Local and semilocal density functional computations for crystals of 1-alkyl-3-methyl-imidazolium salts

The accuracy and reliability of popular density functional approximations for the compounds giving origin to room temperature ionic liquids have been assessed by computing the T=0 K crystal structure of several 1-alkyl-3-methyl-imidazolium salts. Two prototypical exchange-correlation approximations have been considered, i.e., the local density approximation (LDA) and one gradient corrected scheme [PBE-GGA, Phys. Rev. Lett. 77, 3865 (1996)]. Comparison with low-temperature x-ray diffraction data shows that the equilibrium volume predicted by either approximations is affected by large errors, nearly equal in magnitude (~10%), and of opposite sign. In both cases the error can be traced to a poor description of the intermolecular interactions, while the intramolecular structure is fairly well reproduced by LDA and PBE-GGA. The PBE-GGA optimization of atomic positions within the experimental unit cell provides results in good agreement with the x-ray structure. The correct system volume can also be restored by supplementing PBE-GGA with empirical dispersion terms reproducing the r-6 attractive tail of the van der Waals interactions.

Direct Sensing in Liquids Using Whispering-Gallery-Mode Droplet Resonators

Liquid droplets suspended by the tip of a thin wire, a glass capillary, or a needle form high-Q optical resonators, thanks to surface tension. Under gravity equilibrium conditions, the maximum drop diameter is approximately 1.5 mm for paraffin oil (volume ∼ 0.5 μL) using, for instance, a silica fiber with 250 μm thickness. Whispering gallery modes are excited by a free-space near-infrared laser that is frequency locked to the cavity resonance. The droplet cavity serves as a miniature laboratory for sensing of chemical species and particles.

Ion Association in [bmim][PF6]/Naphthalene Mixtures: An Experimental and Computational Study

Mixtures of room temperature ionic liquids (IL) with neutral organic molecules provide a valuable testing ground to investigate the interplay of the ionic and molecular-dipolar state in dense Coulomb systems at near ambient conditions. In the present study, the viscosity eta and the ionic conductivity a of 1-n-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6])/naphthalene mixtures at T = 80 degrees C have been measured at 10 stoichiometries spanning the composition range from pure naphthalene to pure [bmim][PF6]. The viscosity grows nearly monotonically with increasing IL mole fraction (x), whereas the conductivity per ion displays a clear peak at x approximate to 15%. The origin of this maximum has been investigated using molecular dynamics simulations based on a classical force field. Snapshots of the simulated samples show that the conductivity maximum is due to the gradual transition in the IL component from an ionic state at high x to a dipolar fluid made of neutral ion pairs at low x. At concentrations x <0.20 the ion pairs condense into molecular-thin filaments bound by dipolar forces and extending in between nanometric droplets of IL. These results are confirmed and complemented by the computation of dynamic and transport properties in [bmim][PF6]/naphthalene mixtures at low IL concentration.

Evaluation of the antiangiogenic potential of AQ4N.

Purpose: A number of cytotoxic chemotherapy agents tested at low concentrations show antiangiogenic properties with limited cytotoxicity, e.g., cyclophosphamide, tirapazamine, and mitoxantrone. AQ4N is a bioreductive alkylaminoanthraquinone that is cytotoxic when reduced to AQ4; hence, it can be used to target hypoxic tumor cells. AQ4N is structurally similar to mitoxantrone and was evaluated for antiangiogenic properties without the need for bioreduction.

Experimental Design:The effect of AQ4N and fumagillin on human microvascular endothelial cells (HMEC-1) was measured using a variety ofin vitro assays, i.e., 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide, wound scrape, tubule formation, rat aortic ring, and invasion assays. Low-dose AQ4N (20 mg/kg) was also given in vivo to mice bearing a tumor in a dorsal skin flap.

Results:AQ4N (10-11to10-5mol/L) hadno effect on HMEC-1viability. AQ4N (10-9to10-5mol/L) caused a sigmoidal dose-dependent inhibition of endothelial cell migration in the wound scrape model. Fumagillin showed a similar response over a lower dose range (10-13 to 10-9 mol/L); however, the maximal inhibition was less (25% versus 43% for AQ4N). AQ4N inhibited HMEC-1 cell contacts on Matrigel (10-8 to 10-5 mol/L), HMEC-1 cell invasion, and sprouting in rat aorta explants. Immunofluorescence staining with tubulin, vimentim, dynein, and phalloidin revealed that AQ4N caused disruption to the cell cytoskeleton. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap.

