MPK-09, a small molecule inspired from bioactive styryllactone restores the wild-type function of mutant p53

In the search for more efficacious and less toxic cancer drugs, the tumor suppressor p53 protein has long been a desirable therapeutic target. In the recent past, few independent studies have demonstrated that the antitumor activity of wild-type p53 can be restored in cancer cells harboring mutant form of p53 using small molecule activators. In this study, we describe a novel small molecule MPK-09, which is selective and highly potent against allele specific p53 mutations mainly, R175H, R249S, R273H, R273C, and E285K. Except E285K, all other mutations tested are among the six ``hot spot'' p53 mutations reported in majority of human cancer. Furthermore, our study conclusively demonstrates that the apoptotic activity of the small molecule MPK-09 against cancer cells harboring R273C and E285K mutations is due to restoration of the wild-type conformation to the corresponding mutant form of p53.

Novel procedure for the estimation of swelling pressures of compacted bentonites based on diffuse double layer theory

Bentonite clays are proven to be attractive as buffer and backfill material in high-level nuclear waste repositories around the world. A quick estimation of swelling pressures of the compacted bentonites for different clay-water-electrolyte interactions is essential in the design of buffer and backfill materials. The theoretical studies on the swelling behavior of bentonites are based on diffuse double layer (DDL) theory. To establish theoretical relationship between void ratio and swelling pressure (e versus P), evaluation of elliptic integral and inverse analysis are unavoidable. In this paper, a novel procedure is presented to establish theoretical relationship of e versus P based on the Gouy-Chapman method. The proposed procedure establishes a unique relationship between electric potentials of interacting and non-interacting diffuse clay-water-electrolyte systems. A procedure is, thus, proposed to deduce the relation between swelling pressures and void ratio from the established relation between electric potentials. This approach is simple and alleviates the need for elliptic integral evaluation and also the inverse analysis. Further, application of the proposed approach to estimate swelling pressures of four compacted bentonites, for example, MX 80, Febex, Montigel and Kunigel V1, at different dry densities, shows that the method is very simple and predicts solutions with very good accuracy. Moreover, the proposed procedure provides continuous distributions of e versus P and thus it is computationally efficient when compared with the existing techniques.

N-Terminal disordered domain of saccharomyces cerevisiae Hop1 protein Is dispensable for DNA binding, bridging, and synapsis of double-stranded DNA molecules but is ecessary for spore formation

The cytological architecture of the synaptonemal complex (SC), a meiosis-specific proteinaceous structure, is evolutionarily conserved among eukaryotes. However, little is known about the biochemical properties of SC components or the mechanisms underlying their roles in meiotic chromosome synapsis and recombination. Functional analysis of Saccharomyces cerevisiae Hop1, a key structural component of SC, has begun to reveal important insights into its function in interhomolog recombination. Previously, we showed that Hop1 is a structure-specific DNA-binding protein, exhibits higher binding affinity for the Holliday junction, and induces structural distortion at the core of the junction. Furthermore, Hop1 promotes DNA condensation and intra- and intermolecular synapsis between duplex DNA molecules. Here, we show that Hop1 possesses a modular domain organization, consisting of an intrinsically disordered N-terminal domain and a protease-resistant C-terminal domain (Hop1CTD). Furthermore, we found that Hop1CTD exhibits strong homotypic as well as heterotypic protein protein interactions, and its biochemical activities were similar to those of the full-length Hop1 protein. However, Hop1CTD failed to complement the meiotic recombination defects of the Delta hop1 strain, indicating that both N- and C-terminal domains of Hop1 are essential for meiosis and spore formation. Altogether, our findings reveal novel insights into the structure-function relationships of Hop1 and help to further our understanding of its role in meiotic chromosome synapsis and recombination.

Plasmons in spatially separated rolled-up electron-hole double-layer systems

Using the two-component random phase approximation, we report the collective mode spectrum of a quasi-one-dimensional spatially separated electron-hole double-layer system characterized by rolled-up type-II band aligned quantum wells. We find two intra-subband collective excitations, which can be classified into optic and acoustic plasmon branches, and several inter-subband plasmon modes. At the long wavelength limit and up to a given wave vector, our model predicts and admits an undamped acoustic branch, which always lies in the gap between the intra-subband electron and hole continua, and an undamped optic branch residing within the gap between the inter-subband electron and hole continua, for all values of the electron-hole charge separations. This theoretical investigation suggests that the low-energy and Landau-undamped plasmon modes might exist based on quasi-one-dimensional, two-component spatially separated electron-hole plasmas, and their possibility could be experimentally examined. (C) 2013 AIP Publishing LLC.

