Jacalin-carbohydrate interactions: distortion of the ligand molecule as a determinant of affinity

Jacalin is among the most thoroughly studied lectins. Its carbohydrate-binding site has also been well characterized. It has been postulated that the lower affinity of beta-galactosides for jacalin compared with beta-galactosides is caused by steric interactions of the substituents in the former with the protein. This issue has been explored energetically and structurally using different appropriate carbohydrate complexes of jacalin. It turns out that the earlier postulation is not correct. The interactions of the substituent with the binding site remain essentially the same irrespective of the anomeric nature of the substitution. This is achieved through a distortion of the sugar ring in beta-galactosides. The difference in energy, and therefore in affinity, is caused by a distortion of the sugar ring in beta-galactosides. The elucidation of this unprecedented distortion of the ligand as a strategy for modulating affinity is of general interest. The crystal structures also provide a rationale for the relative affinities of the different carbohydrate ligands for jacalin.

Targeting Mycobacterium tuberculosis Topoisomerase I by Small-Molecule Inhibitors

We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and Mycobacterium tuberculosis cells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison the Mycobacterium tuberculosis and Mycobacterium smegmatis topoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules.

Mycobacterium tuberculosis has diminished capacity to counteract redox stress induced by elevated levels of endogenous superoxide

Mycobacterium tuberculosis (Mtb) has evolved protective and detoxification mechanisms to maintain cytoplasmic redox balance in response to exogenous oxidative stress encountered inside host phagocytes. In contrast, little is known about the dynamic response of this pathogen to endogenous oxidative stress generated within Mtb. Using a noninvasive and specific biosensor of cytoplasmic redox state of Mtb, we for first time discovered a surprisingly high sensitivity of this pathogen to perturbation in redox homeostasis induced by elevated endogenous reactive oxygen species (ROS). We synthesized a series of hydroquinone-based small molecule ROS generators and found that ATD-3169 permeated mycobacteria to reliably enhance endogenous ROS including superoxide radicals. When Mtb strains including multidrug-resistant (MDR) and extensively drug-resistant (XDR) patient isolates were exposed to this compound, a dose-dependent, long-lasting, and irreversible oxidative shift in intramycobacterial redox potential was detected. Dynamic redox potential measurements revealed that Mtb had diminished capacity to restore cytoplasmic redox balance in comparison with Mycobacterium smegmatis (Msm), a fast growing nonpathogenic mycobacterial species. Accordingly, Mtb strains were extremely susceptible to inhibition by ATD-3169 but not Msm, suggesting a functional linkage between dynamic redox changes and survival. Microarray analysis showed major realignment of pathways involved in redox homeostasis, central metabolism, DNA repair, and cell wall lipid biosynthesis in response to ATD-3169, all consistent with enhanced endogenous ROS contributing to lethality induced by this compound. This work provides empirical evidence that the cytoplasmic redox poise of Mtb is uniquely sensitive to manipulation in steady-state endogenous ROS levels, thus revealing the importance of targeting intramycobacterial redox metabolism for controlling TB infection. (C) 2015 The Authors. Published by Elsevier Inc.

COMPOSITE AND MULTI-SCALE COMPLIANT MECHANISMS FOR MANIPULATION AND MECHANICAL CHARACTERIZATION

In this paper, we integrate two or more compliant mechanisms to get enhanced functionality for manipulating and mechanically characterizing the grasped objects of varied size (cm to sub-mm), stiffness (1e5 to 10 N/m), and materials (cement to biological cells). The concepts of spring-lever (SL) model, stiffness maps, and non-dimensional kinetoelastostatic maps are used to design composite and multi-scale compliant mechanisms. Composite compliant mechanisms comprise two or more different mechanisms within a single elastic continuum while multi-scale ones possess the additional feature of substantial difference in the sizes of the mechanisms that are combined into one. We present three applications: (i) a composite compliant device to measure the failure load of the cement samples; (ii) a composite multi-scale compliant gripper to measure the bulk stiffness of zebrafish embryos; and (iii) a compliant gripper combined with a negative-stiffness element to reduce the overall stiffness. The prototypes of all three devices are made and tested. The cement sample needed a breaking force of 22.5 N; the zebrafish embryo is found to have bulk stiffness of about 10 N/m; and the stiffness of a compliant gripper was reduced by 99.8 % to 0.2 N/m.

pi-Electron rich small molecule sensors for the recognition of nitroaromatics

Selective and discriminative detection of -NO2 containing high energy organic compounds such as picric acid (PA), 2,4,6-trinitrotoluene (TNT) and dinitrotoluene (DNT) has become a challenging task due to concerns over national security, criminal investigations and environment protections. Among various known detection methods, fluorescence techniques have gained special attention in recent time. A wide variety of fluorescent chemosensors have been developed for nitroaromatic explosive detection. In this review article, we provide an overview of the recent developments made in small molecule-based turn-off fluorescent sensors for nitroaromatic explosives with special focus on organic and H-bonded supramolecular sensors. The fluorescent sensors discussed in this review are classified and organized according to their functionality and their recognition of nitroaromatics by fluorescence quenching.

