bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women?
Authors: Harvey Philip W. , Darbre Philippa
Published: June 2004

In the decade that has elapsed since the suggestion that exposure of the foetal/developing male to environmental oestrogens could be the cause of subsequent reproductive and developmental effects in men, there has been little deﬁnitive research to provide conclusions to the hypothesis. Issues of exposure and low potency of environmental oestrogens may have reduced concerns. However, the hypothesis that chemicals applied in body care cosmetics (including moisturizers, creams, sprays or lotions applied to axilla or chest or breast areas) may be affecting breast cancer incidence in women presents a different case scenario, not least in the consideration of the exposure issues. The speciﬁc cosmetic type is not relevant but the chemical ingredients in the formulations and the application to the skin is important. The most common group of body care cosmetic formulation excipients, namely p‐hydroxybenzoic acid esters or parabens, have been shown recently to be oestrogenic in vitro and in vivo and now have been detected in human breast tumour tissue, indicating absorption (route and causal associations have yet to be conﬁrmed). The hypothesis for a link between oestrogenic ingredients in underarm and body care cosmetics and breast cancer is forwarded and reviewed here in terms of: data on exposure to body care cosmetics and parabens, including dermal absorption; paraben oestrogenicity; the role of oestrogen in breast cancer; detection of parabens in breast tumours; recent epidemiology studies of underarm cosmetics use and breast cancer; the toxicology database; the current regulatory status of parabens and regulatory toxicology data uncertainties. Notwithstanding the major public health issue of the causes of the rising incidence of breast cancer in women, this call for further research may provide the ﬁrst evidence that environmental factors may be adversely affecting human health by endocrine disruption, because exposure to oestrogenic chemicals through application of body care products (unlike diffuse environmental chemical exposures) should be amenable to evaluation, quantiﬁcation and control. The exposure issues are clear and the exposed population is large, and these factors should provide the necessary impetus to investigate this potential issue of public health. Copyright © 2004 John Wiley & Sons, Ltd.
Inﬂuence of iron (56Fe2O3 or 54Fe2O3) in the upregulation of cytochrome P4501A1 by benzo[a]pyrene in the respiratory tract of Sprague‐Dawley rats
Authors: Garçon Guillaume , Gosset Pierre , Maunit Benoît , Zerimech Farid , Creusy Colette , Muller Jean‐François , Shirali Pirouz
Published: June 2004

Any inﬂuence of iron in polycyclic aromatic hydrocarbon (PAH)/iron oxide mixtures on the capacity of PAHs to induce metabolizing enzymes will be one of the ways that iron oxides can affect PAH carcinogenicity. Because cytochromes P450 (CYPs) are haemoproteins, it will be of interest to investigate the possible involvement of Fe2O3 in benzo[a]pyrene (BaP)/Fe2O3 mixtures on the induction of CYP1A1 enzymes in the lung. Male Sprague‐Dawley rats were instilled intratracheally with haematite (56Fe2O3 or 54Fe2O3, 3 mg), BaP (3 mg) or BaP (3 mg) coated onto haematite (56Fe2O3 or 54Fe2O3) particles (3 mg). Firstly, mRNA expressions of cyp1a1 were studied. Secondly, protein concentrations and catalytic activities (7‐ethoxyresoruﬁn O‐deethylase: EROD) of CYP1A1 were determined. Thirdly, 54Fe from BaP/54Fe2O3 mixtures in microsomal proteins was studied using time‐of‐ﬂight laser microprobe mass spectrometry (ToF‐LMMS). Statistically signiﬁcant increases in mRNA expressions, protein concentrations and catalytic activities of CYP1A1 were observed in animals exposed to BaP, to BaP coated onto 56Fe2O3 particles or to BaP coated onto 54Fe2O3 particles versus controls. Both of the BaP/Fe2O3 mixtures induced higher CYP1A1 protein levels and EROD activities than BaP alone. Iron oxide particles per se did not affect mRNA levels of cyp1a1 but only enhanced BaP‐mediated increases of CYP1A1 protein levels and activity. The ToF‐LMMS spectrum proﬁles showed that the 54Fe/56Fe ratio in the microsomes of BaP coated onto 54Fe2O3 particle‐instilled animals was 1.3 instead of the theoretical ratio (i.e. 0.063) observed in BaP coated onto 56Fe2O3 particle‐instilled animals. Taken together, these novel data support the hypothesis that the Fe2O3‐induced increases of the metabolic activation of BaP might rely on the property of Fe2O3 particles to enhance the BaP‐induced translation rate of the cyp1a1 gene into functional haemoproteins. Copyright © 2004 John Wiley & Sons, Ltd.
Casual cell surface remodeling using biocompatible lipid‐poly(ethylene glycol)(n): Development of stealth cells and monitoring of cell membrane behavior in serum‐supplemented conditions
Authors: Chung Hyeyoung A. , Kato Koich , Itoh Chika , Ohhashi Syunsuke , Nagamune Teruyuki
Published: June 2004

Control of the cell surface allows modulation of the cell's biological response, producing practical applications and satisfying scientific interests. Consequently, to meet such goals and interests, diverse approaches were developed in cell surface engineering techniques. Poly(ethylene glycol) (PEG) intermediates were widely employed to modify proteins, enzymes, artificial surfaces, liposomes, and drugs for practical usage. PEGylation was also used for modification of cell surface properties. A method was recently developed for the rapid incorporation of proteins into mammalian cell membranes using lipid‐PEG(n) derivatives under physiological conditions. This is a rapid and homogeneous method to incorporate lipid‐PEG(n), which was used as a model to study the modification of cellular properties and cell–cell interactions. Because the stability of molecules incorporated into the cell surface shows the usefulness of the anchoring technique, it was also investigated whether potential factors such as time, the concentration of the incorporated lipid‐PEG(n), and the type of medium affect this incorporation. At concentrations greater than 10 μM, when dual typed lipid‐PEG(n) was incorporated into erythrocytes, antigenic recognition was dramatically attenuated, resulting in the successful development of stealth cells. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 70A: 179–185, 2004
Changes of optical properties of dental nano‐filled resin composites after curing and thermocycling
Authors: Lee Yong‐Keun , Lim Bum‐Soon , Rhee Sang‐Hoon , Yang Hyeong‐Cheol , Powers John M
Published: June 2004