Conclusions:This combination of assays has shown that AQ4N possesses antiangiogenic effects in normoxic conditions, which could potentially contribute to antitumor activity

Hypoxia selects for androgen independent LNCaP cells with a more malignant geno- and phenotype.

Hypoxia confers resistance to common cancer therapies, however, it has also has been shown to result in genetic alterations which may allow a survival advantage and increase the tumorigenic properties of cancer cells. Additionally, it may exert a selection pressure, allowing expansion of tumor cells with a more aggressive phenotype. To further assess the role of hypoxia in malignant progression in prostate cancer we exposed human androgen dependent prostate cancer cells (LNCaP) to cycles of chronic hypoxia and isolated a subline, LNCaP-H1. This article describes the partial characterization of this cell line. The LNCaP-H1 subline showed altered growth characteristics and exhibited androgen independent growth both in vitro and in vivo. Furthermore, these cells were resistant to mitochondrial-mediated apoptosis, probably since the endogenous levels of Bax was lower and Bcl-2 higher than in the parental LNCaP cells. Microarray analysis revealed that a complex array of pathways had differential gene expression between the 2 cell lines, with LNCaP-H1 cells exhibiting a genetic profile which suggests that they may be more likely metastasize to distant organs, especially bone. This was supported by an in vitro invasion assay, and an in vivo metastasis study. This study shows that hypoxia can select for androgen independent prostate cancer cells which have a survival advantage and are more likely to invade and metastasize.

Spontaneous spin polarization and electron localization in constrained geometries: The Wigner transition in nanowires

The Wigner transition in a jellium model of cylindrical nanowires has been investigated by density-functional computations using the local spin-density approximation. A wide range of background densities rho(b) has been explored from the nearly ideal metallic regime (r(s)=[3/4 pi rho(b)](1/3)=1) to the high correlation limit (r(s)=100). Computations have been performed using an unconstrained plane wave expansion for the Kohn-Sham orbitals and a large simulation cell with up to 480 electrons. The electron and spin distributions retain the cylindrical symmetry of the Hamiltonian at high density, while electron localization and spin polarization arise nearly simultaneously in low-density wires (r(s)similar to 30). At sufficiently low density (r(s)>= 40), the ground-state electron distribution is the superposition of well defined and nearly disjoint droplets, whose charge and spin densities integrate almost exactly to one electron and 1/2 mu(B), respectively. Droplets are arranged on radial shells and define a distorted lattice whose structure is intermediate between bcc and fcc. Dislocations and grain boundaries are apparent in the droplets' configuration found by our simulations. Our computations aim at modeling the behavior of experimental low-carried density systems made of lightly doped semiconductor nanostructures or conducting polymers.

Chk1 Suppresses a Caspase-2 Apoptotic Response to DNA Damage that Bypasses p53, Bcl-2, and Caspase-3

Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore ?-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after ?-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy. © 2008 Elsevier Inc. All rights reserved.

Mechanistic studies of amide bond scission during acidolytic deprotection of Pip containing peptide.

Unusual TFA catalyzed cleavage reaction is reported for peptide containing pipecolic acid residues. Although the use of TFA under standard cleavage conditions is sufficiently mild to prevent degradation of the desired products. the amide bond between consecutive pipecolic acid residues is unexpectedly hydrolyzed by standard TFA treatment. The hydrolysis is proposed to proceed via an oxazolinium ion intermediate, This mechanism is supported by H/D exchange as observed by ESI-MS and NMR experiments.

Malondialdehyde scavenging and aldose-derived Schiff bases' transglycation properties of synthetic histidyl-hydrazide carnosine analogs.

Second-generation carnosine analogs bearing the histidyl-hydrazide moiety have been synthesized and tested for their efficiency in scavenging malondialdehyde (MDA) derived from lipid peroxidation and for their ability to reverse the glycation process in the glucose-ethylamine Schiff base model. The data obtained indicate that this class of compounds maintains the activity profile of carnosine and is a suitable candidate for the treatment of disorders caused by oxidative stress.