mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold theta-burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function. Neuropsychopharmacology (2009) 34, 2057-2071; doi:10.1038/npp.2009.30; published online 18 March 2009

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323: 147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G alpha(15). Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative co-operativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G(i/o)-coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G(i/o) signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.

An anthrax subunit vaccine candidate based on protective regions of Bacillus anthracis protective antigen and lethal factor

Studies have confirmed the key role of Bacillus anthracis protective antigen (PA) in the US and UK human anthrax vaccines. However, given the tripartite nature of the toxin, other components, including lethal factor (LF), are also likely to contribute to protection. We examined the antibody and T cell responses to PA and LF in human volunteers immunized with the UK anthrax vaccine (AVP). Individual LF domains were assessed for immunogenicity in mice when given alone or with PA. Based on the results obtained, a novel fusion protein comprising D1 of LF and the host cell-binding domain of PA (D4) was assessed for protective efficacy. Murine protection studies demonstrated that both full-length LF and D1 of LF conferred complete protection against a lethal intraperitoneal challenge with B. anthracis STI spores. Subsequent studies with the LFD1-PAD4 fusion protein showed a similar level of protection. LF is immunogenic in humans and is likely to contribute to the protection stimulated by AVP. A single vaccine comprising protective regions from LF and PA would simplify production and confer a broader spectrum of protection than that seen with PA alone.

Multipartite optomechanical entanglement from competing nonlinearities

We investigate the nature of the three-mode interaction inside an optomechanically active microtoroid with a sizable ?(2) coefficient. Experimental techniques are quickly advancing to the point where structures with the necessary properties can be made, and we argue that these provide a natural setting in which to observe rich dynamics leading, for instance, to genuine tripartite steady-state entanglement. We also show that this approach lends itself to a full characterization of the three-mode state of the system.

The major facilitator superfamily transporter MdtM contributes to intrinsic resistance of Escherichia coli to quaternary ammonium compounds

OBJECTIVES:
Quaternary ammonium compounds (QACs) are used extensively as biocides and their misuse may be contributing to the development of bacterial resistance. Although the major intrinsic resistance to QACs of Gram-negative bacteria is mediated by the action of tripartite multidrug transporters of the resistance-nodulation-division family, we aimed to test if the promiscuity of the recently characterized major facilitator superfamily multidrug transporter, MdtM, from Escherichia coli enabled it also to function in the efflux of QACs.
METHODS:
The ability of the major facilitator mdtM gene product, when overexpressed from multicopy plasmid, to protect E. coli cells from the toxic effects of a panel of seven QACs was determined using growth inhibition assays in liquid medium. Interaction between QACs and MdtM was studied by a combination of substrate binding assays using purified protein in detergent solution and transport assays using inverted vesicles.
RESULTS:
E. coli cells that overproduced MdtM were less susceptible to the cytotoxic effects of each of the QACs tested compared with cells that did not overproduce the transporter. Purified MdtM bound each QAC with micromolar affinity and the protein utilized the electrochemical proton gradient to transport QACs across the cytoplasmic membrane. Furthermore, the results suggested a functional interaction between MdtM and the tripartite resistance-nodulation-division family AcrAB-TolC efflux system.
CONCLUSIONS:
The results support a hitherto unidentified capacity for a single-component multidrug transporter of the major facilitator superfamily, MdtM, to function in the efflux of a broad range of QACs and thus contribute to the intrinsic resistance of E. coli to these compounds.

