A quantitative determination of reaction mechanisms from density functional theory calculations: Fischer-Tropsch synthesis on flat and stepped cobalt surfaces

We systematically investigated the mechanism of the C-1 + C-1 coupling reactions using density functional theory. The activation energies of C-1 + C-1 coupling and carbon hydrogenation reactions on both flat and stepped surfaces were calculated and analyzed. Moreover, the coverages of adsorbed C-1 species were estimated, and the reaction rates of all possible C-1 + C-1 coupling pathways were quantitatively evaluated. The results suggest that the reactions of CH2 + CH2 and CH3 + C at steps are most likely to be the key C-1 + C-1 coupling steps in FT synthesis on Co catalysts. The reactions of C-2 + C-1 and C-3 + C-1 coupling also were studied; the results demonstrate that in addition to the pathways of RCH + CH2 and RCH2 + C, the coupling of RC + C and RC + CH also may contribute to the chain growth after C-1. (C) 2008 Elsevier Inc. All rights reserved.

Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4)

This Letter describes the synthesis and SAR of the novel positive allosteric modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson's disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041. (C) 2009 Elsevier Ltd. All rights reserved.

Solid phase synthesis of Smac/DIABLO-derived peptides using a 'Safety-Catch' resin:Identification of potent XIAP BIR3 antagonists

The N-terminal sequence of the Smac/DIABLO protein is known to be involved in binding to the BIR3 domain of the anti-apoptotic proteins IAPs, antagonizing their action. Short peptides and peptide mimetics based on the first 4-residues of Smac/DIABLO have been demonstrated to re-sensitize resistant cancer cells, over-expressing IAPs, to apoptosis. Based on the well-defined structural basis for this interaction, a small focused library of C-terminal capped Smac/DIABLO-derived peptides was designed in silico using docking to the XIAP BIR3 domain. The top-ranked computational hits were conveniently synthesized employing Solid Phase Synthesis (SPS) on an alkane sulfonamide 'Safety-Catch' resin. This novel approach afforded the rapid synthesis of the target peptide library with high flexibility for the introduction of various C-terminal amide-capping groups. The library members were obtained in high yield (>65%) and purity (>85%), upon nucleophilic release from the activated resin by treatment with various amine nucleophiles. In vitro caspase-9 activity reconstitution assays of the peptides in the presence of the recombinant BIR3-domain of human XIAP (500nM) revealed N-methylalanyl-tertiarybutylglycinyl-4-(R)-phenoxyprolyl-N-biphenylmethyl carboxamide (11a) to be the most potent XIAP BIR3 antagonist of the series synthesized inducing 93% recovery of caspase-9 activity, when used at 1µM concentration. Compound (11a) also demonstrated moderate cytotoxicity against the breast cancer cell lines MDA-MB-231 and MCF-7, compared to the Smac/DIABLO-derived wild-type peptide sequences that were totally inactive in the same cell lines.

Photocatalytic organic synthesis in an NMR tube:CC coupling of phenoxyacetic acid and acrylamide

NMR was used to study the semiconductor photocatalytic (SPC) CC coupling of phenoxyacetic acid (PAA) with acrylamide (ACM) in an NMR tube photoreactor. Using an NMR tube with a sol-gel titania inner coating as a photoreactor, this reaction is relatively clean, forming only 1 product, 4-phenoxybutanamide (4-PB), in yields up to 78%. This SPC reaction is used to assess the activity of the sol-gel titania coating as a function of their annealing temperature, which alters the surface area and phase of the titania, and the general reusability of the TiO coated NMR tubes. The optimum temperature range for annealing the sol-gel titania films is between 450 °C and 800 °C, with the maximum yield and rate attained at 450 °C. Despite a decrease in the initial rates of formation of 4-PB above an annealing temperature of 450 °C, the final product yields remained similar, giving maximum yields within 60 min of irradiation. The reusability study reveals that the activity of the sol-gel titania can quickly deteriorate with repeated use due to the adsorption of yellow/brown coloured, insoluble, most likely organic polymeric, material and its screening effect on the underlying photocatalyst. The titania can, however, be restored to its original activity by a simple heat treatment at 450 °C for 30 min.