The objective was to evaluate the color changes after curing, polishing, and thermocycling of a nano‐filled resin composite. A nano‐filled composite was grouped into two shades of enamel (EN) and translucent (TL). One hybrid composite was used as a control (CL). Color of specimens of 10 mm in diameter and 2 mm in thickness was measured on a reflection spectrophotometer with SCE geometry under the D65 illumination over white and black backgrounds. Color before curing and after curing, polishing and thermocycling was measured. Color change (ΔE), translucency parameter (TP), and contrast ratio (CR) were compared. Average ΔE after curing was 4.6 in the EN group and 10.4 in the TL group compare to 2.9 in CL. Polishing caused average ΔE of 3.3–3.6, which was not different by the shade group (p > 0.05). After 2000 cycles of thermocycling, average ΔE was 1.4–1.8, which was not different by the shade group (p > 0.05). TP values increased after curing in the EN group, but decreased in the TL group (p < 0.05). TP values after thermocycling decreased in the EN group but did not change in TL (p = 0.05). TP values of TL shades were higher than those of EN regardless of specimen conditions (p < 0.05). Changes in CR values showed similar trends to those of TP values in translucency. Changes of color and translucency after curing, polishing, and thermocycling varied by the shade group. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 71B: 16–21, 2004
Influence of the aspect ratio of bioactive nanofillers on rheological behavior of PMMA‐based orthopedic materials
Authors: Liu Tse‐Ying , Chen San‐Yuan , Liu Dean‐Mo
Published: June 2004

In this investigation, calcium‐deficient hydroxyapatite (CDHA) nanocrystals with needle‐like geometry were synthesized and incorporated with Poly(methyl methacrylate), PMMA, to form CDHA–PMMA nanocomposites. Rheological behaviors of the PMMA–CDHA melting suspensions were systematically investigated in terms of solid loading and aspect ratio of the CDHA nanoparticles. The maximum solid loadings of nano‐CDHA particles with aspect ratios of 7.2, 10.4, and 17 were determined to be 28, 31, and 57%, respectively. An increase in solid concentrations causes pronounced shear‐thinning behavior. This result suggests that a strong interaction, including Van der Waals attraction and mechanical interlocking, between the nano‐CDHA particles makes the nanocomposite mixture more non‐Newtonian. Furthermore, it was found that packing efficiency and yield strength in the suspension were strongly influenced by the aspect ratio, especially above the critical value of 8.8. The obtained critical aspect ratio and solid content provide not only appropriate design in the PMMA–CDHA polymeric suspension for fabrication process but also optimal conditions for the fabrication of orthopedic devices via injection molding or extrusion. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 71B: 116–122, 2004
Ab initio direct dynamics studies on the reaction of H atom with CH3CH2Cl
Authors: Sheng Li , Li Ze‐Sheng , Liu Jing‐Yao , Xiao Jing‐Fa , Sun Chia‐Chung
Published: June 2004

The multiple channel reaction H + CH3CH2Cl → products has been studied by the ab initio direct dynamics method. The potential energy surface information is calculated at the MP2/6‐311G(d,p) level of theory. The energies along the minimum energy path are further improved by single‐point energy calculations at the PMP4(SDTQ)/6‐311+G(3df,2p) level of theory. For the reaction, four reaction channels (one chlorine abstraction, one α‐hydrogen abstraction, and two β‐hydrogen abstractions) have been identified. The rate constants for each reaction channel are calculated by using canonical variational transition state theory incorporating the small‐curvature tunneling correction in the temperature range 298–5000 K. The total rate constants, which are calculated from the sum of the individual rate constants, are in good agreement with the experimental data. The calculated temperature dependence of the branching fractions indicates that for the title reaction, H‐abstraction reaction is the major reaction channel in the whole temperature range 298–5000 K. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 72–82, 2004
Peptide backbone reconstruction using dead‐end elimination and a knowledge‐based forcefield
Authors: Adcock Stewart A.
Published: June 2004

A novel, yet simple and automated, protocol for reconstruction of complete peptide backbones from Cα coordinates only is described, validated, and benchmarked. The described method collates a set of possible backbone conformations for each set of residue triads from a structural library derived from the PDB. The optimal permutation of these three residue segments of backbone conformations is determined using the dead‐end elimination (DEE) algorithm. Putative conformations are evaluated using a pairwise‐additive knowledge‐based forcefield term and a fragment overlap term. The protocol described in this report is able to restore the full backbone coordinates to within 0.2–0.6 Å of the actual crystal structure from Cα coordinates only. In addition, it is insensitive to errors in the input Cα coordinates with RMSDs of 3.0 Å, and this is illustrated through application to deliberately distorted Cα traces. The entire process, as described, is rapid, requiring of the order of a few minutes for a typical protein on a typical desktop PC. Approximations enable this to be reduced to a few seconds, although this is at the expense of prediction accuracy. This compares very favorably to previously published methods, being sufficiently fast for general use and being one of the most accurate methods. Because the method is not restricted to the reconstruction from only Cα coordinates, reconstruction based on Cβ coordinates is also demonstrated. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 16–27, 2004
Development and validation of COMPASS force field parameters for molecules with aliphatic azide chains
Authors: McQuaid Michael J. , Sun Huai , Rigby David
Published: June 2004

