Absence of a dose-rate effect in the transformation of C3H 10T1/2 cells by α-particles

The findings of Hill et al. (1984) on the greatly enhanced transformation frequencies at very low dose rates of fission neutrons induced us to perform an analogous study with -particles at comparable dose rates. Transformation frequencies were determined with γ-rays at high dose rate (0·5 Gy/min), and with -particles at high (0·2 Gy/min) and at low dose rates (0·83-2·5 mGy/min) in the C3H 10T1/2 cell system. α-particles were substantially more effective than γ-rays, both for cell inactivation and for neoplastic transformation at high and low dose rates. The relative biological effectiveness (RBE) for cell inactivation and for neoplastic transformation was of similar magnitude, and ranged from about 3 at an -particle dose of 2 Gy to values of the order of 10 at 0·25 Gy. In contrast to the experiments of Hill et al. (1984) with fission neutrons, no increased transformation frequencies were observed when the -particle dose was protracted over several hours

Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor

β-blockers are widely used to improve symptoms and prolong life in heart disease primarily by inhibiting the actions of endogenous catecholamines at the β1-adrenoceptor. There are two common naturally occurring polymorphisms within the human β1-adrenoceptor sequence: Ser or Gly at position 49 in the N-terminus and Gly or Arg at position 389 in the C-terminus and some clinical studies have suggested that expression of certain variants may be associated with disease and affect response to treatment with β-blockers. The β1-adrenoceptor also exists in two agonist conformations - a high affinity catecholamine conformation and a low affinity secondary agonist conformation. Receptor-effector coupling and intracellular signalling from the different conformations may be affected by the polymorphic variants. Here, we examine in detail the molecular pharmacology of the β1-adrenoceptor polymorphic variants with respect to ligand affinity, efficacy, activation of the different agonist conformations and signal transduction and determine whether the polymorphic variants do indeed affect this secondary conformation. Stable cell lines expressing the wildtype and polymorphic variants were constructed and receptor pharmacology examined using whole cell binding and intracellular secondary messenger techniques. There was no difference in affinity for agonists and antagonists at the human wildtype β1-adrenoceptor (Ser49/Gly389) and the polymorphic variants Gly49/Gly389 and Ser49/Arg389. Furthermore, the polymorphic variant receptors both have two active agonist conformations with pharmacological properties similar to the wildtype receptor. Although the polymorphism at position 389 is thought to occur in an intracellular domain important for Gs-coupling, the two agonist conformations of the polymorphic variants stimulate intracellular signalling pathways, including Gs-cAMP intracellular signalling, in a manner very similar to that of the wildtype receptor

Nonlinear Dirac and diffusion equations in 1 + 1 dimensions from stochastic considerations

We generalize the method of obtaining the fundamental linear partial differential equations such as the diffusion and Schrodinger equation, Dirac and telegrapher's equation from a simple stochastic consideration to arrive at certain nonlinear form of these equations. The group classification through one parameter group of transformation for two of these equations is also carried out.Comment: 18 pages, Latex file, some equations corrected and group analysis in one more case adde

The role of aerodynamic forces in a mathematical model for suspension bridges

In a fish-bone model for suspension bridges studied by us in a previous paper we introduce linear aerodynamic forces. We numerically analyze the role of these forces and we theoretically show that they do not influence the onset of torsional oscillations. This suggests a new explanation for the origin of instability in suspension bridges: it is a combined interaction between structural nonlinearity and aerodynamics and it follows a precise pattern. This gives an answer to a long-standing question about the origin of torsional instability in suspension bridges

Kinetics of the reduction of wilt-type and mutant cytochrome c-550 by methylamin dehydrogenase and amicyanin from thiobacillus-versutus

Macromolecular Biochemistr

A multi-model assessment of the impact of sea spray geoengineering on cloud droplet number

