Chemical Interrogation of the Malaria Kinome

Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1358 small‐molecule kinase inhibitors to evaluate the role of both the human and the malaria kinomes in Plasmodium infection of liver cells, the parasites' obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood‐stage malaria. Most of the screening hits inhibited both liver‐ and blood‐stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests that several kinases are essential to malaria parasites, including cyclin‐dependent kinases (CDKs), glycogen synthase kinases, and phosphoinositide‐3‐kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual‐stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development.     

Dielectric and Magnetodielectric Properties of R2NiMnO6 (R = Nd,Eu, Gd,Dy, and Y)

We have prepared polycrystalline R₂NiMnO₆ (R = Nd, Eu, Gd, Dy, and Y) samples by conventional solid‐state reaction and all the samples have shown monoclinic structure with P2₁/n space group. With the decrease in rare‐earth ionic size (<r_R>), the <Ni–O–Mn> bond angle decreases, correspondingly a decrease in ferromagnetic (FM) Curie temperature is noticed. In the dielectric measurement, the dielectric anomaly shifts to high temperature with the decrease in the <r_R> and shows no correlation with the FM Curie temperature and hints the absence of apparent magnetodielectric (MD) coupling. Appearance of multiple relaxations in the dielectric study suggests the electrical heterogeneity of the system. The dielectric/impedance analysis has revealed a close correlation between dc conductivity and the dielectrics; in fact, both dc resistivity and the grain relaxations follow the variable range hopping mechanism. The thermal activation of charge carriers at the grain boundary led to Maxwell–Wagner interfacial polarization. Finally, dielectric study under magnetic field showed no effect, it implies that not only the intrinsic MD is absent, but also the extrinsic MD due to the lack of magnetoresistance.     

Altering the ordering and disordering of a triangular nanographene at room temperature

Molecular self-organization has the potential to serve as an efficient and versatile tool for the spontaneous creation of low-dimensional nanostructures on surfaces. We demonstrate how the subtle balance between intermolecular interactions and molecule-surface interactions can be altered by modifying the environment or through manipulation by means of the tip in a scanning tunnelling microscope (STM) at room temperature. We show how this leads to the distinctive ordering and disordering of a triangular nanographene molecule, the trizigzag-hexa-peri-hexabenzocoronenes-phenyl-6 (trizigzagHBC-Ph6), on two different surfaces: graphite and Au(111). The assembly of submonolayer films on graphite reveals a sixfold packing symmetry under UHV conditions, whereas at the graphite-phenyloctane interface, they reorganize into a fourfold packing symmetry, mediated by the solvent molecules. On Au(111) under UHV conditions in the multilayer films we investigated, although disorder prevails with the molecules being randomly distributed, their packing behaviour can be altered by the scanning motion of the tip. The asymmetric diode-like current-voltage characteristics of the molecules are retained when deposited on both substrates. This paper highlights the importance of the surrounding medium and any external stimulus in influencing the molecular organization process, and offers a unique approach for controlling the assembly of molecules at a desired location on a substrate.     

Robust imposition of Dirichlet boundary conditions on embedded surfaces

We develop both stable and stabilized methods for imposing Dirichlet constraints on embedded, three‐dimensional surfaces in finite elements. The stable method makes use of the vital vertex algorithm to develop a stable space for the Lagrange multipliers together with a novel discontinuous set of basis functions for the multiplier field. The stabilized method, on the other hand, follows a Nitsche type variational approach for three‐dimensional surfaces. Algorithmic and implementational details of both methods are provided. Several three‐dimensional benchmark problems are studied to compare and contrast the accuracy of the two approaches. The results indicate that both methods yield optimal rates of convergence in various quantities of interest, with the primary differences being in the surface flux. The utility of the domain integral for extracting accurate surface fluxes is demonstrated for both techniques. Copyright © 2011 John Wiley & Sons, Ltd.     

Modelling cell motility and chemotaxis with evolving surface finite elements

We present a mathematical and a computational framework for the modelling of cell motility. The cell membrane is represented by an evolving surface, with the movement of the cell determined by the interaction of various forces that act normal to the surface. We consider external forces such as those that may arise owing to inhomogeneities in the medium and a pressure that constrains the enclosed volume, as well as internal forces that arise from the reaction of the cells'' surface to stretching and bending. We also consider a protrusive force associated with a reaction–diffusion system (RDS) posed on the cell membrane, with cell polarization modelled by this surface RDS. The computational method is based on an evolving surface finite-element method. The general method can account for the large deformations that arise in cell motility and allows the simulation of cell migration in three dimensions. We illustrate applications of the proposed modelling framework and numerical method by reporting on numerical simulations of a model for eukaryotic chemotaxis and a model for the persistent movement of keratocytes in two and three space dimensions. Movies of the simulated cells can be obtained from http://homepages.warwick.ac.uk/∼maskae/CV_Warwick/Chemotaxis.html.     

