Assessment of aromatic amides in printed food contact materials: analysis of potential cleavage to primary aromatic amines during simulated passage through the gastrointestinal tract.

Recent analyses conducted by German official food control reported detection of the aromatic amides N-(2,4-dimethylphenyl)acetamide (NDPA), N-acetoacetyl-m-xylidine (NAAX) and 3-hydroxy-2-naphthanilide (Naphthol AS) in cold water extracts from certain food contact materials made from paper or cardboard, including paper straws, paper napkins, and cupcake liners. Because aromatic amides may be cleaved to potentially genotoxic primary amines upon oral intake, these findings raise concern that transfer of NDPA, NAAX and Naphthol AS from food contact materials into food may present a risk to human health. The aim of the present work was to assess the stability of NDPA, NAAX and Naphthol AS and potential cleavage to 2,4-dimethylaniline (2,4-DMA) and aniline during simulated passage through the gastrointestinal tract using static in vitro digestion models. Using the digestion model established by the National Institute for Public Health and the Environment (RIVM, Bilthoven, NL) and a protocol recommended by the European Food Safety Authority, potential hydrolysis of the aromatic amides to the respective aromatic amines was assessed by LC-MS/MS following incubation of the aromatic amides with digestive fluid simulants. Time-dependent hydrolysis of NDPA and NAAX resulting in formation of the primary aromatic amine 2,4-DMA was consistently observed in both models. The highest rate of cleavage of NDPA and NAAX was recorded following 4 h incubation with 0.07 M HCl as gastric-juice simulant, and amounted to 0.21% and 0.053%, respectively. Incubation of Naphthol AS with digestive fluid simulants did not give rise to an increase in the concentration of aniline above the background that resulted from the presence of aniline as an impurity of the test compound. Considering the lack of evidence for aniline formation from Naphthol AS and the extremely low rate of hydrolysis of the amide bonds of NDPA and NAAX during simulated passage through the gastrointestinal tract that gives rise to only very minor amounts of the potentially mutagenic and/or carcinogenic aromatic amine 2,4-DMA, risk assessment based on assumption of 100% cleavage to the primary aromatic amines would appear to overestimate health risks related to the presence of aromatic amides in food contact materials.

Novel dengue virus NS2B/NS3 protease inhibitors.

Dengue fever is a severe, widespread, and neglected disease with more than 2 million diagnosed infections per year. The dengue virus NS2B/NS3 protease (PR) represents a prime target for rational drug design. At the moment, there are no clinical PR inhibitors (PIs) available. We have identified diaryl (thio)ethers as candidates for a novel class of PIs. Here, we report the selective and noncompetitive inhibition of the serotype 2 and 3 dengue virus PR in vitro and in cells by benzothiazole derivatives exhibiting 50% inhibitory concentrations (IC50s) in the low-micromolar range. Inhibition of replication of DENV serotypes 1 to 3 was specific, since all substances influenced neither hepatitis C virus (HCV) nor HIV-1 replication. Molecular docking suggests binding at a specific allosteric binding site. In addition to the in vitro assays, a cell-based PR assay was developed to test these substances in a replication-independent way. The new compounds inhibited the DENV PR with IC50s in the low-micromolar or submicromolar range in cells. Furthermore, these novel PIs inhibit viral replication at submicromolar concentrations.

Photoisomerization among ring-open merocyanines. I. Reaction dynamics and wave-packet oscillations induced by tunable femtosecond pulses.

