Kinetics and mechanism of ketone enolization mediated by magnesium bis(hexamethyldisilazide)

Magnesium bis(hexamethyldisilazide), Mg(HMDS)(2), reacts with substoichiometric amounts of propiophenone in toluene solution at ambient temperature to form a 74:26 mixture of the enolates (E)- and (Z)-[(HMDS)(2)Mg(2)(mu-HMDS){mu-OC(Ph)=CHCH(3)}], (E)-1 and (Z)-1, which contain a pair of three-coordinate metal centers bridged by an amide and an enolate group. The compositions of (E)-1 and (Z)-1 were confirmed by solution NMR studies and also by crystallographic characterization in the solid state. Rate studies using UV-vis spectroscopy reveal the rapid and complete formation of a reaction intermediate, 2, between the ketone and magnesium, which undergoes first-order decay with rate constants independent of the concentration of excess Mg(HMDS)(2) (DeltaH++ = 17.2 +/- 0.8 kcal/mol, DeltaS++ = -11 +/- 3 cal/mol.K). The intermediate 2 has been characterized by low-temperature (1)H NMR, diffusion-ordered NMR, and IR spectroscopy and investigated by computational studies, all of which are consistent with the formulation of 2 as a three-coordinate monomer, (HMDS)(2)Mg{eta(1)-O=C(Ph)CH(2)CH(3)}. Further support for this structure is provided by the synthesis and structural characterization of two model ketone complexes, (HMDS)(2)Mg(eta(1)-O=C(t)Bu(2)) (3) and (HMDS)(2)Mg{eta(1)-O=C((t)Bu)Ph} (4). A large primary deuterium isotope effect (k(H)/k(D) = 18.9 at 295 K) indicates that proton transfer is the rate-limiting step of the reaction. The isotope effect displays a strong temperature dependence, indicative of tunneling. In combination, these data support the mechanism of enolization proceeding through the single intermediate 2 via intramolecular proton transfer from the alpha carbon of the bound ketone to the nitrogen of a bound hexamethyldisilazide.     

Clonal structure and variation in virulence of Salmonella enteritidis isolated from mice, chickens, and humans

The clonal analysis of a diverse collection of Salmonella Enteritidis indicates that most strains belong to a single multilocus genotype (i.e., ET-3) regardless of phage type, geographic origin, or time of isolation that spanned over 2 decades (1978 to 2004). Attachment and invasion assays, however, indicate that, among ET-3 isolates, there is a distinct invasive bacterial subpopulation that is more readily recovered from eggs and clinical cases in humans than from chicken cecal samples. These observations support the hypothesis that the specialized ability of S. Enteritidis to infect the avian reproductive tract and contaminate eggs has been critical in its emergence as a frequent cause of human illness.     

Selective phase masking to reduce material saturation in holographic data storage systems

Emerging networks and applications require enormous data storage. Holographic techniques promise high-capacity storage, given resolution of a few remaining technical issues. In this paper, we propose a technique to overcome one such issue: mitigation of large magnitude peaks in the stored image that cause material saturation resulting in readout errors. We consider the use of ternary data symbols, with modulation in amplitude and phase, and use a phase mask during the encoding stage to reduce the probability of large peaks arising in the stored Fourier domain image. An appropriate mask is selected from a predefined set of pseudo-random masks by computing the Fourier transform of the raw data array as well as the data array multiplied by each mask. The data array or masked array with the lowest Fourier domain peak values is recorded. On readout, the recorded array is multiplied by the mask used during recording to recover the original data array. Simulations are presented that demonstrate the benefit of this approach, and provide insight into the appropriate number of phase masks to use in high capacity holographic data storage systems.     

