Simulation model for shapiro time delay and light deflection experiments

The time delay experiment proposed by I.I. Shapiro in 1964 and conducted in the seventies was the most precise experiment of general relativity until that time. Further experimentation has improved the accuracy level of both the time delay and the light deflection experiments. A simulation model is proposed that involves only a simple mass and time transformation factor involving velocity of light. The light deflection and the time delay experiments are numerically simulated using this model that does not use the general relativistic equations. The computed values presented in this paper compare well with recent levels of accuracy of their respective experimental results.     

The preparation of hot-pressed chalcogenide spinels. II. Stoichiometry and optical transparency in CdCr2S4 and CoCr2S4

The compounds CdCr₂S₄ and CoCr₂S₄ have been hot pressed into disks that are highly transparent in the infrared. Stoichiometry has been altered by varying the $\text{Cr}{}^{\mathrm{3+}}\text{M}{}^{\mathrm{2+}}$ ratio, where M²⁺ is Cd²⁺ or Co²⁺. The effects of nonstoichiometry on optical transmission were determined. Excess M²⁺ attenuates the transmission much more than excess Cr³⁺.     

Free energy derivatives: A new method for probing the convergence problem in free energy calculations

The convergence behavior of free energy calculations has been explored in more detail than in any previously reported work, using a model system of two neon atoms in a periodic box of water. We find that for thermodynamic integration-type free energy calculations as much as a nanosecond or more molecular dynamics sampling is required to obtain a fully converged value for a single λ point of the integrand. The concept of “free energy derivatives” with respect to the individual parameters of the force field is introduced. This formalism allows the total convergence of the simulation to be deconvoluted into components. A determination of the statistical “sampling ratio” from these simulations indicates that for window-type free energy calculations carried out in a periodic waterbox of typical size at least 0.6 ps of sampling should be performed at each window (0.7 ps if constraint contributions to the free energy are being determined). General methods to estimate and reduce the error in thermodynamic integration and free energy perturbation calculations are discussed. We show that the difficulty in applying such methods is determining a reliable estimate of the correlation length from a short series of data. © 1994 by John Wiley & Sons, Inc.     

A Novel Electron-Conformational Approach to Molecular Modeling for QSAR by Identification of Pharmacophore and Anti-Pharmacophore Shielding

Abstract

A novel method of pharmacophore identification and activity prediction in structure-activity (structure-property) relationships is worked out as an essential extension and improvement of previous publications. In this method each conformation of the molecular systems in the training set of the SAR problem is presented by both electronic structure and geometry parameters arranged in a matrix form. Multiple comparisons of these matrices for the active and inactive compounds allows one to separate a smaller number of matrix elements that are common for all the active compounds and are not present in the same arrangement in the inactive ones. This submatrix of activity represents the pharmacophore (Pha).

By introducing the Anti-Pharmacophore Shielding (APS) defined as molecular groups and competing charges outside the Pha that hinder the proper docking of the Pha with the bioreceptor, the procedure of Pha identification is essentially reduced to the treatment of a smaller number of simplest in structure most active and inactive compounds. A simple empirical scheme is suggested to estimate the APS numerically, while the contributions of different conformations of the same compound are taken into account by means of Boltzmann distribution. This enables us to make approximate quantitative predictions of activities.

In application to rice blast activity we reached an approximately 100% (within experimental error) prediction probability of the activity qualitatively (yes, no), and with r ² = 70% quantitatively.     

The preparation of hot-pressed chalcogenide spinels

The preparation of chalcogenide spinel powders is reviewed. Microcrystalline powders are formed by the thermal reaction of mixtures of anhydrous cadmium and chromium chlorides or coprecipitated cadmium and chromium hydroxides with H₂S, Ar + CS₂, or H₂ + Se. These spinel powders are hot pressed to form highly dense, polycrystalline disks. The effects of pressing variables on optical absorption coefficients are given. The spinel powders and hot-pressed disks are characterized and optical spectra, refractive index, and Faraday rotation data are given.     