Falcon: A Graph Manipulation Language for Heterogeneous Systems

Graph algorithms have been shown to possess enough parallelism to keep several computing resources busy-even hundreds of cores on a GPU. Unfortunately, tuning their implementation for efficient execution on a particular hardware configuration of heterogeneous systems consisting of multicore CPUs and GPUs is challenging, time consuming, and error prone. To address these issues, we propose a domain-specific language (DSL), Falcon, for implementing graph algorithms that (i) abstracts the hardware, (ii) provides constructs to write explicitly parallel programs at a higher level, and (iii) can work with general algorithms that may change the graph structure (morph algorithms). We illustrate the usage of our DSL to implement local computation algorithms (that do not change the graph structure) and morph algorithms such as Delaunay mesh refinement, survey propagation, and dynamic SSSP on GPU and multicore CPUs. Using a set of benchmark graphs, we illustrate that the generated code performs close to the state-of-the-art hand-tuned implementations.

Kernelization complexity of possible winner and coalitional manipulation problems in voting

In the POSSIBLE WINNER problem in computational social choice theory, we are given a set of partial preferences and the question is whether a distinguished candidate could be made winner by extending the partial preferences to linear preferences. Previous work has provided, for many common voting rules, fixed parameter tractable algorithms for the POSSIBLE WINNER problem, with number of candidates as the parameter. However, the corresponding kernelization question is still open and in fact, has been mentioned as a key research challenge 10]. In this paper, we settle this open question for many common voting rules. We show that the POSSIBLE WINNER problem for maximin, Copeland, Bucklin, ranked pairs, and a class of scoring rules that includes the Borda voting rule does not admit a polynomial kernel with the number of candidates as the parameter. We show however that the COALITIONAL MANIPULATION problem which is an important special case of the POSSIBLE WINNER problem does admit a polynomial kernel for maximin, Copeland, ranked pairs, and a class of scoring rules that includes the Borda voting rule, when the number of manipulators is polynomial in the number of candidates. A significant conclusion of our work is that the POSSIBLE WINNER problem is harder than the COALITIONAL MANIPULATION problem since the COALITIONAL MANIPULATION problem admits a polynomial kernel whereas the POSSIBLE WINNER problem does not admit a polynomial kernel. (C) 2015 Elsevier B.V. All rights reserved.

Molecular Dynamics Simulation of Peeling a DNA Molecule on Substrate

Molecular dynamics (MD) simulations are performed to study adhesion and peeling of a short fragment of single strand DNA (ssDNA) molecule from a graphite surface. The critical peel-off force is found to depend on both the peeling angle and the elasticity of ssDNA. For the short ssDNA strand under investigation, we show that the simulation results can be explained by a continuum model of an adhesive elastic band on substrate. The analysis suggests that it is often the peak value, rather than the mean value, of adhesion energy which determines the peeling of a nanoscale material.

Flexible representations of dynamics are used in object manipulation.

To manipulate an object skillfully, the brain must learn its dynamics, specifying the mapping between applied force and motion. A fundamental issue in sensorimotor control is whether such dynamics are represented in an extrinsic frame of reference tied to the object or an intrinsic frame of reference linked to the arm. Although previous studies have suggested that objects are represented in arm-centered coordinates [1-6], all of these studies have used objects with unusual and complex dynamics. Thus, it is not known how objects with natural dynamics are represented. Here we show that objects with simple (or familiar) dynamics and those with complex (or unfamiliar) dynamics are represented in object- and arm-centered coordinates, respectively. We also show that objects with simple dynamics are represented with an intermediate coordinate frame when vision of the object is removed. These results indicate that object dynamics can be flexibly represented in different coordinate frames by the brain. We suggest that with experience, the representation of the dynamics of a manipulated object may shift from a coordinate frame tied to the arm toward one that is linked to the object. The additional complexity required to represent dynamics in object-centered coordinates would be economical for familiar objects because such a representation allows object use regardless of the orientation of the object in hand.

