Understanding the dehydrogenation mechanism of tetrahydrocarbazole over palladium using a combined experimental and density functional theory approach

The mechanism of the dehydrogenation of tetrahydrocarbazole to carbazole over palladium has been examined for the first time. By use of a combination of deuterium exchange experiments and density functional theory calculations, a detailed reaction profile for the aromatization of tetrahydrocarbazole has been identified and validated by experiment. As with many dehydrogenation reactions, the initial hydrogen abstraction is found to have the highest reaction barrier. Tetrahydrocarbazole has four hydrogens which can, in principle, be cleaved initially; however, the theory and experiment show that the reaction is dominated by the cleavage of the carbon hydrogens at the carbon atoms in positions 1 and 4. The two pathways originating from these two C-H bond cleavage processes are found to have similar reaction energy profiles and both contribute to the overall reaction.

Proposed wavelet-neurofuzzy combined system for power qualityviolations detection and diagnosis

A system for the identification of power quality violations is proposed. It is a two-stage system that employs the potentials of the wavelet transform and the adaptive neurofuzzy networks. For the first stage, the wavelet multiresolution signal analysis is exploited to denoise and then decompose the monitored signals of the power quality events to extract its detailed information. A new optimal feature-vector is suggested and adopted in learning the neurofuzzy classifier. Thus, the amount of needed training data is extensively reduced. A modified organisation map of the neurofuzzy classifier has significantly improved the diagnosis efficiency. Simulation results confirm the aptness and the capability of the proposed system in power quality violations detection and automatic diagnosis

Clusters, liquids and crystals of dialkylimidazolium salts. A combined perspective from ab initio computer simulations

We summarize results obtained by a combination of ab initio and classical computer simulations of dialkylimidazolium ionic liquids in different states of aggregation, from crystals to liquids and clusters. Unusual features arising from the competition between electrostatic, dispersion, and hydrogen-bonding interactions are identified at the origin of observed structural patterns. We also discuss the way Brønsted acids interact with ionic liquids leading to the formation of hydrogen-bonded anions.

Prediction- and simulation-error based perceptron training: Solution space analysis and a novel combined training scheme

Previous papers have noted the difficulty in obtaining neural models which are stable under simulation when trained using prediction-error-based methods. Here the differences between series-parallel and parallel identification structures for training neural models are investigated. The effect of the error surface shape on training convergence and simulation performance is analysed using a standard algorithm operating in both training modes. A combined series-parallel/parallel training scheme is proposed, aiming to provide a more effective means of obtaining accurate neural simulation models. Simulation examples show the combined scheme is advantageous in circumstances where the solution space is known or suspected to be complex. (c) 2006 Elsevier B.V. All rights reserved.

Nutrient regulation of pancreatic beta-cell function in diabetes: problems and potential solutions

increasing prevalence of obesity combined with longevity will produce an epidemic of Type 2 (non-insulin-dependent) diabetes in the next 20 years. This. disease is associated with defects in insulin secretion, specifically abnormalities of insulin secretory kinetics and pancreatic beta-cell glucose responsiveness. Mechanisms underlying beta-cell dysfunction include glucose toxicity, lipotoxicity and beta-cell hyperactivity. Defects at various sites in beta-cell signal transduction pathways contribute, but no single lesion can account for the common form of Type 2 diabetes. Recent studies highlight diverse beta-cell actions of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). These intestinal hormones target the beta-cell to stimulate glucose-dependent insulin secretion through activation of protein kinase A and associated pathways. Both increase gene expression and proinsulin biosynthesis, protect against apoptosis and stimulate replication/neogenesis of beta-cells. Incretin hormones therefore represent an exciting future multi-action solution to correct beta-cell defect in Type 2 diabetes.

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells.

Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

Phase I Study Of The Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, In Combination With Temozolomide in Patients with Advanced Solid Tumors

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy.

Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated.

Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen.

Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.