Dynamic Internal Cavities of Dendrimers as Constrained Media. A Study of Photochemical Isomerizations of Stilbene and Azobenzene Using Poly(alkyl aryl ether) Dendrimers

Dendritic rnicroenvironments defined by dynamic internal cavities of a dendrimer were probed through geometric isomerization of stilbene and azobenzene. A third-generation poly(alkyl aryl ether) dendrimer with hydrophilic exterior and hydrophobic interior was used as a reaction cavity in aqueous medium. The dynamic inner cavity sizes were varied by utilizing alkyl linkers that connect the branch junctures from ethyl to n-pentyl moiety (C(2)G(3)-C(5)G(3)). Dendrimers constituted with n-pentyl linker were found to afford higher solubilities of stilbene and azobenzene. Direct irradiation of trans-stilbene showed that C(5)G(3) and C(4)G(3) dendrimers afforded considerable phenanthrene formation, in addition to cis-stilbene, whereas C(3)G(3) and C(2)G(3) gave only cis-stilbene. An electron-transfer sensitized trans-cis isomerization, using cresyl violet perchlorate as the sensitizer, also led to similar results. Thermal isomerization of cis-azobenzene to trans-azobenzene within dendritic microenvironments revealed that the activation energy of the cis- to trans-isomer was increasing in the series C(5)G(3) < C(4)G(3) < C(3)G(3)

PAMAM Dendrimer-Drug Interactions: Effect of pH on the Binding and Release Pattern

Understanding the dendrimer-drug interaction is of great importance to design and optimize the dendrimer-based drug delivery system. Using atomistic molecular dynamics (MD) simulations, we have analyzed the release pattern of four ligands (two soluble drugs, namely, salicylic acid (Sal), L-alanine (Ala), and two insoluble drugs, namely, phenylbutazone (Pbz) and primidone (Prim)), which were initially encapsulated inside the ethylenediamine (EDA) cored polyamidoamine (PAMAM) dendrimer using the docking method. We have computed the potential of mean force (PMF) variation with generation 5 (G5)-PAMAM dendrimer complexed with drug molecules using umbrella sampling. From our calculated PMF values, we observe that soluble drugs (Sal and Ala) have lower energy barriers than insoluble drugs (Pbz and Prim). The order of ease of release pattern for these drugs from G5 protonated PAMAM dendrimer was found to be Ala > Sal > Prim > Pbz. In the case of insoluble drugs (Prim and Pbz), because of larger size, we observe much nonpolar contribution, and thus, their larger energy barriers can be reasoned to van der Waals contribution. From the hydrogen bonding analysis of the four PAMAM drug complexes under study, we found intermolecular hydrogen bonding to show less significant contribution to the free energy barrier. Another interesting feature appears while calculating the PMF profile of G5NP (nonprotonated)-PAMAM Pbz and G5NP (nonprotonated)-PAMAM-Sal complex. The PMF was found to be less when the drug is bound to nonprotonated dendrimer compared to the protonated dendrimer. Our results suggest that encapsulation of the drug molecule into the host PAMAM dendrimer should be carried out at higher pH values (near pH 10). When such complex enters the human body, the pH is around 7.4 and at that physiological pH, the dendrimer holds the drug tightly. Hence the release of drug can occur at a controlled rate into the bloodstream. Thus, our findings provide a microscopic picture of the encapsulation and controlled release of drugs in the case of dendrimer-based host-guest systems.

