Endoplasmic Reticulum Stress-Mediated Activation of p38 MAPK, Caspase-2 and Caspase-8 Leads to Abrin-Induced Apoptosis

Abrin from Abrus precatorius plant is a potent protein synthesis inhibitor and induces apoptosis in cells. However, the relationship between inhibition of protein synthesis and apoptosis is not well understood. Inhibition of protein synthesis by abrin can lead to accumulation of unfolded protein in the endoplasmic reticulum causing ER stress. The observation of phosphorylation of eukaryotic initiation factor 2 alpha and upregulation of CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein), important players involved in ER stress signaling by abrin, suggested activation of ER stress in the cells. ER stress is also known to induce apoptosis via stress kinases such as p38 MAPK and JNK. Activation of both the pathways was observed upon abrin treatment and found to be upstream of the activation of caspases. Moreover, abrin-induced apoptosis was found to be dependent on p38 MAPK but not JNK. We also observed that abrin induced the activation of caspase-2 and caspase-8 and triggered Bid cleavage leading to mitochondrial membrane potential loss and thus connecting the signaling events from ER stress to mitochondrial death machinery.

Insights into the AIEE of 1,8-Naphthalimides (NPIs): Inverse Effects of Intermolecular Interactions in Solution and Aggregates

Systematic structural perturbation has been used to fine-tune and understand the luminescence properties of three new 1,8-naphthalimides (NPIs) in solution and aggregates. The NPIs show blue emission in the solution state and their fluorescence quantum yields are dependent upon their molecular rigidity. In concentrated solutions of the NPIs, intermolecular interactions were found to quench the fluorescence due to the formation of excimers. In contrast, upon aggregation (in THF/H2O mixtures), the NPIs show aggregation-induced emission enhancement (AIEE). The NPIs also show moderately high solid-state emission quantum yields (ca. 10-12.7 %). The AIEE behaviour of the NPIs depends on their molecular rigidity and the nature of their intermolecular interactions. The NPIs 1-3 show different extents of intermolecular (pi-pi and C-H center dot center dot center dot O) interactions in their solid-state crystal structures depending on their substituents. Detailed photophysical, computational and structural investigations suggest that an optimal balance of structural flexibility and intermolecular communication is necessary for achieving AIEE characteristics in these NPIs.

A 3.8-V earth-abundant sodium battery electrode

Rechargeable lithium batteries have ushered the wireless revolution over last two decades and are now matured to enable green automobiles. However, the growing concern on scarcity and large-scale applications of lithium resources have steered effort to realize sustainable sodium-ion batteries, Na and Fe being abundant and low-cost charge carrier and redox centre, respectively. However, their performance is limited owing to low operating voltage and sluggish kinetics. Here we report a hitherto-unknown material with entirely new composition and structure with the first alluaudite-type sulphate framework, Na2Fe2(SO4)(3), registering the highest-ever Fe3+/ Fe2+ redox potential at 3.8V (versus Na, and hence 4.1V versus Li) along with fast rate kinetics. Rare-metal-free Na-ion rechargeable battery system compatible with the present Li-ion battery is now in realistic scope without sacrificing high energy density and high power, and paves way for discovery of new earth-abundant sustainable cathodes for large-scale batteries.

Fine-tuning solid-state luminescence in NPIs (1,8-naphthalimides): impact of the molecular environment and cumulative interactions

An investigation of a series of seven angular ``V'' shaped NPIs (1-7) is presented. The effect of substitution of these structurally similar NPIs on their photophysical properties in the solution-state and the solid-state is presented and discussed in light of experimental and computational findings. Compounds 1-7 show negligible to intensely strong emission yields in their solid-state depending on the nature of substituents appended to the oxoaryl moiety. The solution and solid-state properties of the compounds can be directly correlated with their structural rigidity, nature of substituents and intermolecular interactions. The versatile solid-state structures of the NPI siblings are deeply affected by the pendant substituents. All of the NPIs (1-7) show antiparallel dimeric pi-pi stacking interactions in their solid-state which can further extend in a parallel, alternate, orthogonal or lateral fashion depending on the steric and electronic nature of the C-4' substituents. Structural investigations including Hirshfeld surface analysis methods reveal that where strongly interacting systems show weak to moderate emission in their condensed states, weakly interacting systems show strong emission yields under the same conditions. The nature of packing and extended structures also affects the emission colors of the NPIs in their solid-states. Furthermore, DFT computational studies were utilized to understand the molecular and cumulative electronic behaviors of the NPIs. The comprehensive studies provide insight into the condensed-state luminescence of aggregationprone small molecules like NPIs and help to correlate the structure-property relationships.

t-Na-2(VO)P2O7: A 3.8 V Pyrophosphate Insertion Material for Sodium-Ion Batteries

