DNA as Tunable Adaptor for siRNA Polyplex Stabilization and Functionalization

siRNA and microRNA are promising therapeutic agents, which are engaged in a natural mechanism called RNA interference that modulates gene expression posttranscriptionally. For intracellular delivery of such nucleic acid triggers, we use sequence-defined cationic polymers manufactured through solid phase chemistry. They consist of an oligoethanamino amide core for siRNA complexation and optional domains for nanoparticle shielding and cell targeting. Due to the small size of siRNA, electrostatic complexes with polycations are less stable, and consequently intracellular delivery is less efficient. Here we use DNA oligomers as adaptors to increase size and charge of cargo siRNA, resulting in increased polyplex stability, which in turn boosts transfection efficiency. Extending a single siRNA with a 181-nucleotide DNA adaptor is sufficient to provide maximum gene silencing aided by cationic polymers. Interestingly, this simple strategy was far more effective than merging defined numbers (4-10) of siRNA units into one DNA scaffolded construct. For DNA attachment, the 3' end of the siRNA passenger strand was beneficial over the 5' end. The impact of the attachment site however was resolved by introducing bioreducible disulfides at the connection point. We also show that DNA adaptors provide the opportunity to readily link additional functional domains to siRNA. Exemplified by the covalent conjugation of the endosomolytic influenza peptide INF-7 to siRNA via a DNA backbone strand and complexing this construct with a targeting polymer, we could form a highly functional polyethylene glycol-shielded polyplex to downregulate a luciferase gene in folate receptor-positive cells

Voltage and temperature dependence of the grain boundary tunneling magnetoresistance in manganites

We have performed a systematic analysis of the voltage and temperature dependence of the tunneling magnetoresistance (TMR) of grain boundaries (GB) in the manganites. We find a strong decrease of the TMR with increasing voltage and temperature. The decrease of the TMR with increasing voltage scales with an increase of the inelastic tunneling current due to multi-step inelastic tunneling via localized defect states in the tunneling barrier. This behavior can be described within a three-current model for magnetic tunnel junctions that extends the two-current Julliere model by adding an inelastic, spin-independent tunneling contribution. Our analysis gives strong evidence that the observed drastic decrease of the GB-TMR in manganites is caused by an imperfect tunneling barrier.Comment: to be published in Europhys. Lett., 8 pages, 4 figures (included

Sub-unit cell layer-by-layer growth of Fe3O4, MgO, and Sr2RuO4 thin films

The use of oxide materials in oxide electronics requires their controlled epitaxial growth. Recently, it was shown that Reflection High Energy Electron Diffraction (RHEED) allows to monitor the growth of oxide thin films even at high oxygen pressure. Here, we report the sub-unit cell molecular or block layer growth of the oxide materials Sr2RuO4, MgO, and magnetite using Pulsed Laser Deposition (PLD) from stoichiometric targets. Whereas for perovskites such as SrTiO3 or doped LaMnO3 a single RHEED intensity oscillation is found to correspond to the growth of a single unit cell, in materials where the unit cell is composed of several molecular layers or blocks with identical stoichiometry, a sub-unit cell molecular or block layer growth is established resulting in several RHEED intensity oscillations during the growth of a single unit-cell

Epitaxial growth and magnetic properties of Sr2CrReO6 thin films

The double perovskite Sr2CrReO6 is an interesting material for spintronics, showing ferrimagnetism up to 635 K with a predicted high spin polarization of about 86%. We fabricated Sr2CrReO6 epitaxial films by pulsed laser deposition on (001)-oriented SrTiO3 substrates. Phase-pure films with optimum crystallographic and magnetic properties were obtained by growing at a substrate temperature of 700 degree C in pure O2 of 6.6x10-4 mbar. The films are c-axis oriented, coherently strained, and show less than 20% anti-site defects. The magnetization curves reveal high saturation magnetization of 0.8 muB per formula unit and high coercivity of 1.1 T, as well as a strong magnetic anisotropy.Comment: accepted for publicatio

Precise redox-sensitive cleavage sites for improved bioactivity of siRNA lipopolyplexes