Effect of composition, solvent exchange liquid and drying method on the porous structure of phenol-formaldehyde gels

Organic gels have been synthesized by sol–gel polycondensation of phenol (P) and formaldehyde (F) catalyzed by sodium carbonate (C). The effect of synthesis parameters such as phenol/catalyst ratio (P/C), solvent exchange liquid and drying method, on the porous structure of the gels have been investigated. The total and mesopore volumes of the PF gels increased with increasing P/C ratio in the range of P/C B 8, after this both properties started to decrease with P/C ratio for P/C[8 and the gel with P/C = 8 showed the highest total and mesopore volumes of 1.281 and 1.279 cm3 g-1 respectively. The gels prepared by freeze drying possessed significantly higher porosities than the vacuum dried gels. The pore volume and average pore diameter of the freeze dried gels were significantly higher than those of the vacuum dried gels. T-butanol emerged as the preferred solvent for the removal of water from the PF hydrogel prior to drying, as significantly higher pore volumes and specific surface areas were obtained in the corresponding dried gels. The results showed that freeze drying with t-butanol and lower P/C ratios were favourable conditions for the synthesis of highly mesoporous phenol–formaldehyde gels.

Induction of hypertrophic responsiveness of cardiomyocytes to neuropeptide Y in response to pressure overload.

To determine whether neuropeptide Y (NPY)-related mechanisms become activated with progression of cardiac hypertrophy in vivo, protein mass and de novo protein synthesis (incorporation of [(14)C]Phe, 0.1 muCi ml(-1)) were assessed in cardiomyocytes, obtained from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (8, 12, 16, 20, and 24 weeks of age), and cultured for 24 h. NPY (10(-8) M) increased protein mass of cardiomyocytes from 16-week-old SHRs by 9.2 +/- 2.1% (n = 8, P

HI observations of the high-velocity cloud in the direction of M 92

We present wide-field neutral hydrogen (H I) Lovell telescope multibeam, and Dominion Radio Astrophysical Observatory Hi synthesis observations, of the high velocity cloud (HVC) located in the general direction of the globular cluster M92. This cloud is part of the larger Complex C and lies at velocities between similar to -80 and -130 km s(-1) in the Local Standard of Rest. The Lovell telescope observations, of resolution 12 arcmin spatially and 3.0 km s(-1) in velocity, fully sampling a 3.1 degrees x 12.6 degrees RA-Dec grid, have found that this part of HVC Complex C comprises two main condensations, lying approximately north-south in declination, separated by similar to2 degrees and being parallel to the Galactic plane. At this resolution, peak values of the brightness temperature and Hi column density of similar to1.4 K and similar to5 x 10(19) cm(-2) are determined, with relatively high values of the full width half maximum velocity (FWHM) of similar to 22 km s(-1) being observed, equivalent to a gas kinetic temperature, in the absence of turbulence and geometric effects of similar to 10 000 K. Each of these properties, as well as the sizes of the clouds, are similar in the two components. The DRAO observations, towards the Northern HVC condensation, are the first high-resolution Hi spectra of Complex C. When smoothed to a resolution of 3 arcmin, they identify several Hi intensity peaks with column densities in the range 4-7 x 10(19) cm(-2). Further smoothing of these data to 6 arcmin resolution tentatively indicates that parts of the HVC consist of two velocity components, of similar brightness temperature, separated by similar to7 km s(-1) in velocity, and with FWHM velocity widths of similar to5-7 km s(-1). No IRAS 60 or 100 micron flux is associated with the M92 HVC. Cloud properties are briefly discussed and compared to previous observations of HVCs.

A complex zinc finger controls the enzymatic activities of nidovirus helicases.