Periodically Grafted Amphiphilic Copolymers: Nonionic Analogues of Ionenes

We describe a novel class of periodically grafted amphiphilic copolymers (PGACs) that could serve as nonionic functional mimics of ionenes, the primary difference being that the periodically occurring charged units along the backbone of ionenes are replaced by hydrophilic oligoethylene glycol segments. The synthesis and properties of this new class of segmented polymers that carry a hydrophobic alkylene polyester backone with periodically placed hydrophilic oligo(oxyethylene) pendant units are presented. When the length of the intervening alkylene segment is adequately long, 22-carbons in this case, and the pendant unit is a hexaethylene glycol monomethyl ether (HEG) segment, the polymer chain appears to adopt a folded zigzag conformation, reminiscent of the accordion-type structure formed by cationic ionenes. This transformation is driven by the intrinsic immiscibility of the alkylene and HEG segments and is reinforced by the strong tendency for long chain alkylene segments to crystallize in a paraffinic lattice. Evidence of the formation of such structures comes from the AFM images, which reveal the formation of remarkably flat pancake-like aggregates that are formed by the lateral aggregation of individually collapsed polymer chains; importantly, the heights of these structures match well with the lamellar layer-spacing obtained from SAXS studies of bulk samples. DSC studies further confirm the crystallization of the intervening alkylene segments, especially when they are long (C22), suggesting the formation of the folded zigzag structures. In a suitably designed PGAC that carries diacetylene units symmetrically placed within the alkylene segment, attempts were made to cross-polymerize the diacetylene units and generate PEGylated nanoparticles. However, these attempts were unsuccessful demonstrating the very stringent geometric requirements for the topotactic polymerization of diacetylenes.

A Numerical Scheme for Three-Dimensional Front Propagation and Control of Jordan Mode

As an example of a front propagation, we study the propagation of a three-dimensional nonlinear wavefront into a polytropic gas in a uniform state and at rest. The successive positions and geometry of the wavefront are obtained by solving the conservation form of equations of a weakly nonlinear ray theory. The proposed set of equations forms a weakly hyperbolic system of seven conservation laws with an additional vector constraint, each of whose components is a divergence-free condition. This constraint is an involution for the system of conservation laws, and it is termed a geometric solenoidal constraint. The analysis of a Cauchy problem for the linearized system shows that when this constraint is satisfied initially, the solution does not exhibit any Jordan mode. For the numerical simulation of the conservation laws we employ a high resolution central scheme. The second order accuracy of the scheme is achieved by using MUSCL-type reconstructions and Runge-Kutta time discretizations. A constrained transport-type technique is used to enforce the geometric solenoidal constraint. The results of several numerical experiments are presented, which confirm the efficiency and robustness of the proposed numerical method and the control of the Jordan mode.

Guided Wave based Damage Detection in a Composite T-joint using 3D Scanning Laser Doppler Vibrometer

Composite T-joints are commonly used in modern composite airframe, pressure vessels and piping structures, mainly to increase the bending strength of the joint and prevents buckling of plates and shells, and in multi-cell thin-walled structures. Here we report a detailed study on the propagation of guided ultrasonic wave modes in a composite T-joint and their interactions with delamination in the co-cured co-bonded flange. A well designed guiding path is employed wherein the waves undergo a two step mode conversion process, one is due to the web and joint filler on the back face of the flange and the other is due to the delamination edges close to underneath the accessible surface of the flange. A 3D Laser Doppler Vibrometer is used to obtain the three components of surface displacements/velocities of the accessible face of the flange of the T-joint. The waves are launched by a piezo ceramic wafer bonded on to the back surface of the flange. What is novel in the proposed method is that the location of any change in material/geometric properties can be traced by computing a frequency domain power flow along a scan line. The scan line can be chosen over a grid either during scan or during post-processing of the scan data off-line. The proposed technique eliminates the necessity of baseline data and disassembly of structure for structural interrogation.

Regioselective synthesis and antimicrobial studies of ester linked 1,4-disubstituted 1,2,3-bistriazoles

A series of 1,4-disubstituted 1,2,3-bistriazoles was synthesized via click chemistry by cycloaddition of various bisalkynes with benzyl/2-phenylethyl azide. Synthesized triazoles were characterized by IR, H-1 NMR, C-13 NMR and mass spectral techniques. All the compounds were evaluated for antibacterial/antifungal activities and found to possess moderate to good antimicrobial activities. Further the docking study for the most active compound against DNA Gyrase was also carried out. (C) 2012 Elsevier Ltd. All rights reserved.

