COMT and ANKK1 gene-gene interaction modulates contextual updating of mental representations.

The differential expression of the dopamine transmitter through its prefrontostriatal pathway has been proposed to account for individual differences in the updating of higher order task representations. Here we examined the interaction between two polymorphic variations of genes involved in the regulation of prefrontal and striatal dopamine (catechol-O-methyltransferase-COMT and ANKK1) on the neural mechanisms of task-set switching. A task-cueing paradigm was employed to measure behavioral costs and a scalp-recorded specific brain potential (novelty-P3) associated to distinct context updating operations in the face of either sensory or task novelty. The interaction between the COMT and ANKK1 genes was evidenced by corresponding specific behavioral costs and novelty-P3 amplitude enhancements reflecting task-set updating mechanisms. This effect was found only in individuals combining genes that yielded a balance between dopamine concentrations and receptor densities. Individuals displaying a putative "unbalance" showed enhanced novelty-P3 responses to all sensory changes, indicative of a task-set updating to sensory cues in a task-context independent fashion. These results support the epistasis of COMT and ANKK1 phenotypes in the flexible control of contextual information in humans.

The role of the dopamine transporter DAT1 genotype on the neural correlates of cognitive flexibility.

Cognitive flexibility, the ability to adapt goal-oriented behaviour in response to changing environmental demands, varies widely amongst individuals, yet its underlying neural mechanisms are not fully understood. Neuropharmacological and human clinical studies have suggested a critical role for striatal dopaminergic function mediated by the dopamine transporter (DAT). The present study aimed at revealing the role of the DAT in the individual brain response stereotypy underlying cognitive flexibility. A task-switching protocol was administered to a sample divided according to the presence or absence of the 9-repeat (9R) allele of the DAT1 polymorphism, while registering behavioural and electrophysiological novelty-P3 responses. The absence of the 9R (higher gene expression) is related to less striatal DA availability. Individuals lacking the 9R (9R-) showed specific response time (RT) increases for sensory change and task-set reconfiguration, as well as brain modulations not observed in participants with the 9R allele (9R+), suggesting that task performance of the former group depended on immediate local context. In contrast, individuals displaying high striatal DA showed larger RT costs than 9R- individuals to any sensory change, with no further increase for task-set reconfiguration, and a larger early positive brain response irrespective of the task condition, probably reflecting larger inhibition of any previous interference as well as stronger activation of the current task set. However, the polymorphic groups did not differ in their mean RTs in trials requiring task-set reconfiguration. This distinct stereotypy of cerebral responses reveals different patterns of cognitive control according to the DAT1 gene polymorphism.

Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities.

The aim of this study was to clarify which cognitive mechanisms underlie Trail Making Test (TMT) direct and derived scores. A comprehensive review of the literature on the topic was carried out to clarify which cognitive factors had been related to TMT performance. Following the review, we explored the relative contribution from working memory, inhibition/interference control, task-switching ability, and visuomotor speed to TMT performance. Forty-one healthy old subjects participated in the study and performed a battery of neuropsychological tests including the TMT, the Digit Symbol subtest [Wechsler Adult Intelligence Scale (Third Version) (WAIS-III)], a Finger Tapping Test, the Digits Forward and Backward subtests (WAIS-III), Stroop Test, and a task-switching paradigm inspired in the Wisconsin Card Sorting Test. Correlation and regression analyses were used in order to clarify the joint and unique contributions from different cognitive factors to the prediction of TMT scores. The results suggest that TMT-A requires mainly visuoperceptual abilities, TMT-B reflects primarily working memory and secondarily task-switching ability, while B-A minimizes visuoperceptual and working memory demands, providing a relatively pure indicator of executive control abilities.

Structure-effect relation of C18 long-chain fatty acids in the reduction of body weight in rats.

