Theoretical insights into the mechanism of carbon monoxide (CO) release from CO-releasing molecules

We used density functional theory to investigate the capacity for carbon monoxide (CO) release of five newly synthesized manganese-containing CO-releasing molecules (CO-RMs), namely CORM-368 (1), CORM-401 (2), CORM-371 (3), CORM-409 (4), and CORM-313 (5). The results correctly discriminated good CO releasers (1 and 2) from a compound unable to release CO (5). The predicted Mn-CO bond dissociation energies were well correlated (R(2) ≈0.9) with myoglobin (Mb) assay experiments, which quantified the formation of MbCO, and thus the amount of CO released by the CO-RMs. The nature of the Mn-CO bond was characterized by natural bond orbital (NBO) analysis. This allowed us to identify the key donor-acceptor interactions in the CO-RMs, and to evaluate the Mn-CO bond stabilization energies. According to the NBO calculations, the charge transfer is the major source of Mn-CO bond stabilization for this series. On the basis of the nature of the experimental buffers, we then analyzed the nucleophilic attack of putative ligands (L' = HPO(4)(2-), H(2)PO(4)(-), H(2)O, and Cl(-)) at the metal vacant site through the ligand-exchange reaction energies. The analysis revealed that different L'-exchange reactions were spontaneous in all the CO-RMs. Finally, the calculated second dissociation energies could explain the stoichiometry obtained with the Mb assay experiments.     

Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase

The ceramides are a family of bioactive lipid‐derived messengers involved in the control of cellular senescence, inflammation, and apoptosis. Ceramide hydrolysis by acid ceramidase (AC) stops the biological activity of these substances and influences survival and function of normal and neoplastic cells. Because of its central role in the ceramide metabolism, AC may offer a novel molecular target in disorders with dysfunctional ceramide‐mediated signaling. Here, a class of benzoxazolone carboxamides is identified as the first potent and systemically active inhibitors of AC. Prototype members of this class inhibit AC with low nanomolar potency by covalent binding to the catalytic cysteine. Their metabolic stability and high in vivo efficacy suggest that these compounds may be used as probes to investigate the roles of ceramide in health and disease, and that this scaffold may represent a promising starting point for the development of novel therapeutic agents.     

An investigation into the teaching of mathematics to undergraduate economics students

This article attempts to present a novel application of a method of measuring accuracy for academic success predictors that could be used as a standard. This procedure is known as the receiver operating characteristic (ROC) curve, which comes from statistical decision techniques. The statistical prediction techniques provide predictor models and their goodness-of-fit; in addition, ROC analysis allows to assess the accuracy of the ability to discriminate from success and failures cases of a classifier or predictive model, and so it could be considered complementary to others more commonly used. Thus, the ROC curve is used to compare and interpret the relative contribution of each university entrance factor in the correct classification as success or failure of the academic performance, as well as to establish cut-off scores for admissions and counselling purposes. It is revealed that the ROC analysis allows us to identify the better university entrance factor for each subject in predicting students’ academic success.     

Eroding market stability by proliferation of financial instruments

We contrast Arbitrage Pricing Theory (APT), the theoretical basis for the development of financial instruments, with a dynamical picture of an interacting market, in a simple setting. The proliferation of financial instruments apparently provides more means for risk diversification, making the market more efficient and complete. In the simple market of interacting traders discussed here, the proliferation of financial instruments erodes systemic stability and it drives the market to a critical state characterized by large susceptibility, strong fluctuations and enhanced correlations among risks. This suggests that the hypothesis of APT may not be compatible with a stable market dynamics. In this perspective, market stability acquires the properties of a common good, which suggests that appropriate measures should be introduced in derivative markets, to preserve stability.     

Density functional study of the enzymatic reaction catalyzed by a cyclin-dependent kinase

Density functional theory (DFT) calculations were carried out to study the molecular mechanism of the phosphoryl transfer reaction catalyzed by cyclin-dependent kinases (CDKs). The DFT study presented here shows that CDKs catalyze the phosphoryl transfer reaction from ATP to the serine substrate through a single step mechanism with a SN2-like transition state.     

Computational study of phosphatase activity in soluble epoxide hydrolase: high efficiency through a water bridge mediated proton shuttle

Recently, a new branch of fatty acid metabolism has been opened by the novel phosphatase activity found in the N-terminal domain of the, hence bifunctional, soluble epoxide hydrolase (sEH). Importantly, this finding has also provided a new site for drug targeting in sEH's activity regulation. Classical MD and hybrid Car-Parrinello QM/MM calculations have been performed to investigate the reaction mechanism of the phosphoenzyme intermediate formation in the first step of the catalysis. The results support a concerted multi-event reaction mechanism: (1) a dissociative in-line nucleophilic substitution for the phosphoryl transfer reaction; (2) a double proton transfer involved in the formation of a good leaving group in the transition state. The presence of a water bridge in the substrate/enzyme complex allowed an efficient proton shuttle, showing its key role in speeding up the catalysis. The calculated free energy of the favored catalytic pathway is approximately 19 kcal/mol, in excellent agreement with experimental data.     

Joseph covariance formula adaptation to Square-Root Sigma-Point Kalman filters

Nonlinear Dynamics - The development of a reliable Sense And Avoid (SAA) system is one of the limiting aspects for the integration into civil airspace of unmanned aerial vehicles, for which the...     

Conductance of lithium,sodium and potassium nitrates in acetonitrile-water and ethanol-water isodielectric mixtures at 25°C

Precise conductance measurements of solutions of lithium, sodium and potassium nitrates were made at 25°C in acetonitrile-water and ethanol-water isodielectric mixtures, containing up to 15 mole percent organic-solvent, and the data analyzed by the 1978–80 Fuoss conductance equations. Single ion conductances were determined with the help of transference numbers in the case of ethanol-water mixtures. Ion-pair association constants are discussed in terms of contact and solvent-separated ion-pairs and were found to be almost equal to those for the halides. The anion appears more sensitive than the cations to the solvent structure in mixtures rich in water.