Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design,Synthesis, X-ray Structure and Therapeutic Potential

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(−)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2′,6′-dimethoxy-4′-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (K_i = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [³⁵S]GTPγS binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC₅₀ = 2.59 nM, E_(max) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.     

Separate Quantification of Doubly and SinglyC-Labeled Metabolites by HSQC-FilteredJSpectroscopy

NMR detection of multiply labeled compounds in biological samples is often used to follow metabolic pathways. Detection of protons bound to¹³C atoms offers a more sensitive approach than direct¹³C detection, but generally results in the loss of carbon–carbon coupling information. We have modified an HSQC sequence to refocus the carbon chemical shifts in order to obtain a proton-correlated¹³C homonuclearJspectrum, which allows us to measure singly and doubly labeled compounds in the same spectrum.     

Conductivity studies on PEO:NaClO3 electrolyte system with different plasticizers

A new ion conducting solid polymer electrolyte thin film based on Polyethylene oxide (PEO) with NaClO₃ salt is prepared by solution-casting method. The solvation of salt with PEO has been confirmed by X-ray diffraction and IR spectral studies. Plasticizer effects were studied in PEO:NaClO₃ system by using low molecular weight polyethylene glycol (PEG), dimethyl formamide (DMF) and propylene carbonate(PC). AC conductivity in the temperature range (308–378 K) was measured to evaluate the conductivity of the polymer electrolytes. From the conductivity data, it was found that the conductivity value of pure PEO increases 10²–10⁴ order of magnitude with the addition of salts as well as plasticizers. From the transference number experiments, it was confirmed that the charge transport in these electrolyte is mainly due to the ions (t_ion≈0.94). Finally, the conductivity value of all PEO: NaClO₃ systems were compared.     

Expanding Students' Conceptions of the Arithmetic Mean

The arithmetic mean is the most commonly used measure of central tendancy; nevertheless, many students who can add all the elements of a data set and then divide that sum by the number of elements do not truly understand the concept of mean. This article presents four activities designed to help elementary and middle school students develop a concept of mean. To bring about a desirable level of understanding, all computational formulae and algorithms in mathematics should be preceded by experience emphasizing conceptual understanding. Since that is not the normal instructional sequence for the arithmetic mean, the activities presented in the article assume previous exposure to the computational algorithm for the arithmetic mean.     

Relative hyperbolicity and Artin groups

This paper considers the question of relative hyperbolicity of an Artin group with regard to the geometry of its associated Deligne complex. We prove that an Artin group is weakly hyperbolic relative to its finite (or spherical) type parabolic subgroups if and only if its Deligne complex is a Gromov hyperbolic space. For a two-dimensional Artin group the Deligne complex is Gromov hyperbolic precisely when the corresponding Davis complex is Gromov hyperbolic, that is, precisely when the underlying Coxeter group is a hyperbolic group. For Artin groups of FC type we give a sufficient condition for hyperbolicity of the Deligne complex which applies to a large class of these groups for which the underlying Coxeter group is hyperbolic. The key tool in the proof is an extension of the Milnor-Svarc Lemma which states that if a group G admits a discontinuous, co-compact action by isometries on a Gromov hyperbolic metric space, then G is weakly hyperbolic relative to the isotropy subgroups of the action.      

A theory of order-disorder transition during crystallization of binary systems2

A theory is presented describing the order-disorder transition in binary crystals growing on the condition of supersaturation from nonsolid phases. The theory applies to systems that crystallize with an almost perfectly ordered structure if exposed to conditions close to thermodynamic equilibrium. Based on a model that assumes incorporation and detachment of single atoms to occur at the kink sites of mono-atomic steps existing at an otherwise smooth crystal surface a kinetic master equation for the time dependence of configuration probabilities has been formulated. Several simplifying assumptions have been employed. Any solution for the steady-state conditions depends on a roughness parameter λ, the far-order parameter η, the incorporation frequency ω₊ and a parameter q, related to the atomic interaction energies. The solutions are discussed for conditions prevailing near equilibrium with η 1 and within the range of order-disorder transition with η 0. The analysis reveals that for different incorporation frequencies different critical values of the parameter q exist for which a transition from an ordered to a disordered phase is predicted to occur. Each of these critical values of q corresponds to a critical transition temperature T_t.     

Dualities and the phase diagram of the p-clock model

A new “bond-algebraic” approach to duality transformations provides a very powerful technique to analyze elementary excitations in the classical two-dimensional XY and p-clock models. By combining duality and Peierls arguments, we establish the existence of non-Abelian symmetries, the phase structure, and transitions of these models, unveil the nature of their topological excitations, and explicitly show that a continuous U(1) symmetry emerges when p?5. This latter symmetry is associated with the appearance of discrete vortices and Berezinskii-Kosterlitz-Thouless-type transitions. We derive a correlation inequality to prove that the intermediate phase, appearing for p?5, is critical (massless) with decaying power-law correlations.     

Mach-Zehnder all-fiber interferometer using two in-series fattened fiber gratings

We present an all-fiber Mach-Zehnder interferometer consisting of two consecutive fattened sections of dispersion-shifted fiber that act as in-series long period fiber gratings. The proposed Mach-Zehnder interferometer shows a broad fringe pattern ranging from 1000 to 1500 nm and is stable against changes in temperature and strain. By tapering a section of 5mm in length to 50% diameter between the fattened sections we observe an increased sensitivity to temperature changes. The measured temperature and strain sensitivities were in the range of 9–17 pm/°C and 1.44–2.9 pm/μɛ, respectively.     

Models of collective cell motion for cell populations with different aspect ratio: Diffusion,proliferation and travelling waves

Continuum, partial differential equation models are often used to describe the collective motion of cell populations, with various types of motility represented by the choice of diffusion coefficient, and cell proliferation captured by the source terms. Previously, the choice of diffusion coefficient has been largely arbitrary, with the decision to choose a particular linear or nonlinear form generally based on calibration arguments rather than making any physical connection with the underlying individual-level properties of the cell motility mechanism. In this work we provide a new link between individual-level models, which account for important cell properties such as varying cell shape and volume exclusion, and population-level partial differential equation models. We work in an exclusion process framework, considering aligned, elongated cells that may occupy more than one lattice site, in order to represent populations of agents with different sizes. Three different idealisations of the individual-level mechanism are proposed, and these are connected to three different partial differential equations, each with a different diffusion coefficient; one linear, one nonlinear and degenerate and one nonlinear and nondegenerate. We test the ability of these three models to predict the population-level response of a cell spreading problem for both proliferative and nonproliferative cases. We also explore the potential of our models to predict long time travelling wave invasion rates and extend our results to two-dimensional spreading and invasion. Our results show that each model can accurately predict density data for nonproliferative systems, but that only one does so for proliferative systems. Hence great care must be taken to predict density data with varying cell shape.