OBJECTIVE: To investigate the relationship between chemical structure and physiological effect, the efficacy and the molecular mechanisms involved in the reduction of body weight by C18 fatty acids (stearic, elaidic, oleic, linoleic and 2-hydroxyoleic acids (2-OHOA)). DESIGN: Ad libitum fed, lean Wistar Kyoto rats treated orally with up to 600 mg kg(-1) of the fatty acids or vehicle every 12 h for 7 days. Besides, starved rats and rats pairfed to the 2-OHOA-treated group served as additional controls under restricted feeding conditions. MEASUREMENTS: Body weight, food intake, weight of various fat depots, plasma leptin, hypothalamic neuropeptides, uncoupling proteins (UCP) in white (WAT) and brown adipose tissue (BAT) and phosphorylation level of cyclic AMP (cAMP) response element-binding protein (CREB) in WAT. RESULTS: Only treatment with oleic acid and 2-OHOA induced body weight loss (3.3 and 11.4%, respectively) through reduction of adipose fat mass. Food intake in these rats was lower, although hypothalamic neuropeptide and plasma leptin levels indicated a rise in orexigenic status. Rats pairfed to the 2-hydroxyoleic group only lost 6.3% body weight. UCP1 expression and phosphorylation of CREB was drastically increased in WAT, but not BAT of 2-OHOA-treated rats, whereas no UCP1 expression could be detected in WAT of rats treated with oleic acid. CONCLUSION: Both cis-configured monounsaturated C18 fatty acids (oleic acid and 2-OHOA) reduce body weight, but the introduction of a hydroxyl group in position 2 drastically increases loss of adipose tissue mass. The novel molecular mechanism unique to 2-hydroxyoleic, but not oleic acid, implies induction of UCP1 expression in WAT by the cAMP/PKA pathway-dependent transcription factor CREB, most probably as part of a transdifferentiation process accompanied by enhanced energy expenditure.

Prefrontal modulation of visual processing in humans.

Single neuron, evoked potential and metabolic techniques show that attention influences visual processing in extrastriate cortex. We provide anatomical, electrophysiological and behavioral evidence that prefrontal cortex regulates neuronal activity in extrastriate cortex during visual discrimination. Event-related potentials (ERPs) were recorded during a visual detection task in patients with damage in dorsolateral prefrontal cortex. Prefrontal damage reduced neuronal activity in extrastriate cortex of the lesioned hemisphere. These electrophysiological abnormalities, beginning 125 ms after stimulation and lasting for another 500 ms, were accompanied by behavioral deficits in detection ability in the contralesional hemifield. The results provide evidence for intrahemispheric prefrontal modulation of visual processing.

Surface Termination of Fe3O4(111) Films Studied by CO Adsorption Revisited.

Although the (111) surface of Fe3O4 (magnetite) has been investigated for more than 20 years, substantial controversy remains in the literature regarding the surface termination proposed based on structural and adsorption studies. The present article provides density functional theory results that allow to rationalize experimental results of infrared reflection-absorption spectroscopy and temperature-programmed desorption studies on CO adsorption, thus leading to a unified picture in which the Fe3O4(111) surface is terminated by a 1/4 monolayer of tetrahedrally coordinated Fe3+ ions on top of a close-packed oxygen layer as previously determined by low energy electron diffraction. However, surface defects play a crucial role in adsorption properties and may dominate chemical reactions on Fe3O4(111) when exposed to the ambient.

Trail Making Test in traumatic brain injury, schizophrenia, and normal ageing: sample comparisons and normative data.