Testing genuine multipartite nonlocality in phase spacea

We demonstrate genuine three-mode nonlocality based on phase-space formalism. A Svetlichny-type Bell inequality is formulated in terms of the s-parametrized quasiprobability function. We test such a tool using exemplary forms of three-mode entangled states, identifying the ideal measurement settings required for each state. We thus verify the presence of genuine three-mode nonlocality that cannot be reproduced by local or nonlocal hidden variable models between any two out of three modes. In our results, GHZ- and W-type nonlocality can be fully discriminated. We also study the behavior of genuine tripartite nonlocality under the effects of detection inefficiency and dissipation induced by local thermal environments. Our formalism can be useful to test the sharing of genuine multipartite quantum correlations among the elements of some interesting physical settings, including arrays of trapped ions and intracavity ultracold atoms. DOI: 10.1103/PhysRevA.87.022123

Driven optomechanical systems for mechanical entanglement distribution

We consider the distribution of entanglement from a multimode optical driving source to a network of remote and independent optomechanical systems. By focusing on the tripartite case, we analyse the effects that the features of the optical input states have on the degree and sharing structure of the distributed, fully mechanical, entanglement. This study, which is conducted looking at the mechanical steady state, highlights the structure of the entanglement distributed among the nodes and determines the relative efficiency between bipartite and tripartite entanglement transfer. We discuss a few open points, some of which are directed towards the bypassing of such limitations.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=0.052) and UK bipolar disorder case-control cohorts (P=0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11,707 cases and 10 carriers in 21,204 controls (meta-analysis CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

A single-component multidrug transporter of the major facilitator superfamily is part of a network that protects Escherichia coli from bile salt stress

Resistance to high concentrations of bile salts in the human intestinal tract is vital for the survival of enteric bacteria such as Escherichia coli. Although the tripartite AcrAB-TolC efflux system plays a significant role in this resistance, it is purported that other efflux pumps must also be involved. We provide evidence from a comprehensive suite of experiments performed at two different pH values (7.2 and 6.0) that reflect pH conditions that E. coli may encounter in human gut that MdtM, a single-component multidrug resistance transporter of the major facilitator superfamily, functions in bile salt resistance in E. coli by catalysing secondary active transport of bile salts out of the cell cytoplasm. Furthermore, assays performed on a chromosomal ΔacrB mutant transformed with multicopy plasmid encoding MdtM suggested a functional synergism between the single-component MdtM transporter and the tripartite AcrAB-TolC system that results in a multiplicative effect on resistance. Substrate binding experiments performed on purified MdtM demonstrated that the transporter binds to cholate and deoxycholate with micromolar affinity, and transport assays performed on inverted vesicles confirmed the capacity of MdtM to catalyse electrogenic bile salt/H(+) antiport.

Multimode entanglement and telecloning in a noisy environment

We address the generation, propagation, and application of multipartite continuous variable entanglement in a noisy environment. In particular, we focus our attention on the multimode entangled states achievable by second-order nonlinear crystals-i.e., coherent states of the SU(m,1) group-which provide a generalization of the twin-beam state of a bipartite system. The full inseparability in the ideal case is shown, whereas thresholds for separability are given for the tripartite case in the presence of noise. We find that entanglement of tripartite states is robust against thermal noise, both in the generation process and during propagation. We then consider coherent states of SU(m,1) as a resource for multipartite distribution of quantum information and analyze a specific protocol for telecloning, proving its optimality in the case of symmetric cloning of pure Gaussian states. We show that the proposed protocol also provides the first example of a completely asymmetric 1 -> m telecloning and derive explicitly the optimal relation among the different fidelities of the m clones. The effect of noise in the various stages of the protocol is taken into account, and the fidelities of the clones are analytically obtained as a function of the noise parameters. In turn, this permits the optimization of the telecloning protocol, including its adaptive modifications to the noisy environment. In the optimized scheme the clones' fidelity remains maximal even in the presence of losses (in the absence of thermal noise), for propagation times that diverge as the number of modes increases. In the optimization procedure the prominent role played by the location of the entanglement source is analyzed in details. Our results indicate that, when only losses are present, telecloning is a more effective way to distribute quantum information than direct transmission followed by local cloning.

Quantum and classical properties of the fields generated by two interlinked second-order non-linear interactions

We consider two interlinked non-linear interactions occurring simultaneously in a single chi((2)) crystal. Classical and quantum working regimes are considered and their peculiar properties analysed. In particular, we describe an experiment, realized in the classical regime, that verifies the holographic nature of the process, and predict, for the quantum regime, the generation of a fully inseparable tripartite Gaussian state of light that can be used to support a general 1--> 2 continuous variable telecloning protocol.