Experimental Study on 42.7-Gb/s Forward-Error-Correction Performance Under Burst Errors

We describe a novel method to experimentally investigate the performances of forward-error-correction (FEC) codes in the presence of burst errors with various burst length and duty cycle. Using this method, we observe that the coding gains of two commercial 42.7-Gb/s FEC codes are greatly reduced by long and dense error bursts. A correlation between the FEC performance and the FEC burst-error correction length is clearly shown. In addition, the measurement also shows an increase in coding gain in cases with certain short error bursts as compared to the reference case of steady-state white Gaussian noise.     

10-Gb/s upgrade of bidirectional CWDM systems using electronic equalization and FEC

We discuss options for upgrading coarse wavelength-division multiplexed (CWDM) optical access links over standard single-mode fiber (SSMF) by increasing per-channel data rates from 2.5 to 10 Gb/s. We identify electronic equalization and forward error correction (FEC) as the enabling technologies to overcome the dispersion limit of SSMF. In addition, we show how FEC enhances the tolerance to in-band crosstalk, and paves the way toward fully bidirectional CWDM transmission. Due to the lack of CWDM sources rated for 10-Gb/s operation, we demonstrate full-spectrum (1310 to 1610 nm) 10-Gb/s CWDM transmission over standard-dispersion fiber using uncooled, directly modulated lasers specified for 2.5 Gb/s. All 16 CWDM channels could be transmitted over more than 40 km, yielding a capacity-times-distance product of 6.4 Tb/s/km. The longest transmission distance (80 km) was achieved at 1610 nm, equivalent to 1600 ps/nm of chromatic dispersion.     

Evidences for diabetes and insulin mimetic activity of medicinal plants: Present status and future prospects

Diabetes mellitus (DM) is a considerable systemic metabolic disorder to exhibit various metabolic and cardiovascular disorders, mainly hyperglycemia. The global projected estimate of diabetes in 2030 will be about 439 million adults, out of which 300 million expected are of type-2 diabetes mellitus (T2DM). The present knowledge revealed responsible factors, occurrence and mechanism of these factors involved in the DM diseases. Hence, the aim of this review is to address and summarize the causes, plant resources, importance, present status and future programmes for diabetes control. The present review answers the contemporary present questions raised in the scientific field on DM. Two major problems are explained in detail about the autoimmune attack or dysfunction of β-cell and insulin resistance involved for Type 1 and Type 2 DM, respectively. Though there are various approaches to reduce the ill effects of diabetes and its secondary complications, many preferred herbal formulations due to lesser side effects and low cost. For this reason still it is getting increased attention in searching antidiabetic medicinal plants for hot research and to develop targeted medicine. Recurrence of islet autoimmunity lesson from pancreatic islet cell transplantation to cure T1D was outlined. With these highlights, the review summarizes the current knowledge on diabetes occurrence, factors (environmental and genetics), and types (I, II, gestation, and secondary DM), antidiabetic plants, sources for insulin mimetic plant principle compounds and their target mechanism with current and future trusted research areas for controlling of DM.     

Effect of Nerodilol and Carvone on in vitro Permeation of Nicorandil Across Rat Epidermal Membrane

ABSTRACT

The objective of the study was to investigate the effect of nerodilol and carvone on the in vitro transdermal delivery of nicorandil so as to fabricate a membrane-moderated transdermal therapeutic system. The in vitro permeation studies were carried across the rat epidermal membrane from the hydroxypropyl methylcellulose (HPMC) gels (prepared with 70:30 v/v ethanol–water) containing selected concentrations of a terpene such as nerodilol (0% w/w, 4% w/w, 8% w/w, 10% w/w, or 12% w/w) or carvone (0% w/w, 4% w/w, 8% w/w, 12% w/w, or 16% w/w). The amount of nicorandil permeated (Q₂₄) from HPMC gel drug reservoir without a terpene was 3424.6 ± 51.4 μg/cm², and the corresponding flux of the drug was 145.5 ± 2.2 μg/cm²· h. The flux of nicorandil increased with an increase in terpene concentration in HPMC gel. It was increased ranging from 254.9 ± 3.1 to 375.7 ± 3.2 μg/cm²·h or 207.6 ± 4.7 to 356.7 ± 15.3 μg/cm²· h from HPMC gels containing nerodilol (4% w/w to 12% w/w) or carvone (4% w/w to 16% w/w), respectively. Nerodilol increased the flux of nicorandil by about 2.62-folds whereas carvone increased the flux of the drug by about 2.49-folds across the rat epidermal membrane. The results of the Fourier Transform Infrared (FT-IR) study indicated that the enhanced in vitro transdermal delivery of nicorandil might be due to the partial extraction of stratum corneum lipids by nerodilol or carvone. It was concluded that the terpenes, nerodilol and carvone, produced a marked penetration enhancing effect on the transdermal delivery of nicorandil that could be used in the fabrication of membrane-moderated transdermal therapeutic systems.