Nidoviruses (Coronaviridae, Arteriviridae, and Roniviridae) encode a nonstructural protein, called nsp10 in arteriviruses and nsp13 in coronaviruses, that is comprised of a C-terminal superfamily 1 helicase domain and an N-terminal, putative zinc-binding domain (ZBD). Previously, mutations in the equine arteritis virus (EAV) nsp10 ZBD were shown to block arterivirus reproduction by disrupting RNA synthesis and possibly virion biogenesis. Here, we characterized the ATPase and helicase activities of bacterially expressed mutant forms of nsp10 and its human coronavirus 229E ortholog, nsp13, and correlated these in vitro activities with specific virus phenotypes. Replacement of conserved Cys or His residues with Ala proved to be more deleterious than Cys-for-His or His-for-Cys replacements. Furthermore, denaturation-renaturation experiments revealed that, during protein refolding, Zn2+ is essential for the rescue of the enzymatic activities of nidovirus helicases. Taken together, the data strongly support the zinc-binding function of the N-terminal domain of nidovirus helicases. nsp10 ATPase/helicase deficiency resulting from single-residue substitutions in the ZBD or deletion of the entire domain could not be complemented in trans by wild-type ZBD, suggesting a critical function of the ZBD in cis. Consistently, no viral RNA synthesis was detected after transfection of EAV full-length RNAs encoding ATPase/helicase-deficient nsp10 into susceptible cells. In contrast, diverse phenotypes were observed for mutants with enzymatically active nsp10, which in a number of cases correlated with the activities measured in vitro. Collectively, our data suggest that the ZBD is critically involved in nidovirus replication and transcription by modulating the enzymatic activities of the helicase domain and other, yet unknown, mechanisms.

Fully fluorinated imidodiphosphinate shells for visible- and NIR-Emitting lanthanides: Hitherto unexpected effects of sensitizer fluorination on lanthanide emission properties

In this paper we demonstrate that the effect of aromatic C-F substitution in ligands does not always abide by conventional wisdom for ligand design to enhance sensitisation for visible lanthanide emission, in contrast with NIR emission for which the same effect coupled with shell formation leads to unprecedented long luminescence lifetimes. We have chosen an imidodiphosphinate ligand, N-{P,P-di-(pentafluorophinoyl)}-P,P-dipentafluoro-phenylphosphinimidic acid (HF(20)tpip), to form ideal fluorinated shells about all visible- and NIR-emitting lanthanides. The shell, formed by three ligands, comprises twelve fully fluorinated aryl sensitiser groups, yet no-high energy X-H vibrations that quench lanthanide emission. The synthesis, full characterisation including X-ray and NMR analysis as well as the photophysical properties of the emissive complexes [Ln(F(20)tpip)(3)], in which Ln=Nd, Sm, Eu, Gd, Tb, Dy, Er, Yb, Y, Gd, are reported. The photophysical results contrast previous studies, in which fluorination of alkyl chains tends to lead to more emissive lanthanide complexes for both visible and NIR emission. Analysis of the fluorescence properties of the HF(20)tpip and [Gd(F(20)tpip)(3)] reveals that there is a low-lying state at around 715 nm that is responsible for partially quenching of the signal of the visible emitting lanthanides and we attribute it to a pi-sigma* state. However, all visible emitting lanthanides have long lifetimes and unexpectedly the [Dy(F(20)tpip)(3)] complex shows a lifetime of 0.3 ms, indicating that the elimination of high-energy vibrations from the ligand framework is particularly favourable for Dy. The NIR emitting lanthanides show strong emission signals in powder and solution with unprecedented lifetimes. The luminescence lifetimes of [Nd(F(20)tpip)(3)], [Er(F(20)tpip)(3)] and [Yb(F(20)tpip)(3)] in deuteurated acetonitrile are 44, 741 and 1111 mu s. The highest value observed for the [Yb(F(20)tpip)(3)] complex is more than half the value of the Yb ion radiative lifetime.

