Polyunsaturated fatty acids of the n-6 and n-3 series: effects on postprandial lipid and apolipoprotein levels in healthy men

OBJECTIVE: The present study was carried out to determine effects of test meals of different fatty acid compositions on postprandial lipoprotein and apolipoprotein metabolism. DESIGN: The study was a randomized, single blind design. SETTING: The study was carried out in the Clinical Investigation Unit of the Royal Surrey County Hospital. SUBJECTS: Twelve male normal subjects with an average age of 22.4 +/- 1.4 years (mean +/- SD) were selected from the student population of the University of Surrey; one subject dropped out of the study because he found the test meal unpalatable. INTERVENTIONS: The subjects were given three evening test meals on three separate occasions, in which the oils used were either a mixed oil (rich in saturated fatty acids and approximated the fatty acid intake of the current UK diet), corn oil (rich in n-6 fatty acids), or fish oil (rich in n-3 fatty acids) 40 g of the oil under investigation were incorporated into a rice-based test meal. Triacylglycerol-rich lipoproteins-triacylglycerol (TRL-TAG), TRL-cholesterol (TRL-cholesterol), plasma-TAG, plasma cholesterol (T-C), and serum apolipoprotein A-I and B (apo A-I and B) responses were measured. Postprandial responses were followed for 11 h. RESULTS: Postprandial plasma-TAG responses, calculated as incremental areas under the response curves (IAUC) were significantly reduced following the fish oil meal [365.5 +/- 145.4 mmol/l x min (mean +/- SD)[ compared with the mixed oil meal (552.0 +/- 141.7 mmol/l x min) (P < 0.05) and there was a strong trend towards the same direction in the TRL-TAG responses. In all instances, plasma-and TRL-TAG showed a biphasic response with increased concentrations occurring at 1h and between 3 and 7h postprandially. TRL-cholesterol, T-C, and serum apo A-I and B responses to the three meals were similar. CONCLUSIONS: The findings support the view that fish oils decrease postprandial lipaemia and this may be an important aspect of their beneficial effects in reducing risk of coronary heart disease (CHD). Further work is required to determine the mechanisms responsible for this effect.

Anisotropic refinement of the structure of Thermoascus aurantiacusxylanase I

The isotropic crystallographic model of the structure of xylanase I from Thermoascus aurantiacus (TAXI) has now been refined anisotropically at 1.14 Å resolution to a standard residual of R = 11.1% for all data. TAXI is amongst the five largest proteins deposited in the Protein Data Bank to have been refined with anisotropic displacement parameters (ADPs) at this level of resolution. The anisotropy analysis revealed a more isotropic distribution of anisotropy than usually observed previously. Adding ADPs resulted in high-quality electron-density maps which revealed discrepancies from the previously suggested primary sequences for this enzyme. Side-chain conformational disorder was modelled for 16 residues, including Trp275, a bulky residue at the active site. An unrestrained refinement was consistent with the protonation of the catalytic acid/base glutamate and the deprotonation of the nucleophile glutamate, as required for catalysis. The thermal stability of TAXI is reinterpreted in the light of the new refined model.

Synthesis of new phosphino amino alcohol ligands via ortho-alkyllithiation reactions. Versatile coordination behavior toward copper(I) and palladium(II)

2-[Methyl(2-methylphenyl)amino]ethanol undergoes an ortho-alkyllithiation reaction with n-butyllithium to lead to a new mixed benzyllithium−lithium alkoxide. This organolithium species reacts with PPh2Cl, with selective P−C bond formation, to afford the ligand 2-[methyl(2-((diphenylphosphino)methyl)phenyl)amino]ethanol L1. The coordination of the ligand L1 to copper(I) leads to the complex [Cu(L1)2](BF4), whose structure has been determined by an X-ray diffraction study. In the solid state, one of the ligands acts as a monodentate phosphine while the other adopts a tridentate P,N,O coordination mode. A variable-temperature 31P NMR study demonstrated the existence of an equilibrium between the two modes in solution, with a coalescence temperature of ca. 0 °C, indicating a double-hemilabile behavior for the nitrogen and the oxygen functions. L1 reacts with [Pd(Me)(Cl)(COD)] to give a dinuclear complex in which the ligand appears to behave as a bridging anionic P,O ligand. Such a complex could serve as a model for a key intermediate in the proposed mechanism for the homogeneous catalysis of the methoxycarbonylation of propyne by certain palladium(II) complexes containing P,N ligands. L1 can undergo a second ortho-alkylmetalation reaction with n-butyllithium which, after addition of PPh2Cl, provides the new ligand 2-{methyl[2-(bis(diphenylphosphino)methyl)phenyl]amino}ethanol (L2) in high yield.

