Interaction of nucleic acids with carbon nanotubes and dendrimers

Nucleic acid interaction with nanoscale objects like carbon nanotubes (CNTs) and dendrimers is of fundamental interest because of their potential application in CNT separation, gene therapy and antisense therapy. Combining nucleic acids with CNTs and dendrimers also opens the door towards controllable self-assembly to generate various supra-molecular and nano-structures with desired morphologies. The interaction between these nanoscale objects also serve as a model system for studying DNA compaction, which is a fundamental process in chromatin organization. By using fully atomistic simulations, here we report various aspects of the interactions and binding modes of DNA and small interfering RNA (siRNA) with CNTs, graphene and dendrimers. Our results give a microscopic picture and mechanism of the adsorption of single- and double-strand DNA (ssDNA and dsDNA) on CNT and graphene. The nucleic acid-CNT interaction is dominated by the dispersive van der Waals (vdW) interaction. In contrast, the complexation of DNA (both ssDNA and dsDNA) and siRNA with various generations of poly-amido-amine (PAMAM) dendrimers is governed by electrostatic interactions. Our results reveal that both the DNA and siRNA form stable complex with the PAMAM dendrimer at a physiological pH when the dendrimer is positively charged due to the protonation of the primary amines. The size and binding energy of the complex increase with increase in dendrimer generation. We also give a summary of the current status in these fields and discuss future prospects.

Inclusion of body doping in compact models for fully-depleted common double gate MOSFET adapted to gate-oxide thickness asymmetry

Since it is difficult to find the analytical solution of the governing Poisson equation for double gate MOSFETs with the body doping term included, the majority of the compact models are developed for undoped-body devices for which the analytical solution is available. Proposed is a simple technique to included a body doping term in such surface potential based common double gate MOSFET models also by taking into account any differences between the gate oxide thickness. The proposed technique is validated against TCAD simulation and found to be accurate as long as the channel is fully depleted.

Threshold voltage modeling under size quantization for ultra-thin silicon double-gate metal-oxide-semiconductor field-effect transistor

We report on the threshold voltage modeling of ultra-thin (1 nm-5 nm) silicon body double-gate (DG) MOSFETs using self-consistent Poisson-Schrodinger solver (SCHRED). We define the threshold voltage (V th) of symmetric DG MOSFETs as the gate voltage at which the center potential (Φ c) saturates to Φ c (s a t), and analyze the effects of oxide thickness (t ox) and substrate doping (N A) variations on V th. The validity of this definition is demonstrated by comparing the results with the charge transition (from weak to strong inversion) based model using SCHRED simulations. In addition, it is also shown that the proposed V t h definition, electrically corresponds to a condition where the inversion layer capacitance (C i n v) is equal to the oxide capacitance (C o x) across a wide-range of substrate doping densities. A capacitance based analytical model based on the criteria C i n v C o x is proposed to compute Φ c (s a t), while accounting for band-gap widening. This is validated through comparisons with the Poisson-Schrodinger solution. Further, we show that at the threshold voltage condition, the electron distribution (n(x)) along the depth (x) of the silicon film makes a transition from a strong single peak at the center of the silicon film to the onset of a symmetric double-peak away from the center of the silicon film. © 2012 American Institute of Physics.

Ultrahigh-temperature metamorphism from an unusual corundum plus orthopyroxene intergrowth bearing Al-Mg granulite from the Southern Marginal Zone, Limpopo Complex, South Africa

The Southern Marginal Zone of the Limpopo Complex is composed of granite-greenstone cratonic rocks reworked by a Neoarchean high-grade tectono-metamorphic event. Petrographic and mineral chemical characterization of an Al-Mg granulite from this zone is presented here. The granulite has a gneissic fabric with distinct Al-rich and Si-rich layers, with the former preserving the unusual lamellar (random and regular subparallel) intergrowths of corundum and symplectic intergrowth of spinel with orthopyroxene. The Al-rich layer preserves mineral assemblages such as rutile with orthopyroxene + sillimanite +/- A quartz, Al-rich orthopyroxene (similar to 11 wt%), spinel + quartz, and corundum in possible equilibrium with quartz, while the Si-rich layer preserves antiperthites and orthopyroxene + sillimanite +/- A quartz, all considered diagnostic of ultrahigh-temperature metamorphism. Application of Al-in-opx thermometry, ternary feldspar thermometry and construction of suitable pressure-temperature phase diagrams, compositional and model proportion isopleth results indicate P-T conditions as high as similar to 1,050-1,100 A degrees C, and similar to 10-12 kbars for the Al-Mg granulite. Our report of ultrahigh-temperature conditions is significant considering that the very high temperature was reached during decompression of an otherwise high-pressure granulite complex (clockwise P-T path), whereas most other ultrahigh-temperature granulites are linked to magma underplating at the base of the crust (counterclockwise P-T path).

