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

Classification of minimal actions of a compact Kac algebra with amenable dual

We show the uniqueness of minimal actions of a compact Kac algebra with amenable dual on the AFD factor of type II$_1$. This particularly implies the uniqueness of minimal actions of a compact group. Our main tools are a Rohlin type theorem, the 2-cohomology vanishing theorem, and the Evans-Kishimoto type intertwining argument.Comment: 68 pages, Introduction rewritten; minor correction

Canalizing Kauffman networks: non-ergodicity and its effect on their critical behavior

Boolean Networks have been used to study numerous phenomena, including gene regulation, neural networks, social interactions, and biological evolution. Here, we propose a general method for determining the critical behavior of Boolean systems built from arbitrary ensembles of Boolean functions. In particular, we solve the critical condition for systems of units operating according to canalizing functions and present strong numerical evidence that our approach correctly predicts the phase transition from order to chaos in such systems.Comment: to be published in PR

A photoisomerizable muscarinic antagonist. Studies of binding and of conductance relaxations in frog heart

These experiments employ the photoisomerizable compound, 3,3'-bis- [alpha-(trimethylammonium)methyl]azobenzene (Bis-Q), to study the response to muscarinic agents in frog myocardium. In homogenates from the heart, trans-Bis-Q blocks the binding of [3H]-N-methylscopolamine to muscarinic receptors. In voltage-clamped atrial trabeculae, trans- Bis-Q blocks the agonist-induced potassium conductance. The equilibrium dose-response curve for carbachol is shifted to the right, suggesting competitive blockade. Both the biochemical and electrophysiological data yield a dissociation constant of 4-5 microM for trans-Bis-Q; the cis configuration is severalfold less potent as a muscarinic blocker. Voltage-clamped preparations were exposed simultaneously to carbachol and Bis-Q and were subjected to appropriately filtered flashes (less than 1 ms duration) from a xenon flashlamp. Trans leads to cis and cis leads to trans photoisomerizations cause small (less than 20%) increases and decreases, respectively, in the agonist-induced current. The relaxation follows an S-shaped time course, including an initial delay or period of zero slope. The entire waveform is described by [1 - exp(-kt)]n. At 23 degrees C, k is approximately 3 s-1 and n is 2. Neither k nor n is affected when: (a) [Bis-Q] is varied between 5 and 100 microM; (b) [carbachol] is varied between 1 and 50 microM; (c) carbachol is replaced by other agonists (muscarine, acetylcholine, or acetyl-beta-methylcholine); or (d) the voltage is varied between the normal resting potential and a depolarization of 80 mV. However, in the range of 13-30 degrees C, k increases with temperature; the Q10 is between 2 and 2.5. In the same range, n does not change significantly. Like other investigators, we conclude that the activation kinetics of the muscarinic K+ conductance are not determined by ligand-receptor binding, but rather by a subsequent sequence of two (or more) steps with a high activation energy

Ferromagnetic Phase Transition in Barabasi-Albert Networks

Ising spins put onto a Barabasi-Albert scale-free network show an effective phase transition from ferromagnetism to paramagnetism upon heating, with an effective critical temperature increasing as the logarithm of the system size. Starting with all spins up and upon equilibration pinning the few most-connected spins down nucleates the phase with most of the spins down.Comment: 8 pages including figure

Editorial

Gemeenskappe se prioriteite in gesondheidsdiensThere are other human retroviruses too - a note on myelopathy associated with HTLV-IIs there a need for surgical oncologists' in South Africa

Understanding student early departure from a Master of Public Health programme in South Africa

Background. Student departure from university without completing a qualification is a major concern in higher education. Higher Education South Africa reported that in undergraduate studies, 35% of students depart after the first year and only 15% of students who enrol complete their degree within the minimum permissible time. At postgraduate level, the departure from Masters programmes in South Africa (SA) ranged from 30% to 67% in 2010. Early departure refers to students who leave an academic programme within the first semester of commencing their studies. At one SA university, there were a total of 109 first-time Master of Public Health (MPH) student registrations in 2013 and 2014. By the end of the first semester in the respective years, a total of 27 students actively deregistered from the programme and 11 students did not sit the first-semester examinations, representing an aggregate 35% rate of early departure. The factors associated with early departure at the University of KwaZulu-Natal are not well understood.Objective. To understand factors associated with early departure in the MPH programme at the University of KwaZulu-Natal.Method. A mixed-methods design was implemented. Students who departed within the first semester of commencing the MPH programme in 2013/2014 were followed up. Data were collected using self-administered questionnaires and in-depth interviews.Results. Failure to balance work and academic obligations with poor time management, stress and academic demands related to the programme, and insufficient academic progress were found to be associated with student early departure from the MPH programme.Conclusion. Student early departure from the MPH programme was influenced by multifaceted factors. Senior students can mentor new students as early as possible in their programme. The orientation block should include development activities such as time management, stress management and effective study skills to assist mature students to cope with the demands of part-time postgraduate studies

Cooling and heating by adiabatic magnetization in the Ni50_{50}Mn34_{34}In16_{16} magnetic shape memory alloy

We report on measurements of the adiabatic temperature change in the inverse magnetocaloric Ni$_{50}$Mn$_{34}$In$_{16}$ alloy. It is shown that this alloy heats up with the application of a magnetic field around the Curie point due to the conventional magnetocaloric effect. In contrast, the inverse magnetocaloric effect associated with the martensitic transition results in the unusual decrease of temperature by adiabatic magnetization. We also provide magnetization and specific heat data which enable to compare the measured temperature changes to the values indirectly computed from thermodynamic relationships. Good agreement is obtained for the conventional effect at the second-order paramagnetic-ferromagnetic phase transition. However, at the first order structural transition the measured values at high fields are lower than the computed ones. Irreversible thermodynamics arguments are given to show that such a discrepancy is due to the irreversibility of the first-order martensitic transition.Comment: 5 pages, 4 figures. Accepted for publication in the Physical Review

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