The study of chiral adsorption systems using synchrotron- based structural and spectroscopic techniques: stereospecific adsorption of serine on Au-modified chiral Cu{531} surfaces

We apply modern synchrotron-based structural techniques to the study of serine adsorbed on the pure andAumodified intrinsically chiral Cu{531} surface. XPS and NEXAFS data in combination with DFT show that on the pure surface both enantiomers adsorb in l4 geometries (with de-protonated b-OH groups) at low coverage and in l3 geometries at saturation coverage. Significantly larger enantiomeric differences are seen for the l4 geometries, which involve substrate bonds of three side groups of the chiral center, i.e. a three-point interaction. The l3 adsorption geometry, where only the carboxylate and amino groups form substrate bonds, leads to smaller but still significant enantiomeric differences, both in geometry and the decomposition behavior. When Cu{531} is modified by the deposition of 1 and 2ML Au the orientations of serine at saturation coverage are significantly different from those on the clean surface. In all cases, however, a l3 bond coordination is found at saturation involving different numbers of Au atoms, which leads to relatively small enantiomeric differences.

Photo-induced phase transitions in azobenzene-doped liquid crystals

The effect of irradiation (UV-visible light) on a nematic liquid crystal doped with a photoactive azobenzene derivative was investigated. The selective irradiation results in either an E implies Z or Z implies E isomerization of the azobenzene unit. The effect of the isomerization is to cause a reversible depression of the liquid crystal to isotropic (LC implies l) phase transition temperature of the doped mixture, which can be monitored optically as an isothermal phase transition. This depression also results in a biphasic liquid crystal+isotropic region which is discussed. The authors investigate the cause and magnitude of the phase depression as a function of the amount of doped 4-butyl-4'-methoxyazobenzene (photoactive unit) in 4-cyano-4'-n-pentylbiphenyl (liquid crystal unit), and as a function of the percentage conversion of E implies Z (caused by isomerization) in the azobenzene. The photostationary state of the doped mixtures achieved by Z implies E isomerization is considered and its effect upon the transition temperature of the mixture and response time of the system is discussed. They discuss the implications of the photostationary state with regards to the reversibility of the photo-induced phase transition and hence potential applications.

Structural and morphological studies of the dipeptide based L-Pro-L-Val organocatalytic gels and their rheological behaviour

Organocatalytic gels based on the dipeptide sequence L-Pro-L-Val have been studied by two different FTIR techniques. This suggests a different arrangement of the gelator molecules in the self-assembled fibers depending on the organic solvent employed. In acetonitrile and nitromethane the structure of the supramolecular aggregates is similar and provides similar catalytic properties (supramolecularenhancement of basicity). In contrast, the self-assembled fibers obtained in toluene clearly presented a different molecular arrangement consistent with its different catalytic behaviour (enamine-based catalysis). In addition these gels have been studied by microscopy and rheology.

Identification of critical residues in the active site of porcine membrane-bound aminopeptidase P

The membrane-bound form of mammalian aminopeptidase P (AP-P; EC 3.4. 11.9) is a mono-zinc-containing enzyme that lacks any of the typical metal binding motifs found in other zinc metalloproteases. To identify residues involved in metal binding and catalysis, sequence and structural information was used to align the sequence of porcine membrane-bound AP-P with other members of the peptidase clan MG, including Escherichia coli AP-P and methionyl aminopeptidases. Residues predicted to be critical for activity were mutated and the resultant proteins were expressed in COS-1 cells. Immunoelectrophoretic blot analysis was used to compare the levels of expression of the mutant proteins, and their ability to hydrolyze bradykinin and Gly-Pro-hydroxyPro was assessed. Asp449, Asp460, His523, Glu554, and Glu568 are predicted to serve as metal ion ligands in the active site, and mutagenesis of these residues resulted in fully glycosylated proteins that were catalytically inactive. Mutation of His429 and His532 also resulted in catalytically inactive proteins, and these residues, by analogy with E. coli AP-P, are likely to play a role in shuttling protons during catalysis. These studies indicate that mammalian membrane-bound AP-P has an active-site configuration similar to that of other members of the peptidase clan MG, which is compatible with either a dual metal ion model or a single metal ion in the active site. The latter model is consistent, however, with the known metal stoichiometry of both the membrane-bound and cytosolic forms of AP-P and with a recently proposed model for methionyl aminopeptidase.

