Specific Design of Titanium(IV) Phenolato Chelates Yields Stable and Accessible,Effective and Selective Anticancer Agents

Octahedral titanium(IV) complexes of phenolato hexadentate ligands were developed and showed very high stability for days in water solutions. In vitro cytotoxicity studies showed that, whereas tetrakis(phenolato) systems are generally of low activity presumably due to inaccessibility, smaller bis(phenolato)bis(alkoxo) complexes feature high anticancer activity and accessibility even without formulations, also toward a cisplatin‐resistant cell line. An all‐aliphatic control complex was unstable and inactive. A leading phenolato complex also revealed: 1) high durability in fully aqueous solutions; accordingly, negligible loss of activity after preincubation for three days in medium or in serum; 2) maximal cellular accumulation and induction of apoptosis following 24–48 h of administration; 3) reduced impact on noncancerous fibroblast cells; 4) in vivo efficacy toward lymphoma cells in murine model; 5) high activity in NCI‐60 panel, with average GI₅₀ of 4.6±2 μm . This newly developed family of Ti^IV complexes is thus of great potential for anticancer therapy.     

Detoxification of Chemical Warfare Agents Using a Zr6‐Based Metal–Organic Framework/Polymer Mixture

Owing to their high surface area, periodic distribution of metal sites, and water stability, zirconium‐based metal–organic frameworks (Zr₆‐MOFs) have shown promising activity for the hydrolysis of nerve agents GD and VX, as well as the simulant, dimethyl 4‐nitrophenylphosphate (DMNP), in buffered solutions. A hurdle to using MOFs for this application is the current need for a buffer solution. Here the destruction of the simulant DMNP, as well as the chemical warfare agents (GD and VX) through hydrolysis using a MOF catalyst mixed with a non‐volatile, water‐insoluble, heterogeneous buffer is reported. The hydrolysis of the simulant and nerve agents in the presence of the heterogeneous buffer was fast and effective.     

Chemical action: what is it,and why does it really matter?

Nanotechnology, as with many technologies before it, places a strain on existing legislation and poses a challenge to all administrative agencies tasked with regulating technology-based products. It is easy to see how statutory schemes become outdated, as our ability to understand and affect the world progresses. In this article, we address the regulatory problems that nanotechnology posses for the Food and Drug Administration’s (FDA) classification structure for “drugs” and “devices.” The last major modification to these terms was in 1976, with the enactment of the Medical Device Amendments. There are serious practical differences for a classification as a drug or device in terms of time to market and research. Drugs are classified, primarily, as acting by “chemical action.” We lay out some legal, philosophic, and scientific tools that serve to provide a useful, as well as legally and scientifically faithful, distinction between drugs and devices for the purpose of regulatory classification. These issues we raise are worth the consideration of anyone who is interested in the regulation of nano-products or other novel technologies.     

Robust Optimal Service Analysis of Single-Server Re-Entrant Queues

We generalize the analysis of J.A. Ball, M.V. Day, and P. Kachroo (Mathematics of Control, Signals, and Systems, vol. 12, pp. 307–345, 1999) to a fluid model of a single server re-entrant queue. The approach is to solve the Hamilton-Jacobi-Isaacs equation associated with optimal robust control of the system. The method of staged characteristics is generalized from Ball et al. (1999) to construct the solution explicitly. Formulas are developed allowing explicit calculations for the Skorokhod problem involved in the system equations. Such formulas are particularly important for numerical verification of conditions on the boundary of the nonnegative orthant. The optimal control (server) strategy is shown to be of linear-index type. Dai-type stability properties are discussed. A modification of the model in which new customers are allowed only at a specified entry queue is considered in 2 dimensions. The same optimal strategy is found in that case as well.     

High-throughput approaches for the discovery and optimization of new olefin polymerization catalysts

The discovery of new olefin polymerization catalysts is currently a time-intensive trial-and-error process with no guarantee of success. A fully integrated high-throughput screening workflow for the discovery of new catalysts for polyolefin production has been implemented at Symyx Technologies. The workflow includes the design of the metal-ligand libraries using custom-made computer software, automated delivery of metal precursors and ligands into the reactors using a liquid-handling robot, and a rapid primary screen that serves to assess the potential of each metalligand-activator combination as an olefin polymerization catalyst. "Hits" from the primary screen are subjected to secondary screens using a 48-cell parallel polymerization reactor. Individual polymerization reactions are monitored in real time under conditions that provide meaningful information about the performance capabilities of each catalyst. Rapid polymer characterization techniques support the primary and secondary screens. We have discovered many new and interesting catalyst classes using this technology.     

How electron flow controls the thermochemistry of the addition of olefins to nickel dithiolenes: predictions by density functional theory

The reaction of a nickel dithiolene complex (1) and ethylene is a two-step process, in which the trans-product (2) forms first in the direct addition of the olefin to 1, while the more thermodynamically stable cis-product (3) involves isomerization of 2. The introduction of electron-withdrawing groups (cyano or trifluoromethyl) not only significantly lowers the activation energy (TS1) for the formation of trans-product, but it also strongly stabilizes the products (2, 3) such that they are favored by the free energy. However, these substituents leave the barrier for the conformational transformation step (TS2) nearly unchanged. On reduction, the previously favored adduct is now strongly disfavored.     

Modulation gap detection: effects of modulation rate, carrier separation, and mode of presentation.

Modulation gap detection (MGD) is a procedure that measures the sensitivity to an interruption in the modulation pattern imposed upon one or more carrier frequencies. The MGD task was developed to test conditions where a temporal event traverses frequency, but without a concomitant interruption in the spectral continuity of the stimulus. This contrasts with across-frequency gap detection where there is an inherent spectral discontinuity associated with the temporal gap, and where there is a marked decline in performance when the markers of the temporal gap are widely separated in frequency. The purpose of this study was to test the hypothesis that a wideband temporal analysis will be facilitated if there exists a spectral continuity throughout the temporal event. Experiment 1 established the procedure of MGD and indicated that a modulation rate of 8 Hz was optimal for the task. Experiment 2 showed that performance declined markedly when the carrier frequencies of the modulation markers were widely separated in frequency. This finding indicates that spectral continuity across the temporal event is not a sufficient prerequisite for the auditory system to undertake a wideband temporal analysis. Experiment 3 revealed that dichotic MGD also results in poor performance, similar to that seen for widely separated carrier frequencies in the monaural case. This supports the hypothesis that the "channels" across which temporal events are poorly processed do not necessarily correspond to peripheral frequency channels.     

Isotopy Stable Dynamics Relative to Compact Invariant Sets

Let f be an orientation-preserving homeomorphism of a compactorientable manifold. Sufficient conditions are given for thepersistence of a collection of periodic points under isotopyof f relative to a compact invariant set A. Two main applicationsare described. In the first, A is the closure of a single discreteorbit of f, and f has a Smale horseshoe, all of whose periodicorbits persist; in the second, A is a minimal invariant Cantorset obtained as the limit of a sequence of nested periodic orbits,all of which are shown to persist under isotopy relative toA. 1991 Mathematics Subject Classification: 58F20, 58F15.