Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085.

Ordering on multiple lengthscales in a series of side group liquid crystal block copolymers containing a cholesteryl-based mesogen

Hierarchical ordering in a side group liquid crystal block copolymer is investigated by differential scanning calorimetry, polarized optical microscopy, small-angle X-ray and neutron scattering (SAXS and SANS) and transmission electron microscopy (TEM). A series of block copolymers with a range of compositions was prepared by atom transfer radical polymerization, comprising a polystyrene block and a poly(methyl methacrylate) block bearing chiral cholesteryl mesogens. Smectic ordering is observed as well as microphase separation of the block copolymer. Lamellar structures were observed for far larger volume fractions than for coil-coil copolymers (up to a volume fraction of liquid crystal block, f(LC) = 0.8). A sample with f(LC) = 0.86 exhibited a hexagonal-packed cylinder morphology, as confirmed by SAXS and TEM. The matrix comprised the liquid crystal block, with the mesogens forming smectic layers. For the liquid crystal homopolymer and samples with high f(LC), a smectic-smectic phase transition was observed below the clearing point. At low temperature, the smectic phase comprises coexisting domains with monolayer S-A,S-1 coexisting with interdigitated S-A,S-d domains. At high temperature a SA,1 phase is observed. This is the only structure observed for samples with lower f(LC). These unprecedented results point to the influence of block copolymer microphase separation on the smectic ordering.

The synthesis and cytotoxic evaluation of a series of benzodioxole substituted titanocenes

Using 6-benzo[1,3]dioxolefulvene (1a), a series of benzodioxole substituted titanocenes was synthesized. The benzyl-substituted titanocene bis[(benzo[1,3]dioxole)-5-methylcyclopentadienyl] titanium (IV) dichloride (2a) was synthesized from the reaction of Super Hydride with 1a. An X-ray determined crystal structure was obtained for 2a. The ansa-titanocene (1,2-di(cyclopentadienyl)1,2-di-(benzo[1,3]dioxole)-ethanediyl) titanium(IV) dichloride (2b) was synthesized by reductive dimerisation of la with titanium dichloride. The diarylmethyl substituted titanocene bis(di(benzo[1,3]dioxole)-S-methylcyclopentadienyl) titanium(IV) dichloride (20 was synthesized by reacting la with the para-lithiated benzodioxole followed by transmetallation with titanium tetrachloride. When titanocenes 2a-c were tested against pig kidney (LLC-PK) cells inhibitory concentrations (IC50) of 2.8 X 10(-4), 1.6 x 10(-4) and 7.6 x 10(-5) m, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, when compared with unsubstituted titanocene dichloride, but are not as impressive as values obtained for titanocenes previously synthesized using the above methods. Copyright (c) 2006 John Wiley & Sons, Ltd.

A preliminary evaluation of cognitive-behaviour therapy for clinical perfectionism: a case series

Objective: The construct of 'clinical perfectionism' has been developed in response to criticisms that other approaches have failed to yield advances in the treatment of the type of self-oriented perfectionism that poses a clinical problem. The primary aim of this study was to conduct a preliminary investigation into the efficacy of a theory-driven, cognitive-behavioural intervention for 'clinical perfectionism'. Design. A multiple baseline single case series design was used. Method: A specific, 10-session cognitive-behavioural intervention to address clinical perfectionism in eating disorders was adapted to allow its use in nine patients referred with a range of axis I disorders and clinical perfectionism. Results: The intervention led to clinically significant improvements in self-referential perfectionism from pretreatment to follow-up for six of the nine participants on two perfectionism measures and for three of the nine participants on the measure of clinical perfectionism. Statistically significant improvements from pre- to post-intervention for the group as a whole were found on all three measures. The improvements were maintained at follow-up. Conclusions: The finding that clinical perfectionism is improved in the majority of participants is particularly encouraging given that perfectionism has traditionally been viewed as a personality characteristic resistant to change. These preliminary findings warrant replication in a larger study.

Enhancing dominant modes in nonstationary time series by means of the symbolic resonance analysis

We present the symbolic resonance analysis (SRA) as a viable method for addressing the problem of enhancing a weakly dominant mode in a mixture of impulse responses obtained from a nonlinear dynamical system. We demonstrate this using results from a numerical simulation with Duffing oscillators in different domains of their parameter space, and by analyzing event-related brain potentials (ERPs) from a language processing experiment in German as a representative application. In this paradigm, the averaged ERPs exhibit an N400 followed by a sentence final negativity. Contemporary sentence processing models predict a late positivity (P600) as well. We show that the SRA is able to unveil the P600 evoked by the critical stimuli as a weakly dominant mode from the covering sentence final negativity. (c) 2007 American Institute of Physics. (c) 2007 American Institute of Physics.

