To investigate the involvement of polyphenol-protein complexes in health, the interactions between bioactive polyphenols and neurotensin were examined by structural NMR and molecular modeling. Neurotensin is a linear bioactive tridecapeptide and polyphenols seem to affect the NT metabolism. We studied the polyphenols resveratrol and its glucoside the piceid in order to observe the possible role of glucose group and the penta-O-galloyl-D-glucopyranose (PGG). NMR data and molecular modeling showed that interaction occurred with the three polyphenols involving hydrophobic stacking and hydrogen bonds. Moreover, the peptide primary sequence plays a role in the specificity of complex formation.

Cognitive and anatomical data in a healthy cohort of adults.

We present data from a sample of 190 healthy adults including assessments of 4 cognitive factor scores, 12 cognitive tests, and 115 MRI-assessed neuroanatomical variables (cortical thicknesses, cortical and sub-cortical volumes, fractional anisotropy, and radial diffusivity). These data were used in estimating underlying sources of individual variation via independent component analysis (Watson et al., In press) [25].

Effects of dolichol on membrane permeability.

Small vesicles containing the tetra-anionic fluorescent probe calcein were prepared by sonication of mixtures of plant phosphatidylethanolamine, plant phosphatidylcholine, and dolichol. Following chromatography, the isolated vesicles were found to retain entrapped calcein over the temperature range of 15 to 40 degrees C. Utilizing an assay measuring the fluorescence quenching of entrapped calcein by cobalt ions, the presence of dolichol in the membranes was found to promote the permeability of the phospholipid bilayers to the divalent cation. The permeability was shown to be dependent on temperature with an increase in rate of 17-fold between 15 and 35 degrees C although the plant phospholipids used in these experiments have no known phase transition within this temperature range. The incorporated dolichol was distributed uniformly throughout the vesicle population. Similar vesicles prepared from phosphatidylethanolamine and phosphatidylcholine without added dolichol, from phosphatidylcholine alone, or with phosphatidylcholine and dolichol were far less permeable to the divalent cation under the same assay conditions. These results demonstrate that dolichols have significant effects on the permeability properties of phospholipid bilayers that contain phosphatidylethanolamine.

Phosphorus-31 and water proton relaxation in living erythrocytes. Application to uremia.

We measured the spin-lattice and spin-spin relaxation times (T1 and T2, respectively) and the nuclear Overhauser effect (NOE) of 31P nuclei of 2,3-diphosphoglycerate (2,3-DPG) in living erythrocytes. The relaxation of water protons was also studied. Phosphorus relaxation is pH-dependent due to a modification of the binding of 2,3-DPG to hemoglobin. We compared the results obtained with normal and uremic erythrocytes. In uremic erythrocytes the 31P relaxation rates are increased, but the intraerythrocytic pH variation in uremic erythrocytes cannot itself explain this increase. A possible role of dialysable substances may explain the increased relaxation rate.

Additional data about thermolysin specificity in buffer- and glycerol-containing media.

Synthesis and use of various substrates permit an improved approach to thermolysin-peptide recognition and elucidation of several new criteria affecting enzyme specificity. Nature and position of the recognized residue, role of adjacent amino acids, lateral chain hydrophobicity, and volume and length of peptides were all considered. Hydrolysis reactions were also carried out in the presence of glycerol; the effect of microenvironment modifications was quantitative, for example in inducing variations in catalytic reaction rates, and also qualitative, such as in influencing affinity.

High-resolution NMR studies of transmembrane cation transport in uremic patients.

Cation transport in erythrocytes of some uremic patients is impaired. Most studies have focused on the defect of the erythrocyte Na+/K+ pump in these diseased states. Herein, this cation transport defect was studied by using nuclear magnetic resonance spectroscopy (NMR) which is a non-invasive method permitting study on living erythrocytes. Firstly, we verified that the Na+ transport defect in uremic erythrocytes was not due to non-specific causes such as membrane alteration or a modification of the intracellular metabolism. The proton relaxation data, determined using a paramagnetic doping method, are consistent with a lack of erythrocytic membrane damage in uremic patients. Also, 31P-NMR results showed that in our experimental conditions, uremic and normal erythrocytes exhibit similar variations of ATP level over time. Lastly, the use of anionic paramagnetic shift reagent in 23Na-NMR revealed a defect in the Na+/K+ pump of erythrocytes from uremic patients with high Nain concentration. This defect seems to be due to a reduced number of pump units and to the presence of an endogenous inhibitor in uremic plasma.

A 3-dimensional model building by homology of the HFE protein: molecular consequences and application to antibody development.