A variant peptide of buffalo colostrum beta-lactoglobulin inhibits angiotensin I-converting enzyme activity

beta-lactoglobulin is a rich source of bioactive peptides. The LC-MS separated tryptic peptides of buffalo colostrum beta-lactoglobulin (BLG-col) were computed based on MS-MS fragmentation for de novo sequencing. Among the selected peptides (P1-P8), a variant was detected with methionine at position 74 instead of glutamate. The sequences of two peptides were identical to hypocholesterolemic peptides whereas the remaining peptides were in accordance with buffalo milk beta-lactoglobulin. Comparative sequence analysis of BLG-col to milk beta-lactoglobulin was carried out using CLUSTALW2 and a molecular model for BLG-col was constructed (PMDB ID-PM0076812). The synthesized variant pentapeptide (IIAMK, m/z-576 Da) was found to inhibit angiotensin I-converting enzyme (ACE) with an IC50 of 498 +/- 2 mu M, which was rationalized through docking simulations using Molgrow virtual docker. (C) 2012 Elsevier Masson SAS. All rights reserved.

A Rhodanine Derivative CCR-11 Inhibits Bacterial Proliferation by Inhibiting the Assembly and GTPase Activity of FtsZ

A perturbation of FtsZ assembly dynamics has been shown to inhibit bacterial cytokinesis. In this study, the antibacterial activity of 151 rhodanine compounds was assayed using Bacillus subtilis cells. Of 151 compounds, eight strongly inhibited bacterial proliferation at 2 mu M. Subsequently, we used the elongation of B. subtilis cells as a secondary screen to identify potential FtsZ-targeted antibacterial agents. We found that three compounds significantly increased bacterial cell length. One of the three compounds, namely, CCR-11 (E)-2-thioxo-5-({3-(trifluoromethyl)phenyl]furan-2-yl}methylene) thiazolidin-4-one], inhibited the assembly and GTPase activity of FtsZ in vitro. CCR-11 bound to FtsZ with a dissociation constant of 1.5 +/- 0.3 mu M. A docking analysis indicated that CCR-11 may bind to FtsZ in a cavity adjacent to the T7 loop and that short halogen oxygen, H-bonding, and hydrophobic interactions might be important for the binding of CCR-11 with FtsZ. CCR-11 inhibited the proliferation of B. subtilis cells with a half-maximal inhibitory concentration (IC50) of 1.2 +/- 0.2 mu M and a minimal inhibitory concentration of 3 mu M. It also potently inhibited proliferation of Mycobacterium smegmatis cells. Further, CCR-11 perturbed Z-ring formation in B. subtilis cells; however, it neither visibly affected nucleoid segregation nor altered the membrane integrity of the cells. CCR-11 inhibited HeLa cell proliferation with an IC50 value of 18.1 +/- 0.2,mu M (similar to 15 x IC50 of B. subtilis cell proliferation). The results suggested that CCR-11 inhibits bacterial cytokinesis by inhibiting FtsZ assembly, and it can be used as a lead molecule to develop FtsZ-targeted antibacterial agents.

Evolution of quantum discord and its stability in two-qubit NMR systems

We investigate evolution of quantum correlations in ensembles of two-qubit nuclear spin systems via nuclear magnetic resonance techniques. We use discord as a measure of quantum correlations and the Werner state as an explicit example. We, first, introduce different ways of measuring discord and geometric discord in two-qubit systems and then describe the following experimental studies: (a) We quantitatively measure discord for Werner-like states prepared using an entangling pulse sequence. An initial thermal state with zero discord is gradually and periodically transformed into a mixed state with maximum discord. The experimental and simulated behavior of rise and fall of discord agree fairly well. (b) We examine the efficiency of dynamical decoupling sequences in preserving quantum correlations. In our experimental setup, the dynamical decoupling sequences preserved the traceless parts of the density matrices at high fidelity. But they could not maintain the purity of the quantum states and so were unable to keep the discord from decaying. (c) We observe the evolution of discord for a singlet-triplet mixed state during a radio-frequency spin-lock. A simple relaxation model describes the evolution of discord, and the accompanying evolution of fidelity of the long-lived singlet state, reasonably well.

