Hippurate: the natural history of a mammalian-microbial co-metabolite

Hippurate, the glycine conjugate of benzoic acid, is a normal constituent of the endogenous urinary metabolite profile and has long been associated with the microbial degradation of certain dietary components, hepatic function and toluene exposure, and is also commonly used as a measure of renal clearance. Here we discuss the potential relevance of hippurate excretion with regards to normal endogenous metabolism and trends in excretion relating to gender, age, and the intestinal microbiota. Additionally, the significance of hippurate excretion with regards to disease states including obesity, diabetes, gastrointestinal diseases, impaired renal function, psychological disorders and autism, as well as toxicity and parasitic infection, are considered.

Analysis and compensation of I/Q imbalance in MIMO transmit-receive diversity systems

In wireless communication systems, all in-phase and quadrature-phase (I/Q) signal processing receivers face the problem of I/Q imbalance. In this paper, we investigate the effect of I/Q imbalance on the performance of multiple-input multiple-output (MIMO) maximal ratio combining (MRC) systems that perform the combining at the radio frequency (RF) level, thereby requiring only one RF chain. In order to perform the MIMO MRC, we propose a channel estimation algorithm that accounts for the I/Q imbalance. Moreover, a compensation algorithm for the I/Q imbalance in MIMO MRC systems is proposed, which first employs the least-squares (LS) rule to estimate the coefficients of the channel gain matrix, beamforming and combining weight vectors, and parameters of I/Q imbalance jointly, and then makes use of the received signal together with its conjugation to detect the transmitted signal. The performance of the MIMO MRC system under study is evaluated in terms of average symbol error probability (SEP), outage probability and ergodic capacity, which are derived considering transmission over Rayleigh fading channels. Numerical results are provided and show that the proposed compensation algorithm can efficiently mitigate the effect of I/Q imbalance.

Inhibition of the cardiac Na+ channel Nav1.5 by carbon monoxide

Sub-lethal carbon monoxide (CO) exposure is frequently associated with myocardial arrhythmias and our recent studies have demonstrated that these may be attributable to modulation of cardiac Na+ channels, causing an increase in the late current and an inhibition of the peak current. Using a recombinant expression system, we demonstrate that CO inhibits peak human Nav1.5 current amplitude without activation of the late Na+ current observed in native tissue. Inhibition was associated with a hyperpolarizing shift in the steady-state inactivation properties of the channels and was unaffected by modification of channel gating induced by anemone toxin (rATX-II). Systematic pharmacological assessment indicated that no recognised CO-sensitive intracellular signalling pathways appeared to mediate CO inhibition of Nav1.5. Inhibition was, however, markedly suppressed by inhibition of nitric oxide (NO) formation, but NO donors did not mimic or occlude channel inhibition by CO, indicating that NO alone did not account for the actions of CO. Exposure of cells to dithiothreitol immediately before CO exposure also dramatically reduced the magnitude of current inhibition. Similarly, L-cysteine and N-ethylmaleimide significantly attenuated the inhibition caused by CO. In the presence of DTT and the NO inhibitor L-NAME, the ability of CO to inhibit Nav1.5 was almost fully prevented. Our data indicate that inhibition of peak Na+ current (which can lead to Brugada-syndrome like arrhythmias) occurs via a mechanism distinct from induction of the late current, requires NO formation and is dependent on channel redox state.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, nitric oxide and cGMP levels, as well as regulate MAP kinase signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide (CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Reforming theatre in Farnese Parma: the case of the Accademia degli Innominati (1574-1608)

The essay explores the socio-cultural role of the main academy in Parma, the Innominati (1574-1608), which flourished in the years when the Farnese dynasty was beginning to assert more forcefully its political control over the new state of Parma and Piacenza. The Innominati was from the start associated with the ruling dynasty, who must have recognized the importance of its cultural activities to strengthening their regime, particularly in the absence of a strong local university. This essay explores the institution’s contested position within the cultural landscape – as reflected also in its membership of courtiers, clergymen, and feudal aristocrats with more ambivalent relations with the Farnese. In particular, the focus falls on the theatrical activities of the group during the 1580s, a decade which saw the establishment of the Parma Index (1580) and the succession of the internationally celebrated Duke Alessandro Farnese (1587). Based on the little surviving evidence it is argued that the Academy in the 1580s became a creative hub for theatrical experimentation – through theoretical debate and composition, and possibly even performance. However, as relations between the Farnese and the local elites, especially feudal aristocrats, became more contested the Academy’s theatrical production and the public memory of this became increasingly controlled.