To establish force‐field‐based (molecular) modeling capability that will accurately predict condensed‐phase thermophysical properties for materials containing aliphatic azide chains, potential parameters for atom types unique to such chains have been developed and added to the COMPASS force field. The development effort identified the need to define four new atom types: one for each of the three azide nitrogen atoms and one for the carbon atom bonded to the azide. Calculations performed with the expanded force field yield (gas‐phase) molecular structures and vibrational frequencies for hydrazoic acid, azidomethane, and the anti and gauche forms of azidoethane in good agreement with values determined experimentally and/or through computational quantum mechanics. Liquid densities calculated via molecular dynamics (MD) simulations were also in good agreement with published values for 13 of 15 training set compounds, the exceptions being hydrazoic acid and azidomethane. Of the 13 compounds whose densities are well simulated, nine have experimentally determined heats of vaporization reported in the open literature, and in all of these cases, MD simulated values for this property are in reasonable agreement with the published values. Simulations with the force field also yielded reasonable density estimates for a series of 2‐azidoethanamines that have been synthesized and tested for use as hydrazine‐alternative fuels. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 61–71, 2004
DFT‐GIAO calculations of 19F NMR chemical shifts for perfluoro compounds
Authors: Fukaya Haruhiko , Ono Taizo
Published: June 2004

The 19F NMR shieldings for 53 kinds of perfluoro compounds were calculated by the B3LYP‐GIAO method using the 6‐31G(d), 6‐31+G(d), 6‐31G(d,p), 6‐31++G(d,p), 6‐311G(d,p), 6‐311++G(d,p), 6‐311G(2d,2p), 6‐311++G(2d,2p), 6‐311++G(2df,2p), 6‐311++G(3d,2p), and 6‐311++G(3df,2p) basis sets. The diffuse functions markedly reduce the difference between the calculated and experimental chemical shifts. The calculations using the 6‐31++G(d,p) basis set give the chemical shifts within 10 ppm deviations from experimental values except for the fluorine nuclei attached to an oxygen atom, a four‐ and a six‐coordinated sulfur atom, and FC(CF3)2 attached to a sulfur atom. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 51–60, 2004
Semiempirical PM5 molecular orbital study on chlorophylls and bacteriochlorophylls: Comparison of semiempirical, ab initio, and density functional results
Authors: Linnanto Juha , Korppi‐Tommola Jouko
Published: June 2004

The semiempirical PM5 method has been used to calculate fully optimized structures of magnesium‐bacteriochlorin, magnesium‐chlorin, magnesium‐porphin, mesochlorophyll a, chlorophylls a, b, c1, c2, c3, and d, and bacteriochlorophylls a, b, c, d, e, f, g, and h with all homologous structures. Hartree‐Fock/6‐31G* ab initio and density functional B3LYP/6‐31G* methods were used to optimize structures of methyl chlorophyllide a, chlorophyll c1, and methyl bacteriochlorophyllides a and c for comparison. Spectroscopic transition energies of the chromophores and their 1:1 or 1:2 solvent complexes were calculated with the Zindo/S CIS method. The self‐consistent reaction field model was used to estimate solvent shifts. The PM5 calculations predict planar structure of the porphyrin ring and central position of the four coordinated magnesium atoms in all pigments studied, in accord with the experimental, ab initio, and density functional results, a significant improvement as compared to the older semiempirical PM3 approach. Only small differences in PM5 and B3LYP/6‐31G* or Hartree‐Fock/6‐31G* minimum energy geometries of the reference molecules were observed. Calculations show that in 1:1 solvent complexes, where the magnesium atom is five coordinated, the magnesium atom is shifted out of the plane of the porphyrin ring towards the solvent molecule, while the hexa coordinated 1:2 complexes are again planar. The PM5 method gives atomic charges that are comparable with those obtained from the Hartree‐Fock/6‐31G* and B3LYP/6‐31G* calculations. The single point ZINDO/S CIS calculations with PM5 minimum energy structure gave excellent correlations between calculated and experimental transition energies of the chlorophylls and bacteriochlorophylls studied. Such correlations may be used for prediction of transition energies of the chromophores in protein binding sites. Calculations also predict existence of dark electronic states below the main Soret absorption band in all chromophores studied. The results suggest that the semiempirical PM5 method is a fairly reliable and computationally efficient method in predicting molecular parameters of porphyrin‐like molecules. © 2003 Wiley Periodicals, Inc. J Comput Chem 1: 123–137, 2004
CHARMM fluctuating charge force field for proteins: I parameterization and application to bulk organic liquid simulations
Authors: Patel Sandeep , Brooks Charles L.
Published: June 2004