AAK1 identified as an inhibitor of neuregulin-1/ErbB4-dependent neurotrophic factor signaling using integrative chemical genomics and proteomics

Target identification remains challenging for the field of chemical biology. We describe an integrative chemical genomic and proteomic approach combining the use of differentially active analogs of small molecule probes with stable isotope labeling by amino acids in cell culture-mediated affinity enrichment, followed by subsequent testing of candidate targets using RNA interference-mediated gene silencing. We applied this approach to characterizing the natural product K252a and its ability to potentiate neuregulin-1 (Nrg1)/ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4)-dependent neurotrophic factor signaling and neuritogenesis. We show that AAK1 (adaptor-associated kinase 1) is a relevant target of K252a, and that the loss of?AAK1?alters ErbB4 trafficking and expression levels,?providing evidence for a previously unrecognized role for AAK1 in Nrg1-mediated neurotrophic?factor signaling. Similar strategies should lead to the discovery of novel targets for therapeutic development.     

A new approach to the furan degradation problem involving ozonolysis of the trans-enedione and its use in a cost-effective synthesis of eplerenone

[reaction: see text] Whereas ozonization of furan 3a affords little or no carboxylic acid 5, ozonization of the corresponding trans-enedione 6 afforded carboxylic acid 5 in 82.4% yield (cryst., overall from furan, 100 g scale; after workup with dimethyl sulfide, followed by mildly basic hydrogen peroxide). This new approach to furan degradation is showcased in a cost-effective synthesis of eplerenone, an important new medicine for cardiovascular indications.     

Technical aspects and evaluation methodology for the application of two automated brain MRI tumor segmentation methods in radiation therapy planning

The purpose of this study was to design the steps necessary to create a tumor volume outline from the results of two automated multispectral magnetic resonance imaging segmentation methods and integrate these contours into radiation therapy treatment planning. Algorithms were developed to create a closed, smooth contour that encompassed the tumor pixels resulting from two automated segmentation methods: k-nearest neighbors and knowledge guided. These included an automatic three-dimensional (3D) expansion of the results to compensate for their undersegmentation and match the extended contouring technique used in practice by radiation oncologists. Each resulting radiation treatment plan generated from the automated segmentation and from the outlining by two radiation oncologists for 11 brain tumor patients was compared against the volume and treatment plan from an expert radiation oncologist who served as the control. As part of this analysis, a quantitative and qualitative evaluation mechanism was developed to aid in this comparison. It was found that the expert physician reference volume was irradiated within the same level of conformity when using the plans generated from the contours of the segmentation methods. In addition, any uncertainty in the identification of the actual gross tumor volume by the segmentation methods, as identified by previous research into this area, had small effects when used to generate 3D radiation therapy treatment planning due to the averaging process in the generation of margins used in defining a planning target volume.     

Characterization of a trace by-product of the synthesis of the protease inhibitor tipranavir (PNU-140690)

Tipranavir^TM (PNU-140690) is a protease inhibitor under clinical investigation for the treatment of human acquired immunodeficiency syndrome (AIDS). During scale-up synthesis of clinical quantities of the bulk drug, a colored, transient by-product of the final coupling reaction was observed. Quantities of this colored, transient chemical species were too low (<<0.1%) for characterization by conventional spectroscopic methods. It was, however, possible to isolate sufficient material for characterization based on mass spectrometry and submicro inverse-detection gradient (SMIDG) nmr methods by methanol stripping of silica gel that had been used in purification of bulk drug. This process afforded an enriched feedstock from which small quantities of this highly colored and unstable (halflife < 18 hours in methanol and < 10 minutes in acetone) trace contaminant could be isolated by semi preparative reversed phase hplc. The impurity was identified as an unstable Zincke salt formed by the condensation of two molecules of the anilino precursor and the pyridine used as a base in the final step of the synthetic process. Following identification of this impurity, efforts were undertaken to engineer it out of the synthetic process.