Empirical mode decomposition: a novel technique for the study of tremor time series

Tremor is a clinical feature characterized by oscillations of a part of the body. The detection and study of tremor is an important step in investigations seeking to explain underlying control strategies of the central nervous system under natural (or physiological) and pathological conditions. It is well established that tremorous activity is composed of deterministic and stochastic components. For this reason, the use of digital signal processing techniques (DSP) which take into account the nonlinearity and nonstationarity of such signals may bring new information into the signal analysis which is often obscured by traditional linear techniques (e.g. Fourier analysis). In this context, this paper introduces the application of the empirical mode decomposition (EMD) and Hilbert spectrum (HS), which are relatively new DSP techniques for the analysis of nonlinear and nonstationary time-series, for the study of tremor. Our results, obtained from the analysis of experimental signals collected from 31 patients with different neurological conditions, showed that the EMD could automatically decompose acquired signals into basic components, called intrinsic mode functions (IMFs), representing tremorous and voluntary activity. The identification of a physical meaning for IMFs in the context of tremor analysis suggests an alternative and new way of detecting tremorous activity. These results may be relevant for those applications requiring automatic detection of tremor. Furthermore, the energy of IMFs was visualized as a function of time and frequency by means of the HS. This analysis showed that the variation of energy of tremorous and voluntary activity could be distinguished and characterized on the HS. Such results may be relevant for those applications aiming to identify neurological disorders. In general, both the HS and EMD demonstrated to be very useful to perform objective analysis of any kind of tremor and can therefore be potentially used to perform functional assessment.

Electronic transitions and bonding properties in a series of five-coordinate “16-electron” complexes [Mn(CO)3(L2)]− (L2=chelating redox-active π-donor ligand)

In this article we present for the first time accurate density functional theory (DFT) and time-dependent (TD) DFT data for a series of electronically unsaturated five-coordinate complexes [Mn(CO)(3)(L-2)](-), where L-2 stands for a chelating strong pi-donor ligand represented by catecholate, dithiolate, amidothiolate, reduced alpha-diimine (1,4-dialkyl-1,4-diazabutadiene (R-DAB), 2,2'-bipyridine) and reduced 2,2'-biphosphinine types. The single-crystal X-ray structure of the unusual compound [Na(BPY)][Mn(CO)(3)(BPY)]center dot Et2O and the electronic absorption spectrum of the anion [Mn(CO)(3)(BPY)](-) are new in the literature. The nature of the bidentate ligand determines the bonding in the complexes, which varies between two limiting forms: from completely pi-delocalized diamagnetic {(CO)(3)Mn-L-2}(-) for L-2 = alpha-diimine or biphosphinine, to largely valence-trapped {(CO)(3)Mn-1-L-2(2-)}(-) for L-2(2-) = catecholate, where the formal oxidation states of Mn and L-2 can be assigned. The variable degree of the pi-delocalization in the Mn(L-2) chelate ring is indicated by experimental resonance Raman spectra of [Mn(CO)(3)(L-2)](-) (L-2=3,5-di-tBu-catecholate and iPr-DAB), where accurate assignments of the diagnostically important Raman bands have been aided by vibrational analysis. The L-2 = catecholate type of complexes is known to react with Lewis bases (CO substitution, formation of six-coordinate adducts) while the strongly pi-delocalized complexes are inert. The five-coordinate complexes adopt usually a distorted square pyramidal geometry in the solid state, even though transitions to a trigonal bipyramid are also not rare. The experimental structural data and the corresponding DFT-computed values of bond lengths and angles are in a very good agreement. TD-DFT calculations of electronic absorption spectra of the studied Mn complexes and the strongly pi-delocalized reference compound [Fe(CO)(3)(Me-DAB)] have reproduced qualitatively well the experimental spectra. Analyses of the computed electronic transitions in the visible spectroscopic region show that the lowest-energy absorption band always contains a dominant (in some cases almost exclusive) contribution from a pi(HOMO) -> pi*(LUMO) transition within the MnL2 metallacycle. The character of this optical excitation depends strongly on the composition of the frontier orbitals, varying from a partial L-2 -> Mn charge transfer (LMCT) through a fully delocalized pi(MnL2) -> pi*(MnL2) situation to a mixed (CO)Mn -> L-2 charge transfer (LLCT/MLCT). The latter character is most apparent in the case of the reference complex [Fe(CO)(3)(Me-DAB)]. The higher-lying, usually strongly mixed electronic transitions in the visible absorption region originate in the three lower-lying occupied orbitals, HOMO - 1 to HOMO - 3, with significant metal-d contributions. Assignment of these optical excitations to electronic transitions of a specific type is difficult. A partial LLCT/MLCT character is encountered most frequently. The electronic absorption spectra become more complex when the chelating ligand L-2, such as 2,2'-bipyridine, features two or more closely spaced low-lying empty pi* orbitals.