Empowering the Shamed Self: Recognition and Critical Social Work

Summary: This article provides a review of the contribution of Axel Honneth’s model of recognition for critical social work. While Honneth’s tripartite conceptualisation of optimal identity-formation is positively appraised, his analysis of the link between misrecognition, the experience of shame and eventual sense of moral outrage, is contested. Drawing on a range of sources, including the sociology of shame, Honneth’s ideas about the emotional antecedents of emancipatory action are revised to guide critical social work with misrecognised service users.

Findings: The intellectual background to Honneth’s recognition model, emanating from leading German philosophers, is described and its application to social work set out. Even so, Honneth’s model is found to be deficient in one primary regard: its assumption about the emotional antecedents to quests for withheld recognition is misapprehended. In particular, the argument in this article is that the ubiquitous emotion of shame, which Honneth argues flows from misrecognition, must be carefully addressed through the medium of relationship, otherwise it might lead to repressed shame and frustrated attempts at social struggle. To this end, a social work process is delineated for dealing with shame, following episodes of misrecognition.

Applications: Honneth’s model of recognition, along with revised ideas about how to recognise and manage shame, is incorporated into a conceptual framework for critical social work practice. With this renewed understanding of the impact of shame, following misrecognition, social workers should be better equipped conceptually to enable service users to take action for empowerment.

Long-range multipartite entanglement close to a first-order quantum phase transition

We provide insight into the quantum correlations structure present in strongly correlated systems beyond the standard framework of bipartite entanglement. To this aim we first exploit rotationally invariant states as a test bed to detect genuine tripartite entanglement beyond the nearest neighbor in spin-1/2 models. Then we construct in a closed analytical form a family of entanglement witnesses which provides a sufficient condition to determine if a state of a many-body system formed by an arbitrary number of spin-1/2 particles possesses genuine tripartite entanglement, independently of the details of the model. We illustrate our method by analyzing in detail the anisotropic XXZ spin chain close to its phase transitions, where we demonstrate the presence of long-range multipartite entanglement near the critical point and the breaking of the symmetries associated with the quantum phase transition.

Dynamics of interacting Dicke model in a coupled-cavity array

We consider the dynamics of an array of mutually interacting cavities, each containing an ensemble of N two-level atoms. By exploring the possibilities offered by ensembles of various dimensions and a range of atom-light and photon-hopping values, we investigate the generation of multisite entanglement, as well as the performance of excitation transfer across the array, resulting from the competition between on-site nonlinearities of the matter-light interaction and intersite photon hopping. In particular, for a three-cavity interacting system it is observed that the initial excitation in the first cavity completely transfers to the ensemble in the third cavity through the hopping of photons between the adjacent cavities. Probabilities of the transfer of excitation of the cavity modes and ensembles exhibit characteristics of fast and slow oscillations governed by coupling and hopping parameters, respectively. In the large-hopping case, by seeding an initial excitation in the cavity at the center of the array, a tripartite W state, as well as a bipartite maximally entangled state, is obtained, depending on the interaction time. Population of the ensemble in a cavity has a positive impact on the rate of excitation transfer between the ensembles and their local cavity modes. In particular, for ensembles of five to seven atoms, tripartite W states can be produced even when the hopping rate is comparable to the cavity-atom coupling rate. A similar behavior of the transfer of excitation is observed for a four-coupled-cavity system with two initial excitations.

Experimental linear-optics simulation of multipartite non-locality in the ground state of a quantum Ising ring

Critical phenomena involve structural changes in the correlations of its constituents. Such changes can be reproduced and characterized in quantum simulators able to tackle medium-to-large-size systems. We demonstrate these concepts by engineering the ground state of a three-spin Ising ring by using a pair of entangled photons. The effect of a simulated magnetic field, leading to a critical modification of the correlations within the ring, is analysed by studying two- and three-spin entanglement. In particular, we connect the violation of a multipartite Bell inequality with the amount of tripartite entanglement in our ring.