A first‐generation fluctuating charge (FQ) force field to be ultimately applied for protein simulations is presented. The electrostatic model parameters, the atomic hardnesses, and electronegativities, are parameterized by fitting to DFT‐based charge responses of small molecules perturbed by a dipolar probe mimicking a water dipole. The nonbonded parameters for atoms based on the CHARMM atom‐typing scheme are determined via simultaneously optimizing vacuum water‐solute geometries and energies (for a set of small organic molecules) and condensed phase properties (densities and vaporization enthalpies) for pure bulk liquids. Vacuum solute‐water geometries, specifically hydrogen bond distances, are fit to 0.19 Å r.m.s. error, while dimerization energies are fit to 0.98 kcal/mol r.m.s. error. Properties of the liquids studied include bulk liquid structure and polarization. The FQ model does indeed show a condensed phase effect in the shifting of molecular dipole moments to higher values relative to the gas phase. The FQ liquids also appear to be more strongly associated, in the case of hydrogen bonding liquids, due to the enhanced dipolar interactions as evidenced by shifts toward lower energies in pair energy distributions. We present results from a short simulation of NMA in bulk TIP4P‐FQ water as a step towards simulating solvated peptide/protein systems. As expected, there is a nontrivial dipole moment enhancement of the NMA (although the quantitative accuracy is difficult to assess). Furthermore, the distribution of dipole moments of water molecules in the vicinity of the solutes is shifted towards larger values by 0.1–0.2 Debye in keeping with previously reported work. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 1–15, 2004
Extension of the PDDG/PM3 and PDDG/MNDO semiempirical molecular orbital methods to the halogens
Authors: Tubert‐Brohman Ivan , Guimarães Cristiano Ruch Werneck , Repasky Matthew P. , Jorgensen William L.
Published: June 2004

The new semiempirical methods, PDDG/PM3 and PDDG/MNDO, have been parameterized for halogens. For comparison, the original MNDO and PM3 were also reoptimized for the halogens using the same training set; these modified methods are referred to as MNDO′ and PM3′. For 442 halogen‐containing molecules, the smallest mean absolute error (MAE) in heats of formation is obtained with PDDG/PM3 (5.6 kcal/mol), followed by PM3′ (6.1 kcal/mol), PDDG/MNDO (6.6 kcal/mol), PM3 (8.1 kcal/mol), MNDO′ (8.5 kcal/mol), AM1 (11.1 kcal/mol), and MNDO (14.0 kcal/mol). For normal‐valent halogen‐containing molecules, the PDDG methods also provide improved heats of formation over MNDO/d. Hypervalent compounds were not included in the training set and improvements over the standard NDDO methods with sp basis sets were not obtained. For small haloalkanes, the PDDG methods yield more accurate heats of formation than are obtained from density functional theory (DFT) with the B3LYP and B3PW91 functionals using large basis sets. PDDG/PM3 and PM3′ also give improved binding energies over the standard NDDO methods for complexes involving halide anions, and they are competitive with B3LYP/6‐311++G(d,p) results including thermal corrections. Among the semiempirical methods studied, PDDG/PM3 also generates the best agreement with high‐level ab initio G2 and CCSD(T) intrinsic activation energies for SN2 reactions involving methyl halides and halide anions. Finally, the MAEs in ionization potentials, dipole moments, and molecular geometries show that the parameter sets for the PDDG and reoptimized NDDO methods reduce the MAEs in heats of formation without compromising the other important QM observables. © 2003 Wiley Periodicals, Inc. J Comput Chem 1: 138–150, 2004
New reaction simulator “LUMMOX” and its application for prediction of catalytic activities
Authors: Motoki Takao , Shiga Akinobu
Published: June 2004

We developed a new reaction simulator, “LUMMOX.” It is an intermolecular interaction analyzer based on the theories of paired interacting orbitals (PIOs) and localized frontier orbitals (LFOs) that have been developed by Fujimoto et al. (Fukui, K.; Koga, N.; Fujimoto, H. J Am Chem Soc 1981, 103, 196; Fujimoto, H.; Koga, N.; Fukui, K. J Am Chem Soc 1981, 103, 7452; Fujimoto, H.; Satoh, S. J Phys Chem 1994, 98, 1436). LUMMOX runs on a Windows PC and displays graphic representation of orbital interactions. Prediction of activities, selectivities, and molecular weight of olefin polymerization catalysts are presented using PIO analysis and LFO calculation. Not only computational chemists but also experimental chemists can easily use this new system for catalyst design or molecular design from the point of view of orbital interaction. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 106–111, 2004
Systematic quantum chemical study of DNA‐base tautomers
Authors: Piacenza M. , Grimme S.
Published: June 2004

The relative energies of the energetically low‐lying tautomers of pyridone, cytosine, uracil, thymine, guanine, and iso‐cytosine are studied by a variety of different quantum chemical methods. In particular, we employ density functional theory (DFT) using the six functionals HCTH407, PBE, BP86, B‐LYP, B3‐LYP, and BH‐LYP, and the ab initio methods Hartree‐Fock (HF), standard second‐order Møller‐Plesset perturbation theory (MP2), an improved version of it (SCS‐MP2), and quadratic configuration interaction including single and double excitations (QCISD) and perturbative triple corrections [QCISD(T)]. A detailed basis set study is performed for the formamide/formamidic acid tautomeric pair. In general, large AO basis sets of at least valence triple‐ζ quality including f‐functions (TZV) are employed, which are found to be necessary for an accurate energetic description of the various structures. The performance of the more approximate methods is evaluated with QCISD(T)/TZV(2df,2dp) data taken as reference. In general it is found that DFT is not an appropriate method for the problem. For the tautomers of pyridone and cytosine, most density functionals, including the popular B3‐LYP hybrid, predict a wrong energetic order, and only for guanine, the correct sequence of tautomers is obtained with all functionals. Out of the density functionals tested, BH‐LYP, which includes a rather large fraction of HF exchange, performs best. A consistent description of the nonaromatic versus aromatic tautomers seems to be a general problem especially for pure, nonhybrid functionals. Tentatively, this could be assigned to the exchange potentials used while the functional itself, including the correlation part, seems to be appropriate. Out of the ab initio methods tested, the new SCS‐MP2 approach seems to perform best because it effectively reduces some outliers obtained with standard MP2. It outperforms the much more costly QCISD method and seems to be a very good compromise between computational effort and accuracy. © 2003 Wiley Periodicals, Inc. J Comput Chem 1: 83–98, 2004
Theoretical study of the internal conversion of sulfoxide precursors of poly‐isothianaphthene and related polymers
Authors: Claes Luc , François Jean‐Pierre , Deleuze Michael S.
Published: June 2004

