Probing Hydrogen Bonding to Bound Dioxygen in Synthetic Models for Heme Proteins: The Importance of Precise Geometry

Distal hydrogen bonding in natural dioxygen binding proteins is crucial for the discrimination between different potential ligands such as O₂ or CO. In the present study, we probe the chemical requirements for proper distal hydrogen bonding in a series of synthetic model compounds for dioxygen‐binding heme proteins. The model compounds 1‐Co to 7‐Co bear different distal residues. The hydrogen bonding in their corresponding dioxygen adducts is directly measured by pulse EPR spectroscopy. The geometrical requirements for this interaction to take place were found to be narrow and very specific. Only two model complexes, 1‐Co and 7‐Co , form a hydrogen bond to bound dioxygen, which was characterized in terms of geometry and nature of the bond. The geometry and dipolar nature of this interaction in 1‐Co ‐O₂ is more similar to the one in natural cobalt myoglobin (Co‐Mb), making 1‐Co the best model compound in the entire series.     

Remote points and the like in pointfree topology

A point p of β, where X is a Tychonoff space, is called a remote point if for any nowhere dense D ⊆, X, p ∉ cl_βx D. A subset S of X is called round if whenever the closure in βX of a zero-set of X contains S, then it is a neighborhood of S. The purpose of this paper is to study these notions in the pointfree context. In the process, we introduce N-homomorphisms and show how the Stone extension of an N-homomorphism transfers remote points back and forth.      

Enhancement of radiosensitivity of oral carcinoma cells by iodinated chlorin p6 copper complex in combination with synchrotron X‐ray radiation

The combination of synchrotron X‐ray radiation and metal‐based radiosensitizer is a novel form of photon activation therapy which offers the advantage of treating malignant tumors with greater efficacy and higher precision than conventional radiation therapy. In this study the anticancer cytotoxic efficacy of a new chlorophyll derivative, iodinated chlorin p₆ copper complex (ICp₆‐Cu), combined with synchrotron X‐ray radiation (8–10 keV) in two human oral cancer cell lines is explored. Pre‐treatment of cells with 20 µM and 30 µM ICp₆‐Cu for 3 h was found to enhance the X‐ray‐induced cytotoxicity with sensitization enhancement ratios of 1.8 and 2.8, respectively. ICp₆‐Cu localized in cytoplasm, mainly in lysosomes and endoplasmic reticulum, and did not cause any cytotoxicity alone. The radiosensitization effect of ICp₆‐Cu accompanied a significant increase in the level of reactive oxygen species, damage to lysosomes, inhibition of repair of radiation‐induced DNA double‐strand breaks, increase in cell death and no significant effect on cell cycle progression. These results demonstrate that ICp₆‐Cu is a potential agent for synchrotron photon activation therapy of cancer.     

The effect of pH and surfactant on the aggregation behavior of chlorin p6: a fluorescence spectroscopic study

Steady state and time-resolved fluorescence properties of chlorin P6, a potential drug for photodynamic therapy, have been investigated as functions of pH. A decrease in pH of the medium has been shown to cause protonation of the ionizable carboxylic acid side chain, leading to an increase in hydrophobicity and consequent aggregation. The aggregates dissociate on further protonation. The dissociation is explained in terms of formation of cations and their mutual repulsion. A synchronous fluorescence spectroscopic study revealed the presence of two anionic forms in equilibrium at physiological pH, with a shift in the equilibrium on slight decrease in the pH. The anionic nature of chlorin P6 in aqueous solutions at physiological pH has been confirmed by complexation with surfactants. The nature of the charge on the headgroups of the surfactants has been found to govern the formation of chlorin-surfactant complexes.     