Electronic properties of 4,4 ',5,5 '-tetramethyl-2,2 '-biphosphinine (tmbp) in the redox series fac-[Mn(Br)(CO)(3)(tmbp)], [Mn(CO)(3)(tmbp)](2), and [Mn(CO)(3)(tmbp)](-): crystallographic, spectroelectrochemical, and DFT computational study

Stepwise electrochemical reduction of the complex fac-[Mn(Br)(CO)(3)(tmbp)] (tmbp = 4,4',5,5'-tetramethyl-2,2'-biphosphinine) produces the dimer [Mn(CO)(3)(tmbp)](2) and the five-coordinate anion [Mn(CO)(3)(tmbp)](-). All three members of the redox series have been characterized by single-crystal X-ray diffraction. The crystallographic data provide valuable insight into the localization of the added electrons on the (carbonyl)manganese and tmbp centers. In particular, the formulation of the two-electron-reduced anion as [Mn-0(CO)(3)(tmbp(-))](-) also agrees with the analysis of its IR nu(CO) wavenumbers and with the results of density functional theoretical (DFT) MO calculations on this compound. The strongly delocalized pi-bonding in the anion stabilizes its five-coordinate geometry and results in the appearance of several mixed Mn-to-tmbp charge-transfer/IL(tmbp) transitions in the near-UV-vis spectral region. A thorough voltammetric and UV-vis/IR spectroelectrochemical study of the reduction path provided evidence for a direct formation of [Mn(CO)(3)(tmbp)](-) via a two-electron ECE mechanism involving the [Mn(CO)(3)(tmbp)](.) radical transient. At ambient temperature [Mn(CO)(3)(tmbp)](-) reacts rapidly with nonreduced fac-[Mn(Br)(CO)(3)(tmbp)] to produce [Mn(CO)(3)(tmbp)](2). Comparison with the analogous 2,2'-bipyridine complexes has revealed striking similarity in the bonding properties and reactivity, despite the stronger pi-acceptor character of the tmbp ligand.

Bayesian model averaging and identification of structural breaks in time series

Bayesian Model Averaging (BMA) is used for testing for multiple break points in univariate series using conjugate normal-gamma priors. This approach can test for the number of structural breaks and produce posterior probabilities for a break at each point in time. Results are averaged over specifications including: stationary; stationary around trend and unit root models, each containing different types and number of breaks and different lag lengths. The procedures are used to test for structural breaks on 14 annual macroeconomic series and 11 natural resource price series. The results indicate that there are structural breaks in all of the natural resource series and most of the macroeconomic series. Many of the series had multiple breaks. Our findings regarding the existence of unit roots, having allowed for structural breaks in the data, are largely consistent with previous work.

Transatlantic spaces: production, location and style in 1960s-1970s action-adventure TV series

This paper argues that transatlantic hybridity connects space, visual style and ideological point of view in British television action-adventure fiction of the 1960s–1970s. It analyses the relationship between the physical location of TV series production at Elstree Studios, UK, the representation of place in programmes, and the international trade in television fiction between the UK and USA. The TV series made at Elstree by the ITC and ABC companies and their affiliates linked Britishness with an international modernity associated with the USA, while also promoting national specificity. To do this, they drew on film production techniques that were already common for TV series production in Hollywood. The British series made at Elstree adapted versions of US industrial organization and television formats, and made programmes expected to be saleable to US networks, on the basis of British experiences in TV co-production with US companies and of the international cinema and TV market.

Time series multistep-ahead predictability estimation and ranking

A predictability index was defined as the ratio of the variance of the optimal prediction to the variance of the original time series by Granger and Anderson (1976) and Bhansali (1989). A new simplified algorithm for estimating the predictability index is introduced and the new estimator is shown to be a simple and effective tool in applications of predictability ranking and as an aid in the preliminary analysis of time series. The relationship between the predictability index and the position of the poles and lag p of a time series which can be modelled as an AR(p) model are also investigated. The effectiveness of the algorithm is demonstrated using numerical examples including an application to stock prices.

Dual-orthogonal radial basis function networks for nonlinear time series prediction

A new structure of Radial Basis Function (RBF) neural network called the Dual-orthogonal RBF Network (DRBF) is introduced for nonlinear time series prediction. The hidden nodes of a conventional RBF network compare the Euclidean distance between the network input vector and the centres, and the node responses are radially symmetrical. But in time series prediction where the system input vectors are lagged system outputs, which are usually highly correlated, the Euclidean distance measure may not be appropriate. The DRBF network modifies the distance metric by introducing a classification function which is based on the estimation data set. Training the DRBF networks consists of two stages. Learning the classification related basis functions and the important input nodes, followed by selecting the regressors and learning the weights of the hidden nodes. In both cases, a forward Orthogonal Least Squares (OLS) selection procedure is applied, initially to select the important input nodes and then to select the important centres. Simulation results of single-step and multi-step ahead predictions over a test data set are included to demonstrate the effectiveness of the new approach.