In the present contribution, we theoretically investigate the suitability of the sulfoxide route for the synthesis of conjugated polymers of relevance for the fabrication of low‐band gap materials with improved characteristics. The study focuses specifically on the internal elimination (Ei) reactions of sulfoxide precursors of model oligomers of trans‐ and cis‐poly‐isothianaphtene (PITN), trans‐poly‐isothianaphtene vinylene (PITNV), and trans‐poly‐(ethylene dioxythiophene vinylene) (PEDOTV). These reactions have been characterized in detail by means of Density Functional Theory, along with the MPW1K functional (Modified Perdew‐Wang 1‐parameter model for kinetics). © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 40–50, 2004
Improving the efficiency and reliability of free energy perturbation calculations using overlap sampling methods
Authors: Lu Nandou , Kofke David A. , Woolf Thomas B.
Published: June 2004

A challenge in free energy calculation for complex molecular systems by computer simulation is to obtain a reliable estimate within feasible computational time. In this study, we suggest an answer to this challenge by exploring a simple method, overlap sampling (OS), for producing reliable free‐energy results in an efficient way. The formalism of the OS method is based on ensuring sampling of important overlapping phase space during perturbation calculations. This technique samples both forward and reverse free energy perturbation (FEP) to improve the free‐energy calculation. It considers the asymmetry of the FEP calculation and features an ability to optimize both the precision and the accuracy of the measurement without affecting the simulation process itself. The OS method is tested at two optimization levels: no optimization (simple OS), and full optimization (equivalent to Bennett's method), and compared to conventional FEP techniques, including the widely used direct FEP averaging method, on three alchemical mutation systems: (a) an anion transformation in water solution, (b) mutation between methanol and ethane, and (c) alchemical change of an adenosine molecule. It is consistently shown that the reliability of free‐energy estimates can be greatly improved using the OS techniques at both optimization levels, while the performance of Bennett's method is particularly striking. In addition, the efficiency of a calculation can be significantly improved because the method is able to (a) converge to the right answer quickly, and (b) work for large perturbations. The basic two‐stage OS method can be extended to admit additional stages, if needed. We suggest that the OS method can be used as a general perturbation technique for computing free energy differences in molecular simulations. © 2003 Wiley Periodicals, Inc. J Comput Chem 1: 28–39, 2004
Testing electronic structure methods for describing intermolecular H · · · H interactions in supramolecular chemistry
Authors: Casadesús Ricard , Moreno Miquel , González‐Lafont àngels , Lluch José M. , Repasky Matthew P.
Published: June 2004

In this article a wide variety of computational approaches (molecular mechanics force fields, semiempirical formalisms, and hybrid methods, namely ONIOM calculations) have been used to calculate the energy and geometry of the supramolecular system 2‐(2′‐hydroxyphenyl)‐4‐methyloxazole (HPMO) encapsulated in β‐cyclodextrin (β‐CD). The main objective of the present study has been to examine the performance of these computational methods when describing the short range H · · · H intermolecular interactions between guest (HPMO) and host (β‐CD) molecules. The analyzed molecular mechanics methods do not provide unphysical short H · · · H contacts, but it is obvious that their applicability to the study of supramolecular systems is rather limited. For the semiempirical methods, MNDO is found to generate more reliable geometries than AM1, PM3 and the two recently developed schemes PDDG/MNDO and PDDG/PM3. MNDO results only give one slightly short H · · · H distance, whereas the NDDO formalisms with modifications of the Core Repulsion Function (CRF) via Gaussians exhibit a large number of short to very short and unphysical H · · · H intermolecular distances. In contrast, the PM5 method, which is the successor to PM3, gives very promising results. Our ONIOM calculations indicate that the unphysical optimized geometries from PM3 are retained when this semiempirical method is used as the low level layer in a QM:QM formulation. On the other hand, ab initio methods involving good enough basis sets, at least for the high level layer in a hybrid ONIOM calculation, behave well, but they may be too expensive in practice for most supramolecular chemistry applications. Finally, the performance of the evaluated computational methods has also been tested by evaluating the energetic difference between the two most stable conformations of the host(β‐CD)‐guest(HPMO) system. © 2003 Wiley Periodicals, Inc. J Comput Chem 25: 99–105, 2004
Ground‐ and excited‐state properties of DNA base molecules from plane‐wave calculations using ultrasoft pseudopotentials
Authors: Preuss M. , Schmidt W. G. , Seino K. , Furthmüller J. , Bechstedt F.
Published: June 2004

We present equilibrium geometries, vibrational modes, dipole moments, ionization energies, electron affinities, and optical absorption spectra of the DNA base molecules adenine, thymine, guanine, and cytosine calculated from first principles. The comparison of our results with experimental data and results obtained by using quantum chemistry methods show that in specific cases gradient‐corrected density‐functional theory (DFT‐GGA) calculations using ultrasoft pseudopotentials and a plane‐wave basis may be a numerically efficient and accurate alternative to methods employing localized orbitals for the expansion of the electron wave functions. © 2003 Wiley Periodicals, Inc. J Comput Chem 1: 112–122, 2004
A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands
Authors: Jung Dawoon , Floyd Jie , Gund Tamara M.
Published: June 2004