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson`s Disease

Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher`s disease, among patients with Parkinson`s disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson`s disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson`s disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Conclusions Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson`s disease.

Revision of the Asian spider genus Pandava Lehtinen (Araneae: Titanoecidae): description of five new species and first record of Titanoecidae from Africa

The spider genus Pandava Lehtinen previously included two species, P. laminata (Thorell) and P. hunanensis Yin and Bao, known from Asia and the Pacific Islands. The genus is diagnosed by the reduced tegular process on the male palp and the anterior position of the copulatory openings on the female epigynum. In this paper, we present updated descriptions for the known species of Pandava and we describe five new species: Pandava shiva sp. nov. from Pakistan, Pandava sarasvati sp. nov. from Myanmar; Pandava ganesha sp. nov., Pandava kama sp. nov. and Pandava ganga sp. nov., all from India. We also update the generic distribution including the first records of Titanoecidae from Africa.

Synergistic acceleration of thyroid hormone degradation by phenobarbital and the PPAR alpha agonist WY14643 in rat hepatocytes

Energy balance is maintained by controlling both energy intake and energy expenditure. Thyroid hormones play a crucial role in regulating energy expenditure. Their levels are adjusted by a tight feed back-control led regulation of thyroid hormone production/incretion and by their hepatic metabolism. Thyroid hormone degradation has previously been shown to be enhanced by treatment with phenobarbital or other antiepileptic drugs due to a CAR-dependent induction of phase 11 enzymes of xenobiotic metabolism. We have recently shown, that PPAR alpha agonists synergize with phenobarbital to induce another prototypical CAR target gene, CYP2B1. Therefore, it was tested whether a PPAR alpha agonist could enhance the phenobarbital-dependent acceleration of thyroid hormone elimination. In primary cultures of rat hepatocytes the apparent half-life of T3 was reduced after induction with a combination of phenobarbital and the PPARa agonist WY14643 to a larger extent than after induction with either Compound alone. The synergistic reduction of the half-life could be attributed to a synergistic induction of CAR and the CAR target genes that code for enzymes and transporters involved in the hepatic elimination of T3, such as OATP1A1, OATP1A3, UGT1A3 and UCT1A10. The PPAR alpha-dependent CAR induction and the subsequent induction of T3-eliminating enzymes might be of physiological significance for the fasting-incluced reduction in energy expenditure by fatty acids as natural PPARa ligands. The synergism of the PPAR alpha agonist WY14643 and phenobarbital in inducing thyroid hormone breakdown might serve as a paradigm for the synergistic disruption of endocrine control by other combinations of xenobiotics. (C) 2009 Elsevier Inc. All rights reserved.

Observation of two-magnon bound states in the spin-1 anisotropic Heisenberg antiferromagnetic chain system NiCl2-4SC(NH2)(2)

Results of systematic tunable-frequency ESR studies of the spin dynamics in NiCl2-4SC(NH2)(2) (known as DTN), a gapped S = 1 chain system with easy-plane anisotropy dominating over the exchange coupling (large-D chain), are presented. We have obtained direct evidence for two-magnon bound states, predicted for S = 1 large-D spin chains in the fully spin-polarized (FSP) phase. The frequency-field dependence of the corresponding excitations was calculated using the set of parameters obtained earlier [S.A. Zvyagin, et al., Phys. Rev. Lett. 98 (2007) 047205]. Very good agreement between the calculations and the experiment was obtained. It is argued that the observation of transitions from the ground to two-magnon bound states might indicate a more complex picture of magnetic interactions in DTN, involving a finite in-plane anisotropy. (C) 2007 Elsevier B.V. All rights reserved.