Functional model for catecholase-like activity: A mechanistic approach with manganese(III) complexes of salen type Schiff base ligands

Three new Mn(III) complexes [MnL1(OOCH)(OH2)] (1), [MnL2(OH2)(2)][Mn2L22(NO2)(3)] (2) and [Mn2L21(NO2)(2)] (3) (where H2L1 = H(2)Me(2)Salen = 2,7-bis(2-hydroxyphenyl)-2,6-diazaocta-2,6-diene and H2L2 = H(2)Salpn = 1,7-bis(2-hydroxyphenyl)-2,6-diazahepta-1,6-diene) have been synthesized. X-ray crystal structure analysis reveals that 1 is a mononuclear species whereas 2 contains a mononuclear cationic and a dinuclear nitrite bridged (mu-1 kappa O:2 kappa O') anionic unit. Complex 3 is a phenoxido bridged dimer containing terminally coordinated nitrite. Complexes 1-3 show excellent catecholase-like activity with 3,5-di-tert-butylcatechol (3,5-DTBC) as the substrate. Kinetic measurements suggest that the rate of catechol oxidation follows saturation kinetics with respect to the substrate and first order kinetics with respect to the catalyst. Formation of bis(mu-oxo)dimanganese(III,III) as an intermediate during the course of reaction is identified from ESI-MS spectra. The characteristic six line EPR spectra of complex 2 in the presence of 3,5-DTBC supports the formation of manganese(II)-semiquinonate as an intermediate species during the catalytic oxidation of 3,5-DTBC.

When long-range zero-lag synchronization is feasible in cortical networks

Many studies have reported long-range synchronization of neuronal activity between brain areas, in particular in the beta and gamma bands with frequencies in the range of 14–30 and 40–80 Hz, respectively. Several studies have reported synchrony with zero phase lag, which is remarkable considering the synaptic and conduction delays inherent in the connections between distant brain areas. This result has led to many speculations about the possible functional role of zero-lag synchrony, such as for neuronal communication, attention, memory, and feature binding. However, recent studies using recordings of single-unit activity and local field potentials report that neuronal synchronization may occur with non-zero phase lags. This raises the questions whether zero-lag synchrony can occur in the brain and, if so, under which conditions. We used analytical methods and computer simulations to investigate which connectivity between neuronal populations allows or prohibits zero-lag synchrony. We did so for a model where two oscillators interact via a relay oscillator. Analytical results and computer simulations were obtained for both type I Mirollo–Strogatz neurons and type II Hodgkin–Huxley neurons. We have investigated the dynamics of the model for various types of synaptic coupling and importantly considered the potential impact of Spike-Timing Dependent Plasticity (STDP) and its learning window. We confirm previous results that zero-lag synchrony can be achieved in this configuration. This is much easier to achieve with Hodgkin–Huxley neurons, which have a biphasic phase response curve, than for type I neurons. STDP facilitates zero-lag synchrony as it adjusts the synaptic strengths such that zero-lag synchrony is feasible for a much larger range of parameters than without STDP.

A mesoscopic modelling approach to anaesthetic action on brain electrical activity

Relating the measurable, large scale, effects of anaesthetic agents to their molecular and cellular targets of action is necessary to better understand the principles by which they affect behavior, as well as enabling the design and evaluation of more effective agents and the better clinical monitoring of existing and future drugs. Volatile and intravenous general anaesthetic agents (GAs) are now known to exert their effects on a variety of protein targets, the most important of which seem to be the neuronal ion channels. It is hence unlikely that anaesthetic effect is the result of a unitary mechanism at the single cell level. However, by altering the behavior of ion channels GAs are believed to change the overall dynamics of distributed networks of neurons. This disruption of regular network activity can be hypothesized to cause the hypnotic and analgesic effects of GAs and may well present more stereotypical characteristics than its underlying microscopic causes. Nevertheless, there have been surprisingly few theories that have attempted to integrate, in a quantitative manner, the empirically well documented alterations in neuronal ion channel behavior with the corresponding macroscopic effects. Here we outline one such approach, and show that a range of well documented effects of anaesthetics on the electroencephalogram (EEG) may be putatively accounted for. In particular we parameterize, on the basis of detailed empirical data, the effects of halogenated volatile ethers (a clinically widely used class of general anaesthetic agent). The resulting model is able to provisionally account for a range of anaesthetically induced EEG phenomena that include EEG slowing, biphasic changes in EEG power, and the dose dependent appearance of anomalous ictal activity, as well as providing a basis for novel approaches to monitoring brain function in both health and disease.

Modeling the effects of anesthesia on the electroencephalogram

Changes to the electroencephalogram (EEG) observed during general anesthesia are modeled with a physiological mean field theory of electrocortical activity. To this end a parametrization of the postsynaptic impulse response is introduced which takes into account pharmacological effects of anesthetic agents on neuronal ligand-gated ionic channels. Parameter sets for this improved theory are then identified which respect known anatomical constraints and predict mean firing rates and power spectra typically encountered in human subjects. Through parallelized simulations of the eight nonlinear, two-dimensional partial differential equations on a grid representing an entire human cortex, it is demonstrated that linear approximations are sufficient for the prediction of a range of quantitative EEG variables. More than 70 000 plausible parameter sets are finally selected and subjected to a simulated induction with the stereotypical inhaled general anesthetic isoflurane. Thereby 86 parameter sets are identified that exhibit a strong “biphasic” rise in total power, a feature often observed in experiments. A sensitivity study suggests that this “biphasic” behavior is distinguishable even at low agent concentrations. Finally, our results are briefly compared with previous work by other groups and an outlook on future fits to experimental data is provided.

