Rates and Equilibria for a Photoisomerizable Antagonist at the Acetylcholine Receptor of Electrophorus Electroplaques

Voltage-jump and light-flash experiments have been performed on isolated Electrophorus electroplaques exposed simultaneously to nicotinic agonists and to the photoisomerizable compound 2,2'-bis-[α-(trimethylammonium)methyl]-azobenzene (2BQ). Dose-response curves are shifted to the right in a nearly parallel fashion by 2BQ, which suggests competitive antagonism; dose-ratio analyses show apparent dissociation constants of 0.3 and 1 µM for the cis and trans isomers, respectively. Flash-induced trans → cis concentration jumps produce the expected decrease in agonist-induced conductance; the time constant is several tens of milliseconds. From the concentration dependence of these rates, we conclude that the association and dissociation rate constants for the cis-2BQ-receptor binding are approximately ~ 10^8 M^(-1) s^(-1) and 60 s^(-1) at 20ºC; the Q_(10) is 3. Flash-induced cis → trans photoisomerizations produce molecular rearrangements of the ligand-receptor complex, but the resulting relaxations probably reflect the kinetics of buffered diffusion rather than of the interaction between trans-2BQ and the receptor. Antagonists seem to bind about an order of magnitude more slowly than agonists at nicotinic receptors

A covalently bound photoisomerizable agonist. Comparison with reversibly bound agonists at electrophorus electroplaques

After disulphide bonds are reduced with dithiothreitol, trans-3-(alpha-bromomethyl)-3’-[alpha-(trimethylammonium)methyl]azobenzene (trans-QBr) alkylates a sulfhydryl group on receptors. The membrane conductance induced by this “tethered agonist” shares many properties with that induced by reversible agonists. Equilibrium conductance increases as the membrane potential is made more negative; the voltage sensitivity resembles that seen with 50 [mu]M carbachol. Voltage- jump relaxations follow an exponential time-course; the rate constants are about twice as large as those seen with 50 mu M carbachol and have the same voltage and temperature sensitivity. With reversible agonists, the rate of channel opening increases with the frequency of agonist-receptor collisions: with tethered trans-Qbr, this rate depends only on intramolecular events. In comparison to the conductance induced by reversible agonists, the QBr-induced conductance is at least 10-fold less sensitive to competitive blockade by tubocurarine and roughly as sensitive to “open-channel blockade” bu QX-222. Light-flash experiments with tethered QBr resemble those with the reversible photoisomerizable agonist, 3,3’,bis-[alpha-(trimethylammonium)methyl]azobenzene (Bis-Q): the conductance is increased by cis {arrow} trans photoisomerizations and decreased by trans {arrow} cis photoisomerizations. As with Bis-Q, ligh-flash relaxations have the same rate constant as voltage-jump relaxations. Receptors with tethered trans isomer. By comparing the agonist-induced conductance with the cis/tans ratio, we conclude that each channel’s activation is determined by the configuration of a single tethered QBr molecule. The QBr-induced conductance shows slow decreases (time constant, several hundred milliseconds), which can be partially reversed by flashes. The similarities suggest that the same rate-limiting step governs the opening and closing of channels for both reversible and tethered agonists. Therefore, this step is probably not the initial encounter between agonist and receptor molecules

Lattice dynamics and structural stability of ordered Fe3Ni, Fe3Pd and Fe3Pt alloys

We investigate the binding surface along the Bain path and phonon dispersion relations for the cubic phase of the ferromagnetic binary alloys Fe3X (X = Ni, Pd, Pt) for L12 and DO22 ordered phases from first principles by means of density functional theory. The phonon dispersion relations exhibit a softening of the transverse acoustic mode at the M-point in the L12-phase in accordance with experiments for ordered Fe3Pt. This instability can be associated with a rotational movement of the Fe-atoms around the Ni-group element in the neighboring layers and is accompanied by an extensive reconstruction of the Fermi surface. In addition, we find an incomplete softening in [111] direction which is strongest for Fe3 Ni. We conclude that besides the valence electron density also the specific Fe-content and the masses of the alloying partners should be considered as parameters for the design of Fe-based functional magnetic materials.Comment: Revised version, accepted for publication in Physical Review

Structural motifs of pre-nucleation clusters

Structural motifs of pre-nucleation clusters prepared in single, optically levitated supersaturated aqueous aerosol microparticles containing CaBr2 as a model system are reported. Cluster formation is identified by means of X-ray absorption in the Br K-edge regime. The salt concentration beyond the saturation point is varied by controlling the humidity in the ambient atmosphere surrounding the 15–30 μm microdroplets. This leads to the formation of metastable supersaturated liquid particles. Distinct spectral shifts in near-edge spectra as a function of salt concentration are observed, in which the energy position of the Br K-edge is red-shifted by up to 7.1 ± 0.4 eV if the dilute solution is compared to the solid. The K-edge positions of supersaturated solutions are found between these limits. The changes in electronic structure are rationalized in terms of the formation of pre- nucleation clusters. This assumption is verified by spectral simulations using first-principle density functional theory and molecular dynamics calculations, in which structural motifs are considered, explaining the experimental results. These consist of solvated CaBr2 moieties, rather than building blocks forming calcium bromide hexahydrates, the crystal system that is formed by drying aqueous CaBr2 solutions

An Obstruction to Quantization of the Sphere

In the standard example of strict deformation quantization of the symplectic sphere $S^2$, the set of allowed values of the quantization parameter $\hbar$ is not connected; indeed, it is almost discrete. Li recently constructed a class of examples (including $S^2$) in which $\hbar$ can take any value in an interval, but these examples are badly behaved. Here, I identify a natural additional axiom for strict deformation quantization and prove that it implies that the parameter set for quantizing $S^2$ is never connected.Comment: 23 page. v2: changed sign conventio

On the Structure of the Fusion Ideal

We prove that there is a finite level-independent bound on the number of relations defining the fusion ring of positive energy representations of the loop group of a simple, simply connected Lie group. As an illustration, we compute the fusion ring of $G_2$ at all levels

Association Between Long-Term Cognitive Decline in Vietnam Veterans With TBI and Caregiver Attachment Style.

OBJECTIVE: To examine whether a caregiver's attachment style is associated with patient cognitive trajectory after traumatic brain injury (TBI). SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: Forty Vietnam War veterans with TBI and their caregivers. MAIN OUTCOME MEASURE: Cognitive performance, measured by the Armed Forces Qualification Test percentile score, completed at 2 time points: preinjury and 40 years postinjury. DESIGN: On the basis of caregivers' attachment style (secure, fearful, preoccupied, dismissing), participants with TBI were grouped into a high or low group. To examine the association between cognitive trajectory of participants with TBI and caregivers' attachment style, we ran four 2 × 2 analysis of covariance on cognitive performances. RESULTS: After controlling for other factors, cognitive decline was more pronounced in participants with TBI with a high fearful caregiver than among those with a low fearful caregiver. Other attachment styles were not associated with decline. CONCLUSION AND IMPLICATION: Caregiver fearful attachment style is associated with a significant decline in cognitive status after TBI. We interpret this result in the context of the neural plasticity and cognitive reserve literatures. Finally, we discuss its impact on patient demand for healthcare services and potential interventions