Automatic energy-momentum conserving time integrators for hyperelastic waves

An energy-momentum conserving time integrator coupled with an automatic finite element algorithm is developed to study longitudinal wave propagation in hyperelastic layers. The Murnaghan strain energy function is used to model material nonlinearity and full geometric nonlinearity is considered. An automatic assembly algorithm using algorithmic differentiation is developed within a discrete Hamiltonian framework to directly formulate the finite element matrices without recourse to an explicit derivation of their algebraic form or the governing equations. The algorithm is illustrated with applications to longitudinal wave propagation in a thin hyperelastic layer modeled with a two-mode kinematic model. Solution obtained using a standard nonlinear finite element model with Newmark time stepping is provided for comparison. (C) 2012 Elsevier B.V. All rights reserved.

Control of a Duct Flow Network for Wind Display in a Virtual Environment

Control of flow in duct networks has a myriad of applications ranging from heating, ventilation, and air-conditioning to blood flow networks. The system considered here provides vent velocity inputs to a novel 3-D wind display device called the TreadPort Active Wind Tunnel. An error-based robust decentralized sliding-mode control method with nominal feedforward terms is developed for individual ducts while considering cross coupling between ducts and model uncertainty as external disturbances in the output. This approach is important due to limited measurements, geometric complexities, and turbulent flow conditions. Methods for resolving challenges such as turbulence, electrical noise, valve actuator design, and sensor placement are presented. The efficacy of the controller and the importance of feedforward terms are demonstrated with simulations based upon an experimentally validated lumped parameter model and experiments on the physical system. Results show significant improvement over traditional control methods and validate prior assertions regarding the importance of decentralized control in practice.

VAM applied to dimensional reduction of non-linear hyperelastic plates

This work aims at dimensional reduction of non-linear isotropic hyperelastic plates in an asymptotically accurate manner. The problem is both geometrically and materially non-linear. The geometric non-linearity is handled by allowing for finite deformations and generalized warping while the material non-linearity is incorporated through hyperelastic material model. The development, based on the Variational Asymptotic Method (VAM) with moderate strains and very small thickness to shortest wavelength of the deformation along the plate reference surface as small parameters, begins with three-dimensional (3-D) non-linear elasticity and mathematically splits the analysis into a one-dimensional (1-D) through-the-thickness analysis and a two-dimensional (2-D) plate analysis. Major contributions of this paper are derivation of closed-form analytical expressions for warping functions and stiffness coefficients and a set of recovery relations to express approximately the 3-D displacement, strain and stress fields. Consistent with the 2-D non-linear constitutive laws, 2-D plate theory and corresponding finite element program have been developed. Validation of present theory is carried out with a standard test case and the results match well. Distributions of 3-D results are provided for another test case. (c) 2012 Elsevier Ltd. All rights reserved.

Differential Activities of the Two Closely Related Withanolides, Withaferin A and Withanone: Bioinformatics and Experimental Evidences

