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.     

Preparation of adamantyl derivatives of 1,4‐; 1,6‐ and 1,7‐dihydroxynaphthalenes and assignment of their NMR data

Adamantylation of dihydroxynaphthalenes with the hydroxyl groups on the same or different rings leads to compounds that are convenient starting materials in target‐oriented organic synthesis. Here, we report the ¹H and ¹³C NMR assignments of eight 1‐adamantyl substituted derivatives of 1,4‐; 1,6‐ and 1,7‐dihydroxynaphthalenes. The data acquired and peculiarities of their molecular structure are useful for extrapolation for prompt characterization of compounds containing adamantane, dihydroxynaphthalenes or naphthoquinone units. Copyright © 2013 John Wiley & Sons, Ltd.     

Insensitive Functionals,Inconsistent Gradients,Spurious Minima,and Regularized Functionals in Flow Optimization Problems

We use the simple context of Navier-Stokes flow in a channel with a bump to examine problems caused by the insensitivity of functionals with respect to design parameters, the inconsistency of functional gradient approximations, and the appearance of spurious minima in discretized functionals. We discuss how regularization can help overcome these problems. Along the way, we compare the discretize-then-differentiate and differentiate-then-discretize approaches to optimization, especially as they relate to the issue of inconsistent functional gradients. We close with a discussion of the implications that our observations have on more practical flow control and optimization problems.     

Thermal transitions in and structures of dried polyelectrolytes and polyelectrolyte complexes

Dynamic mechanical analysis (DMA) was used to explore the thermomechanical properties of dried polyelectrolytes and polyelectrolyte complexes (PECs) with different thermal and humidity histories. Although differences in the amount of water remaining in polyelectrolytes and PECs were small for ambient versus dessicator storage, the properties of polyelectrolyte‐based materials were drastically different for different humidity histories. Glass transition temperatures (T_gs) of poly(diallyldimethylammonium chloride) (PDADMAC) were shown to vary by 100 °C, depending on humidity and thermal histories. These parameters also change glassy storage modulus values by 100%. Furthermore, we observe that dried PDADMAC is highly lossy. DMA of dried poly(styrene sulfonate) (PSS) was more complex and did not exhibit a glass transition in the tested range. DMA of a PEC of PDADMAC and PSS revealed a humidity history‐dependent water melt in the first heating cycle, as well as storage modulus values of dried and annealed PECs that only varied by 17–26% over a 275 °C temperature range. Based on these results, we report for the first time humidity history as controlling structure and properties of polyelectrolyte‐based materials. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2017 , 55, 684–691