The Comparative Molecular Field Analysis (CoMFA) was developed to investigate a three‐dimensional quantitative structure activity relationship (3D‐QSAR) model of ligands for the sigma 1 receptor. The starting geometry of sigma‐1 receptor ligands was obtained from the Tripos force field minimizations and conformations were decided from DISCOtech using the SYBYL 6.8. program. The structures of 48 molecules were fully optimized at the ab initio HF/3‐21G* and semiempirical AM1 calculations using GAUSSIAN 98. The electrostatic charges were calculated using several methods such as semiempirical AM1, density functional B3LYP/3‐21G*, and ab initio HF/3‐21G*, MP2/3‐21G* calculations within GAUSSIAN 98. Using the optimized geometries, the CoMFA results derived from the HF/3‐21G method were better than those from AM1. The best CoMFA was obtained from HF/3‐21G* optimized geometry and charges (R2 = 0.977). Using the optimized geometries, the CoMFA results derived from the HF/3‐21G methods were better than those from AM1 calculations. The training set of 43 molecules gave higher R2 (0.989–0.977) from HF/3‐21G* optimized geometries than R2 (0.966–0.911) values from AM1 optimized geometries. The test set of five molecules also suggested that HF/3‐21G* optimized geometries produced good CoMFA models to predict bioactivity of sigma 1 receptor ligands but AM1 optimized geometries failed to predict reasonable bioactivity of sigma 1 receptor ligands using different calculations for atomic charges. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1385–1399, 2004
An evaluation of the radial part of numerical integration commonly used in DFT
Authors: El‐Sherbiny Aisha , Poirier Raymond A.
Published: June 2004

Recently, Gill and Chien introduced a new radial quadrature for multiexponential integrands (MultiExp grid) to deal with the radial part of the numerical integration. In this article, the MultiExp grid is studied and used to integrate the charge density. The MultiExp grid, along with an optimal pruning scheme, performed very well both in terms of accuracy and efficiency compared to other radial mappings commonly used in Density Functional Theory. © 2004 Wiley Periodicals, Inc. J Comput Chem 11: 1378–1384, 2004
Wavelet algorithm for solving integral equations of molecular liquids. A test for the reference interaction site model
Authors: Chuev Gennady N. , Fedorov Maxim V.
Published: June 2004

A new efficient method is developed for solving integral equations based on the reference interaction site model (RISM) of molecular liquids. The method proposes the expansion of site–site correlation functions into the wavelet series and further calculations of the approximating coefficients. To solve the integral equations we have applied the hybrid scheme in which the coarse part of the solution is calculated by wavelets with the use of the Newton–Raphson procedure, while the fine part is evaluated by the direct iterations. The Coifman 2 basis set is employed for the wavelet treatment of the coarse solution. This wavelet basis set provides compact and accurate approximation of site–site correlation functions so that the number of basis functions and the amplitude of the fine part of solution decrease sufficiently with respect to those obtained by the conventional scheme. The efficiency of the method is tested by calculations of SPC/E model of water. The results indicated that the total CPU time to obtain solution by the proposed procedure reduces to 20% of that required for the conventional hybrid method. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1369–1377, 2004
Co‐operation of Gsα and Gβγ in maintaining G2 arrest in xenopus oocytes
Authors: Sheng Yinglun , Montplaisir Véronique , Johné Liu X.
Published: June 2004

Progesterone‐induced oocyte maturation is thought to involve the inhibition of an oocyte adenylyl cyclase and reduction of intracellular cAMP. Our previous studies demonstrated that injection of inhibitors of G protein βγ complex induces hormone‐independent oocyte maturation. In contrast, over‐expression of Xenopus Gβ1 (xGβ1), alone or together with bovine Gγ2, elevates oocyte cAMP and inhibits progesterone‐induced oocyte maturation. To further investigate the mechanism of Gβγ‐induced oocyte maturation, we generated a mutant xGβ1, substituting Asp‐228 for Gly (D228G). An equivalent mutation in the mammalian Gβ1 results in the loss of its ability to activate adenylyl cyclases. Indeed, co‐injection of xGβ1D228G with Gγ2 failed to increase oocyte cAMP or inhibit progesterone‐induced oocyte maturation. To directly demonstrate that oocytes contained a Gβγ‐regulated adenylyl cyclase, we analyzed cAMP formation in vitro by using oocyte membrane preparations. Purified brain Gβγ complexes significantly activated membrane‐bound adenylyl cyclase activities. Multiple adenylyl cyclase isoforms were identified in frog oocytes by PCR using degenerate primers corresponding to highly conserved catalytic amino acid sequences. Among these we identified a partial Xenopus adenylyl cyclase 7 (xAC7) that was 65% identical in amino acid sequence to human AC7. A dominant‐negative mutant of xAC7 induced hormone‐independent oocyte maturation and accelerated progesterone‐induced oocyte maturation. Theses findings suggest that xAC7 is a major component of the G2 arrest mechanism in Xenopus oocytes. © 2005 Wiley‐Liss, Inc.
Multiple signaling conduits regulate global differentiation‐specific gene expression in PC12 cells
Authors: Marek Lindsay , Levresse Valerie , Amura Claudia , Zentrich Eve , Putten Vicki Van , Nemenoff Raphael A. , Heasley Lynn E.
Published: June 2004

