Regarding the validity of the time-dependent Kohn-Sham approach for electron-nuclear dynamics via trajectory surface hopping

The implementation of fewest-switches surface-hopping (FSSH) within time-dependent Kohn-Sham (TDKS) theory [Phys. Rev. Lett. 95, 163001 (2005)] has allowed us to study successfully excited state dynamics involving many electronic states in a variety of molecular and nanoscale systems, including chromophore-semiconductor interfaces, semiconductor and metallic quantum dots, carbon nanotubes and graphene nanoribbons, etc. At the same time, a concern has been raised that the KS orbital basis used in the calculation provides only approximate potential energy surfaces [J. Chem. Phys. 125, 014110 (2006)]. While this approximation does exist in our method, we show here that FSSH-TDKS is a viable option for computationally efficient calculations in large systems with straightforward excited state dynamics. We demonstrate that the potential energy surfaces and nonadiabatic transition probabilities obtained within the TDKS and linear response (LR) time-dependent density functional theories (TDDFT) agree semiquantitatively for three different systems, including an organic chromophore ligating a transition metal, a quantum dot, and a small molecule. Further, in the latter case the FSSH-TDKS procedure generates results that are in line with FSSH implemented within LR-TDDFT. The FSSH-TDKS approach is successful for several reasons. First, single-particle KS excitations often give a good representation of LR excitations. In this regard, DFT compares favorably with the Hartree-Fock theory, for which LR excitations are typically combinations of multiple single-particle excitations. Second, the majority of the FSSH-TDKS applications have been performed with large systems involving simple excitations types. Excitation of a single electron in such systems creates a relatively small perturbation to the total electron density summed over all electrons, and it has a small effect on the nuclear dynamics compared, for instance, with thermal nuclear fluctuations. In such cases an additional, classical-path approximation can be made. Third, typical observables measured in time-resolved experiments involve averaging over many initial conditions. Such averaging tends to cancel out random errors that may be encountered in individual simulated trajectories. Finally, if the flow of energy between electronic and nuclear subsystems is insignificant, the ad hoc FSSH procedure is not required, and a straightforward mean-field, Ehrenfest approach is sufficient. Then, the KS representation provides rigorously a convenient and efficient basis for numerically solving the TDDFT equations of motion.     

Mixed brominated/chlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls: Simultaneous congener-selective determination in food

Of the 4600 individual poly-halogenated (bromo-chloro) dibenzo-p-dioxins, dibenzo-furans (PXDD/Fs) and 9180 poly-halogenated biphenyls (PXBs), 19 compounds were selected for analysis in food, based on current toxicological knowledge, chemical configuration, type and degree of halogenation, and the limited knowledge on environmental occurrence levels. The selection was also tempered by the availability of reliable analytical standards. The analytical methodology designed to allow simultaneous determination of PXDD/Fs and PXBs, was based on internal standardisation with (13)C(12) labelled compounds and high resolution mass spectrometry and involved a new separation procedure using dual activated carbon column fractionation. In order to unambiguously measure these compounds a practical, higher mass resolution (13,500-15,000 res) was used, coupled with a judicious choice of analyte ions and relative ion ratios. Further specificity was incorporated by exploiting the differences in chromatographic retention from those of potential interferants. The methodology was validated and used to measure occurrence levels of these contaminants in different matrices such as milk, meat, fish, eggs, offal, shellfish and soil. The limits of detection achieved by this methodology ranged from 0.005 to 0.02ngkg(-1) fat for foods. The analyses revealed the presence of both PXDD/Fs and PXBs, with the latter occurring to a greater extent, followed by PXDFs. This work represents the first targeted approach to measuring a range of individual PXDD/Fs and PXBs simultaneously.     

Ascent properties for pairs of modules

Given a flat local ring homomorphism \({R \rightarrow S}\) and two finitely generated R-modules M and N, we describe conditions under which the modules \({{\rm Tor}^{R}_{i}(M,N)}\) and \({{\rm Ext}^{i}_{R}(M,N)}\) have S-module structures that are compatible with their R-module structures.     