Upon ultraviolet excitation, photochromic spiropyran compounds can be converted by a ring-opening reaction into merocyanine molecules, which in turn can form several isomers differing by cis and trans configurations in the methine bridge. Whereas the spiropyran-merocyanine conversion reaction of the nitro-substituted indolinobenzopyran 6-nitro-1',3',3'-trimethylspiro[2H-1-benzopyran-2,2'-indoline] (6-nitro BIPS) has been studied extensively in theory and experiments, little is known about photoisomerization among the merocyanine isomers. In this article, we employ femtosecond transient absorption spectroscopy with variable excitation wavelengths to investigate the excited-state dynamics of the merocyanine in acetonitrile at room temperature, where exclusively the trans-trans-cis (TTC) and trans-trans-trans (TTT) isomers contribute. No photochemical ring-closure pathways exist for the two isomers. Instead, we found that (18±4)% of excited TTC isomers undergo an ultrafast excited-state cis→trans photoisomerization to TTT within 200 fs, while the excited-state lifetime of TTC molecules that do not isomerize is 35 ps. No photoisomerization was detected for the TTT isomer, which relaxes to the ground state with a lifetime of roughly 160 ps. Moreover, signal oscillations at 170 cm(-1) and 360 cm(-1) were observed, which can be ascribed to excited-state wave-packet dynamics occurring in the course of the TTC→TTT isomerization. The results of high-level time-dependent density functional theory in conjunction with polarizable continuum models are presented in the subsequent article [C. Walter, S. Ruetzel, M. Diekmann, P. Nuernberger, T. Brixner, and B. Engels, J. Chem. Phys. 140, 224311 (2014)].

Photoisomerization among ring-open merocyanines. II. A computational study.

The photochemical isomerization of the trans-trans-cis to the trans-trans-trans isomer of the merocyanine form of 6-nitro BIPS, which has been studied with femtosecond transient absorption spectroscopy [S. Ruetzel, M. Diekmann, P. Nuernberger, C. Walter, B. Engels, and T. Brixner, J. Chem. Phys. 140, 224310 (2014)], is investigated using time-dependent density functional theory in conjunction with polarizable continuum models. Benchmark calculations against SCS-ADC(2) evaluate the applicability of the CAM-B3LYP functional. Apart from a relaxed scan in the ground state with additional computation of the corresponding excitation energies, which produces the excited-state surface vertical to the ground-state isomerization coordinate, a relaxed scan in the S1 gives insight into the geometric changes orthogonal to the reaction coordinate and the fluorescence conditions. The shape of the potential energy surface (PES) along the reaction coordinate is found to be highly sensitive to solvation effects, with the method of solvation (linear response vs. state-specific) being critical. The shape of the PES as well as the computed harmonic frequencies in the S1 minima are in line with the experimental results and offer a straightforward interpretation.

Multidimensional spectroscopy of photoreactivity.

Coherent multidimensional electronic spectroscopy is commonly used to investigate photophysical phenomena such as light harvesting in photosynthesis in which the system returns back to its ground state after energy transfer. By contrast, we introduce multidimensional spectroscopy to study ultrafast photochemical processes in which the investigated molecule changes permanently. Exemplarily, the emergence in 2D and 3D spectra of a cross-peak between reactant and product reveals the cis-trans photoisomerization of merocyanine isomers. These compounds have applications in organic photovoltaics and optical data storage. Cross-peak oscillations originate from a vibrational wave packet in the electronically excited state of the photoproduct. This concept isolates the isomerization dynamics along different vibrational coordinates assigned by quantum-chemical calculations, and is applicable to determine chemical dynamics in complex photoreactive networks.

Multiple reduction of 2,5-bis(borolyl)thiophene: isolation of a negative bipolaron by comproportionation.

The 2,5-bis(borolyl)thiophene 2, a conjugated acceptor-π-acceptor system, can be reduced to the monoradical anion [2](.-) , the dianion [2](2-) , and the tetraanion [2](4-) . The dianion [2](2-) was also prepared by a comproportionation reaction and features an absorption maximum in the near-IR region (λmax =800 nm), which is characteristic of a bipolaron with a quinoidal structure.

The electronic structure of pyracene: a spectroscopic and computational study.