The Trail Making Test (TMT) has been a useful assessment tool to investigate executive function. Several studies have recently improved the existing TMT norms by mean of large samples of healthy individuals stratified by a number of demographic variables from different populations. In contrast, criticisms have been raised about the utility of norms from healthy samples to detect changes across time in clinical samples where TMT performance used to be altered. In addition, few studies have compared groups of patients with deficits in TMT performance, making it difficult to decide whether a single set of norms is sufficient to assess different clinical populations. We provide normative data from three large samples of patients with traumatic brain injury (TBI) (n=90), schizophrenia spectrum disorders (n=127), and healthy Spanish speakers (n=223). Differences between healthy participants and patients in all TMT direct (TMT-A, TMT-B) and derived (B-A, B:A, B-A/A) scores were found. TMT performance was poorer in TBI patients than in schizophrenia patients except for the B:A and B-A/A scores, suggesting a similar underlying executive deficit. Normal ageing impaired both direct and derived TMT indices, as revealed by lower scores in the healthy elderly group (55-80 years old) as compared with young (16-24) and middle-aged (25-54) healthy participants. Three different sets of norms stratified by age, education, or both are presented for clinical use. Recommendations on TMT scores are made for future research.

Hyperthermic intraperitoneal chemotherapy with paclitaxel or cisplatin in patients with stage III-C/IV ovarian cancer. Is there any difference?

OBJETIVE: To compare the results of the administration of HIPEC with Paclitaxel or Cisplatin after cytoreduction in patients with stage IIIC-IV ovarian cancer, especially focused on disease-free survival. PATIENTS: We retrospectively analyzed a consecutive series of patients operated after being diagnosed with stage III-C/IV serous epithelial ovarian carcinoma. Patients included in the study were treated between January 2008 and March 2015. After cytoreduction, Paclitaxel (doses of 60 mg/m(2)O or Cisplatin (doses of 75 mg/m(2)) were used. RESULTS: A total of 111 patients were included. Median age was 61 years. In 60 of them (54%) Paclitaxel was used during HIPEC treatment and 51 patients (46%) were treated with Cisplatin. PCI was similar between groups (PCI = 11 in both cases). Median follow up was 34 months (12-96 months). The median disease free survival in Paclitaxel Group was 27 months and 33 months in Cisplatin Group (p = 0.551). In patients treated with Paclitaxel disease free survival rates at 1, 2, and 3 years were 79%, 60% and 46%. In patients treated with Cisplatin disease free survival at 1, 2, and 3 years were 64%, 50% and 40% respectively. After a multivariate analysis, incomplete cytoreduction (HR: 6.54, 95% CI 2.98-10.17, p < 0.01) and PCI >11 (HR: 2.15, 95% CI 1.42-6.68, p < 0.05) were identified as independent factors associated with a reduced disease-free survival. Cystotatic used was not relevant regarding disease free survival analysis. CONCLUSION: HIPEC with paclitaxel or cisplatin after cytoreduction in patients with ovarian cancer IIIC-IV has not shown different results in disease-free survival outcomes.

Alloy oxidation as a route to chemically active nanocomposites of gold atoms in a reducible oxide matrix.

While nanoparticles are being pursued actively for a number of applications, dispersed atomic species have been explored far less in functional materials architectures, primarily because composites comprising dispersed atoms are challenging to synthesize and difficult to stabilize against sintering or coarsening. Here we show that room temperature oxidation of Au-Sn alloys produces nanostructures whose surface is terminated by a reducible amorphous oxide that contains atomically dispersed Au. Analysis of the oxidation process shows that the dispersal of Au in the oxide can be explained by predominant oxygen anion diffusion and kinetically limited metal mass transport, which restrict phase separation due to a preferential oxidation of Sn. Nanostructures prepared by oxidation of nanoscale Au-Sn alloys with intermediate Au content (30-50%) show high activity in a CO-oxidation probe reaction due to a cooperative mechanism involving Au atoms as sites for CO adsorption and reaction to CO2 embedded in a reducible oxide that serves as a renewable oxygen reservoir. Our results demonstrate a reliable approach toward nanocomposites involving oxide-embedded, atomically dispersed noble metal species.

Correction: Alloy oxidation as a route to chemically active nanocomposites of gold atoms in a reducible oxide matrix.

Correction for 'Alloy oxidation as a route to chemically active nanocomposites of gold atoms in a reducible oxide matrix' by P. Sutter et al., Nanoscale Horiz., 2016, 1, 212-219.

Heterogeneous DNA binding modes of berenil.

