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Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-D-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca 2ϩ assays (EC 50 ϭ 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 M) and competed for binding of3 H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) ϭ 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED ϭ 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED ϭ 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED ϭ 1 mg/kg i.p.) and reduced impulsivity in the fivechoice serial reaction time test (MED ϭ 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.The metabotropic glutamate receptor (mGlu) receptor family includes eight G-protein-coupled receptor (GPCR) subtypes classified on the basis of structural homology, Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.136580.ABBREVIATIONS: mGlu, metabotropic glutamate receptor; GPCR, G-protein-coupled receptor; PAM, positive allosteric modulator; CPPHA, 2, NMDA, MPEP,

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The nuclear mineralocorticoid receptor (MR), a high-affinity receptor for glucocorticoids, is highly expressed in the hippocampus where it underpins cognitive, behavioural and neuroendocrine regulation. Increased neuronal MR expression occurs early in the response to cellular injury in vivo and in vitro and is associated with enhanced neuronal survival. To determine whether increased neuronal MR might be causal in protecting against ischaemic damage in vivo we generated a forebrain-specific MR-overexpressing transgenic mouse (MR-Tg) under the control of the CamKII alpha promoter, and subjected mice to transient cerebral global ischaemia induced by bilateral common carotid artery occlusion for 20 min. We also separately assessed the effects of MR overexpression on hypothalamic-pituitary-adrenal (HPA) axis activity and cognitive and affective functions in noninjured animals. Our results showed that MR-Tg mice had significantly reduced neuronal death following transient cerebral global ischaemia compared to wild-type littermates. This effect was not associated with alterations in basal or poststress HPA axis function or in arterial blood pressure. MR-Tg mice also demonstrated improved spatial memory retention, reduced anxiety and altered behavioural response to novelty. The induction of neuronal MR appears to offer a protective response which has potential therapeutic implications in cerebral ischaemia and cognitive and affective disorders.

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Nikkomycin Z inhibits chitin synthase in vitro but does not exhibit antifungal activity against many pathogens. Assays of chitin synthase isozymes and growth assays with isozyme mutants were used to demonstrate that nikkomycin Z is a selective inhibitor of chitin synthase 3. (20,25).In vitro effects of nikkomycin Z. The availability of mutant strains that express or overexpress single chitin synthase activities makes it possible to obtain extracts containing individual chitin synthase enzymes. We prepared digitonin-treated cell extracts from wild-type S288C cells (14) (Chsl is the predominant chitin synthase activity found in extracts of wild-type cells treated with trypsin) and cells that contain high-copy-number CHS2 (SSY563-9B or ECY36-3D [YEp352-CHS2]) (Table 1). For a 250-mg cell pellet (an original culture volume of -100 ml is usually sufficient), 750 ,u1 of 1% digitonin-25 mM MES (morpholineethanesulfonic acid; pH 6.3) was added and the cells were shaken at 30°C for 15 min. They were centrifuged at -12,000 X g for 5 min, and the pellet was washed with 2.7 ml of 25 mM MES, pH 6.3. The pellet was resuspended in a total volume of 750 ,u1 of 25 mM MES, pH 6.3-33% glycerol.Membranes from strain ECY36-3C were prepared for Chs3 assays by a modification of the method of Orlean (20). Cells were washed once in 50 mM Tris-HCl, pH 8.0-5 mM MgCl2, and after membranes were prepared, they were resuspended in the same buffer containing 33% glycerol.Enzyme assays were performed to measure the in vitro sensitivity of the three chitin synthases to nikkomycin Z and/or polyoxin D (both from Calbiochem). The cells were first

Multiferroic materials are of considerable interest due to the intriguing science and application potential. Effects of the Ru dopant on the structural, electrical, domain structure, and ferromagnetic properties of multiferroic BiFeO 3 (BFO) polycrystalline film have been studied. The Ru-doped BFO film (BFRO) possesses a lower electrical conductivity, uniform morphology, larger domain size, and hence fewer domain walls. The BFRO film shows a well-saturated P-E hysteresis loop with an improved remnant polarization close to 99 µC/cm 2 . The saturated magnetizations of the BFO and BFRO film are 8.69 and 16.53 emu/cm 3 , respectively, under a maximum magnetic field of 5000 Oe. The improved ferroelectric, ferromagnetic, and dielectric properties of the BFRO film are ascribed to the reduced concentration of defects and defect dipole complex, valence effect of Ru ions, and a different domain behavior. The enhanced magnetic properties of BFRO arise due to the distorted spin cycloid and canting angle of Fe ions in the Ru-doped BFO film.

Summary The role of imaging in myeloma has gained increasing importance over the past few years. The recently revised definition of myeloma from the International Myeloma Working Group (IMWG) includes cross sectional imaging as a method to define bone disease and also incorporates its use in the disease definition for patients with suspected smouldering myeloma. The National Institute for Health and Care Excellence myeloma guidelines also recommend cross sectional imaging for patients with suspected myeloma. There is also increasing use of imaging in disease assessments and the International Myeloma Working Group has recently incorporated imaging in defining new response categories of minimal residual disease negativity, with or without imaging‐based evidence of disease. Plain X‐rays have previously been the standard imaging modality included in a myeloma work up at presentation but evidence is mounting for use of cross‐sectional modalities such as computed tomography (CT), magnetic resonance imaging (MRI) and 18fluoro‐deoxyglucose (18F‐FDG) positron emission tomography (PET)/CT. Funding and therefore availability of newer imaging techniques remains a barrier. Here, we propose an evidence‐based approach to the use and technical application of the latest imaging modalities at diagnosis and in the follow‐up of patients with myeloma and plasmacytoma.