Coarse differentiation and quantitative nonembeddability for Carnot groups

We give lower bound estimates for the macroscopic scale of coarse differentiability of Lipschitz maps from a Carnot group with the Carnot–Carathéodory metric (G,_dcc)$(G,d_{cc})$ to a few different classes of metric spaces. Using this result, we derive lower bound estimates for quantitative nonembeddability of Lipschitz embeddings of G   into a metric space (X,_dX)$(X,d_X)$ if X is either an Alexandrov space with nonpositive or nonnegative curvature, a superreflexive Banach space, or another Carnot group that does not admit a biLipschitz homomorphic embedding of G  . For the same targets, we can further give lower bound estimates for the biLipschitz distortion of every embedding f:B(n)→X$f:B(n)\to X$, where B(n)$B(n)$ is the ball of radius n of a finitely generated nonabelian torsion-free nilpotent group G. We also prove an analogue of Bourgain's discretization theorem for Carnot groups and show that Carnot groups have nontrivial Markov convexity. These give the first examples of metric spaces that have nontrivial Markov convexity but cannot biLipschitzly embed into Banach spaces of nontrivial Markov convexity.     

Exploiting Complementary Second-sphere Effects in Supramolecular Coordination Solids

In the design of extended supramolecular solids, reliable synthons are a valuable commodity. This work concerns the complementary second-sphere coordination interactions between a highly preorganized hexasulphonated ligand, L, and aquated metal ions. Four second-sphere inclusion complexes [M(H²O)⁶]² L ·(S)³ (M/S: Mg/acetone, 1; Zn/acetone, 2, Mg/dioxane, 3; Zn/dioxane, 4) and three extended networks {[(M(H²O)³)²(L)]·(H²O)^14.5}^∞ (M=Cr, 5; Fe, 6; Al, 7) have been structurally characterized by X-ray crystallography. The second-sphere effects on the stabilization of the primary coordination sphere are illustrated by TGA experiments. In these assemblies, the potential of a new supramolecular synthon is illustrated, that being the complementary hydrogen-bonding interaction between cis-aquo ligands and sulphonate oxygen atoms.     

Bayesian Models Leveraging Bioactivity and Cytotoxicity Information for Drug Discovery

1. Download : Download high-res image (190KB)
2. Download : Download full-size image

Highlights? Including efficacy and cytotoxicity data improves performance of computational models ? Antitubercular hits, leads, and chemical probes were identified using Bayesian models ? The most advanced compound provides significant in vitro activity and in vivo safety ? Demonstrated orders-of-magnitude higher hit rates than current HTS practices     

Multiplexed tyrosine kinase activity detection in cancer cells using a hydrogel immobilized substrate

Kinases play a key role in cellular signaling, and the overactivation or overexpression of these kinases has been linked to a variety of cancers. Tyrosine kinase inhibitors treat the mechanism of these cancers by targeting the specific kinases that are overactive. Some patients, however, do not respond to these inhibitors or develop resistance to these inhibitors during treatment. Additionally, even within cancers of the same tissue type, different kinases may be overactive in different patients. For example, some lung cancers overexpress epidermal growth factor receptor (EGFR) and respond to EGFR inhibitors, whereas other lung cancers do not overexpress EGFR and receive no benefit from this treatment. Even among patients exhibiting EGFR overexpression, some do not respond to EGFR kinase inhibitors because other kinases, such as Met kinase, are also overactivated. Here we describe a quantitative and specific multiplexed microfluidic assay using a hydrogel immobilized substrate for measuring the kinase activity of Met and Abl kinase from cancer cells. We immobilized kinase-specific substrates on macroporous hydrogel micropillars in microchannels. These microchannels were incubated with 6 μl of a kinase reaction solution containing cancer cell lysate, and we measured kinase activity via fluorescence detection of a phosphotyrosine antibody. We showed that the assay can specifically measure the activity of both Met and Abl kinase within one microchannel and has the potential to measure the activity of as many as five kinases within one microchannel. The assay also detected Met kinase inhibition from lysates of cancer cells grown in the Met kinase inhibitor PHA665752.

A facile and regioselective synthesis of rimonabant through an enamine-directed 1,3-dipolar cycloaddition

Rimonabant is a high-potency cannabinoid type-1 (CB₁) receptor inverse agonist that has recently been approved in the European Union as a treatment for obesity. Current methods of synthesis require several steps that have long reaction times and/or lack regioselectivity. Here we present a novel, regioselective synthesis of rimonabant though an enamine-directed 1,3-dipolar cycloaddition. In addition, we present a new and more reactive hydrazonoyl halide for the generation of the requisite nitrile imine dipole.     

A new asymmetric synthesis of the natural enantiomer of the indolizidino[8,7-b]indole alkaloid (+)-harmicine

We report a novel, facile and asymmetric approach for the synthesis of the indole alkaloid (+)-harmicine via a highly diastereoselective N-acyliminium cyclization reaction as a key synthetic step, and verify the relative stereochemistry of the key synthetic intermediate in this approach through X-ray crystallography.