Background and Purpose: Withanolides are naturally occurring chemical compounds. They are secondary metabolites produced via oxidation of steroids and structurally consist of a steroid-backbone bound to a lactone or its derivatives. They are known to protect plants against herbivores and have medicinal value including anti-inflammation, anti-cancer, adaptogenic and anti-oxidant effects. Withaferin A (Wi-A) and Withanone (Wi-N) are two structurally similar withanolides isolated from Withania somnifera, also known as Ashwagandha in Indian Ayurvedic medicine. Ashwagandha alcoholic leaf extract (i-Extract), rich in Wi-N, was shown to kill cancer cells selectively. Furthermore, the two closely related purified phytochemicals, Wi-A and Wi-N, showed differential activity in normal and cancer human cells in vitro and in vivo. We had earlier identified several genes involved in cytotoxicity of i-Extract in human cancer cells by loss-of-function assays using either siRNA or randomized ribozyme library. Methodology/Principal Findings: In the present study, we have employed bioinformatics tools on four genes, i.e., mortalin, p53, p21 and Nrf2, identified by loss-of-function screenings. We examined the docking efficacy of Wi-N and Wi-A to each of the four targets and found that the two closely related phytochemicals have differential binding properties to the selected cellular targets that can potentially instigate differential molecular effects. We validated these findings by undertaking parallel experiments on specific gene responses to either Wi-N or Wi-A in human normal and cancer cells. We demonstrate that Wi-A that binds strongly to the selected targets acts as a strong cytotoxic agent both for normal and cancer cells. Wi-N, on the other hand, has a weak binding to the targets; it showed milder cytotoxicity towards cancer cells and was safe for normal cells. The present molecular docking analyses and experimental evidence revealed important insights to the use of Wi-A and Wi-N for cancer treatment and development of new anti-cancer phytochemical cocktails.

A Bifunctional Enzyme That Has Both Monoacylglycerol Acyltransferase and Acyl Hydrolase Activities

Monoacylglycerol acyltransferase (MGAT) catalyzes the synthesis of diacylglycerol, the precursor of triacylglycerol biosynthesis and an important signaling molecule. Here, we describe the isolation and characterization of the peanut (Arachis hypogaea) MGAT gene. The soluble enzyme utilizes invariant histidine-62 and aspartate-67 residues of the acyltransferase motif for its MGAT activity. A sequence analysis revealed the presence of a hydrolase (GXSXG) motif, and enzyme assays revealed the presence of monoacylglycerol (MAG) and lysophosphatidylcholine (LPC) hydrolytic activities, indicating the bifunctional nature of the enzyme. The overexpression of the MGAT gene in yeast (Saccharomyces cerevisiae) caused an increase in triacylglycerol accumulation. Similar to the peanut MGAT, the Arabidopsis (Arabidopsis thaliana) homolog (At1g52760) also exhibited both acyltransferase and hydrolase activities. Interestingly, the yeast homolog lacks the conserved HX4D motif, and it is deficient in the acyltransferase function but exhibits MAG and LPC hydrolase activities. This study demonstrates the presence of a soluble MGAT/hydrolase in plants. The predicted three-dimensional homology modeling and substrate docking suggested the presence of two separate substrate (MAG and LPC)-binding sites in a single polypeptide. Our study describes a soluble bifunctional enzyme that has both MGAT and hydrolase functions.

Premixed flame response to equivalence ratio fluctuations: Comparison between reduced order modeling and detailed computations

Combustion instability events in lean premixed combustion systems can cause spatio-temporal variations in unburnt mixture fuel/air ratio. This provides a driving mechanism for heat-release oscillations when they interact with the flame. Several Reduced Order Modelling (ROM) approaches to predict the characteristics of these oscillations have been developed in the past. The present paper compares results for flame describing function characteristics determined from a ROM approach based on the level-set method, with corresponding results from detailed, fully compressible reacting flow computations for the same two dimensional slot flame configuration. The comparison between these results is seen to be sensitive to small geometric differences in the shape of the nominally steady flame used in the two computations. When the results are corrected to account for these differences, describing function magnitudes are well predicted for frequencies lesser than and greater than a lower and upper cutoff respectively due to amplification of flame surface wrinkling by the convective Darrieus-Landau (DL) instability. However, good agreement in describing function phase predictions is seen as the ROM captures the transit time of wrinkles through the flame correctly. Also, good agreement is seen for both magnitude and phase of the flame response, for large forcing amplitudes, at frequencies where the DL instability has a minimal influence. Thus, the present ROM can predict flame response as long as the DL instability, caused by gas expansion at the flame front, does not significantly alter flame front perturbation amplitudes as they traverse the flame. (C) 2012 The Combustion Institute. Published by Elsevier Inc. All rights reserved.