Lipo-oligomers have been proven as potent siRNA carriers based on stable electrostatic and hydrophobic complex formation and endosomal membrane destabilization. Although high stability of siRNA polyplexes is desirable in the extracellular space and cellular uptake, intracellular disassembly is important for the cytosolic release of siRNA and RNA-induced silencing complex formation. To improve the release, bioreducible sequence-defined lipo-oligomers were synthesized by solid-phase assisted synthesis using the disulfide building block Fmoc-succinoyl-cystamine for precise positioning of a disulfide unit between a lipophilic diacyl (bis-myristyl, bis-stearyl or bis-cholestanyl) domain and an ionizable oligocationic siRNA binding unit. Reducible siRNA polyplexes show higher gene silencing efficacy and lower cytotoxicity than their stable analogs, consistent with glutathione-triggered siRNA release and reduced lytic activity

Elastic Constants of Quantum Solids by Path Integral Simulations

Two methods are proposed to evaluate the second-order elastic constants of quantum mechanically treated solids. One method is based on path-integral simulations in the (NVT) ensemble using an estimator for elastic constants. The other method is based on simulations in the (NpT) ensemble exploiting the relationship between strain fluctuations and elastic constants. The strengths and weaknesses of the methods are discussed thoroughly. We show how one can reduce statistical and systematic errors associated with so-called primitive estimators. The methods are then applied to solid argon at atmospheric pressures and solid helium 3 (hcp, fcc, and bcc) under varying pressures. Good agreement with available experimental data on elastic constants is found for helium 3. Predictions are made for the thermal expectation value of the kinetic energy of solid helium 3.Comment: 9 pages doublecolumn, 6 figures, submitted to PR

HIFI spectroscopy of low-level water transitions in M82

We present observations of the rotational ortho-water ground transition, the two lowest para-water transitions, and the ground transition of ionised ortho-water in the archetypal starburst galaxy M82, performed with the HIFI instrument on the Herschel Space Observatory. These observations are the first detections of the para-H2O(111-000) (1113\,GHz) and ortho-H2O+(111-000) (1115\,GHz) lines in an extragalactic source. All three water lines show different spectral line profiles, underlining the need for high spectral resolution in interpreting line formation processes. Using the line shape of the para-H2O(111-000) and ortho-H2O+(111-000) absorption profile in conjunction with high spatial resolution CO observations, we show that the (ionised) water absorption arises from a ~2000 pc^2 region within the HIFI beam located about ~50 pc east of the dynamical centre of the galaxy. This region does not coincide with any of the known line emission peaks that have been identified in other molecular tracers, with the exception of HCO. Our data suggest that water and ionised water within this region have high (up to 75%) area-covering factors of the underlying continuum. This indicates that water is not associated with small, dense cores within the ISM of M82 but arises from a more widespread diffuse gas component.Comment: 5 pages, 4 figures. Accepted for publication in A&

Large two-level magnetoresistance effect in doped manganite grain boundary junctions

We performed a systematic analysis of the tunneling magnetoresistance (TMR) effect in single grain boundary junctions formed in epitaxial La(2/3)Ca(1/3)MnO(3) films deposited on SrTiO(3) bicrystals. For magnetic fields H applied parallel to the grain boundary barrier, an ideal two-level resistance switching behavior with sharp transitions is observed with a TMR effect of up to 300% at 4.2 K and still above 100% at 77 K. Varying the angle between H and the grain boundary results in differently shaped resistance vs H curves. The observed behavior is explained within a model of magnetic domain pinning at the grain boundary interface.Comment: 4 pages, 3 figures, to appear in Phys. Rev. B (Rapid Comm.

deepregression: A Flexible Neural Network Framework for Semi-Structured Deep Distributional Regression

In this paper we describe the implementation of semi-structured deep distributional regression, a flexible framework to learn conditional distributions based on the combination of additive regression models and deep networks. Our implementation encompasses (1) a modular neural network building system based on the deep learning library TensorFlow for the fusion of various statistical and deep learning approaches, (2) an orthogonalization cell to allow for an interpretable combination of different subnetworks, as well as (3) pre-processing steps necessary to set up such models. The software package allows to define models in a user-friendly manner via a formula interface that is inspired by classical statistical model frameworks such as mgcv. The package's modular design and functionality provides a unique resource for both scalable estimation of complex statistical models and the combination of approaches from deep learning and statistics. This allows for state-of-the-art predictive performance while simultaneously retaining the indispensable interpretability of classical statistical models