We report a synthetic, spectroscopic and computational study of the polycyclic aromatic molecule pyracene, which contains aliphatic five-membered rings annealed to a naphthalene chromophore. An improved route to synthesize the compound is described. Gas-phase IR and solid-state Raman spectra agree with a ground-state D2h structure. The electronically excited S1 A(1)B3u state has been studied by resonance-enhanced multiphoton ionisation. An adiabatic excitation energy T0 = 30,798 cm(-1) (3.818 eV) was determined. SCS-ADC(2) calculations found a D2h minimum energy structure of the S1 state and yielded an excitation energy of +3.98 eV, including correction for zero point vibrational energy. The spectrum shows a rich low-frequency vibrational structure that can be assigned to the overtones of out-of-plane deformation modes of the five-membered rings by comparison with computations. The appearance of these modes as well as the frequency reduction in the excited state indicate that the potential in the S1 state is very flat. At higher excess energies most bands can be assigned to fundamentals, overtones and combination bands of either totally symmetric ag modes or of b2g modes that appear due to vibronic coupling. Lifetimes between 43 ns and 76 ns were measured for a number of vibronic bands. For the S2 state an equilibrium geometry with a non-planar carbon framework was computed. In addition a signal from the pyracene dimer was present. The spectrum shows several broad and structureless transitions. The origin band has a maximum at around 329 nm (30,400 cm(-1)). Again lifetimes between 60 ns and 70 ns were found. The dimer ion signal rises within less than 10 ps. Computations show that a crossed geometry with the long axis of one unit aligned with the short axis of the second constitutes the most stable structure. The broadening of the bands is most likely caused by excimer formation.

Oligo(borolyl)benzenes--synthesis and properties.

Herein, we report the synthesis of boroles that are linked by a conjugated phenylene spacer. The characterization of these compounds was completed by NMR and UV/Vis spectroscopy, as well as X-ray crystal diffraction. Furthermore, the coordination behavior of these oligoboroles towards five electronically and sterically disparate pyridine derivatives was studied and revealed fundamental differences in the properties of the resulting adducts. The experimental results were supported by density functional theory (DFT) calculations that showed a charge-transfer effect upon formation of the pyridine-4-carbonitrile adduct. By chemical reduction of a tris(borolyl)-substituted benzene derivative, a hexaanion was isolated as a result of a two-electron reduction of each borolyl moiety. The interaction of the borolyl units through the aryl spacer, and the possible increase of the Lewis acidity due to the conjugation of the borolyl moieties, were investigated by base transfer reactions.

Extraversion and its positive emotional core--further evidence from neuroscience.

Converging evidence from self-report data demonstrated that extraversion and dispositional positive affect are systematically related. Several authors therefore considered positive affect as the conceptual core of extraversion. Because the ventral striatum is regarded as a core region in the physiological basis of extraversion, the present study examines the importance of this neural substrate with a special focus on positive affect. Baseline cerebral blood flow was measured in 38 participants and regressed to the extraversion and dispositional positive affect scales. Partial correlational and indirect-effects analyses indicated that striatal blood flow was no longer associated with extraversion when positive affect was statistically controlled. In contrast, when extraversion was statistically controlled, striatal blood flow was still associated with positive affect. This finding suggests that the striatal region is not a biological basis of extraversion per se. Rather, this region sustains positive affect, which in turn appears to be a core feature of extraversion.

A clear correlation between the diradical character of 1,3-dipoles and their reactivity toward ethylene or acetylene.