A Bayesian approach to tracking in single molecule fluorescence microscopy

Using fluorescence microscopy with single molecule sensitivity it is now possible to follow the movement of individual fluorophore tagged molecules such as proteins and lipids in the cell membrane with nanometer precision. These experiments are important as they allow many key biological processes on the cell membrane and in the cell, such as transcription, translation and DNA replication, to be studied at new levels of detail. Computerized microscopes generate sequences of images (in the order of tens to hundreds) of the molecules diffusing and one of the challenges is to track these molecules to obtain reliable statistics such as speed distributions, diffusion patterns, intracellular positioning, etc. The data set is challenging because the molecules are tagged with a single or small number of fluorophores, which makes it difficult to distinguish them from the background, the fluorophore bleaches irreversibly over time, the number of tagged molecules are unknown and there is occasional loss of signal from the tagged molecules. All these factors make accurate tracking over long trajectories difficult. Also the experiments are technically difficulty to conduct and thus there is a pressing need to develop better algorithms to extract the maximum information from the data. For this purpose we propose a Bayesian approach and apply our technique to synthetic and a real experimental data set.

Visualization of molecule interaction between antigen and antibody - One of ellipsometric imaging applications

It is to investigate molecule interactions between antigen and antibody with ellipsometric imaging technique and demonstrate some features and possibilities offered by applications of the technique. Molecule interaction is an important interest for molecule biologist and immunologist. They have used some established methods such as immufluorcence, radioimmunoassay and surface plasma resonance, etc, to study the molecule interaction. At the same time, experimentalists hope to use some updated technique with more direct visual results. Ellipsometric imaging is non-destructive and exhibits a high sensitivity to phase transitions with thin layers. It is capable of imaging local variations in the optical properties such as thickness due to the presence of different surface concentration of molecule or different deposited molecules. If a molecular mono-layer (such as antigen) with bio-activity were deposited on a surface to form a sensing surface and then incubated in a solution with other molecules (such as antibody), a variation of the layer thickness when the molecules on the sensing surface reacted with the others in the solution could be observed with ellipsometric imaging. Every point on the surface was measured at the same time with a high sensitivity to distinguish the variation between mono-layer and molecular complexes. Ellipsometric imaging is based on conventional ellipsometry with charge coupled device (CCD) as detector and images are caught with computer with image processing technique. It has advantages of high sensitivity to thickness variation (resolution in the order of angstrom), big field of view (in square centimeter), high sampling speed (a picture taken within one second), and high lateral resolution (in the order of micrometer). Here it has just shown one application in study of antigen-antibody interaction, and it is possible to observe molecule interaction process with an in-situ technique.

Manipulation of domain wall dynamics in amorphous microwires through the magnetoelastic anisotropy

We studied the effect of magnetoelastic anisotropy on domain wall (DW) dynamics and remagnetization process of magnetically bistable Fe-Co-rich microwires with metallic nucleus diameters (from 1.4 to 22 mu m). We manipulated the magnetoelastic anisotropy applying the tensile stresses and changing the magnetostriction constant and strength of the internal stresses. Microwires of the same composition of metallic nucleus but with different geometries exhibit different magnetic field dependence of DW velocity with different slopes. Application of stresses resulted in decrease of the DW velocity, v, and DW mobility, S. Quite fast DW propagation (v until 2,500 m/s at H about 30 A/m) has been observed in low magnetostrictive magnetically bistable Co56Fe8Ni10Si10B16 microwires. Consequently, we observed certain correlation between the magnetoelastic energy and DW dynamics in microwires: decreasing the magnetoelastic energy, K (me), DW velocity increases.

Adsorption of formaldehyde molecule on the intrinsic and Al-doped graphene: a first principle study

To search for a high sensitivity sensor for formaldehyde (H2CO), We investigated the adsorption of H2CO on the intrinsic and Al-doped graphene sheets using density functional theory (DFT) calculations. Compared with the intrinsic graphene, the Al-doped graphene system has high binding energy value and short connecting distance, which are caused by the chemisorption of H2CO molecule. Furthermore, the density of states (DOS) results show that orbital hybridization could be seen between H2CO and Al-doped graphene sheet, while there is no evidence for hybridization between the H2CO molecule and the intrinsic graphene sheet. Therefore, Al-doped graphene is expected to be a novel chemical sensor for H2CO gas. We hope our calculations are useful for the application of graphene in chemical sensor.