Pyrid-2-yl and 2-CyanoPhenyl fused heterocyclic compounds as human P2X_{3} inhibitors: a combined approach based on homology modelling,docking and QSAR analysis

P2X receptors are hetero-oligomeric proteins that function as membrane ion channels and are gated by extracellular ATP. The hP2X $_{3}$ subunit is a constituent of the channels on a subset of sensory neurons involved in pain signaling, where ATP released by damaged and inflamed tissue can initiate action potentials. Hence, the inhibition of ATP-activated P2X $_{3}$ receptor is an exciting approach for the treatment of inflammatory and neuropathic pain. Recently, the crystal structures of zebrafish P2X $_{4}$ (zP2X $_{4})$ were obtained in closed, apo state (PDB ID: 3I5D) and ATP-bound, open state (PDB ID: 4DW1). These structures were used to develop a homology model of human P2X $_{3}$ (hP2X $_{3})$ in order to identify through docking studies, the binding modes of known P2X $_{3}$ inhibitors and their key active site interactions, along with a pharmacophore-based 3D-QSAR model for a series of 136 Pyrid-2-yl and 2-CyanoPhenyl fused heterocyclic compounds. These 3D-QSAR models have been developed with different combinations of training and test set divisions obtained by random separation, Jarvis–Patrick clustering, K-means clustering and sphere exclusion methods. The best predictive 3D-QSAR model resulted in training set R $^{2 }$ of 0.75, internal test set Q $^{2}$ of 0.74, Pearson-R value of 0.87 and root mean square error of 0.37. The information generated by the pharmacophore model and docking analyses using the homology model provides valuable clues to design novel potent hP2X $_{3}$ inhibitors.     

The role of pendant amines in the breaking and forming of molecular hydrogen catalyzed by nickel complexes

We present the results of a comprehensive theoretical investigation of the role of pendant amine ligands in the oxidation of H(2) and formation of H(2) by [Ni(P(R)(2)N(R')(2))(2)](2+) electrocatalysts (P(R)(2)N(R')(2) is the 1,5-R'-3,7-R derivative of 1,5-diaza-3,7-diphosphacyclooctane, in which R and R' are aryl or alkyl groups). We focus our analysis on the thermal steps of the catalytic cycle, as they are known to be rate-determining for both H(2) oxidation and production. We find that the presence of pendant amine functional groups greatly facilitates the heterolytic H(2) bond cleavage, resulting in a protonated amine and a Ni hydride. Only one single positioned pendant amine is required to serve this function. The pendant amine can also effectively shuttle protons to the active site, making the redistribution of protons and the H(2) evolution a very facile process. An important requirement for the overall catalytic process is the positioning of at least one amine in close proximity to the metal center. Indeed, only protonation of the pendant amines on the metal center side (endo position) leads to catalytically active intermediates, whereas protonation on the opposite side of the metal center (exo position) leads to a variety of isomers, which are detrimental to catalysis.     

Functional tolerance in an isoreticular series of highly porous metal-organic frameworks

A series of highly porous University of Michigan Crystalline Material (UMCM-1) type Zn-based metal-organic frameworks (MOFs) were synthesized from mono- and bi-functionalized benzenedicarboxylate (BDC) ligands. In total, 16 new functionalized UMCM-1 derivatives were obtained by a combination of pre- and postsynthetic functionalization. Through postsynthetic modification (PSM), amino-halo bifunctional MOFs were converted into amide-halo materials via solid-state acylation reactions. A series of bifunctional MOFs containing Cl, Br, and I groups revealed that PSM conversion is not affected by the size of the halide, only by the steric bulk of the reagent used in these solid-state organic transformations.     

In vivo encapsulation of nucleic acids using an engineered nonviral protein capsid

In Nature, protein capsids function as molecular containers for a wide variety of molecular cargoes. Such containers have great potential for applications in nanotechnology, which often require encapsulation of non-native guest molecules. Charge complementarity represents a potentially powerful strategy for engineering novel encapsulation systems. In an effort to explore the generality of this approach, we engineered a nonviral, 60-subunit capsid, lumazine synthase from Aquifex aeolicus (AaLS), to act as a container for nucleic acid. Four mutations were introduced per subunit to increase the positive charge at the inner surface of the capsid. Characterization of the mutant (AaLS-pos) revealed that the positive charges lead to the uptake of cellular RNA during production and assembly of the capsid in vivo. Surprisingly, AaLS-pos capsids were found to be enriched with RNA molecules approximately 200-350 bases in length, suggesting that this simple charge complementarity approach to RNA encapsulation leads to both high affinity and a degree of selectivity. The ability to control loading of RNA by tuning the charge at the inner surface of a protein capsid could illuminate aspects of genome recognition by viruses and pave the way for the development of improved RNA delivery systems.