A series of nine 1,3-dipoles, belonging to the families of diazonium betaines, nitrilium betaines, and azomethine betaines, has been studied by means of the breathing-orbital valence bond ab initio method. Each 1,3-dipole is described as a linear combination of three valence bond structures, two zwitterions and one diradical, for which the weights in the total wave function can be quantitatively estimated. In agreement with an early proposition of Harcourt, the diradical character of 1,3-dipoles is shown to be a critical feature to favor 1,3-dipolar cycloaddition. Within each family, a linear relationship is evidenced between the weight of the diradical structure in the 1,3-dipole and the barrier to cycloaddition to ethylene or acetylene, with correlation coefficients of 0.98-1.00. The barrier heights also correlate very well with the transition energies from ground state to pure diradical states of the 1,3-dipoles at equilibrium geometry. Moreover, the weight of the diradical structure is shown to increase significantly in all 1,3-dipoles from their equilibrium geometries to their distorted geometries in the transition states. A mechanism for 1,3-dipolar cycloaddition is proposed, in which the 1,3-dipole first distorts so as to reach a reactive state that possesses some critical diradical character and then adds to the dipolarophile with little or no barrier. This mechanism is in line with the recently proposed distortion/interaction energy model of Ess and Houk and their finding that the barrier heights for the cycloaddition of a given 1,3-dipole to ethylene and acetylene are nearly the same, despite the exothermicity difference (Ess, D. H. and Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187).

Resting cerebral blood flow, attention, and aging.

Aging is accompanied by a decline of fluid cognitive functions, e.g., a slowing of information processing, working memory, and division of attention. This is at least partly due to structural and functional changes in the aging brain. Although a decrement of resting cerebral blood flow (CBF) has been positively associated with cognitive functions in patients with brain diseases, studies with healthy participants have revealed inconsistent results. Therefore, we investigated the relation between resting cerebral blood flow and cognitive functions (tonic and phasic alertness, selective and divided attention) in two samples of healthy young and older participants. We found higher resting CBF and better cognitive performances in the young than in the older sample. In addition, resting CBF was inversely correlated with selective attention in the young and with tonic alertness in the elderly participants. This finding is discussed with regard to the neural efficiency hypothesis of human intelligence.

Latent state-trait structure of cerebral blood flow in a resting state.

Cerebral blood flow (CBF) is an important parameter for the study of brain function. The present paper examines to what extent CBF in a resting state reflects a stable latent trait and to what extent it reflects phasic situational effects. In 38 healthy subjects resting CBF was measured with continuous arterial spin labeling. Data analyses were performed within the methodological framework of latent state-trait theory, which allows the decomposition of the measured variables into temporally stable differences, occasion-specific fluctuations, and measurement errors. For most of the regions of interest, about 70% of the observed variance in resting CBF was determined by individual differences on a latent physiological trait whereas about 20% of the variance was due to occasion-specific influences. Thus, an aggregation across measurement occasions is not necessary in order to yield a stable physiological trait.

Skull thickness and magnitude of EEG alpha activity.

OBJECTIVE: Electroencephalographic (EEG) research on the physiological basis of individual differences in personality or intelligence commonly presumes that between-subjects differences of EEG alpha activity reflect individual differences in brain functions. However, non-functional sources of variance such as individual differences in skull thickness may significantly contribute to individual differences in the magnitude of EEG amplitudes. Aim of the present study was to assess the association between skull thickness and the magnitude of EEG alpha activity. METHODS: A 58-channel EEG was recorded from 49 subjects in resting states at three occasions of measurement each 5 weeks apart. Skull thickness was assessed with proton-weighted images of the head that were acquired with a 1.5 T magnetic resonance imaging (MRI) scanner. RESULTS: There was only a mediocre association between EEG alpha power at frontal, temporal, and parietal sites and the thickness of the underlying skull, with correlations ranging between r = -.36 and r = .10. CONCLUSIONS: This finding suggests that intracranial sources contribute much more variance to the surface EEG than do variations in skull thickness. SIGNIFICANCE: Skull thickness may be neglected as a potent source of error when individual differences in brain activity are indexed by the magnitude of EEG alpha activity.

Reproducibility of continuous arterial spin labeling perfusion MRI after 7 weeks.