Detailed investigation of a gamma-cyclodextrin inclusion complex with L-thyroxine for improved pharmaceutical formulations

Thyroxine is a naturally occurring human hormone produced by the thyroid gland. Clinical applications of thyroxine to treat several chronic disorders are limited by poor water solubility and instability under physiological conditions. An inclusion complex of levo-thyroxine (l-thyroxine), the active form of the hormone with gamma cyclodextrin (gamma-CD) has been obtained and studied with the aim of improving oral delivery rather than the injection formulation of the sodium salt. In addition to greater patient acceptability, inclusion complexes often improve aqueous solubility and bioavailability, stability, and reduce toxicity of drugs, thus providing enhanced pharmaceutical formulations. Physicochemical characterization of the inclusion complex was carried out using Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy and proton nuclear magnetic resonance spectroscopy. Intermolecular dipolar interactions for the inclusion complex were also studied using 2 dimensional ROESY experiments. Formation of the inclusion complex between the protons H3 and H5 of cyclodextrin with aromatic protons of thyroxine was confirmed by their dipolar interaction. Molecular modelling was used to understand the basis for the complex formation and predict the formation of other complexes. Interestingly, we found that l-thyroxine forms an inclusion complex only with the larger gamma-CD and not with other available alpha and beta forms.

An Exported Heat Shock Protein 40 Associates with Pathogenesis-Related Knobs in Plasmodium falciparum Infected Erythrocytes

Cell surface structures termed knobs are one of the most important pathogenesis related protein complexes deployed by the malaria parasite Plasmodium falciparum at the surface of the infected erythrocyte. Despite their relevance to the disease, their structure, mechanisms of traffic and their process of assembly remain poorly understood. In this study, we have explored the possible role of a parasite-encoded Hsp40 class of chaperone, namely PFB0090c/PF3D7_0201800 (KAHsp40) in protein trafficking in the infected erythrocyte. We found the gene coding for PF3D7_0201800 to be located in a chromosomal cluster together with knob components KAHRP and PfEMP3. Like the knob components, KAHsp40 too showed the presence of PEXEL motif required for transport to the erythrocyte compartment. Indeed, sub-cellular fractionation and immunofluorescence analysis (IFA) showed KAHsp40 to be exported in the erythrocyte cytoplasm in a stage dependent manner localizing as punctuate spots in the erythrocyte periphery, distinctly from Maurer's cleft, in structures which could be the reminiscent of knobs. Double IFA analysis revealed co-localization of PF3D7_0201800 with the markers of knobs (KAHRP, PfEMP1 and PfEMP3) and components of the PEXEL translocon (Hsp101, PTEX150). KAHsp40 was also found to be in a complex with KAHRP, PfEMP3 and Hsp101 as confirmed by co-immunoprecipitation assay. Our results suggest potential involvement of a parasite encoded Hsp40 in chaperoning knob assembly in the erythrocyte compartment.

A versatile resolving agent for diffusion edited separation of enantiomers, complex mixtures and constitutional isomers

The study is the first report of the utilization of a crown ether as a new and versatile resolving agent for the diffusion edited separation of enantiomers, complex mixtures and constitutional isomers. As a consequence of different binding affinities of enantiomers of a chiral molecule and individual components of the complex mixtures with the crown ether, the molecules diffuse at different rates. The enhanced separation achieved due to matrix assisted diffusion permitted their separation in the diffusion dimension. The generality and wide utility of the new resolving agent and the methodology are demonstrated on diverse examples, such as an organic chiral molecule, constitutional isomers and complex mixture of molecules possessing different functional groups that possess nearly identical molecular weights.

Novel tetranuclear distorted open-cubane copper complex containing oximate bridges: Synthesis, crystal structure, DNA binding and cleavage activity

The synthesis, molecular structure, DNA binding and nuclease activity of Cu4O4 open-cubane tetranuclear copper(II) complex with 3-2-(ethyl amino)ethyl]imino]-2-butanoneoxime (HL) are reported for the first time. The neutral tetranuclear Cu4L4(ClO4)(4)] complex crystallizes in tetragonal space group P (4) over bar2(1)c with the unit cell parameters; a = 13.798(4) angstrom, b = 13.798(4) angstrom, c = 14.119(6) angstrom, V = 2688(16) angstrom(3), Z = 8, R = 0.0636. Symmetrically equivalent copper atoms exhibit a CuN3O3 elongated distorted octahedral coordination environment, with three nitrogen atoms of the L ligand and one oxime-oxygen atom of second L ligand at equatorial positions, one oxime-oxygen atom of the third L ligand and perchlorate oxygen at axial positions. The complex shows quasireversible cyclic voltammetric response at 0.805 V (Delta E-p = 277 mV) at 100 mV s (1) in DMF for the Cu(II)/Cu(I) redox couple. The binding study of the complex with calf-thymus DNA has been investigated using absorption spectrophotometry. The complex shows strong nuclease activity on stranded pBR 322 plasmid DNA in the presence of hydrogen peroxide and marginal nuclease activity in the presence of reducing agent (dithiothreitol). (C) 2012 Elsevier B. V. All rights reserved.