Isothermal titration calorimetry (ITC) profiles of berenil bound to different DNAs show that, despite the strong preference of berenil for AT-rich regions in DNA, it can bind to other DNA sequences significantly. The ITC results were used to quantify the binding of berenil, and the thermodynamic profiles were obtained using natural DNAs as well as synthetic polynucleotides. ITC binding isotherms cannot be simply described when a single set of identical binding sites is considered, except for poly[d(A-T)2]. Ultraviolet melting of DNA and differential scanning calorimetry were also used to quantify several aspects of the binding of berenil to salmon testes DNA. We present evidence for secondary binding sites for berenil in DNA, corresponding to G+C rich sites. Berenil binding to poly[d(G-C)2] is also observed. Circular dichroism experiments showed that binding to GC-rich sites involves drug intercalation. Using a molecular modeling approach we demonstrate that intercalation of berenil into CpG steps is sterically feasible.

Interaction of anthracyclines with nucleotides and related compounds studied by spectroscopy.

Interaction of the antitumour anthracyclines with mononucleotides and related compounds can be assessed through the perturbation of the spectral properties of the drugs. Purine-derived compounds induce spectral changes more efficiently than pyrimidine derivatives. No marked differences are observed when mono-, di- or triphosphate derivatives, deoxy forms, nucleosides or free nitrogen bases are used for the experiments. Visible absorbance data indicate the existence of a drug/purine nucleotide complex in solution. Assuming a simple equilibrium, this complex would be of low affinity (Keq 100 M-1). Circular dichroism spectra of daunomycin in the presence of ATP suggest that the resulting daunomycin/ATP complexes are not comparable to those formed by intercalation of the anthracycline into DNA. 31P-NMR of ATP in the presence of daunomycin does not support the notion that anthracycline/nucleotide complex formation involves interaction through the phosphate group(s) of the nucleotide. Analysis of the quenching of the drug's intrinsic fluorescence in the presence of nucleotides indicates a predominantly collisional, dynamic quenching mechanism. Values in the 2-6 mM and 85-100 mM range, respectively, are estimated for the reciprocal of the Stern-Volmer quenching constant for a variety of purine and pyrimidine derivatives. This indicates that purine derivatives are highly efficient quenchers of the fluorescence of anthracyclines, while pyrimidine derivatives are not. The fluorescence lifetime of daunomycin in the absence of quencher and the Stern-Volmer quenching constants obtained for different nucleotides are used to calculate the apparent bimolecular rate constants for collisions between fluorophore and quencher to occur. Values of (2-3) X 10(11) and 1 X 10(10) M-1 X s-1 are obtained, respectively, for purine and pyrimidine derivatives. This suggests a combination of static and dynamic quenching processes for purine compounds, which is consistent with the drug/purine nucleotide complex formation detected by visible absorbance. Because of the high intracellular concentration of certain nucleotides, particularly ATP, the above processes are predicted to be highly significant 'in vivo'.

The Wisconsin Card Sorting Test and the assessment of frontal function: a validation study with event-related potentials.

The Wisconsin Card Sorting Test (WCST) is generally regarded as the prototype of abstract reasoning task and has been routinely used to assess frontal lobe function in a variety of clinical and research contexts. However, there are growing concerns that the WCST fails to discriminate frontal patients from those with lesions in other brain regions or from normals. Event-related potentials (ERP) from frontal, fronto-temporal, temporal, parietal and occipital areas were recorded during the performance of a computerized version of the WCST in order to explore frontal versus non-frontal ERP indexes during WCST activation. The task protocol was contrived to focus on the differences between early and late trials of each WCST series. Cognitive processes underlying these two task conditions have been described as extradimensional and intradimensional shifts in attention, respectively. Differences between early and late WCST trials appeared as soon as 120 msec poststimulus and were associated with a negative field potential centred at the fronto-temporal region of the left hemisphere. Significantly larger amplitudes of the posterior P3b wave for late as compared with early WCST trials also lent support to claims of a strong involvement of working memory mechanisms during WCST performance. Results are discussed in terms of the implications for the utility of ERP measures in clinical neuropsychology.