PC12 cells serve as a model for exploring nerve growth factor (NGF)‐stimulated signal pathways that mediate neural differentiation. We previously demonstrated that neurofilament light chain (NFLC) gene induction by NGF requires collaborative extracellular signal‐regulated kinase (ERK) and c‐Jun N‐terminal kinase (JNK) signaling. Herein, we investigate the broader requirement for integrated ERK and JNK signaling in NGF‐stimulated gene expression. NGF stimulates differentiation as well as maintenance of cell viability while insulin‐like growth factor‐1 (IGF‐1) stimulates only trophic actions in PC12 cells. Affymetrix Genechips were used to identify genes whose expression specifically increased in response to NGF, but not IGF‐1. From the set of NGF‐specific genes, the induction by NGF of ten genes with diverse predicted cellular functions was tested for ERK and JNK pathway requirements using the protein kinase inhibitors, PD98059 and SP600125, respectively. Like NFLC, induction of urokinase plasminogen activator (uPAR), transin/matrix metalloproteinase 3 (MMP3), Fra‐1 and transforming growth factor β1 (TGFβ1) required collaborative ERK and JNK signaling while the increased expression of cortexin, rat collapsin response mediator protein 4 (rCRMP4), rat growth and transformation‐dependent protein (RGT), and synapsin II required neither mitogen‐activated protein kinase (MAPK) pathway. NGF‐induction of the bradykinin B2 receptor and c‐Ret mRNAs was partially inhibited by SP600125, but not PD98059. Reporter constructs containing the promoters for ERK/JNK‐dependent genes (NFLC, transin, uPAR) as well as an ERK/JNK‐independent gene (synapsin II) revealed that both sets of genes required functional Ras signaling for activation by NGF. Integrated signaling through the ERK and JNK MAPKs, therefore, represents a general conduit for NGF‐dependent gene expression, but additional Ras‐dependent signaling pathways distinct from the ERKs and JNKs must contribute as well. Thus, multiple signaling conduits control global differentiation‐specific gene expression in PC12 cells. © 2004 Wiley‐Liss, Inc.
FGF6 mediated expansion of a resident subset of cells with SP phenotype in the C2C12 myogenic line
Authors: Israeli David , Benchaouir Rachid , Ziaei Simindokht , Rameau Philippe , Gruszczynski Carole , Peltekian Elise , Danos Olivier , Garcia Luis
Published: June 2004

Fibroblast growth factor 6 (FGF6) is selectively expressed during muscle development and regeneration. We examined its effect on muscle precursor cells (mpc) by forcing stable FGF6 expression in C2C12 cells in vitro. FGF6 produced in genetically engineered mpc was active, inducing strong morphological changes, altering cell adhesion and compromising their ability to differentiate into myotubes. Expression of MyoD and myogenin, but not of Myf5, was abrogated in FGF6 engineered mpc. These effects were reversed by FGF inhibitors. Ectopic expression of MyoD also restored fiber formation indicating that FGF6 interferes with the myogenic differentiation pathway upstream of MyoD. We also report that in the presence of FGF6, the minor (0.5–2%) subpopulation of cells actively excluding Hoechst 33342 in a verapamil‐dependent manner (SP phenotype) was increased to 15–20% and the expression of the mdr1a gene (but not mdr1b) was upregulated by 400‐fold. Our data establish a previously undescribed link between FGF6—a muscle specific growth factor—and a multidrug resistance gene expressed in stem cells, and suggest a role for FGF6 in the maintenance of a reserve pool of progenitor cells in the skeletal muscle. © 2004 Wiley‐Liss, Inc.
Regulation of inward rectifier K+ channels by shift of intracellular pH dependence
Authors: Collins Anthony , Larson Maureen
Published: June 2004

The mechanistic link between mitochondrial metabolism and inward rectifier K+ channel activity was investigated by studying the effects of a mitochondrial inhibitor, carbonyl cyanide p‐trifluoromethoxyphenylhydrazone (FCCP) on inward rectifiers of the Kir2 subfamily expressed in Xenopus oocytes, using two‐electrode voltage‐clamp, patch‐clamp, and intracellular pH recording. FCCP inhibited Kir2.2 and Kir2.3 currents and decreased intracellular pH, but the pH change was too small to account for the inhibitory effect by itself. However, pre‐incubation of oocytes with imidazole prevented both the pH decrease and the inhibition of Kir2.2 and Kir2.3 currents by FCCP. The pH dependence of Kir2.2 was shifted to higher pH in membrane patches from FCCP‐treated oocytes compared to control oocytes. Therefore, the inhibition of Kir2.2 by FCCP may involve a combination of intracellular acidification and a shift in the intracellular pH dependence of these channels. To investigate the sensitivity of heteromeric channels to FCCP, we studied its effect on currents expressed by heteromeric tandem dimer constructs. While Kir2.1 homomeric channels were insensitive to FCCP, both Kir2.1‐Kir2.2 and Kir2.1‐Kir2.3 heterotetrameric channels were inhibited. These data support the notion that mitochondrial dysfunction causes inhibition of heteromeric inward rectifier K+ channels. The reduction of inward rectifier K+ channel activity observed in heart failure and ischemia may result from the mitochondrial dysfunction that occurs in these conditions. © 2005 Wiley‐Liss, Inc.
FGF2‐mediated upregulation of urokinase‐type plasminogen activator expression requires a MAP‐kinase dependent activation of poly(ADP‐ribose) polymerase
Authors: Caldini Riccardo , Barletta Emanuela , Del Rosso Mario , Giovannelli Lisa , Chevanne Marta
Published: June 2004