Infrared analysis of ion beam irradiated polymers

Irradiation with heavy ions can produce several modifications in the chain structure of polymers. These modifications can be related to scissioning and cross-linking of chemical bonds. which depend on the ion fluence and the density of energy deposited in the material. Stacked thin film Makrofol-KG (R) samples were irradiated with 350 MeV Au(26+) ions and FTIR absorption spectroscopy was used to determine the bond changes in the samples. Data on the absorption bands as a function of the fluence indicated a higher probability for simple-bonds scissioning than for double-bonds scissioning and no dependence on the number of double bonds breaking with ion fluence. Since sample irradiation was done in a non-track-overlapping regime, a novel process for double bonds formation is suggested: the excitation of a site in the material by only one incident ion followed by a double bond formation during the de-excitation process. (C) 2009 Elsevier B.V. All rights reserved.

Quasinormal modes of black holes immersed in a strong magnetic field

We found quasinormal modes, both in time and frequency domains, of the Ernst black holes, that is neutral black holes immersed in an external magnetic field. The Ernst solution reduces to the Schwarzschild solution, when the magnetic field vanishes. It is found that the quasinormal spectrum for massless scalar field in the vicinity of the magnetized black holes acquires an effective ""mass"" mu = 2B vertical bar m vertical bar, where m is the azimuthal number and B is parameter describing the magnetic field. We shall show that in the presence of a magnetic field quasinormal modes are longer lived and have larger oscillation frequencies. The perturbations of higher-dimensional magnetized black holes by Ortaggio and of magnetized dilaton black holes by Radu are considered. (C) 2007 Elsevier B.V. All rights reserved.

A New Approach to the Prediction of Partition Coefficients in Water/Organic Interfaces

In the present work, a new approach for the determination of the partition coefficient in different interfaces based on the density function theory is proposed. Our results for log P(ow) considering a n-octanol/water interface for a large super cell for acetone -0.30 (-0.24) and methane 0.95 (0.78) are comparable with the experimental data given in parenthesis. We believe that these differences are mainly related to the absence of van der Walls interactions and the limited number of molecules considered in the super cell. The numerical deviations are smaller than that observed for interpolation based tools. As the proposed model is parameter free, it is not limited to the n-octanol/water interface.

Determination of amino acids by capillary electrophoresis-electrospray ionization-mass spectrometry: An evaluation of different protein hydrolysis procedures

In this work, a CE equipment, online hyphenated to an IT MS analyzer by a linear sheath liquid interface promoting ESI, was used to develop a method for quantitative determination of amino acids. Under appropriate conditions (BGE composition, 0.8% HCOOH, 20% CH(3)OH; sheath liquid composition, 0.8% HCOOH, 60% methanol; V(ESI), +4.50 W), analytical curves of all amino acids from 3 to 80 mg/L were recorded presenting acceptable linearity (r > 0.99). LODs in the range of 16-172 mu mol/L were obtained. BSA, a model protein, was submitted to different hydrolysis procedures (classical acid and basic, and catalyzed by the H(+) form of a cation exchanger resin) and its amino acid profiles determined. In general, the resin-mediated hydrolysis yields were overall similar or better than those obtained by classical acid or basic hydrolysis. The resulting experimental-to-theoretical BSA concentration ratios served as correction factors for the quantitation of amino acids in Brazil nut resin generated hydrolysates.

Structural and Electronic Properties of Dipyridamole and Derivatives

Quantum mechanical calculations at the B3LYP theory level, together with the 6-31G* basis set, were employed to obtain the energy, ionization potential, and polarizabilites for dipyridamole and derivatives, which are compared with their biological activity. Density functional calculations of the spin densities were performed for radical formed by electron abstraction of dipyridamole and derivatives. The unpaired electron remains in dipyridamole is localized on the nitrogen atoms in the substituent positions 1, 3, 5, 7, 11, 12, 13, 14, with participation of the 9 and 10 carbons in the pyrimido-pyrimidine ring. The antioxidant activity is related with ionization potential, polarizability and Log P.