The French Revolution : a comparison of the attitudes of Edmund Burke and Thomas Paine

By 1789, when the French people were just becoming absorbed in revolutionary activity, both the United States and Britain already enjoyed relatively stable political systems which asserted fundamental rights of each individual and established a protection of these rights against moral and political infringement. To insure the perpetuation of these \u27inalienable\u27 rights, revolutionary Americans fought violently to break the oppressive bonds of a tyrannical monarch. The English, in 1688, more conservatively chose to build upon their existing modes of government. Because the French Revolution sought to abolish many principles on which the British government rested, it would seem logical for Edmund Burke to oppose the overthrow of the French Bourbon monarchy. The French quest for a more democratic rule would also justify Thomas Paine\u27s support of the revolution against the corrupt and crumbling monarchy of Louis XVI. However, while each of these men did hold these respective positions, Burke\u27s Reflections on The Revolution in France, and Paine\u27s Rights of Man, sprang not from a strong sense of patriotism, nor did they seek to reflect the position of their countrymen. The positions held by these men were simply manifestations of deeply personal philosophic beliefs which represented only a portion of their nation\u27s sentiment

Electrostatic free energy calculations using the generalized solvent boundary potential method

Copyright 2002 American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in The Journal of Chemical Physics and may be found at http://dx.doi.org/10.1063/1.1507108.Free energyperturbation (FEP) calculations using all-atom molecular dynamics simulations with a large number of explicit solvent molecules are a powerful approach to study ligand–macromolecule association processes at the atomic level. One strategy to carry out FEP calculations efficiently and reduce computational time is to consider the explicit dynamics of only a small number of atoms in a localized region around the ligand. Such an approximation is motivated by the observation that the factors governing binding specificity are dominated by interactions in the vicinity of the ligand. However, a straightforward truncation of the system may yield inaccurate results as the influence exerted by the remote regions of the macromolecule and the surrounding solvent through long-range electrostatic effects may be significant. To obtain meaningful results, it is important to incorporate the influence of the remote regions of the ligand–macromolecule complex implicitly using some effective potential. The generalized solvent boundary potential (GSBP) that was developed recently [W. Im, S. Bernèche, and B. Roux, J. Chem. Phys. 114, 2924 (2001)] is an efficient computational method to represent the long-range electrostaticinteractions arising from remote (outer) regions in simulations of a localized (inner) region with a small number of explicit atoms. In the present work, FEP calculations combined with GSBP are used to illustrate the importance of these long-range electrostatic factors in estimation of the charging free energy of an aspartate ligand bound to the aspartyl-tRNA synthetase. Calculations with explicit spherical simulation inner regions of different radii are used to test the accuracy of the GSBP method and also illustrate the importance of explicit protein and solvent dynamics in the free energy estimation. The influence of the represented outer region is tested using separate simulations in which the reaction field and/or the protein static field are excluded. Both components are shown to be essential to obtain quantitatively meaningful results. The ability of implicitly treating the influence of protein fluctuations in the outer region using a protein dielectric constant is examined. It is shown that accurate charging free energy calculations can be performed for this system with a spherical region of 15 to 20 Å radius, which roughly corresponds to 1500–3500 moving atoms. The results indicate that GSBP in combination with FEP calculations is a precise and efficient approach to include long-range electrostatic effects in the study of ligand binding to large macromolecules

Ranking ligand affinity for the DNA minor groove by experiment and simulation

The structural and thermodynamic basis for the strength and selectivity of the interactions of minor-groove binders (MGBs) with DNA is not fully understood. In 2003 we reported the first example of a thiazole containing MGB that bound in a phase shifted pattern that spanned 6 base-pairs rather than the usual 4 (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, nuclear magnetic resonance spectroscopy, isothermal titration calorimetry and molecular dynamics, we have established that the flanking bases around the central 4 being read by the ligand have subtle effects on recognition. We have investigated the effect of these flanking sequences on binding and the reasons for the differences and established a computational method to rank ligand affinity against varying DNA sequences

Relationship between galactomannan structure and physicochemical properties of films produced thereof

In this work five sources of galactomannans, Adenanthera pavonina, Cyamopsis tetragonolobus, Caesalpinia pulcherrima, Ceratonia siliqua and Sophora japonica, presenting mannose/galactose ratios of 1.3, 1.7, 2.9, 3.4 and 5.6, respectively, were used to produce galactomannan-based films. These films were characterized in terms of: water vapour, oxygen and carbon dioxide permeabilities (WVP, O 2 P and CO 2 P); moisture content, water solubility, contact angle, elongation-at-break (EB), tensile strength (TS) and glass transition temperature (T g ). Results showed that films properties vary according to the galactomannan source (different galactose distribution) and their mannose/galactose ratio. Water affinity of mannan and galactose chains and the intermolecular interactions of mannose backbone should also be considered being factors that affect films properties. This work has shown that knowing mannose/galactose ratio of galactomannans is possible to foresee galactomannan-based edible films properties.The authors thank the fellowship (SFRH/BPD/ 72753/2010) from the Fundação para a Ciência e Tecnologia (FCT, Portugal). The authors also thank the FCT Strategic Project of UID/BIO/ 04469/2013 unit, the project RECI/BBB-EBI/0179/2012 (FCOMP-010124-FEDER-027462) and the project BBioInd - Biotechnology and Bioengineering for improved Industrial and Agro-Food processes, REF. NORTE-07-0124-FEDER-000028 Co-funded by the Programa OperacionalRegionaldoNorte(ON.2–ONovoNorte),QREN,FEDER. Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico – FUNCAP, CE Brazil (CI1-0080-00055.01.00/13)

