Futtermittel

Ohne Zusammenfassung     

The effect of antagonists on the conformational exchange of the retinoid X receptor alpha ligand‐binding domain

The effect of retinoid X receptor (RXR) antagonists on the conformational exchange of the RXR ligand‐binding domain (LBD) remains poorly characterized. To address this question, we used nuclear magnetic resonance spectroscopy to compare the chemical shift perturbations induced by RXR antagonists and agonists on the RXRα LBD when partnered with itself as a homodimer and as the heterodimeric partner with the peroxisome proliferator‐activated receptor γ (PPARγ) LBD. Chemical shift mapping on the crystal structure showed that agonist binding abolished a line‐broadening effect caused by a conformational exchange on backbone amide signals for residues in helix H3 and other regions of either the homo‐ or hetero‐dimer, whereas binding of antagonists with similar binding affinities failed to do so. A lineshape analysis of a glucocorticoid receptor‐interacting protein 1 NR box 2 coactivator peptide showed that the antagonists enhanced peptide binding to the RXRα LBD homodimer, but to a lesser extent than that enhanced by the agonists. This was further supported by a lineshape analysis of the RXR C‐terminal residue, threonine 462 (T462) in the homodimer but not in the heterodimer. Contrary to the agonists, the antagonists failed to abolish a line‐broadening effect caused by a conformational exchange on the T462 signal corresponding to the RXRα LBD–antagonist–peptide ternary complex. These results suggest that the antagonists lack the ability of the agonists to shift the equilibrium of multiple RXRα LBD conformations in favor of a compact state, and that a PPARγ LBD‐agonist complex can prevent the antagonist from enhancing the RXRα LBD‐coactivator binding interaction. Copyright © 2009 John Wiley & Sons, Ltd.     

Rapid generation of an anthrax immunotherapeutic from goats using a novel non-toxic muramyl dipeptide adjuvant

Background  

There is a clear need for vaccines and therapeutics for potential biological weapons of mass destruction and emerging diseases. Anthrax, caused by the bacterium Bacillus anthracis, has been used as both a biological warfare agent and bioterrorist weapon previously. Although antibiotic therapy is effective in the early stages of anthrax infection, it does not have any effect once exposed individuals become symptomatic due to B. anthracis exotoxin accumulation. The bipartite exotoxins are the major contributing factors to the morbidity and mortality observed in acute anthrax infections.     

A note on the error analysis of classical Gram–Schmidt

An error analysis result is given for classical Gram–Schmidt factorization of a full rank matrix A into A = QR where Q is left orthogonal (has orthonormal columns) and R is upper triangular. The work presented here shows that the computed R satisfies R ^T R = A ^T A + E where E is an appropriately small backward error, but only if the diagonals of R are computed in a manner similar to Cholesky factorization of the normal equations matrix. At the end of the article, implications for classical Gram–Schmidt with reorthogonalization are noted.A similar result is stated in Giraud et al. (Numer Math 101(1):87–100, 2005). However, for that result to hold, the diagonals of R must be computed in the manner recommended in this work.Jesse Barlow’s research was supported by the National Science Foundation under grant no. CCF-0429481.     

Thrust distribution and decays of the ϒ bound states

We have studied the topologies of hadronic events in e⁺e^- annihilation data taken in the region of the upsilon resonances with the non-magnetic CUSB detectors at CESR. Using a thrust-like variable we compare the decay of ?, ?′ and ?Prime; find for ?″ a significant excess of high thrust events, which we interpret as evidence for electric dipole transitions.     

Point defects and diffusion in NiO

A defect model for NiO is developed and is fit to the electrical-conductivity data [26], the deviation-from-stoichiometry data [7], and the cation-self-diffusion data [14, 17]. This model involves neutral, singly charged, and doubly charged nickel vacancies and charge-compensating electron holes. Both singly and doubly charged cation vacancies are required to explain the data; neutral cation vacancies (if present) are not required by the present data. However, the jump frequencies of the two types of charged cation vacancies are generally not equal; the doubly charged cation vacancy moves with the smaller activation enthalpy. The defect data are quantitatively consistent with the chemical-diffusion data [26] and with a correlation factor?v = 0.75.     

Conformational searching methods for small molecules. I. Study of the sybyl search method

Several methods are available in the literature for the conformational analysis of small molecules. Each of these methods has some advantages and some disadvantages. Also, each of these methods may be expected to perform better or worse on different types of molecules. There is no clear calibration of each of these methods against a “standardized” set of molecules available in the literature. Such a reference work would be useful to the community because it would allow the choice of methods to be based on some facts. We attempted to provide a start to such a calibration in this article with an examination of the SYBYL SEARCH method. Methods for evaluating the performance of this method are described in detail and will be applied to all other available conformational analysis methods in future papers. © John Wiley & Sons, Inc.