Attentional set shifting modulates the target P3b response in the Wisconsin card sorting test.

For years the Wisconsin card sorting test (WCST) has been used as a test of frontal lobe function. Recent event-related potential (ERP) research has shown large differences in the amplitude of P3b responses evoked by early and late trials within each WCST series ([8]: Barceló F., Sanz M., Molina V., Rubia FJ. The Wisconsin Card Sorting Test and the assessment of frontal function: A validation study with event-related potentials. Neuropsychologia 1997;35:399-408). In this study, 16 normal subjects performed a WCST adaptation to investigate the role of attentional set shifting in these WCST P3b effects. Two control tasks were designed to examine whether early-late WCST P3b changes reflect category selection (attention) or category storage (memory) operations. Results suggest both a sharp P3b attenuation during shift WCST trials, followed by a gradual P3b build-up during post-shift trials. This P3b modulation could not be attributed to selection or storage of simple sensory stimulus dimensions, nor was it observed when the new rule was externally prompted by the first card in the WCST series. Instead, WCST P3b changes seem related to the endogenously generated shift in the perceptual rule used to sort the cards (i.e., the shift in set). The gradual build-up in P3b amplitude paralleled a progressive improvement in sorting efficiency over several post-shift WCST trials. A model based on formal theories of visual attention and attentional set shifting is proposed to account for these effects. The model offers firm grounds for prediction and bridges the gap between related clinical and experimental evidence.

Equilibrium binding of daunomycin and adriamycin to calf thymus DNA. Temperature and ionic strength dependence of thermodynamic parameters.

Absorbance and fluorescence quenching monitoring of the binding of the anthracyclines adriamycin (ADM) and daunomycin (DNM) to calf thymus DNA, provides reproducible binding data only when moderate drug/DNA molar ratios are used in the assays. Under these conditions, the fraction of DNA-bound drug, in equilibrium with free anthracycline, which can be reliably detected, ranged from 40-60% to 80-95% of the total added drug, depending upon ionic strength and temperature. Use of the neighbour exclusion model adequately fits such data and predicts that (i) the affinity of ADM for binding to the DNA is always higher than that corresponding to DNM, under similar experimental conditions, (ii) the binding constant for both drugs exhibits a strong salt and temperature dependence, and (iii) the exclusion parameter, indicative of the size of the anthracycline binding sites on the DNA, equals 3.1 +/- 0.4 and 3.3 +/- 0.4 base pairs for ADM and DNM, respectively, and is independent of salt concentration. The salt and temperature dependence of the binding constant is used to estimate the thermodynamic parameters involved in the interaction of the drugs with the DNA. Binding of the drugs is an exothermic process and the binding free energy arises primarily from a large negative enthalpy which, as the entropy, strongly depends upon ionic strength, and is much larger than predicted by polyelectrolyte theory. The enthalpy and entropy changes observed, appear to compensate each other over the entire range of salt concentrations used, and may arise from a complex variety of contributions, including salt-induced changes in secondary structure of the DNA, as indicated by circular dichroism techniques.

Electrophysiological evidence of two different types of error in the Wisconsin Card Sorting Test.

The specificity of the Wisconsin Card Sorting Test (WCST) for assessing frontal lobe pathology remains controversial, although lesion and cerebral blood flow studies continue to suggest a role for the dorsolateral prefrontal cortex in WCST performance. Inconsistencies might derive from the extended use of various WCST scores as equivalent indicators of frontal pathology. In this study, event-related potentials (ERPs) were recorded from 32 normal subjects who committed perseverative and non-perseverative errors. Both types of WCST errors evoked anomalous but distinct ERP patterns over frontal lobe regions. Perseverative errors were also associated with a dysfunctional extrastriate response to stimulation. This evidence suggests that perseverative and non-perseverative errors result from disruptions in two different prefrontal neural networks engaged during card sorting.