Genetic hemochromatosis (GH) is a common inherited disease of iron metabolism affecting 2-5 in 1000 individuals of European origin. A candidate gene for GH, namely HFE has been recently characterized. Structural studies of the protein product of the HFE gene are of major interest for a better understanding of the molecular physiopathology in iron overload. We have built a 3-dimensional model of the HFE protein based on congruent with40% homology of sequence identity with HLA-Aw68, another MHC class I molecule. This work presents the first 3-dimensional structure of HFE available in the public domain (http://swift.embl-heidelberg.de/service/francois). The 3-dimensional characteristics of the protein complexed with the beta2-microglobulin are presented. The model has been used to predict immunogenic loops and to develop an antibody able to recognize a protein exhibiting the same molecular weight as HFE. Structural consequences of two common mutations are debated and evolutionary hypotheses are considered in the discussion of the particular biological activity of HFE. This study shows that a strategy based on homology modeling is sufficient to undertake biological investigations.

Glycerol's influence on the oxidized insulin B-chain conformation in relation to the selectivity variation of subtilisin: an nuclear magnetic resonance and simulated annealing study.

Glycerol, employed to mimic biological media with restricted water activity, has been shown to modify the activity of subtilisin BPN', an endopeptidase, towards the oxidized insulin B-chain, a well-studied substrate (FEBS Lett., 279 (1991) 123-131). Without minimizing the role of the microenvironment on the enzyme, we have studied the effect of glycerol addition on the structure of the enzyme substrate by homonuclear NMR spectroscopy and simulated annealing. Our results show that, in water, the oxidized insulin B-chain tertiary structure loses its central helix (residues B9-B19) and presents a folded structure with a flexible turn (residues B18-B24) in the beta-turn region of the insulin B-chain; whereas, in glycerol, the peptide is more rigid and is not folded. Moreover, in our experimental conditions, glycerol favors beta-strand secondary structure formation. Following these results, hypotheses about the differences observed in enzymatic activity on this substrate in glycerol have been postulated.

Water versus DNA: new insights into proton track-structure modelling in radiobiology and radiotherapy.

Water is a common surrogate of DNA for modelling the charged particle-induced ionizing processes in living tissue exposed to radiations. The present study aims at scrutinizing the validity of this approximation and then revealing new insights into proton-induced energy transfers by a comparative analysis between water and realistic biological medium. In this context, a self-consistent quantum mechanical modelling of the ionization and electron capture processes is reported within the continuum distorted wave-eikonal initial state framework for both isolated water molecules and DNA components impacted by proton beams. Their respective probability of occurrence-expressed in terms of total cross sections-as well as their energetic signature (potential and kinetic) are assessed in order to clearly emphasize the differences existing between realistic building blocks of living matter and the controverted water-medium surrogate. Consequences in radiobiology and radiotherapy will be discussed in particular in view of treatment planning refinement aiming at better radiotherapy strategies.

Abnormalities of one-carbon metabolism in psychiatric disorders: study of methionine adenosyltransferase kinetics and lipid composition of erythrocyte membranes.

Two independent lines of inquiry have implicated some disturbance of one-carbon cycle metabolism in affective disorders. Folic acid deficiency commonly leads to depression, and S-adenosylmethionine has been reported to have antidepressant properties. Methionine adenosyltransferase has been reported to be underactive in depression and schizophrenia and overactive in mania. This study reports the effects on erythrocyte methionine adenosyltransferase (MAT) kinetics (Vmax) of a 2-week treatment in a population of patients housed on a psychiatric research ward. The drug-free schizophrenic patients and depressives had, upon admission, low Vmax values, and the drug-free manic patients had high Vmax values on admission. After 2 weeks of appropriate treatment, the values for all three patient samples showed significant normalization (i.e., the levels rose in schizophrenics and depressives and fell in manics). We have further shown that pretreatment low levels of erythrocyte membrane phosphatidylcholine in depressives and high levels in manics show statistically significant normalization following 2 weeks of pharmacotherapy. The significance of these results is discussed.

Quantitation of xanthurenic acid in rabbit serum using high performance liquid chromatography.

Xanthurenic acid (XA) has been quantified in the serum of normal and vitamin B6-deficient rabbits using high performance liquid chromatography. The concentration of XA in the serum of normal and B6-deficient rabbits was 141 and 2275 ng/ml, respectively. The coefficient of variation for a series of dilutions of standard XA (3.9 to 1000 ng) ranged from 45.5% at the lower limit of the curve to 10.9% at the higher range of the curve. The minimum detectable level was 3.9 ng/ml. Serum samples spiked with reference XA exhibited a parallel dose response. The percentage recovery of XA from serum samples was 80.8%. The procedure, which requires 1 to 2 ml of serum, is sensitive and may be a useful tool for assessing B6 nutritional parameters as well as the physiological role of XA. It offers advantages over urinary procedures because it is more sensitive, more specific, and allows the study of blood levels of XA.

Hepatic protein synthesis and serum aminoacid levels during liver regeneration in young and old malnourished rats.

