Gravin orchestrates protein kinase A and 2-adrenergic receptor signaling critical for synaptic plasticity and memory

A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Furthermore, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK in the CA1 region of the hippocampus are attenuated in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, thereby organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage

The geometry of spontaneous spiking in neuronal networks

The mathematical theory of pattern formation in electrically coupled networks of excitable neurons forced by small noise is presented in this work. Using the Freidlin-Wentzell large deviation theory for randomly perturbed dynamical systems and the elements of the algebraic graph theory, we identify and analyze the main regimes in the network dynamics in terms of the key control parameters: excitability, coupling strength, and network topology. The analysis reveals the geometry of spontaneous dynamics in electrically coupled network. Specifically, we show that the location of the minima of a certain continuous function on the surface of the unit n-cube encodes the most likely activity patterns generated by the network. By studying how the minima of this function evolve under the variation of the coupling strength, we describe the principal transformations in the network dynamics. The minimization problem is also used for the quantitative description of the main dynamical regimes and transitions between them. In particular, for the weak and strong coupling regimes, we present asymptotic formulas for the network activity rate as a function of the coupling strength and the degree of the network. The variational analysis is complemented by the stability analysis of the synchronous state in the strong coupling regime. The stability estimates reveal the contribution of the network connectivity and the properties of the cycle subspace associated with the graph of the network to its synchronization properties. This work is motivated by the experimental and modeling studies of the ensemble of neurons in the Locus Coeruleus, a nucleus in the brainstem involved in the regulation of cognitive performance and behavior

Pioneering strategies in the digital world. Insights from the Axel Springer's case

Digital technologies present some distinctive characteristics: they simultaneously enable pervasive connectivity, immediacy of interactions and wide access to data and computing power. Based on a detailed historical analysis of Axel Springer, we suggest that pioneering strategies in new markets created by the diffusion of digital technologies is negatively moderated by the fit between firms’ legacy core capabilities and those required to enter the new market. We then show that pioneering strategies in non-core legacy markets are instrumental in creating the capabilities necessary for the sustainability of first-mover advantages (FMA) in the legacy core markets. Finally, we show the role of managerial cognition as a key individual-level enabler in achieving pioneering advantages

Integrating group Delphi, fuzzy logic and expert systems for marketing strategy development:the hybridisation and its effectiveness

A hybrid approach for integrating group Delphi, fuzzy logic and expert systems for developing marketing strategies is proposed in this paper. Within this approach, the group Delphi method is employed to help groups of managers undertake SWOT analysis. Fuzzy logic is applied to fuzzify the results of SWOT analysis. Expert systems are utilised to formulate marketing strategies based upon the fuzzified strategic inputs. In addition, guidelines are also provided to help users link the hybrid approach with managerial judgement and intuition. The effectiveness of the hybrid approach has been validated with MBA and MA marketing students. It is concluded that the hybrid approach is more effective in terms of decision confidence, group consensus, helping to understand strategic factors, helping strategic thinking, and coupling analysis with judgement, etc

Periodicity Forcing Words

The Dual Post Correspondence Problem asks, for a given word α, if there exists a non-periodic morphism g and an arbitrary morphism h such that g(α) = h(α). Thus α satisfies the Dual PCP if and only if it belongs to a non-trivial equality set. Words which do not satisfy the Dual PCP are called periodicity forcing, and are important to the study of word equations, equality sets and ambiguity of morphisms. In this paper, a 'prime' subset of periodicity forcing words is presented. It is shown that when combined with a particular type of morphism it generates exactly the full set of periodicity forcing words. Furthermore, it is shown that there exist examples of periodicity forcing words which contain any given factor/prefix/suffix. Finally, an alternative class of mechanisms for generating periodicity forcing words is developed, resulting in a class of examples which contrast those known already

Classification of a supersolid: Trial wavefunctions, Symmetry breakings and Excitation spectra

A state of matter is characterized by its symmetry breaking and elementary excitations. A supersolid is a state which breaks both translational symmetry and internal $U(1)$ symmetry. Here, we review some past and recent works in phenomenological Ginsburg-Landau theories, ground state trial wavefunctions and microscopic numerical calculations. We also write down a new effective supersolid Hamiltonian on a lattice. The eigenstates of the Hamiltonian contains both the ground state wavefunction and all the excited states (supersolidon) wavefunctions. We contrast various kinds of supersolids in both continuous systems and on lattices, both condensed matter and cold atom systems. We provide additional new insights in studying their order parameters, symmetry breaking patterns, the excitation spectra and detection methods.Comment: REVTEX4, 19 pages, 3 figure

Conformational fingerprinting with Raman spectroscopy reveals protein structure as a translational biomarker of muscle pathology