Artificially increasing the albedo of marine boundary layer clouds by the mechanical emission of sea spray aerosol has been proposed as a geoengineering technique to slow the warming caused by anthropogenic greenhouse gases. A previous global model study (Korhonen et al., 2010) found that only modest increases (< 20%) and sometimes even decreases in cloud drop number (CDN) concentrations would result from emission scenarios calculated using a windspeed dependent geoengineering flux parameterisation. Here we extend that work to examine the conditions under which decreases in CDN can occur, and use three independent global models to quantify maximum achievable CDN changes. We find that decreases in CDN can occur when at least three of the following conditions are met: the injected particle number is < 100 cm<sup>−3</sup>, the injected diameter is > 250–300 nm, the background aerosol loading is large (≥ 150 cm<sup>−3</sup>) and the in-cloud updraught velocity is low (< 0.2 m s<sup>−1</sup>). With lower background loadings and/or increased updraught velocity, significant increases in CDN can be achieved. None of the global models predict a decrease in CDN as a result of geoengineering, although there is considerable diversity in the calculated efficiency of geoengineering, which arises from the diversity in the simulated marine aerosol distributions. All three models show a small dependence of geoengineering efficiency on the injected particle size and the geometric standard deviation of the injected mode. However, the achievability of significant cloud drop enhancements is strongly dependent on the cloud updraught speed. With an updraught speed of 0.1 m s<sup>−1</sup> a global mean CDN of 375 cm<sup>−3</sup> (previously estimated to cancel the forcing caused by CO<sub>2</sub> doubling) is achievable in only about 50% of grid boxes which have > 50% cloud cover, irrespective of the amount of aerosol injected. But at stronger updraft speeds (0.2 m s<sup>−1</sup>), higher values of CDN are achievable due to the elevated in-cloud supersaturations. Achieving a value of 375 cm<sup>−3</sup> in regions dominated by stratocumulus clouds with relatively weak updrafts cannot be attained regardless of the number of injected particles, thereby limiting the efficacy of sea spray geoengineering

Hill's Equation with Random Forcing Parameters: Determination of Growth Rates through Random Matrices

This paper derives expressions for the growth rates for the random 2 x 2 matrices that result from solutions to the random Hill's equation. The parameters that appear in Hill's equation include the forcing strength and oscillation frequency. The development of the solutions to this periodic differential equation can be described by a discrete map, where the matrix elements are given by the principal solutions for each cycle. Variations in the forcing strength and oscillation frequency lead to matrix elements that vary from cycle to cycle. This paper presents an analysis of the growth rates including cases where all of the cycles are highly unstable, where some cycles are near the stability border, and where the map would be stable in the absence of fluctuations. For all of these regimes, we provide expressions for the growth rates of the matrices that describe the solutions.Comment: 22 pages, 3 figure

Identification of key residues in transmembrane 4 responsible for the secondary, low-affinity conformation of the human 1-adrenoceptor

The β1-adrenoceptor exists in two agonist conformations/states: 1) a high-affinity state where responses to catecholamines and other agonists (e.g., cimaterol) are potently inhibited by β1-adrenoceptor antagonists, and 2) a low-affinity secondary conformation where agonist responses, particularly CGP12177 [(−)-4-(3-tert-butylamino-2-hydroxypropoxy)-benzimidazol-2-one] are relatively resistant to inhibition by β1-adrenoceptor antagonists. Although both states have been demonstrated in many species (including human), the precise nature of the secondary state is unknown and does not occur in the closely related β2-adrenoceptor. Here, using site-directed mutagenesis and functional measurements of production of a cyclic AMP response element upstream of a secreted placental alkaline phosphatase reporter gene and accumulation of 3H-cAMP, we examined the pharmacological consequences of swapping transmembrane (TM) regions of the human β1- and β2-adrenoceptors, followed by single point mutations, to determine the key residues involved in the β1-adrenoceptor secondary conformation. We found that TM4 (particularly amino acids L195 and W199) had a major role in the generation of the secondary β1-adrenoceptor conformation. Thus, unlike at the human β1-wild-type adrenoceptor, at β1-TM4 mutant receptors, cimaterol and CGP12177 responses were both potently inhibited by antagonists. CGP12177 acted as a simple partial agonist with similar KB and EC50 values in the β1-TM4 but not β1-wild-type receptors. Furthermore pindolol switched from a biphasic concentration response at human β1-wild-type adrenoceptors to a monophasic concentration response in the β1-TM4 mutant receptors. Mutation of these amino acids to those found in the β2-adrenoceptor (L195Q and W199Y), or mutation of a single residue (W199D) in the human β1-adrenoceptor thus abolished this secondary conformation and created a β1-adrenoceptor with only one high-affinity agonist conformation