BACKGROUND: Continuous arterial spin labeling (CASL) is a non-invasive technique for the measurement of cerebral blood flow (CBF). The aim of the present study was to examine the reproducibility of CASL measurements and its suitability to consistently detect differences between groups, regions, and resting states. MATERIALS AND METHODS: Thirty-eight healthy subjects (19 female) were examined at 1.5 T on two measurement occasions that were seven weeks apart. Resting CBF was measured with eyes open and eyes closed. RESULTS: In different regions of interest (ROIs) the repeatability estimates varied between 9 and 19 ml/100 g/min. There were no significant mean differences between occasions in all ROIs (P > 0.05). Greater CBF in the eyes-open than in the eyes-closed state was consistently present in the primary and secondary visual areas. Furthermore, CBF was consistently greater in the right than in the left hemisphere (P < 0.05) and differed between lobes and between arterial territories (P < 0.001). Finally, we consistently observed greater CBF in women than in men (P < 0.001). CONCLUSION: This study demonstrates the suitability of CASL to consistently detect differences between groups, regions, and resting states even after seven weeks. This emphasizes its usefulness for longitudinal designs.

The association of macro- and microstructure of the corpus callosum and language lateralisation.

The present study aimed to examine how differences in functional lateralisation of language are related to interindividual variations in interhemispheric connectivity. Utilising an fMRI silent word-generation paradigm, 89 left- and right-handed subjects were subdivided into four lateralisation subgroups. Applying morphological and diffusion-tensor MRI, midsagittal cross-sectional area as well as quantitative measures of molecular diffusion (anisotropy, mean diffusion) of the corpus callosum were determined to assess interhemispheric connectivity. Statistical analyses revealed group differences in molecular diffusion but not in callosal size, which may be interpreted to reflect a stronger and/or faster interhemispheric connection in strongly left-lateralised subjects as compared to moderately left-lateralised, bilateral, or moderately right-lateralised subjects.

Handedness, dichotic-listening ear advantage, and gender effects on planum temporale asymmetry--a volumetric investigation using structural magnetic resonance imaging.

Previous research has often examined whether the asymmetrical structure of the planum temporale (PT) represents an anatomical correlate of lateralized language-processing functions, gathering diverging empirical evidence by comparing PT asymmetry in subjects with differing handedness, gender, or speech lateralization. Apart from other methodological problems, direct comparisons between studies are hampered by insufficient assessment and consideration of all three potential determinants of structural cerebral asymmetry. Based on volumetric assessment of structural Magnetic Resonance Imaging (MRI) scans of 104 healthy subjects, the present study replicated earlier observations of an overall leftward PT asymmetry, which was found to prevail irrespective of handedness, gender, or dichotic-listening ear advantage. However, the mean magnitude of this leftward asymmetry was not determined by either one of these factors in itself, but varied depending on their specific combination. A clear correspondence between structural and functional asymmetry was only observed among right-handed males. In this particular subgroup, more pronounced structural asymmetry was associated with an enlarged PT on the left side, while the enhanced leftward asymmetry of female sinistrals resulted from smaller adjusted volumes of their right PT. The existence of such complex interactions suggests that future research in this area can only be expected to overcome past inconsistencies by adequately considering handedness, gender, and speech lateralization.

Alteration of cerebral perfusion in patients with idiopathic normal pressure hydrocephalus measured by 3D perfusion weighted magnetic resonance imaging.

OBJECTIVE: It is controversial whether alteration of cerebral perfusion plays an important role in the pathophysiology of patients with idiopathic normal pressure hydrocephalus (NPH) and can help to predict the outcome after shunt surgery. MATERIALS AND METHODS: 28 patients with suspected NPH were examined clinically (Homburg Hydrocephalus Scale, walking test, incontinence protocol) and by 3D dynamic susceptibility based perfusion weighted magnetic resonance imaging (PWI-MRI) before and after cerebrospinal fluid release (spinal tap test, STT). The perfusion parameters (negative integral (NI), time of arrival (T0), time to peak (TTP), mean transit time, and the difference TTP-T0 were analysed. RESULTS: Three different groups of patients were identified preoperatively: In group 1 seven patients showed an increase in the cerebral perfusion and a clinical improvement after STT. The second group (9 patients) also revealed an increase of the cerebral perfusion, but no significant alteration of the clinical assessment could be found. In the third group neither the cerebral perfusion nor the clinical assessment changed. 14 of the 16 patients (group 1 and 2) were examined three months after shunt placement. 11 patients showed a good or excellent result, 2 patients revealed a fair assessment, and only 1 patient had transiently improved. No patient was downgraded after shunting. In the patient group 1 and 2 the NI increased significantly (effect size: 34%), whereas in group 3 no significant alteration of NI was observed. CONCLUSION: PWI-MRI improves the prediction of outcome after shunt placement in patients with NPH and can offer new insights into the pathophysiology.