Bromenium-Catalysed Tandem Ring Opening/Cyclisation of Vinylcyclopropanes and Vinylcyclobutanes: A Metal-Free 3+2+1]/4+2+1] Cascade for the Synthesis of Chiral Amidines and Computational Investigation

We present a detailed study of a 3+2+1] cascade cyclisation of vinylcyclopropanes (VCP) catalysed by a bromenium species (Brd+?Xd-) generated in situ, which results in the synthesis of chiral bicyclic amidines in a tandem one-pot operation. The formation of amidines involves the ring-opening of VCPs with Br?X, followed by a Ritter-type reaction with chloramine-T and a tandem cyclisation. The reaction has been further extended to vinylcyclobutane systems and involves a 4+2+1] cascade cyclisation with the same reagents. The versatility of the methodology has been demonstrated by careful choice of VCPs and VCBs to yield bicyclo4.3.0]-, -4.3.1]- and -4.4.0]amidines in enantiomerically pure form. On the basis of the experimental observations and DFT calculations, a reasonable mechanism has been put forth to account for the formation of the products and the observed stereoselectivity. We propose the existence of a p-stabilised homoallylic carbocation at the cyclopropane carbon as the reason for high stereoselectivity. DFT studies at B3LYP/6-311+G** and M06-2X/6-31+G* levels of theory in gas-phase calculations suggest the ring-opening of VCP is initiated at the p-complex stage (between the double bond and Br?X). This can be clearly perceived from the solution-phase (acetonitrile) calculations using the polarisable continuum model (PCM) solvation model, from which the extent of the ring opening of VCP was found to be noticeably high. Studies also show that the formation of zero-bridge bicyclic amidines is favoured over other bridged bicyclic amidines. The energetics of competing reaction pathways is compared to explain the product selectivity.

3-MANIFOLD GROUPS, KÄHLER GROUPS AND COMPLEX SURFACES

Let G be a Kahler group admitting a short exact sequence 1 -> N -> G -> Q -> 1 where N is finitely generated. (i) Then Q cannot be non-nilpotent solvable. (ii) Suppose in addition that Q satisfies one of the following: (a) Q admits a discrete faithful non-elementary action on H-n for some n >= 2. (b) Q admits a discrete faithful non-elementary minimal action on a simplicial tree with more than two ends. (c) Q admits a (strong-stable) cut R such that the intersection of all conjugates of R is trivial. Then G is virtually a surface group. It follows that if Q is infinite, not virtually cyclic, and is the fundamental group of some closed 3-manifold, then Q contains as a finite index subgroup either a finite index subgroup of the three-dimensional Heisenberg group or the fundamental group of the Cartesian product of a closed oriented surface of positive genus and the circle. As a corollary, we obtain a new proof of a theorem of Dimca and Suciu in Which 3-manifold groups are Kahler groups? J. Eur. Math. Soc. 11 (2009) 521-528] by taking N to be the trivial group. If instead, G is the fundamental group of a compact complex surface, and N is finitely presented, then we show that Q must contain the fundamental group of a Seifert-fibered 3-manifold as a finite index subgroup, and G contains as a finite index subgroup the fundamental group of an elliptic fibration. We also give an example showing that the relation of quasi-isometry does not preserve Kahler groups. This gives a negative answer to a question of Gromov which asks whether Kahler groups can be characterized by their asymptotic geometry.

Complex structural phase transitions in slightly Ca modified Na0.5Bi0.5TiO3

A temperature dependent neutron powder diffraction study, in conjunction with dielectric and ferroelectric characterization, of slightly Ca modified Na0.5Bi0.5TiO3 (NBT) revealed an instability with regard to a non-polar orthorhombic (Pbnm) distortion above room temperature. This intermediate orthorhombic phase has earlier been reported for unmodified NBT by electron diffraction studies, but has never been captured by global (x-ray/neutron) diffraction techniques. Calcium substitution seems to amplify the magnitude of this intermediate orthorhombic distortion thereby making the corresponding superlattice reflections become visible in the neutron diffraction pattern. The study revealed the following sequence of very complex structural evolution with temperature: Cc -> Cc + Pbnm -> Pbnm + P4/mbm -> P4/mbm -> Pm (3) over barm.