Molecular cloning and deduced organization of the pHpG/CNP precursor from the venom of the African forest viper, Atheris squamigera

The discovery that the hypotensive sequela of envenomation by the South American viper, Bothrops jararaca, was mediated by peptides, represented a milestone in drug discovery research that led to the introduction of ACE inhibitors. These bradykinin-potentiating peptides (BPPs) have been found in the venoms of many species of viper and molecular cloning of biosynthetic precursors has revealed that each encodes several different BPPs in tandem with a single copy of a C-type natriuretic peptide (CNP) located at the C-terminus. Venoms of the African forest vipers (Atheris) have been poorly studied possibly because they do not represent a major danger to humans. However, initial studies have indicated that they contain some of the “classical” protein toxins of viper venoms and a novel class of peptide, the polyglycine/polyhistidine (pGpH) peptides. These peptides occur in several molecular forms with different numbers of repetitive glycine and histidine repeats. We have cloned the biosynthetic precursor of A. squamigera pGpH peptides from a venom-derived cDNA library and have confirmed that a single copy of CNP is located at the C-terminus and additionally that, like BPPs in other vipers, pGpH peptides are encoded in tandem within this single precursor. Solid phase peptide synthesis of pGpH peptides has proven to be extremely difficult but is progressing and acquisition of synthetic replicates of each peptide is a necessary prerequisite for systematic pharmacological characterisation as establishment of a biological function for these peptides remains elusive. pGpH peptides may prove to play a role as fundamental as that of the BPPs.

Compromised Spindle Assembly Checkpoint due to Altered Expression of Ubch10 and Cdc20 in Human Papillomavirus Type 16 E6 and E7-Expressing Keratinocytes

Cells expressing human papillomavirus type 16 (HPV-16) E6 and E7 proteins exhibit deregulation of G(2)/M genes, allowing bypass of DNA damage arrest signals. Normally, cells with DNA damage that override the G(2) damage checkpoint would precociously enter mitosis and ultimately face mitotic catastrophe and apoptotic cell death. However, E6/E7-expressing cells (E6/E7 cells) have the ability to enter and exit mitosis in the presence of DNA damage and continue with the next round of the cell cycle. Little is known about the mechanism that allows these cells to gain entry into and exit from mitosis. Here, we show that in the presence of DNA damage, E6/E7 cells have elevated levels of cyclin B, which would allow entry into mitosis. Also, as required for exit from mitosis, cyclin B is degraded in these cells, permitting initiation of the next round of DNA synthesis and cell cycle progression. Proteasomal degradation of cyclin B by anaphase-promoting complex/cyclosome (APC/C) is, in part, due to elevated levels of the E2-conjugating enzyme, Ubch10, and the substrate recognition protein, Cdc20, of APC/C. Also, in E6/E7 cells with DNA damage, while Cdc20 is complexed with BubR1, indicating an active checkpoint, it is also present in complexes free of BubR1, presumably allowing APC/C activity and slippage through the checkpoint.

Metabolism of very low- and low-density lipoproteins isolated from normolipidaemic type 2 (non-insulin-dependent) diabetic patients by human monocyte-derived macrophages

The very low- and low-density lipoprotein fractions were isolated from 16 normolipidaemic Type 2 (non-insulin-dependent) diabetic patients in good to fair glycaemic control and from corresponding age-, sex-, and race-matched, non-diabetic control subjects. Rates of cholesteryl ester synthesis averaged 268 +/- 31 vs 289 +/- 40 pmol 14C-cholesteryl oleate.mg cell protein-1.20 h-1 for very low- and 506 +/- 34 vs 556 +/- 51 pmol 14C-cholesteryl oleate.mg cell protein-1.20 h-1 for low-density lipoproteins isolated from the Type 2 diabetic patients and control subjects, respectively, when they were incubated with human macrophages. A group of approximately one-third of the patients was selected for separate analyses because very low-density lipoproteins isolated from these patients did stimulate more cholesteryl ester synthesis when incubated with macrophages. There were no significant differences in the lipid composition of the lipoproteins isolated from the three groups of subjects. The relative proportion of apoprotein C to apoprotein E was significantly decreased (p less than 0.002) in the very low-density lipoproteins from diabetic patients and was further decreased in samples from these selected diabetic patients. The apoprotein C-I content of very low-density lipoproteins isolated from diabetic patients was increased compared to control subjects and was further increased in samples from the selected diabetic patients (p less than 0.02). There were no significant differences in the proportions of apoproteins C-III-0, C-III-1, or C-III-2 among the three groups. These studies suggest that in normolipidaemic Type 2 diabetic patients, the apoprotein composition of VLDL is abnormal and this may alter VLDL macrophage interactions and thus contribute to the increased prevalence of atherosclerosis in diabetic patients.