Pyrophosphate oxyanionic framework compounds offer a great platform to investigate new battery materials. In our continuing effort to explore pyrophosphate cathodes for sodium-ion batteries, we report, for the first time, the synthesis and use of tetragonal Na-2(VO)P2O7 as a potential sodium-ion insertion material. This material can be easily prepared by using a conventional solid-state route at a relatively low temperature of 400 degrees C. Stabilizing as a tetragonal structure with an open framework, the material offers pathways for Na+ diffusion. The as-synthesized material, with no further cathode optimization, yields a reversible capacity (Q) approaching 80 mAh g(-1) (Q(Theoretical) = 93.4 mAh g(-1)) involving a one electron V5+/V4+ redox potential located at 3.8 V (vs. Na/Na+). Furthermore, the material exhibits decent rate kinetics and reversibility. Combining green synthesis and moderate electrochemical properties, t-Na-2(VO)P2O7 is reported as a new addition to the growing family of pyrophosphate cathodes for sodium-ion batteries.

Logarithmic corrections to extremal black hole entropy in N=2, 4 and 8 supergravity

We compute the logarithmic correction to black hole entropy about exponentially suppressed saddle points of the Quantum Entropy Function corresponding to Z(N) orbifolds of the near horizon geometry of the extremal black hole under study. By carefully accounting for zero mode contributions we show that the logarithmic contributions for quarter-BPS black holes in N = 4 supergravity and one-eighth BPS black holes in N = 8 supergravity perfectly match with the prediction from the microstate counting. We also find that the logarithmic contribution for half-BPS black holes in N = 2 supergravity depends non-trivially on the Z(N) orbifold. Our analysis draws heavily on the results we had previously obtained for heat kernel coefficients on Z(N) orbifolds of spheres and hyperboloids in arXiv:1311.6286 and we also propose a generalization of the Plancherel formula to Z(N) orbifolds of hyperboloids to an expression involving the Harish-Chandra character of sl (2, R), a result which is of possible mathematical interest.

Experimental and theoretical studies on static and dynamic pressure-concentration isotherms of MmNi(5-x)Al(x) (x=0, 0.3, 0.5 and 0.8) hydrides

The static and dynamic pressure concentration isotherms (PCIs) of MmNi(5-x)Al(x). (x = 0, 0.3, 0.5 and 0.8) hydrides were measured at different temperatures using volumetric method. The effect of Al substitution on PCI and thermodynamic properties were studied. The plateau pressure and maximum hydrogen storage capacity decreased with Al content whereas reaction enthalpy increased. The plateau pressure, plateau slope and hysteresis effect was observed more for dynamic PCIs compared to static PCIs. Different mathematical models used for metal hydride-based thermodynamic devices simulation are compared to select suitable model for static and dynamic PCI simulation of MmNi(5)-based hydrides. Few important physical coefficients (partial molar volume, reaction enthalpy, reaction entropy, etc.) useful for development of thermodynamic devices were estimated. A relation has been proposed to correlate aluminium content and physical coefficients for the prediction of unknown PCI. The simulated and experimental PCIs were found matching closely for both static and dynamic conditions. Copyright (C) 2014, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.

Functionality preservation with enhanced mechanical integrity in the nanocomposites of the metal-organic framework, ZIF-8, with BN nanosheets

Metal-organic frameworks (MOFs) and boron nitride both possess novel properties, the former associated with microporosity and the latter with good mechanical properties. We have synthesized composites of the imidazolate based MOF, ZIF-8, and few-layer BN in order to see whether we can incorporate the properties of both these materials in the composites. The composites so prepared between BN nanosheets and ZIF-8 have compositions ZIF-1BN, ZIF-2BN, ZIF-3BN and similar to ZIF-4BN. The composites have been characterized by PXRD, TGA, XPS, electron microscopy, IR, Raman and solid state NMR spectroscopy. The composites possess good surface areas, the actual value decreasing only slightly with the increase in the BN content. The CO2 uptake remains nearly the same in the composites as in the parent ZIF-8. More importantly, the addition of BN markedly improves the mechanical properties of ZIF-8, a feature that is much desired in MOFs. Observation of microporous features along with improved mechanical properties in a MOF is indeed noteworthy. Such manipulation of properties can be profitably exploited in practical applications.

