16 research outputs found
Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases
Artificial endonucleases consisting of a Fokl cleavage domain tethered to engineered zinc-finger DNA-binding proteins have proven useful for stimulating homologous recombination in a variety of cell types. Because the catalytic domain of zinc-finger nucleases (ZFNs) must dimerize to become active, two subunits are typically assembled as heterodimers at the cleavage site. The use of ZFNs is often associated with significant cytotoxicity, presumably due to cleavage at off- target sites. Here we describe a structure- based approach to reducing off- target cleavage. Using in silico protein modeling and energy calculations, we increased the specificity of target site cleavage by preventing homodimerization and lowering the dimerization energy. Cell-based recombination assays confirmed that the modified ZFNs were as active as the original ZFNs but elicit significantly less genotoxicity. The improved safety profile may facilitate therapeutic application of the ZFN technology
Perception of pain following rectal administration of morphine in children: a comparison of a gel and a solution
Using force data to self-pace an instrumented treadmill and measure self-selected walking speed
Chemical characteristics and acid drainage assessment of mine tailings from Akara Gold mine in Thailand
Association between tumor-infiltrating lymphocytes and sentinel lymph node positivity in thin melanoma
Understanding the do-it-yourself consumer: DIY motivations and outcomes
Do-it-yourself (DIY) is an increasingly popular consumer behavior, but little is known about this large consumer segment. We undertake a depth interview study and review diverse literatures to develop a conceptual model of DIY behavior that explores the reasons why consumers DIY and the benefits they receive. The purpose of the model is to improve our understanding of a consumer segment that, in many ways, behaves differently from typical consumers. Research propositions are derived and discussions of implications and ideas for future research follow
Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity
Synergistic effects of social media and traditional marketing on brand sales: capturing the time-varying effects
Tuberculosis progression rates in U.S. Immigrants following screening with interferon-gamma release assays
Arene-fused 1,2-oxazole N-oxides and derivatives. The impact of the N-O dipole and substitution on their aromatic character and reactivity profile. Can it be a useful structure in synthesis? A theoretical insight
DFT calculations have shown that the N-O dipole of benzene- and naphthalene-fused 1,2-oxazole N-oxides causes a distortion of their σ and π frame, concentrated on the 1,2-oxazole ring, such that it increases its susceptibility to opening. The distortion forces the benzene ring into some diene geometry, thus, reducing π delocalization over the bi- or tricyclic structure and ultimately their aromatic character. C-3 substitution has a marked influence mainly on the naphthalene-fused N-oxides. C-5 and particularly C-6 substitution, as the position of most extended interaction with the N-O dipole through the π ring density, contribute to the distortion of the 1,2-oxazole geometry and thereby to the decrease of aromaticity of the structure. Bond uniformity (IA), average bond order (ABO) and Harmonic Oscillator Model of Aromaticity (HOMA) indices have been recruited to measure aromaticity changes. IA and ABO appear to be more credible to 1,2-benzoxazole N-oxides and 1,2-naphthoxazole N-oxides, respectively, while HOMA has been found equally reliable to both. Hardness and dipole moments follow similar trends. Energies, localization and separation of the four frontiers orbitals, i.e. HO, HO-1, and LU, LU+1, indicate a rather notable aromatic character of the N-oxides. Their reactivity profile, portrayed by descriptors such as Fukui and electro(nucleo)philicity Parr functions, shows good agreement with experimental outcomes towards electrophiles but succumbs to discrepancies towards nucleophiles due to the susceptibility of the hetero-ring to opening. The "push-pull" character of the N-O dipole and more importantly the extent of its double bonding direct site selectivity.Peer reviewe