Non-frontal P3b-like activity evoked by the Wisconsin Card Sorting Test.

Event related potentials (ERP) were recorded from 29 electrode positions in 10 normal subjects while they performed a simplified version of the Wisconsin Card Sorting Test (WCST). The design focused on ERP differences between early and late trials within each WCST series. Topographic and dipole analyses confirmed the reliability of two ERP signs: one conspicuous mid-parietal P3b wave and one asymmetrical frontal-temporal component. A three-dipole model accounted for these ERP signs with > 90% accuracy even in individual subjects, and suggests a sub-second activation of temporal-parietal and medial temporal association areas during card sorting. The WCST-related P3b wave is proposed to reflect working memory operations such as template matching and template formation during card sorting.

ORG 2766 fails to improve visual functions in rats with occipital lesions.

Adult rats were trained on a white versus black card discrimination in a circular water tank. Three independent variables were manipulated: lesion (sham, lateral occipital, medial occipital), dose of ORG 2766 administered (0 or 25 micrograms in saline on alternate days for 18 days), and time of administration (during the post-surgical recovery interval or during post-operative testing). Both visual cortical lesions produced a prominent retention deficit and defective pattern vision. Neither post-surgical nor concurrent administration of ORG 2766 improved visual functions. These results, along with a growing body of evidence, challenge the generality of the positive influences of ORG 2766 upon behavioral recovery observed in animals with limbic lesions.

Berenil recognizes and changes the characteristics of adenine and thymine polynucleotide structures.

Using circular dichroism, differential scanning calorimetry and susceptibility to DNAse I cleavage assays, we show that the interaction of berenil, a minor-groove binding drug, with poly(dA-dT).poly(dA-dT) and poly(dA).poly(dT) involves important changes in the polynucleotide conformation. The effect of berenil on poly(dA-dT).poly(dA-dT) comprises a clear alteration in CD spectra even at drug/DNA ratios smaller than the stoichiometric value. Berenil recognizes and binds to the alternating-B conformation of DNA changing it to a new conformation which appears to show some of the peculiarities of poly(dA).poly(dT), possibly through a modification in the helical parameters at the TpA and ApT steps. Such alteration is accompanied by a small calorimetric enthalpy change. Moreover, the calorimetric enthalpy does not change significantly whatever the input ratio of drug to poly(dA-dT).poly(dA-dT), indicating that berenil binding does not substantially alters the enthalpy of transition. In addition to increasing the melting temperature of the polynucleotide, berenil reduces the cooperativity of the poly(dA-dT).poly(dA-dT) transition slightly more than either distamycin or netropsin.

Calorimetric and spectroscopic studies on the poly[d(GA).d(CT)] structural polymorphism induced by zinc.

The interaction of zinc (II) with poly[d(GA).d(CT)] and salmon testes DNA has been investigated by Differential Scanning Calorimetry (DSC) and Circular Dichroism (CD). We have detected and energetically characterized the existence of two different structural forms in poly[d(GA).d(CT)] which behave differently during a DSC experiment. The overall melting of DNA shows two calorimetric transitions at different temperatures. Moreover, the presence of zinc, at an input ratio of ion to nucleotide (r) above two, renders a complex DSC profile which is characterized by a negative enthalpy transition. Besides, the low-temperature transition observed in the presence of zinc is practically reversible after re-cooling/re-heating cycles. Nevertheless, the high-temperature transition characterized by a negative delta H degree cal does not appear in re-heating experiments, and remains stable below 100 degrees C. A calorimetric negative enthalpy transition is also found using salmon DNA in the presence of zinc ions. It seems that the combination of a temperature effect and zinc binding might induce the production of a stable metal-DNA complex, which can also be detected by changes in some bands in the CD profiles. The experimental results show that the presence of DNA structures and binding processes involving a negative calorimetric enthalpy contribution might be more widespread than previously reckoned.