Pharmacology of Cell Adhesion Molecules of the Nervous System

Cell adhesion molecules (CAMs) play a pivotal role in the development and maintenance of the nervous system under normal conditions. They also are involved in numerous pathological processes such as inflammation, degenerative disorders, and cancer, making them attractive targets for drug development. The majority of CAMs are signal transducing receptors. CAM-induced intracellular signalling is triggered via homophilic (CAM-CAM) and heterophilic (CAM - other counter-receptors) interactions, which both can be targeted pharmacologically. We here describe the progress in the CAM pharmacology focusing on cadherins and CAMs of the immunoglobulin (Ig) superfamily, such as NCAM and L1. Structural basis of CAM-mediated cell adhesion and CAM-induced signalling are outlined. Different pharmacological approaches to study functions of CAMs are presented including the use of specific antibodies, recombinant proteins, and synthetic peptides. We also discuss how unravelling of the 3D structure of CAMs provides novel pharmacological tools for dissection of CAM-induced signalling pathways and offers therapeutic opportunities for a range of neurological disorders

Study of the interaction of the Ig2 module of the fibroblast growth factor receptor, FGFR Ig2, with the fibroblast growth factor 1, FGF1, by means of NMR spectroscopy

AbstractFibroblast growth factor (FGF) receptor (FGFR) consists extracellularly of three immunoglobulin (Ig) modules (Ig1–3). Currently, there are two competing models (symmetric and asymmetric) of the FGF–FGFR–heparin complex based on crystal structures. Indirect evidence exists in support of both models. However, it is not clear which model is physiologically relevant. Our aim was to obtain direct, non-crystallographic evidence in support of them. We found by nuclear magnetic resonance that Ig2 could bind to FGF1 not only via the primary site (present in both models), but also via the secondary site (present only in the symmetric model). Thus, our data support the symmetric model

The neural cell adhesion molecule binds to fibroblast growth factor receptor 2

AbstractThe neural cell adhesion molecule (NCAM) can bind to and activate fibroblast growth factor receptor 1 (FGFR1). However, there are four major FGFR isoforms (FGFR1–FGFR4), and it is not known whether NCAM also interacts directly with the other three FGFR isoforms. In this study, we show by surface plasmon resonance analysis that NCAM can bind to FGFR2 with an affinity similar to that for the NCAM–FGFR1 interaction. However, the kinetic parameters for the NCAM–FGFR2 binding are different from those of the NCAM–FGFR1 binding. Both receptors were shown to cycle relatively fast between the NCAM bound and unbound states, although FGFR2 cycling was clearly faster (13 times) than the FGFR1 cycling. Moreover, ATP was more effective in inhibiting the binding of NCAM to FGFR1 than to FGFR2, indicating that the binding sites in NCAM for the two receptors are similar, but not identical

New functionally-enhanced soy proteins as food ingredients with anti-viral activity

Respiratory viruses are a major public health problem because of their prevalence and high morbidity rate leading to considerable social and economic implications. Cranberry has therapeutic potential attributed to a comprehensive list of phytochemicals including anthocyanins, flavonols, and unique A-type proanthocyanidins. Soy flavonoids, including isoflavones, have demonstrated anti-viral effects in vitro and in vivo. Recently, it was demonstrated that edible proteins can efficiently sorb and concentrate cranberry polyphenols, including anthocyanins and proanthocyanins, providing greatly stabilized matrices suitable for food products. The combination of cranberry and soy phytoactives may be an effective dietary anti-viral resource. Anti-viral properties of both cranberry juice-enriched and cranberry pomace polyphenol-enriched soy protein isolate (CB-SPI and CBP-SPI) were tested against influenza viruses (H7N1, H5N3, H3N2), Newcastle disease virus and Sendai virus in vitro and in ovo. In our experiments, preincubation with CB-SPI or CBP-SPI resulted in inhibition of virus adsorption to chicken red blood cells and reduction in virus nucleic acid content up to 16-fold, however, CB-SPI and CBP-SPI did not affect hemagglutination. Additionally, CB-SPI and CBP-SPI inhibited viral replication and infectivity more effectively than the commercially available anti-viral drug Amizon. Results suggest CB-SPI and CBP-SPI may have preventative and therapeutic potential against viral infections that cause diseases of the respiratory and gastro-intestinal tract

Fermions and Loops on Graphs. II. Monomer-Dimer Model as Series of Determinants

We continue the discussion of the fermion models on graphs that started in the first paper of the series. Here we introduce a Graphical Gauge Model (GGM) and show that : (a) it can be stated as an average/sum of a determinant defined on the graph over $\mathbb{Z}_{2}$ (binary) gauge field; (b) it is equivalent to the Monomer-Dimer (MD) model on the graph; (c) the partition function of the model allows an explicit expression in terms of a series over disjoint directed cycles, where each term is a product of local contributions along the cycle and the determinant of a matrix defined on the remainder of the graph (excluding the cycle). We also establish a relation between the MD model on the graph and the determinant series, discussed in the first paper, however, considered using simple non-Belief-Propagation choice of the gauge. We conclude with a discussion of possible analytic and algorithmic consequences of these results, as well as related questions and challenges.Comment: 11 pages, 2 figures; misprints correcte