Neuromuscular disorders are a group of conditions that can result in weakness of skeletal muscles. Examples include fatal diseases such as amyotrophic lateral sclerosis and conditions associated with high morbidity such as myopathies (muscle diseases). Many of these disorders are known to have abnormal protein folding and protein aggregates. Thus, easy to apply methods for the detection of such changes may prove useful diagnostic biomarkers. Raman spectroscopy has shown early promise in the detection of muscle pathology in neuromuscular disorders and is well suited to characterising the conformational profiles relating to protein secondary structure. In this work, we assess if Raman spectroscopy can detect differences in protein structure in muscle in the setting of neuromuscular disease. We utilise in vivo Raman spectroscopy measurements from preclinical models of amyotrophic lateral sclerosis and the myopathy Duchenne muscular dystrophy, together with ex vivo measurements of human muscle samples from individuals with and without myopathy. Using quantitative conformation profiling and matrix factorisation we demonstrate that quantitative ‘conformational fingerprinting’ can be used to identify changes in protein folding in muscle. Notably, myopathic conditions in both preclinical models and human samples manifested a significant reduction in α-helix structures, with concomitant increases in β-sheet and, to a lesser extent, nonregular configurations. Spectral patterns derived through non-negative matrix factorisation were able to identify myopathy with a high accuracy (79% in mouse, 78% in human tissue). This work demonstrates the potential of conformational fingerprinting as an interpretable biomarker for neuromuscular disorders

Non‐negative matrix factorisation of Raman spectra finds common patterns relating to neuromuscular disease across differing equipment configurations, preclinical models and human tissue

Raman spectroscopy shows promise as a biomarker for complex nerve and muscle (neuromuscular) diseases. To maximise its potential, several challenges remain. These include the sensitivity to different instrument configurations, translation across preclinical/human tissues and the development of multivariate analytics that can derive interpretable spectral outputs for disease identification. Nonnegative matrix factorisation (NMF) can extract features from high-dimensional data sets and the nonnegative constraint results in physically realistic outputs. In this study, we have undertaken NMF on Raman spectra of muscle obtained from different clinical and preclinical settings. First, we obtained and combined Raman spectra from human patients with mitochondrial disease and healthy volunteers, using both a commercial microscope and in-house fibre optic probe. NMF was applied across all data, and spectral patterns common to both equipment configurations were identified. Linear discriminant models utilising these patterns were able to accurately classify disease states (accuracy 70.2–84.5%). Next, we applied NMF to spectra obtained from the mdx mouse model of a Duchenne muscular dystrophy and patients with dystrophic muscle conditions. Spectral fingerprints common to mouse/human were obtained and able to accurately identify disease (accuracy 79.5–98.8%). We conclude that NMF can be used to analyse Raman data across different equipment configurations and the preclinical/clinical divide. Thus, the application of NMF decomposition methods could enhance the potential of Raman spectroscopy for the study of fatal neuromuscular diseases

Precision Measurement of the Proton and Deuteron Spin Structure Functions g2 and Asymmetries A2

We have measured the spin structure functions g2p and g2d and the virtual photon asymmetries A2p and A2d over the kinematic range 0.02 < x < 0.8 and 0.7 < Q^2 < 20 GeV^2 by scattering 29.1 and 32.3 GeV longitudinally polarized electrons from transversely polarized NH3 and 6LiD targets. Our measured g2 approximately follows the twist-2 Wandzura-Wilczek calculation. The twist-3 reduced matrix elements d2p and d2n are less than two standard deviations from zero. The data are inconsistent with the Burkhardt-Cottingham sum rule if there is no pathological behavior as x->0. The Efremov-Leader-Teryaev integral is consistent with zero within our measured kinematic range. The absolute value of A2 is significantly smaller than the sqrt[R(1+A1)/2] limit.Comment: 12 pages, 4 figures, 2 table

Absorptive capacity and market orientation in public service provision

This is an Accepted Manuscript of an article published by Taylor & Francis Group in Journal of Strategic Marketing on 05.04.2012, available online at: http://www.tandfonline.com/10.1080/0965254X.2011.643915The application of market orientation to public organisations does not adequately account for the unique features of this context. Drawing on absorptive capacity literature, this is the first study to examine the role of the organisation's learning environment on the market orientation-performance interface for two opposing public management contexts. The research involved a national survey questionnaire to 1060 internal and external public leisure service providers in England. Empirical testing through structural equation modelling revealed that not all dimensions of market orientation are universally positive and marketing scholars should seek to examine and understand market orientation in the context of the organisation and its learning mechanisms, as absorptive capacity has clear and different moderation effects under different management contexts. © 2012 Copyright Taylor and Francis Group, LLC