Exact piezothermoelastic solution of simply-supported orthotropic circular cylindrical panel in cylindrical bending

Summary This work presents an exact piezothermoelastic solution of infinitely long, simply supported, cylindrically orthotropic, piezoelectric, radially polarised, circular cylindrical shell panel in cylindrical bending under thermal and electrostatic excitation. The general solution of the governing differential equations is obtained by separation of variables. The displacements, electric potential and temperature are expanded in appropriate Fourier series in the circumferential coordinate to satisfy the boundary conditions at the simply-supported longitudinal edges. The governing equations reduce to Euler-Cauchy type of ordinary differential equations. Their general solution involves six constants for each Fourier component. These are solved from the algebraic equations obtained by satisfying the boundary conditions at the lateral surfaces. The solution of the inverse problem of inferring the applied temperature field from the given measured distribution of electrical potential difference between the lateral surfaces of the shell has also been presented. Numerical results are presented for typical thermal and electrostatic loadings for various values of radius to thickness ratio.     

Axisymmetric static and dynamic buckling of laminated thick truncated conical cap

Axisymmetric buckling analysis is presented for moderately thick laminated shallow, truncated conical caps under transverse load. Buckling under uniformly distributed loads and ring loads applied statically or as step function loads is considered. Marguerre-type, first-order shear deformation shallow shell theory is formulated in terms of transverse deflection w, the rotation ψ of the normal to the mid-surface and the stress function Φ. The governing equations are solved by the orthogonal point collocation method. Truncated conical caps with a circular opening, which is either free or plugged by a rigid central mass, have been analysed for clamped and simple supports with movable and immovable edge conditions. Typical numerical results are presented illustrating the effect of various parameters.     

Fragment‐Based Discovery of a Dual pan‐RET/VEGFR2 Kinase Inhibitor Optimized for Single‐Agent Polypharmacology

Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment‐based chemical screen led to the identification of a novel RET inhibitor, Pz‐1. Modeling and kinetic analysis identified Pz‐1 as a type II tyrosine kinase inhibitor that is able to bind the “DFG‐out” conformation of the kinase. Importantly, from a single‐agent polypharmacology standpoint, Pz‐1 was shown to be active on VEGFR2, which can block the blood supply required for RET‐stimulated growth. In cell‐based assays, 1.0 nM of Pz‐1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg^?1 day^?1 per os, Pz‐1 abrogated the formation of tumors induced by RET‐mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz‐1 featured no detectable toxicity at concentrations of up to 100.0 mg kg^?1, which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways.     

A multi‐level adaptation model of circulation for the western Indian Ocean

A three‐dimensional, fully non‐linear semi‐diagnostic (adaptation) model is described. This model is used to compute the climatological mean circulation and to understand the role of local, steady forcing of the wind and thermohaline forcing on the observed circulation in the western tropical Indian Ocean. The model consists of equations of motion and continuity, sea surface topography, equations of state and temperature, and salinity diffusion equations. While the sea surface topography equation is solved by a successive overrelaxation technique, the other model equations are solved by a leap‐frog numerical scheme. Two versions of the model, having 18 and 33 levels in the vertical direction, were prepared to study climatological mean circulation in the western tropical Indian Ocean. The first numerical experiment is carried out with the 18‐level adaptation model to study the sensitivity of the solution to different values of eddy coefficients. The main scientific rationale behind these numerical experiments was to obtain the most appropriate values of the eddy coefficients for the realistic computation of climatological circulation in the western tropical Indian Ocean. Three numerical experiments were conducted for the month of February to understand the sensitivity of the model solution to different eddy coefficients. The model reproduced the circulation features during February, even with low values of horizontal and vertical eddy coefficients. In the second experiment, the adaptation model, with 33 levels in the vertical direction, is applied to study the seasonal mean climatological circulation at selected depths during Spring in the western tropical Indian Ocean. Adapted (steady state) results of currents, sea surface topography, temperature and salinity anomaly fields are presented. Reasonable agreement is obtained between the model results on currents and the observational data. The computed anomaly fields for temperature and salinity at selected depths during Spring show that the observed temperature and salinity data were adapted with surface wind, flow field and bottom relief of the ocean and that the observed data were found to be fully smoothed during the adaptation stage. Copyright © 1999 John Wiley & Sons, Ltd.