Microwave, infrared-microwave double resonance, and theoretical studies of C2H4 center dot center dot center dot H2S complex

In this manuscript, rotational spectra of four new isotopologues of the S-H center dot center dot center dot pi bonded C2H4 center dot center dot center dot H2S complex, i.e., C2D4 center dot center dot center dot H2S, C2D4 center dot center dot center dot D2S, C2D4 center dot center dot center dot HDS, and (CCH4)-C-13 center dot center dot center dot H2S have been reported and analyzed. All isotopologues except C2D4 center dot center dot center dot HDS show a four line pattern whereas a doubling of the transition frequencies was observed for C2D4 center dot center dot center dot HDS. These results together with our previous report on the title complex M. Goswami, P. K. Mandal, D. J. Ramdass, and E. Arunan, Chem. Phys. Lett. 393(1-3), 22-27 (2004)] confirm that both subunits (C2H4 and H2S) are involved in large amplitude motions leading to a splitting of each rotational transition to a quartet. Further, the results also confirm that the motions which are responsible for the observed splittings involve both monomers. Molecular symmetry group analysis, considering the interchange of equivalent H atoms in H2S and C2H4 could explain the observed four line pattern and their intensities in the microwave spectrum. In addition, hydride stretching fundamentals of the complex were measured using coherence-converted population transfer Fourier Transform Microwave-infrared (IR-MW double resonance) experiments in the S-H and C-H stretch regions. Changes in the tunneling splittings upon vibrational excitation are consistent with the isotopic dependence of pure rotational transitions. A complexation shift of 2.7-6.5 cm(-1) has been observed in the two fundamental S-H stretching modes of the H2S monomer in the complex. Vibrational pre-dissociation in the bound S-H stretch has been detected whereas the instrument-limited line-shapes in other S-H and C-H stretches indicate slower pre-dissociation rate. Some local perturbations in the vibrational spectra have been observed. Two combination bands have been observed corresponding to both the S-H stretching fundamentals and what appears to be the intermolecular stretching mode at 55 cm(-1). The tunneling splitting involved in the rotation of C2H4 unit has been deduced to be 1.5 GHz from the IR-MW results. In addition, ab initio barrier heights derived for different motions of the monomers support the experimental results and provide further insight into the motions causing the splitting. (C) 2013 AIP Publishing LLC.

The Modified Selenenyl Amide, M-hydroxy Ebselen, Attenuates Diabetic Nephropathy and Diabetes-Associated Atherosclerosis in ApoE/GPx1 Double Knockout Mice

Seleno-organic glutathione peroxidase (GPx) mimetics, including ebselen (Eb), have been tested in in vitro studies for their ability to scavenge reactive oxygen and nitrogen species, including hydrogen peroxide and peroxynitrite. In this study, we investigated the efficacies of two Eb analogues, m-hydroxy ebselen (ME) and ethanol-ebselen (EtE) and compared these with Eb in cell based assays. We found that ME is superior in attenuating the activation of hydrogen peroxide-induced pro-inflammatory mediators, ERK and P38 in human aortic endothelial cells. Consequently, we investigated the effects of ME in an in vivo model of diabetes, the ApoE/GPx1 double knockout (dKO) mouse. We found that ME attenuates plaque formation in the aorta and lesion deposition within the aortic sinus of diabetic dKO mice. Oxidative stress as assessed by 8-OHdG in urine and nitrotyrosine immunostaining in the aortic sinus and kidney tubules, was reduced by ME in diabetic dKO mice. ME also attenuated diabetes-associated renal injury which included tubulointerstitial fibrosis and glomerulosclerosis. Furthermore, the bioactivity of the pro-fibrotic cytokine transforming growth factor-beta (TGF-beta) as assessed by phospho-Smad2/3 immunostaining was attenuated after treatment with ME. TGF-beta-stimulated increases in collagen I and IV gene expression and protein levels were attenuated by ME in rat kidney tubular cells. However, in contrast to the superior activity of ME in in vitro and cell based assays, ME did not further augment the attenuation of diabetes-associated atherosclerosis and renal injury in our in vivo model when compared with Eb. In conclusion, this study strengthens the notion that bolstering GPx-like activity using synthetic mimetics may be a useful therapeutic strategy in lessening the burden of diabetic complications. However, these studies highlight the importance of in vivo analyses to test the efficacies of novel Eb analogues, as in vitro and cell based assays are only partly predictive of the in vivo situation.