Controlling phase separation in La5/8-yPryCa3/8MnO3 (y=0.45) epitaxial thin films by strain disorder

Present study reveals that the length-scale of phase separation in La5/8-yPryCa3/8MnO3 thin films can be controlled by strain disorder invoked during the growth and relaxation process of film. Strain disorder provides an additional degree of freedom to tune colossal magnetoresistance. Magneto-transport measurements following cooling and heating in unequal fields protocol demonstrate that coherent strain stabilizes antiferromagnetic insulating phase, while strain disorder favors ferromagnetic metallic phase. Compared to bulk, antiferromagnetic-insulating phase freezes at lower temperatures in strain disordered films. Raman spectroscopy confirms the coexistence of charge-ordered-insulating and ferromagnetic-metallic phases which are structurally dissimilar and possess P2(1)/m and R-3C like symmetries, respectively. (C) 2015 AIP Publishing LLC.

Transport studies on La0.8-xPr0.2SrxMnO3 manganite films

In this communication, we report the results of the studies on structural, microstructural, transport and magnetotransport behavior of L0.8-xPr0.2SrxMnO3 (LPSMO) (x=0.1, 0.2 and 0.3) manganite films grown on (100) single crystalline SrTiO3 (STO) substrate using low cost chemical solution deposition (CSD) method. Films with similar compositions were also grown using sophisticated pulsed laser deposition (PLD) technique and results of structural and transport studies obtained for CSD grown films were compared with PLD grown films. Structural studies show that all the CSD and PLD grown films possess single crystalline nature with compressive and tensile strain, respectively. Surface morphology, studied using atomic force microscope (AFM), reveals the island like grain morphology in CSD grown films while PLD grown films possess smooth film surfaces. Carrier density dependent transport properties of the films have been discussed in the context of zener double exchange (ZDE) mechanism. Lower resistivity and higher transition temperature (T-p) observed in CSD grown films as compared to PLD grown films have been discussed in the light of structural strain and surface morphology of the films. Various models and mechanisms have been employed to understand the charge transport in CSD and PLD grown films. Also, observation of low temperature resistivity minima behavior in all the CSD and PLD grown LPSMO films has been explained in the context of electron-electron scattering mechanism. (C) 2015 Elsevier B.V. All rights reserved.

A novel DNA intercalator, 8-methoxy pyrimido4 `,5 `:4,5]thieno (2,3-b)quinoline-4(3H)-one induces apoptosis in cancer cells, inhibits the tumor progression and enhances lifespan in mice with tumor

Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and interfere with physiological functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor. Results showed a significant inhibition of tumor growth compared to that of untreated controls. More importantly, mean lifespan of tumor bearing animals treated with MPTQ was significantly higher as compared to that of untreated tumor bearing mice suggesting that the treatment affected viability of cancerous cells, but not of normal cells. Consistent with this, we find that administration of MPTQ to normal mice did not cause any major side effects as observed upon hematological and serum profiling. We also found that MPTQ induces cytotoxicity in cancer cell lines, by activating apoptosis both by intrinsic and extrinsic pathways. Thus, MPTQ could be used as a potential cancer therapeutic agent. (c) 2011 Wiley Periodicals, Inc.

Targeted Modifications in Adeno-Associated Virus Serotype 8 Capsid Improves Its Hepatic Gene Transfer Efficiency In Vivo

Recombinant adeno-associated virus vectors based on serotype 8 (AAV8) have shown significant promise for liver-directed gene therapy. However, to overcome the vector dose dependent immunotoxicity seen with AAV8 vectors, it is important to develop better AAV8 vectors that provide enhanced gene expression at significantly low vector doses. Since it is known that AAV vectors during intracellular trafficking are targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal machinery, we modified specific serine/threonine kinase or ubiquitination targets on the AAV8 capsid to augment its transduction efficiency. Point mutations at specific serine (S)/threonine (T)/lysine (K) residues were introduced in the AAV8 capsid at the positions equivalent to that of the effective AAV2 mutants, generated successfully earlier. Extensive structure analysis was carried out subsequently to evaluate the structural equivalence between the two serotypes. scAAV8 vectors with the wild-type (WT) and each one of the S/T -> Alanine (A) or K-Arginine (R) mutant capsids were evaluated for their liver transduction efficiency in C57BL/6 mice in vivo. Two of the AAV8-S -> A mutants (S279A and S671A), and a K137R mutant vector, demonstrated significantly higher enhanced green fluorescent protein (EGFP) transcript levels (similar to 9- to 46-fold) in the liver compared to animals that received WT-AAV8 vectors alone. The best performing AAV8 mutant (K137R) vector also had significantly reduced ubiquitination of the viral capsid, reduced activation of markers of innate immune response, and a concomitant two-fold reduction in the levels of neutralizing antibody formation in comparison to WT-AAV8 vectors. Vector bio-distribution studies revealed that the K137R mutant had a significantly higher and preferential transduction of the liver (106 vs. 7.7 vector copies/mouse diploid genome) when compared to WT-AAV8 vectors. To further study the utility of the K137R-AAV8 mutant in therapeutic gene transfer, we delivered human coagulation factor IX (h. FIX) under the control of liver-specific promoters (LP1 or hAAT) into C57BL/6 mice. The circulating levels of h. FIX: Ag were higher in all the K137R-AAV8 treated groups up to 8 weeks post-hepatic gene transfer. These studies demonstrate the feasibility of the use of this novel AAV8 vectors for potential gene therapy of hemophilia B.