Perfusion-weighted magnetic resonance imaging in patients with vasospasm: a useful new tool in the management of patients with subarachnoid hemorrhage.

OBJECTIVE: Cerebral vasospasm (VSP) is one of the most important risk factors for the development of a delayed neurological deficit after subarachnoid hemorrhage (SAH). Perfusion-weighted magnetic resonance imaging (pwMRI) provides the possibility of detecting tissue at risk for infarction. The objective of our study was to evaluate the feasibility and impact of pwMRI in the management of SAH patients. METHODS: From a consecutive series of 180 patients experiencing SAH and treated at our institution over a 3-year period, we identified 20 who underwent pwMRI during their acute illness. For these 20 patients, the results of pwMRI were compared with the results of diffusion-weighted MRI, transcranial Doppler sonography, and neurological examinations performed at the same time and with repeated pwMRI examinations of the same patient at different times. RESULTS: Nineteen of 20 patients showed perfusion changes predominantly in the time maps. Fifteen of 19 patients with changes in pwMRI had a neurological deficit at the same time. In 7 of 15 patients with neurological deterioration, transcranial Doppler sonography showed signs of VSP, whereas all 15 patients showed alterations in pwMRI. The areas of perfusion changes in pwMRI correlated well with the neurological deficits of the patients and were larger than the areas of changed diffusion in diffusion-weighted MRI performed at the same time. There were no clinical complications with regard to the pwMRI examinations. CONCLUSION: pwMRI is safe and helpful in the management of patients with VSP after SAH. The sensitivity of pwMRI is higher than that of transcranial Doppler sonography in the detection of decreased perfusion as a result of VSP. pwMRI can detect tissue at risk before definitive infarction occurs and therefore may lead to a change of therapy in those patients.

Effects of handedness and gender on macro- and microstructure of the corpus callosum and its subregions: a combined high-resolution and diffusion-tensor MRI study.

The corpus callosum (CC) represents the major commissural tract connecting the two cerebral hemispheres and is supposed to play crucial integrative role in functional hemispheric specialization. The present study examined whether interindividual variations in macro- and microstructure of the human CC are associated with handedness and gender. Therefore, a combined diffusion-tensor (DTI) and high-resolution morphological MRI study was performed on 34 right- and 33 left-handed subjects of both sexes. The mid-sagittal surface areas and quantitative measures of molecular diffusion (relative anisotropy, mean diffusion) of the total CC and its subregions (genu, truncus, posterior third) were determined. Analysis revealed a larger total callosal area in right- as compared to left-handed subjects and in males as compared to females. Throughout all callosal subregions, anisotropy was found to be increased in left-handed as well as in male subjects, while the mean diffusion was diminished only in left-handers. For the posterior third of the CC, a significant negative correlation (r=-0.34) between anisotropy and area was detected in right-handed subjects. Summarized, significant alterations in the molecular diffusion and in the size of the CC with respect to gender and handedness were revealed in the present study. These findings can be interpreted as handedness- and gender-related differences in macro- and microstructure of the callosal pathways. It was demonstrated that the inspection of the callosal microstructure using DTI yields empirical evidence on interhemispheric connectivity that goes well beyond the information revealed by anatomical measurements alone. Thus, DTI has proven to be a useful additional method in cognitive neuroscience.