Omega-conotoxins GVIA, MVIIA and CVID: SAR and clinical potential

Highly selective N-type voltage-gated calcium (Ca-V) channel inhibitors from cone snail venom (the omega-conotoxins) have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Earlier in 2005, Prialt ( Elan) or synthetic omega-conotoxin MVIIA, was the first omega-conotoxin to be approved by Food and Drug Administration for human use. This review compares the action of three omega-conotoxins, GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved N-type therapeutics that are more useful in the treatment of chronic pain.

Anisotropic viscous models of large-deformation Mohr-Coulomb failure

We have developed a way to represent Mohr-Coulomb failure within a mantle-convection fluid dynamics code. We use a viscous model of deformation with an orthotropic viscoplasticity (a different viscosity is used for pure shear to that used for simple shear) to define a prefered plane for slip to occur given the local stress field. The simple-shear viscosity and the deformation can then be iterated to ensure that the yield criterion is always satisfied. We again assume the Boussinesq approximation, neglecting any effect of dilatancy on the stress field. An additional criterion is required to ensure that deformation occurs along the plane aligned with maximum shear strain-rate rather than the perpendicular plane, which is formally equivalent in any symmetric formulation. We also allow for strain-weakening of the material. The material can remember both the accumulated failure history and the direction of failure. We have included this capacity in a Lagrangian-integration-point finite element code and show a number of examples of extension and compression of a crustal block with a Mohr-Coulomb failure criterion. The formulation itself is general and applies to 2- and 3-dimensional problems.

Short peptide alpha helices induced by multiple metal clips

Alpha helices are key structural components of proteins and important recognition motifs in biology. New techniques for stabilizing short peptide helices could be valuable for studying protein folding, modeling proteins, creating artificial proteins, and may aid the design of inhibitors or mimics of protein function. We previously reported* that 5-15 residue peptides, corresponding to the Zn-binding domain of thermolysin, react with [Pd(en)(ONO,),]in DMF-d’ and 90% H,O 10% DzO to form a 22-membered [Pd(en)(H*ELTH*)]2+ macrocycle that is helical in solution and acts as a template in nucleating helicity in both Cand N- terminal directions within the longer sequences in DMF. ~f~~&g7$$& d&qx~m ~. y AC&q& In water, however, there was less a-helicity observed, testifying to #..q,& &$--Lb &l-- &.$;,J~p?:~~q&~+~~ ’ w w the difficulty of fixing intramolecular amide NH...OC H-bonds in 6,“;;” ( k.$ U”C.a , p d$. competition with the H-bond donor solvent water. To expand the utility of [Pd(en)(H*XXXH*)]*+ as a helix- @r4”8 & oJ#:& &G& @-qd ,‘d@-gyp promoting module in solution, we now report the result that Ac- ‘$4: %$yyy + H*ELTH*H*VTDH*-NH,(l), AC-H*ELTH*AVTDYH*ELTH*- NH, (2) and AC-H*AAAH*H*ELTH*H*VTDH*-NH* (3) react with multiple equivalents of [Pd(en)(ONO,),] to produce exclusively 4-6 respectively in both DMF-d7 and water (90% Hz0 10% D,O). Mass spectrometry, 15N- and 2D ‘H- NMR spectroscopy, and CD spectra were used to characterise the structures 4-6, and their three dimensional structures were calculated from NOE restraints using simulated annealing protocols. Results demonstrate (a) selective coordination of metal ions at (i, i+4) histidine positions in water and DMF, (b) incorporation of 2 and 3 a turn-mimicking modules [Pd(en)(HELTH)]2+ in lo-15 residue peptides, and (c) facile conversion of unstructured peptides into 3- and 4- turn helices of macrocycles, with well defined a-helicity throughout and more structure in DMF than in water.

An FDTD model for calculation of gradient-induced eddy currents in MRI system

In most magnetic resonance imaging (MRI) systems, pulsed magnetic gradient fields induce eddy currents in the conducting structures of the superconducting magnet. The eddy currents induced in structures within the cryostat are particularly problematic as they are characterized by long time constants by virtue of the low resistivity of the conductors. This paper presents a three-dimensional (3-D) finite-difference time-domain (FDTD) scheme in cylindrical coordinates for eddy-current calculation in conductors. This model is intended to be part of a complete FDTD model of an MRI system including all RF and low-frequency field generating units and electrical models of the patient. The singularity apparent in the governing equations is removed by using a series expansion method and the conductor-air boundary condition is handled using a variant of the surface impedance concept. The numerical difficulty due to the asymmetry of Maxwell equations for low-frequency eddy-current problems is circumvented by taking advantage of the known penetration behavior of the eddy-current fields. A perfectly matched layer absorbing boundary condition in 3-D cylindrical coordinates is also incorporated. The numerical method has been verified against analytical solutions for simple cases. Finally, the algorithm is illustrated by modeling a pulsed field gradient coil system within an MRI magnet system. The results demonstrate that the proposed FDTD scheme can be used to calculate large-scale eddy-current problems in materials with high conductivity at low frequencies.

Unprecedented photochemical induced cascading rearrangement of the 3-azabicyclo[3.3.1] nonane skeleton

Certain 3-azabicyclo[3.3.1] nonane derivatives undergo unprecedented stereospecific skeletal cleavage when subjected to light affording a novel heterotricyclic skeleton.

Two-dimensional approximation for tide-induced watertable fluctuations in a sloping sandy beach

The prediction of watertable fluctuations in a coastal aquifer is important for coastal management. However, most previous approaches have based on the one-dimensional Boussinesq equation, neglecting variations in the coastline and beach slope. In this paper, a closed-form analytical solution for a two-dimensional unconfined coastal aquifer bounded by a rhythmic coastline is derived. In the new model, the effect of beach slope is also included, a feature that has not been considered in previous two-dimensional approximations. Three small parameters, the shallow water parameter (epsilon), the amplitude parameter (a) and coastline parameter (beta) are used in the perturbation approximation. The numerical results demonstrate the significant influence of both the coastline shape and beach slopes on tide-driven coastal groundwater fluctuations. (c) 2004 Elsevier Ltd. All rights reserved.

Erratum: Two-Dimensional Failure Modeling with Minimal Repair which appeared in this journal of April 2004, Volume 51:3 on pages 345–362

In this Erratum, we point out the reason for an error in the derivation of a result in our earlier paper, “Two-Dimensional Failure Modeling with Minimal Repair” [1], which appeared in the April 2004 issue of this journal, 51:3, on pages 345–362, and give the correct derivation.