A microblock ionomer in proton exchange membrane electrolysis for the production of high purity hydrogen

Proton exchange membranes (PEM’s) are currently under investigation for membrane water electrolysis (PEMWE) to deliver efficient production of the high purity hydrogen needed to supply emerging clean-energy technologies such as hydrogen fuel cells. The microblock aromatic ionomer described in this work achieves high mechanical strength in an aqueous environment as a result of its designed, biphasic morphology and displays many of the qualities required in a PEM. The new ionomer membrane thus shows good proton conductivity (63 mS cm−1 at 80 °C and 100% RH), while retaining mechanical integrity under high temperature, hydrated conditions. Testing in electrolysis has shown good energy efficiency (1.67 V at 1 A cm−2 and 80 °C, corresponding to 4 kWh/Nm3 of H2), making this ionomer a potential candidate for commercial application in PEMWE.

Complex spatiotemporal haemodynamic response following sensory stimulation in the awake rat

Detailed understanding of the haemodynamic changes that underlie non-invasive neuroimaging techniques such as blood oxygen level dependent functional magnetic resonance imaging is essential if we are to continue to extend the use of these methods for understanding brain function and dysfunction. The use of animal and in particular rodent research models has been central to these endeavours as they allow in-vivo experimental techniques that provide measurements of the haemodynamic response function at high temporal and spatial resolution. A limitation of most of this research is the use of anaesthetic agents which may disrupt or mask important features of neurovascular coupling or the haemodynamic response function. In this study we therefore measured spatiotemporal cortical haemodynamic responses to somatosensory stimulation in awake rats using optical imaging spectroscopy. Trained, restrained animals received non-noxious stimulation of the whisker pad via chronically implanted stimulating microwires whilst optical recordings were made from the contralateral somatosensory cortex through a thin cranial window. The responses we measure from un-anaesthetised animals are substantially different from those reported in previous studies which have used anaesthetised animals. These differences include biphasic response regions (initial increases in blood volume and oxygenation followed by subsequent decreases) as well as oscillations in the response time series of awake animals. These haemodynamic response features do not reflect concomitant changes in the underlying neuronal activity and therefore reflect neurovascular or cerebrovascular processes. These hitherto unreported hyperemic response dynamics may have important implications for the use of anaesthetised animal models for research into the haemodynamic response function.

Following the creation of active gold nanocatalysts from phosphine-stabilized molecular clusters

The phosphine-stabilised gold cluster [Au6(Ph2P-o-tolyl)6](NO3)2 is converted into an active nanocatalyst for the oxidation of benzyl alcohol through low-temperature peroxide-assisted removal of the phosphines, avoiding the high-temperature calcination process. The process was monitored using in-situ X-ray absorption spectroscopy, which revealed that after a certain period of the reaction with tertiary butyl hydrogen peroxide, the phosphine ligands are removed to form nanoparticles of gold which matches with the induction period seen in the catalytic reaction. Density functional theory calculations show that the energies required to remove the ligands from the [Au6Ln]2+ increase significantly with successive removal steps, suggesting that the process does not occur at once but sequentially. The calculations also reveal that ligand removal is accompanied by dramatic re-arrangements in the topology of the cluster core.

[M(CO)4(2,2′-bipyridine)] (M = Cr, Mo, W) as efficient catalysts for electrochemical reduction of CO2 to CO at a gold electrode

Group 6 complexes of the type [M(CO)4(bpy)] (M=Cr, Mo, W) are capable of behaving as electrochemical catalysts for the reduction of CO2 at potentials less negative than those for the reduction of the radical anions [M(CO)4(bpy)].−. Cyclic voltammetric, chronoamperometric and UV/Vis/IR spectro-electrochemical data reveal that five-coordinate [M(CO)3(bpy)]2− are the active catalysts. The catalytic conversion is significantly more efficient in N-methyl-2-pyrrolidone (NMP) compared to tetrahydrofuran, which may reflect easier CO dissociation from 1e−-reduced [M(CO)4(bpy)].− in the former solvent, followed by second electron transfer. The catalytic cycle may also involve [M(CO)4(H-bpy)]− formed by protonation of [M(CO)3(bpy)]2−, especially in NMP. The strongly enhanced catalysis using an Au working electrode is remarkable, suggesting that surface interactions may play an important role, too.