The aim of the present study was to measure protein synthesis in regenerating liver and to evaluate the impact of malnutrition in young and old rats. Two groups of male Wistar rats were used: young rats (4 months old) and old rats (18 months old). The rats were allocated to malnutrition or ordinary food intake for 1 week. Half of each group was sham-operated and the other was partially hepatectomized 2 days before the end of diet manipulation. Hepatic protein synthesis was significantly increased in all hepatectomized groups compared with their respective sham group: young well-nourished hepatectomized rats, 44%; young malnourished hepatectomized rats, 55%; old well-nourished hepatectomized rats, 47%; and old malnourished hepatectomized rats only 21%. Hepatic DNA content was unchanged in all groups and liver RNA content was higher in young malnourished hepatectomized rats (21%, P < 0.05). Serum total amino acid concentration did not change in young well-nourished hepatectomized and young malnourished hepatectomized rats. This value did not show significant changes between old well-nourished hepatectomized and old well-nourished sham, but it increased 14% (P < 0.05) in old malnourished hepatectomized. It was concluded that (a) regeneration is not impaired by malnutrition in young rats and may even be better than in rats eating a normal diet, and (b) the deleterious effect of aging is revealed once old animals are exposed to malnutrition. It is manifested in the decreased rate in hepatic protein synthesis observed in old malnourished hepatectomized rats and in the augmentation of total serum amino acid concentration, where the hypercatabolism induced by hepatectomy is significantly greater.

[Interaction of thiamine diphosphate with magnesium ion]. / Etude de l'interaction de la thiamine diphosphate avec l'ion magnésium.

The action of magnesium ion on the exchange rate of the proton in C2 of thiamine and thiamine diphosphate is studied at different values of pD. Above pD 5 the ion Mg2+ increases this exchange rate. The phenomenon is markedly enhanced for TDP rather than thiamine and increases with pD. Below pD 5 magnesium decreases the exchange rate. This decrease is greater for TDP than for thiamine. The maximum effect is reached at a magnesium concentration of 0.5/1 for thiamine and of 1/1 for TDP. T1 measurements are made for different pH values with and without magnesium ion. Results seem to prove that an increase in pD values from 3.9 to 5.9 leads to an accentuation of the molecules "folded" form. Nevertheless for a given pD value the TDP-Mg complex seems to have a more "folded" form than TDP.

Sleep during acute dopamine D1 agonist SKF 38393 or D1 antagonist SCH 23390 administration in rats.

The effect of the D1 dopamine (DA) receptor agonist SKF 38393 was compared with that produced by the D1-receptor antagonist, SCH 23390, in rats implanted with electrodes for chronic sleep recordings. SKF 38393 (0.1 to 4.0 mg/kg) significantly suppressed rapid-eye-movement sleep (REMS) after the highest dose. SCH 23390 (0.1 to 2.0 mg/kg) increased slow-wave sleep (SWS), whereas wakefulness (W) and REMS were decreased. Pretreatment with SKF 38393 (0.5 mg/kg) prevented the effects of SCH 23390 (0.25 mg/kg) on W and SWS. However, REM sleep showed a further depression. Pretreatment with SKF 38393 (2.0 mg/kg) or SCH 23390 (0.25 mg/kg) failed to modify the increase of SWS and decrease of W induced by D2 receptor agonist bromocriptine (0.5 mg/kg) in a dose that selectively stimulates DA autoreceptors. On the other hand, SCH 23390 (0.25 mg/kg) failed to prevent REMS depression induced by bromocriptine (6.0 mg/kg) in a dose that preferentially acts at postsynaptic sites. Pretreatment with SCH 23390 (0.25 mg/kg) prevented the increase of W and decrease of SWS induced by the 5-HT2 receptor agonist DOI (0.25 mg/kg). Given the "fragility" of REMS in the rat, nonspecific factors could be contributing to its depression after SKF 38389 or SCH 23390 administration. Inhibition of D1 receptors could be responsible for SCH 23390-induced increase of SWS and decrease of W. However, a blockade of 5-HT2 receptors could be partly involved in these effects. Neither SKF 38393 nor SCH 23390 exerted activity on the sleep-wake cycle, which could be considered to reflect effects at DA autoreceptors.

Sleep and waking during acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide (MR 16155) administration in rats.

The present study evaluated the effects of histamine H3 receptor agonist BP 2.94 or H3 receptor antagonist carboperamide (MR 16155) given by oral route on sleep and waking in rats surgically prepared for long-term recordings. BP 2.94 produced a significant increase of slow-wave sleep (SWS) that was related to slight decreases of waking, light sleep, and REM sleep. Carboperamide significantly increased waking and decreased SWS and REM sleep. Pretreatment with carboperamide prevented the effect of BP 2.94 on SWS. It is suggested that the effects of BP 2.94 or carboperamide on sleep and waking could depend on changes in the availability of histamine at the postsynaptic H1 receptor. Alternatively, activation or blockade of the H3 heteroreceptors found in the central catecholamine, indolamine, and acetylcholine nerve endings could inhibit or increase the release of noradrenaline, serotonin, dopamine, and acetylcholine. This would secondarily result in changes of sleep variables.