On representation of the t-J model via spin-charge variables

We show that the t-J Hamiltonian is not in general reduced to H(S,f), where S and f stand for independent ([S,f]=0) SU(2) (spin) generators and spinless fermionic (hole) field, respectively. The proof is based upon an identification of the Hubbard operators with the generators of the su(2|1) superalgebra in the degenerate fundamental representation and ensuing SU(2|1) path integral representation of the partition function.Comment: 15 pages, latex, no figure

Star products, duality and double Lie algebras

Quantization of classical systems using the star-product of symbols of observables is discussed. In the star-product scheme an analysis of dual structures is performed and a physical interpretation is proposed. At the Lie algebra level duality is shown to be connected to double Lie algebras. The analysis is specified to quantum tomography. The classical tomographic Poisson bracket is found.Comment: 22 pages, no figure

Soluble ectodomain of neuroligin 1 decreases synaptic activity by activating metabotropic glutamate receptor 2

Synaptic cell adhesion molecules represent important targets for neuronal activity-dependent proteolysis. Postsynaptic neuroligins (NLs) form trans-synaptic complexes with presynaptic neurexins (NXs). Both NXs and NLs are cleaved from the cell surface by metalloproteases in an activity-dependent manner, releasing a soluble extracellular fragment and membrane-tethered C-terminal fragment. The cleavage of NL1 depresses synaptic transmission, but the mechanism by which this occurs is unknown. Metabotropic glutamate receptor 2 (mGluR2) are located primarily at the periphery of presynaptic terminals, where they inhibit the formation of cyclic adenosine monophosphate (cAMP) and consequently suppress the release of glutamate and decrease synaptic transmission. In the present study, we found that the soluble ectodomain of NL1 binds to and activates mGluR2 in both neurons and heterologous cells, resulting in a decrease in cAMP formation. In a slice preparation from the hippocampus of mice, NL1 inhibited the release of glutamate from mossy fibers that project to CA3 pyramidal neurons. The presynaptic effect of NL1 was abolished in the presence of a selective antagonist for mGluR2. Thus, our data suggest that the soluble extracellular domain of NL1 functionally interacts with mGluR2 and thereby decreases synaptic strength

NGC 5548 in a Low-Luminosity State: Implications for the Broad-Line Region

We describe results from a new ground-based monitoring campaign on NGC 5548, the best studied reverberation-mapped AGN. We find that it was in the lowest luminosity state yet recorded during a monitoring program, namely L(5100) = 4.7 x 10^42 ergs s^-1. We determine a rest-frame time lag between flux variations in the continuum and the Hbeta line of 6.3 (+2.6/-2.3) days. Combining our measurements with those of previous campaigns, we determine a weighted black hole mass of M_BH = 6.54 (+0.26/-0.25) x 10^7 M_sun based on all broad emission lines with suitable variability data. We confirm the previously-discovered virial relationship between the time lag of emission lines relative to the continuum and the width of the emission lines in NGC 5548, which is the expected signature of a gravity-dominated broad-line region. Using this lowest luminosity state, we extend the range of the relationship between the luminosity and the time lag in NGC 5548 and measure a slope that is consistent with alpha = 0.5, the naive expectation for the broad line region for an assumed form of r ~ L^alpha. This value is also consistent with the slope recently determined by Bentz et al. for the population of reverberation-mapped AGNs as a whole.Comment: 24 pages, 3 tables, 7 figures, accepted for publication in Ap

Fermions and Loops on Graphs. I. Loop Calculus for Determinant

This paper is the first in the series devoted to evaluation of the partition function in statistical models on graphs with loops in terms of the Berezin/fermion integrals. The paper focuses on a representation of the determinant of a square matrix in terms of a finite series, where each term corresponds to a loop on the graph. The representation is based on a fermion version of the Loop Calculus, previously introduced by the authors for graphical models with finite alphabets. Our construction contains two levels. First, we represent the determinant in terms of an integral over anti-commuting Grassman variables, with some reparametrization/gauge freedom hidden in the formulation. Second, we show that a special choice of the gauge, called BP (Bethe-Peierls or Belief Propagation) gauge, yields the desired loop representation. The set of gauge-fixing BP conditions is equivalent to the Gaussian BP equations, discussed in the past as efficient (linear scaling) heuristics for estimating the covariance of a sparse positive matrix.Comment: 11 pages, 1 figure; misprints correcte