Studies of grand minima in sunspot cycles by using a flux transport solar dynamo model

We propose that grand minima in solar activity are caused by simultaneous fluctuations in the meridional circulation and the Babcock-Leighton mechanism for the poloidal field generation in the flux transport dynamo model. We present the following results: (a) fluctuations in the meridional circulation are more effective in producing grand minima; (b) both sudden and gradual initiations of grand minima are possible; (c) distributions of durations and waiting times between grand minima seem to be exponential; (d) the coherence time of the meridional circulation has an effect on the number and the average duration of grand minima, with a coherence time of about 30 yr being consistent with observational data. We also study the occurrence of grand maxima and find that the distributions of durations and waiting times between grand maxima are also exponential, like the grand minima. Finally we address the question of whether the Babcock-Leighton mechanism can be operative during grand minima when there are no sunspots. We show that an alpha-effect restricted to the upper portions of the convection zone can pull the dynamo out of the grand minima and can match various observational requirements if the amplitude of this alpha-effect is suitably fine-tuned.

Modeling and analysis of MOS capacitor controlled by independent double gates

This paper, for the first time, explores the charcatersictics of MOS capacitor controlled by independent double gates by numerical simulation and analytical modeling for its possible use in RF circuit design as a varactor. By numerical simulation it is shown how the quasi-static and non-quasi-static characteristics of the first gate capacitance could be tuned by the second gate biases. Effect of body doping and energy quantization are also discussed in this regard. A semi-empirical quasi-static model is also developed by using the existing incomplete Poisson solution of independent double gate transistors. Proposed model, which is valid from accumulation to inversion, is shown to have excellent agreement with numerical simulation for practical bias conditions.

Influence of binder solvent on carbon-layer structure in electrical-double-layer capacitors

Porous activated-carbons with a large surface-area have been the most common materials for electrical-double-layer capacitors (EDLCs). These carbons having a wide pore distribution ranges from micropores to macropores in conjunction with a random pore connection that facilitates the high specific-capacitance values. Pore distribution plays a central role in controlling the capacitance value of EDLCs, since electrolyte distribution inside the active material mainly depends on the pore distribution. This has a direct influence on the distribution of resistance and capacitance values within the electrode. As a result, preparation of electrodes remains a vital issue in realising high-performance EDLCs. Generally, carbon materials along with some binders are dispersed into a solvent and coated onto the current collectors. This study examines the role of binder solvents used for the carbon-ink preparation on the microstructure of the electrodes and the consequent performance of the EDLCs. It is observed that the physical properties of the binder solvent namely its dielectric constant, viscosity and boiling point have important role in determining the pore-size distribution as well as the microstructure of electrodes which influence their specific capacitance values.

Design of double toggle switching mechanisms

Toggle mechanisms are ubiquitous in electrical switches. However, literature for their mechanical design is scarce. This paper defines and classifies the toggle phenomena observed during switching. The concept of double toggle introduced in this paper enables a systematic screening of kinematic structure for the suitability in high performance switches. Seven structural and three kinematic criteria are identified for this purpose. It is also demonstrated that each such feasible kinematic structure lends itself to multiple physical embodiments. Therefore, the theory and procedure presented in this work can be used for design of numerous kinematically distinct mechanisms. One representative mechanical embodiment for a novel double toggle switch, including mass and geometric shape of links has been included in the paper. The switching behavior of the design is validated using Pro/Mechanism (TM). (C) 2013 Elsevier Ltd. All rights reserved.