In-doped multifilled n-type skutterudites with ZT=1.8

In this paper we maximize the thermoelectric (TE) figure of merit, ZT, of n-type skutterudites, (In,Sr,Ba,Yb)(y)Co4Sb12, via three different routes: (i) find the optimum fraction of In as fourth filler (ii) check the influence of powder particle, grain, and crystallite size on the TE properties and (iii) check thermal stability. Filled n-type (Sr, Ba, Yb)(y)Co4Sb12 was mixed in three different proportions with In0.4Co4Sb12, ball milled (regular or high-energy (HB) ball milling) and hot-pressed. Particle size analyses and SEM pictures of the broken surfaces of the hot pressed samples document that only HB produces uniform particles/grains with average crystallite sizes similar to 100 nm, proven by transmission electron microscopy. X-ray Rietveld refinements combined with EDX indicate that in all cases indium entered the icosahedral voids of the skutterudite. Temperature dependent physical properties of all three regularly ball-milled samples show that increasing In-content infers an increasing electrical resistivity, increasing Seebeck coefficient but a decreasing total thermal conductivity. Although ZT (823 K) is in the same range as for the sample without In, the ZT values in the whole temperature range are higher and consequently the TE-conversion efficiency, eta is at least 10% higher. Annealing the samples at 600 degrees C for three days shows minor changes in structure and thermoelectric properties, indicating TE stability. The HB sample, due to uniformly small particles, equally sized grains and crystallites, exhibits a high power factor (4.4 mW/m K-2 at 730 K) and a very low thermal conductivity leading to an outstanding high ZT = 1.8 at 823 K (eta(max) = 17.5%). (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

A Pd-8 Tetrafacial Molecular Barrel as Carrier for Water Insoluble Fluorophore

A new carbazole-based tetraimidazole ligand 1,3,6,8-tetra(1H-imidazol-1-yl)-9-methyl-9H-carbazole (L) has been synthesized. The unsymmetrical nature of L as well as the rotational freedom of imidazole donor moieties around C-N bond make it a special building unit, which upon treatment with cis-(tmeda)Pd(NO3)(2) produced an unprecedented single linkage-isomeric Pd-8 tetrafacial molecular nanobarrel (PSMBR-1) tmeda N,N,N',N'-tetramethylethane-1,2-diamine]. Unlike closed architectures, open barrel architecture of water-soluble PSMBR-1 makes it an ideal host for some water insoluble polyaromatic hydrocarbons in aqueous medium; one such inclusion complex coroneneCPSMBR-1 was characterized by X-ray diffraction study. Moreover, the potential application of PSMER-1 as carrier in aqueous medium for the transportation of water insoluble fluorophore (perylene) for live cell imaging is explored.

Structural insights into N-terminal to C-terminal interactions and implications for thermostability of a (beta/alpha)(8)-triosephosphate isomerase barrel enzyme

Although several factors have been suggested to contribute to thermostability, the stabilization strategies used by proteins are still enigmatic. Studies on a recombinant xylanase from Bacilllus sp. NG-27 (RBSX), which has the ubiquitous (beta/alpha)(8)-triosephosphate isomerase barrel fold, showed that just a single mutation, V1L, although not located in any secondary structural element, markedly enhanced the stability from 70 degrees C to 75 degrees C without loss of catalytic activity. Conversely, the V1A mutation at the same position decreased the stability of the enzyme from 70 degrees C to 68 degrees C. To gain structural insights into how a single extreme N-terminus mutation can markedly influence the thermostability of the enzyme, we determined the crystal structure of RBSX and the two mutants. On the basis of computational analysis of their crystal structures, including residue interaction networks, we established a link between N-terminal to C-terminal contacts and RBSX thermostability. Our study reveals that augmenting N-terminal to C-terminal noncovalent interactions is associated with enhancement of the stability of the enzyme. In addition, we discuss several lines of evidence supporting a connection between N-terminal to C-terminal noncovalent interactions and protein stability in different proteins. We propose that the strategy of mutations at the termini could be exploited with a view to modulate stability without compromising enzymatic activity, or in general, protein function in diverse folds where N and C termini are in close proximity. Database The coordinates of RBSX, V1A and V1L have been deposited in the PDB database under the accession numbers 4QCE, 4QCF, and 4QDM, respectively