Design and Synthesis of a Functional Derivative of the Triazinium Cation and Its Rhodium Complex that Shows Photoinduced DNA Cleavage Activity and Photocytotoxicity

The design and synthesis of an intensely blue rhodium(III) complex 3]+ of a new N,N-donor ligand, 8-(quinolin-8-ylamino)pyrido2,1-c]1,2,4]benzotriazin-11-ium, 2]+, which contains a planar pendant triazinium arm, is described. Structural characterization for 3]+ was carried out by using various spectroscopic techniques and single-crystal X-ray crystallography. The organometallic rhodium(III) compound shows a ligand-based reversible reduction at 0.65 V. The electrochemically reduced compound displays a single-line EPR spectrum that signifies the formation of ligand-based free radicals. Compound 3]+ shows a binding propensity to calf thymus DNA to give a Kapp value of 6.05X105 M1. The parent triazinium salt, pyrido2,1-c]1,2,4]benzotriazin-11-ium 1]+ and the ligand salt 2]+ exhibit photoinduced cleavage of DNA in UV-A light, whereas the reference Rh complex 3]+ photocleaves DNA with red light (647.1 nm). The compounds show photonuclease activities under both aerobic and anaerobic conditions. Mechanistic investigations under aerobic conditions with several inhibitors indicate the formation of hydroxyl radicals by means of a photoredox pathway. Under anaerobic conditions, it is believed that a photoinduced oxidation of DNA mechanism is operative. Compound 3]+ exhibits photocytotoxicity in HeLa cervical cancer cells to give IC50 values of (12+/-0.9) mu M in UV-A light at 365 nm and (31.4+/-1.1) mu M in the dark.

Enhancing the photocytotoxic potential of curcumin on terpyridyl lanthanide(III) complex formation

Lanthanide(III) complexes Ln(R-tpy)(cur)(NO3)(2)] (Ln = La(III) in 1, 2; Gd(III) in 5, 6) and Ln(R-tpy)(scur)(NO3)(2)] (Ln = La(III) in 3, 4; Gd(III) in 7, 8), where R-tpy is 4'-phenyl-2,2':6',2 `'-terpyridine (ph-tpy in 1, 3, 5, 7), 4'-(1-pyrenyl)-2,2':6',2 `'-terpyridine (py-tpy in 2, 4, 6, 8), Hcur is curcumin (in 1, 2, 5, 6) and Hscur is diglucosylcurcumin (in 3, 4, 7, 8), were prepared and their DNA photocleavage activity and photocytotoxicity studied. Complexes La(ph-tpy)(cur)(NO3)(2)] (1) and Gd(ph-tpy)(cur)(NO3)(2)] (5) were structurally characterized. The complexes in aqueous-DMF showed an absorption band near 430 nm and an emission band near 515 nm when excited at 420 nm. The complexes are moderate binders to calf-thymus DNA. They cleave plasmid supercoiled DNA to its nicked circular form in UV-A (365 nm) and visible light (454 nm) via O-1(2) and (OH)-O-center dot pathways. The complexes are remarkably photocytotoxic in HeLa cells in visible light (lambda = 400-700 nm) and are non-toxic in the dark. FACScan analysis of the HeLa cells treated with 2 and 4 showed cell death via an apoptotic pathway. Nuclear localization of 1-4 is evidenced from confocal imaging on HeLa cells. The hydrolytic instability of curcumin gets significantly reduced upon binding to the lanthanide ions while retaining its photocytotoxic potential.

Single-Molecule DNA Analysis Reveals That Yeast Hop1 Protein Promotes DNA Folding and Synapsis: Implications for Condensation of Meiotic Chromosomes

During meiosis, long-range interaction between homologous chromosomes is thought to be crucial for homology recognition, exchange of DNA strands, and production of normal haploid gametes. However, little is known about the identity of the proteins involved and the actual molecular mechanism(s) by which chromosomes recognize and recombine with their appropriate homologous partners. Single-molecule analyses have the potential to provide insights into our understanding of this fascinating and long-standing question. Using atomic force microscopy and magnetic tweezers techniques, we discovered that Hop1 protein, a key structural component of Saccharomyces cerevisiae synaptonemal complex, exhibits the ability to bridge noncontiguous DNA segments into intramolecular stem-loop structures in which the DNA segments appear to be fully synapsed within the filamentous protein stems. Additional evidence suggests that Hop1 folds DNA into rigid protein DNA filaments and higher-order nucleoprotein structures. Importantly, Hop1 promotes robust intra- and intermolecular synapsis between double-stranded DNA molecules, suggesting that juxtaposition of DNA sequences may assist in strand exchange between homologues by recombination-associated proteins. Finally, the evidence from ensemble experiments is consistent with the notion that Hop1 causes rigidification of DNA molecules. These results provide the first direct evidence for long-range protein-mediated DNA DNA synapsis, independent of crossover recombination, which is presumed to occur during meiotic recombination.

An Inhibitor of Nonhomologous End-Joining Abrogates Double-Strand Break Repair and Impedes Cancer Progression

DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.