Glassy dielectric response in Tb2NiMnO6 double perovskite with similarities to a Griffiths phase

Results of frequency-dependent and temperature-dependent dielectric measurements performed on the double-perovskite Tb2NiMnO6 are presented. The real (epsilon(1)(f,T)) and imaginary (epsilon(2)(f,T)) parts of dielectric permittivity show three plateaus suggesting dielectric relaxation originating from the bulk, grain boundaries and the sample-electrode interfaces, respectively. The epsilon(1)(f,T) and epsilon(2)(f,T) are successfully simulated by a RC circuit model. The complex plane of impedance, Z'-Z `', is simulated using a series network with a resistor R and a constant phase element. Through the analysis of epsilon(f,T) using the modified Debye model, two different relaxation time regimes separated by a characteristic temperature, T*, are identified. The temperature variation of R and C corresponding to the bulk and the parameter alpha from modified Debye fit lend support to this hypothesis. Interestingly, the T* compares with the Griffiths temperature for this compound observed in magnetic measurements. Though these results cannot be interpreted as magnetoelectric coupling, the relationship between lattice and magnetism is markedly clear. We assume that the observed features have their origin in the polar nanoregions which originate from the inherent cationic defect structure of double perovskites. Copyright (C) EPLA, 2013

A rapid, efficient, and economical inverse polymerase chain reaction-based method for generating a site saturation mutant library

With the development of deep sequencing methodologies, it has become important to construct site saturation mutant (SSM) libraries in which every nucleotide/codon in a gene is individually randomized. We describe methodologies for the rapid, efficient, and economical construction of such libraries using inverse polymerase chain reaction (PCR). We show that if the degenerate codon is in the middle of the mutagenic primer, there is an inherent PCR bias due to the thermodynamic mismatch penalty, which decreases the proportion of unique mutants. Introducing a nucleotide bias in the primer can alleviate the problem. Alternatively, if the degenerate codon is placed at the 5' end, there is no PCR bias, which results in a higher proportion of unique mutants. This also facilitates detection of deletion mutants resulting from errors during primer synthesis. This method can be used to rapidly generate SSM libraries for any gene or nucleotide sequence, which can subsequently be screened and analyzed by deep sequencing. (C) 2013 Elsevier Inc. All rights reserved.

A Gibbs-ensemble based technique for Monte Carlo simulation of electric double layer capacitors (EDLC) at constant voltage

Current methods for molecular simulations of Electric Double Layer Capacitors (EDLC) have both the electrodes and the electrolyte region in a single simulation box. This necessitates simulation of the electrode-electrolyte region interface. Typical capacitors have macroscopic dimensions where the fraction of the molecules at the electrode-electrolyte region interface is very low. Hence, large systems sizes are needed to minimize the electrode-electrolyte region interfacial effects. To overcome these problems, a new technique based on the Gibbs Ensemble is proposed for simulation of an EDLC. In the proposed technique, each electrode is simulated in a separate simulation box. Application of periodic boundary conditions eliminates the interfacial effects. This in addition to the use of constant voltage ensemble allows for a more convenient comparison of simulation results with experimental measurements on typical EDLCs. (C) 2014 AIP Publishing LLC.

Continuity equation based nonquasi-static charge model for independent double gate MOSFET

Using the numerical device simulation we show that the relationship between the surface potentials along the channel in any double gate (DG) MOSFET remains invariant in QS (quasistatic) and NQS (nonquasi-static) condition for the same terminal voltages. This concept along with the recently proposed `piecewise charge linearization' technique is then used to develop the intrinsic NQS charge model for a Independent DG (IDG) MOSFET by solving the governing continuity equation. It is also demonstrated that unlike the usual MOSFET transcapacitances, the inter-gate transcapacitance of a IDG-MOSFET initially increases with the frequency and then saturates, which might find novel analog circuit application. The proposed NQS model shows good agreement with numerical device simulations and appears to be useful for efficient circuit simulation.

Coconut kernel-derived activated carbon as electrode material for electrical double-layer capacitors

Carbonization of milk-free coconut kernel pulp is carried out at low temperatures. The carbon samples are activated using KOH, and electrical double-layer capacitor (EDLC) properties are studied. Among the several samples prepared, activated carbon prepared at 600 A degrees C has a large surface area (1,200 m(2) g(-1)). There is a decrease in surface area with increasing temperature of preparation. Cyclic voltammetry and galvanostatic charge-discharge studies suggest that activated carbons derived from coconut kernel pulp are appropriate materials for EDLC studies in acidic, alkaline, and non-aqueous electrolytes. Specific capacitance of 173 F g(-1) is obtained in 1 M H2SO4 electrolyte for the activated carbon prepared at 600 A degrees C. The supercapacitor properties of activated carbon sample prepared at 600 A degrees C are superior to the samples prepared at higher temperatures.