Characterization of a K+-induced conformational switch in a human telomeric DNA oligonucleotide using 2-aminopurine fluorescence

Human telomeric DNA consists of tandem repeats of the DNA sequence d(GGGTTA). Oligodeoxynucletotide telomere models such as d[A(GGGTTA)(3)GGG] (Tel22) fold in a cation-dependent manner into quadruplex structures consisting of stacked G-quartets linked by d(TTA) loops. NMR has shown that in Na(+) solutions Tel22 forms a ‘basket’ topology of four antiparallel strands; in contrast, Tel22 in K(+) solutions consists of a mixture of unknown topologies. Our previous studies on the mechanism of folding of Tel22 and similar telomere analogs utilized changes in UV absorption between 270 and 325 nm that report primarily on G-quartet formation and stacking showed that quadruplex formation occurs within milliseconds upon mixing with an appropriate cation. In the current study, we assessed the dynamics and equilibria of folding of specific loops by using Tel22 derivatives in which the dA residues were serially substituted with the fluorescent reporter base, 2-aminopurine (2-AP). Tel22 folding induced by Na(+) or K(+) assessed by changes in 2-AP fluorescence consists of at least three kinetic steps with time constants spanning a range of ms to several hundred seconds. Na(+)-dependent equilibrium titrations of Tel22 folding could be approximated as a cooperative two-state process. In contrast, K(+)-dependent folding curves were biphasic, revealing that different conformational ensembles are present in 1 mM and 30 mM K(+). This conclusion was confirmed by (1)H NMR. Molecular dynamics simulations revealed a K(+) binding pocket in Tel22 located near dA1 that is specific for the so-called hybrid-1 conformation in which strand 1 is in a parallel arrangement. The possible presence of this topologically specific binding site suggests that K(+) may play an allosteric role in regulating telomere conformation and function by modulating quadruplex tertiary structure

Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

34 pages, 6 additional files, 5 tables, 4 figures.[Background ] Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.[Results] Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute’s drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.[Conclusions] For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute’s 60-cell line data set tend to have common structural features.Supported by a grant from the former Spanish Ministry of Education and Science (BFU2007-60998) and the FEDER program of the European Community.Peer reviewe

Targeted Delivery of Chemotherapy Agents Using a Liver Cancer-Specific Aptamer

Using antibody/aptamer-drug conjugates can be a promising method for decreasing toxicity, while increasing the efficiency of chemotherapy.In this study, the antitumor agent Doxorubicin (Dox) was incorporated into the modified DNA aptamer TLS11a-GC, which specifically targets LH86, a human hepatocellular carcinoma cell line. Cell viability tests demonstrated that the TLS11a-GC-Dox conjugates exhibited both potency and target specificity. Importantly, intercalating Dox into the modified aptamer inhibited nonspecific uptake of membrane-permeable Dox to the non-target cell line. Since the conjugates are selective for cells that express higher amounts of target proteins, both criteria noted above are met, making TLS11a-GC-Dox conjugates potential candidates for targeted delivery to liver cancer cells.Considering the large number of available aptamers that have specific targets for a wide variety of cancer cells, this novel aptamer-drug intercalation method will have promising implications for chemotherapeutics in general

Biophysical Characterization of the Strong Stabilization of the RNA Triplex poly(U)•poly(A)*poly(U) by 9-O-(ω-amino) Alkyl Ether Berberine Analogs

Background: Binding of two 9-O-(v-amino) alkyl ether berberine analogs BC1 and BC2 to the RNA triplex poly(U)Npoly(A)*poly(U) was studied by various biophysical techniques. Methodology/Principal Findings: Berberine analogs bind to the RNA triplex non-cooperatively. The affinity of binding was remarkably high by about 5 and 15 times, respectively, for BC1 and BC2 compared to berberine. The site size for the binding was around 4.3 for all. Based on ferrocyanide quenching, fluorescence polarization, quantum yield values and viscosity results a strong intercalative binding of BC1 and BC2 to the RNA triplex has been demonstrated. BC1 and BC2 stabilized the Hoogsteen base paired third strand by about 18.1 and 20.5uC compared to a 17.5uC stabilization by berberine. The binding was entropy driven compared to the enthalpy driven binding of berbeine, most likely due to additional contacts within the grooves of the triplex and disruption of the water structure by the alkyl side chain. Conclusions/Significance: Remarkably higher binding affinity and stabilization effect of the RNA triplex by the amino alkyl berberine analogs was achieved compared to berberine. The length of the alkyl side chain influence in the triplex stabilization phenomena