Poly(ADP‐ribosyl)ation is a post‐translational modification of protein occurring in the nucleus by poly(ADP‐ribose) polymerase enzyme activity. The main role of poly(ADP‐ribose) polymerase system as “nick sensor” and DNA breaks repair is based on its activation via DNA strand breaks. Furthermore, poly(ADP‐ribose) polymerase modifies the binding to DNA of several transcriptional factors by poly(ADP‐ribosyl)ation, thereby regulating also transcriptional gene expression. We have analyzed whether poly(ADP‐ribose) polymerase activity is involved in basic fibroblast growth factor (FGF2)‐mediated upregulation of urokinase‐type plasminogen activator (uPA) mRNA. We demonstrated that specific inhibition of poly(ADP‐ribose) polymerase activity via 3‐aminobenzamide (3ABA) or NAD+ deprivation prevents FGF2‐mediated uPA mRNA over‐expression and cell‐associated plasminogen activator (PA) production in GM7373 endothelial cell line. We verified that FGF2 stimulates poly(ADP‐ribose) polymerase activity by a DNA strand breaks‐independent manner which involves a mitogen‐activated protein kinases (MAPK)‐dependent pathway, as confirmed by using PD98059 inhibitor and anisomycin stimulation. Poly(ADP‐ribose) polymerase involved in this mechanism is mainly the 60 kDa molecular mass isoform, that presents an increase in serine phosphorylation in the presence of FGF2. © 2005 Wiley‐Liss, Inc.
Interleukin 11 signaling in 3T3‐L1 adipocytes
Authors: Tenney Raleigh , Stansfield Karrie , Pekala Phillip H.
Published: June 2004

Interleukin 11 (IL‐11) is an anti‐inflammatory cytokine with receptors located on most cell types and tissues throughout the body. Its anti‐inflammatory properties are mediated through suppression of cytokine synthesis, in large part by prevention of NF‐κB activation. As adipose tissue synthesizes and secretes cytokines involved in establishing insulin resistance and due to the ability of IL‐11 to suppress cytokine synthesis, we initiated an investigation to determine the signal transduction pathways initiated by IL‐11 in adipose tissue. Using the 3T3‐L1 adipocyte cell culture model we demonstrate the rapid activation of the p44/42MAP kinase, PI3‐kinase, and STATs 1 and 3. Activation of MAP kinase is demonstrated to lead to the downstream activation of p90 RSK (ribosomal S6 kinase) as well as ATF‐1 and CREB. PI3‐kinase appears to activate the downstream target of p70 S6 kinase resulting in phosphorylation of ribosomal protein S6. STAT phosphorylation appears to be initiated through PI3‐kinase and to a lesser degree through p44/42 MAP kinase. These studies demonstrate the activation of three major signaling pathways and support a role for IL‐11 in the regulation of both transcription and protein synthesis in fully differentiated adipocytes. © 2005 Wiley‐Liss, Inc.
A Gβγ stimulated adenylyl cyclase is involved in xenopus laevis oocyte maturation
Authors: Guzmán Leonardo , Romo Ximena , Grandy Rodrigo , Soto Ximena , Montecino Martín , Hinrichs Maríavictoria , Olate Juan
Published: June 2004

Xenopus laevis oocyte maturation is induced by the steroid hormone progesterone through a nongenomic mechanism that implicates the inhibition of the effector system adenylyl cyclase (AC). Recently, it has been shown that the G protein βγ heterodimer is involved in oocyte maturation arrest. Since AC is the proposed target for Gβγ action, we considered of importance to identify and characterize the Gβγ regulated AC isoform(s) that are expressed in the Xenopus oocyte. Through biochemical studies, we found that stage VI plasma membrane oocyte AC activity showed attributes of an AC2 isoform. Furthermore, exogenous Gβγ was capable to activate oocyte AC only in the presence of the activated form of Gαs (Gαs‐GTPγS), which is in agreement with the Gγβ conditional activation reported for the mammalian AC2 and AC4 isotypes. In order to study the functional role of AC in oocyte maturation we cloned from a Xenopus oocyte cDNA library a gene encoding an AC with high identity to AC7 (xAC7). Based on this sequence, we constructed a minigene encoding the AC‐Gβγ interacting region (xAC7pep) to block, within the oocyte, this interaction. We found that microinjection of the xAC7pep potentiated progesterone‐induced maturation, as did the AC2 minigene. From these results we can conclude that a Gβγ‐activated AC is playing an important role in Xenopus oocyte meiotic arrest in a Gαs‐GTP dependent manner. © 2005 Wiley‐Liss, Inc.
Survival Capacity of Haploid‐Diploid Goldfish Chimeras
Authors: Tanaka Minoru , Yamaha Etsuro , Arai Katsutoshi
Published: June 2004

In teleosts, haploidy has been considered to be inviable due to the expression of abnormalities during embryogenesis, but the recent report of live haploid‐diploid mosaic fish suggests the probable improvement of survival capacity by adding diploid cells or tissues to haploid embryos. In order to examine such possibilities, two types of haploid‐diploid goldfish chimeric embryos were produced by transplantation of blastoderm between the normally fertilized diploid and the artificially induced gynogenetic haploid: the haploid‐base chimera with the diploid upper half on the haploid lower half blastoderm and the diploid‐base chimera with the haploid upper half on the diploid lower half blastoderm. Fluorescent detection of FITC‐labeled cells, subsequent histochemical detection of biotin‐labeled haploid cells and flow‐cytometrical detection of both haploid and diploid cells proved successful induction of the haploid‐diploid chimera. Both types of chimeric embryos demonstrated much better survival capacity than pure haploid individuals, but all the haploid‐base chimeras died before 10 days after fertilization due to the expression of edema, whereas several diploid‐base chimeras survived until 16 months after fertilization when the experiment was ended. This concluded diploid‐base chimeras became viable by adding diploid cells to haploid embryos. However, the proportion of transplanted haploid cells was reduced and the distribution of these cells was limited to certain organs because survivors exhibited haploid cells only in brain, eye and/or skin. These results suggest possible elimination of haploid cells from the organs originated from ectoderm. J. Exp. Zool. 301A:491–501, 2004. © 2004 Wiley‐Liss, Inc.