Insights into the Staggered Nature of Hydrogenation Reactivity over the 4d Transition Metals

Hydrogenation reactions at transition metal surfaces comprise a key set of reactions in heterogeneous catalysis. In this paper, density functional theory methods are employed to take an in-depth look at this fundamental reaction type. The energetics of hydrogenation of atomic C, N, and O have been studied in some detail over low index Zr, Nb, Mo, Tc, Ru, Rh, and Pd surfaces. Detailed bonding analysis has also been employed to track carefully the chemical changes taking place during reaction. A number of interesting horizontal and vertical trends have been uncovered relating to reactant valency and metal d-band filling. A general correlation has also been found between the reaction barriers and the reaction potential energies. Moreover, when each reaction is considered independently, correlation has been found to improve with decreasing reactant valency. Bonding analysis has pointed to this being related to the relative position of the transition state along the reaction coordinate and has shown that as reactant valency decreases, the transition states become progressively later.

Evaluation of La1−xSrxMnO3 (0 ≤ x < 0.4) synthesised via a modified sol–gel method as mediators for magnetic fluid hyperthermia

A range of lanthanum strontium manganates (La1−xSrxMnO3–LSMO) where 0 ≤ x < 0.4 were prepared using a modified peroxide sol–gel synthesis method. The magnetic nanoparticle (MNP) clusters obtained for each of the materials were characterised using scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and infra-red (IR) spectroscopy in order to confirm the crystalline phases, crystallite size and cluster morphology. The magnetic properties of the materials were assessed using the Superconducting quantum interference device (SQUID) to evaluate the magnetic susceptibility, Curie temperature (Tc) and static hysteretic losses. Induction heating experiments also provided an insight into the magnetocaloric effect for each material. The specific absorption rate (SAR) of the materials was evaluated experimentally and via numerical simulations. The magnetic properties and heating data were linked with the crystalline structure to make predictions with respect to the best LSMO composition for mild hyperthermia (41 °C ≤ T ≤ 46 °C). La0.65Sr0.35MnO3, with crystallite diameter of 82.4 nm, (agglomerate size of ∼10 μm), Tc of 89 °C and SAR of 56 W gMn−1 at a concentration 10 mg mL−1 gave the optimal induction heating results (Tmax of 46.7 °C) and was therefore deemed as most suitable for the purposes of mild hyperthermia, vide infra.

Equilibrium polymerization of cyclic carbonate oligomers. III. Chain branching and the gel transition

Ring-opening polymerization of cyclic polycarbonate oligomers, where monofunctional active sites act on difunctional monomers to produce an equilibrium distribution of rings and chains, leads to a "living polymer." Monte Carlo simulations [two-dimensional (2D) and three-dimensional (3D)] of the effects of single [J. Chem. Phys. 115, 3895 (2001)] and multiple active sites [J. Chem. Phys. 116, 7724 (2002)] are extended here to trifunctional active sites that lead to branching. Low concentrations of trifunctional particles c(3) reduce the degree of polymerization significantly in 2D, and higher concentrations (up to 32%) lead to further large changes in the phase diagram. Gel formation is observed at high total density and sizable c(3) as a continuous transition similar to percolation. Polymer and gel are much more stable in 3D than in 2D, and both the total density and the value of c(3) required to produce high molecular weight aggregates are reduced significantly. The degree of polymerization in high-density 3D systems is increased by the addition of trifunctional monomers and reduced slightly at low densities and low c(3). The presence of branching makes equilibrium states more sensitive (in 2D and 3D) to changes in temperature T. The stabilities of polymer and gel are enhanced by increasing T, and-for sufficiently high values of c(3)-there is a reversible polymer-gel transformation at a density-dependent floor temperature. (C) 2002 American Institute of Physics.