Production of Pure Aqueous 13C‐Hyperpolarized Acetate by Heterogeneous Parahydrogen‐Induced Polarization

A supported metal catalyst was designed, characterized, and tested for aqueous phase heterogeneous hydrogenation of vinyl acetate with parahydrogen to produce ¹³C‐hyperpolarized ethyl acetate for potential biomedical applications. The Rh/TiO₂ catalyst with a metal loading of 23.2 wt % produced strongly hyperpolarized ¹³C‐enriched ethyl acetate‐1‐¹³C detected at 9.4 T. An approximately 14‐fold ¹³C signal enhancement was detected using circa 50 % parahydrogen gas without taking into account relaxation losses before and after polarization transfer by magnetic field cycling from nascent parahydrogen‐derived protons to ¹³C nuclei. This first observation of ¹³C PHIP‐hyperpolarized products over a supported metal catalyst in an aqueous medium opens up new possibilities for production of catalyst‐free aqueous solutions of nontoxic hyperpolarized contrast agents for a wide range of biomolecules amenable to the parahydrogen induced polarization by side arm hydrogenation (PHIP‐SAH) approach.     

Polyelectrolyte-mediated protein adsorption: fluorescent protein binding to individual polyelectrolyte nanospheres

We have used confocal fluorescence microscopy with single molecule sensitivity to characterize uptake and release of fluorescent protein (mEosFP) molecules by individual spherical polyelectrolyte brush (SPB) nanoparticles that were immobilized on a glass surface. The SPB particles consisted of a solid core particle of 100 nm diameter onto which long polyelectrolyte chains were affixed. They could be loaded with up to 30 000 mEosFP molecules in a solvent of low ionic strength. The concentration dependence of protein loading can be described with a simple bimolecular binding model, characterized by an equilibrium dissociation coefficient of 0.5 microM. Essentially complete release of the bound proteins was observed after increasing the ionic strength by adding 250 mM NaCl to the solvent. Fluorescence emission spectra and time-resolved fluorescence intensity decays were measured on individual, mEosFP-loaded SPB nanoparticles, and also on the dissolved mEosFP before and after adsorption. These results indicate that the mEosFP molecules remained structurally intact in this procedure. Hence, the present investigation demonstrates unambiguously that polyelectrolyte-mediated protein adsorption onto SPB particles presents a viable process for protein immobilization.     

Solvothermal Synthesis of [Cr7S8(en)8Cl2]Cl3 ⋅ 2H2O with Magnetically Frustrated [Cr7S8]5+ Double-Cubes**

A novel transition metal chalcohalide [Cr₇S₈(en)₈Cl₂]Cl₃ ⋅ 2H₂O, with [Cr₇S₈]⁵⁺ dicubane cationic clusters, has been synthesized by a low temperature solvothermal method, using dimethyl sulfoxide (DMSO) and ethylenediamine (en) solvents. Ethylenediamine ligand exhibits bi- and monodentate coordination modes; in the latter case ethylenediamine coordinates to Cr atoms of adjacent clusters, giving rise to a 2D polymeric structure. Although magnetic susceptibility shows no magnetic ordering down to 1.8 K, a highly negative Weiss constant, θ=−224(2) K, obtained from Curie-Weiss fit of inverse susceptibility, suggests strong antiferromagnetic (AFM) interactions between S=3/2 Cr(III) centers. Due to the complexity of the system with (2S+1)⁷=16384 microstates from seven Cr³⁺ centers, a simplified model with only two exchange constants was used for simulations. Density-functional theory (DFT) calculations yielded the two exchange constants to be J₁=−21.4 cm⁻¹ and J₂=−30.2 cm⁻¹, confirming competing AFM coupling between the shared Cr³⁺ center and the peripheral Cr³⁺ ions of the dicubane cluster. The best simulation of the experimental data was obtained with J₁=−20.0 cm⁻¹ and J₂=−21.0 cm⁻¹, in agreement with the slightly stronger AFM exchange within the triangles of the peripheral Cr³⁺ ions as compared to the AFM exchange between the central and peripheral Cr³⁺ ions. This compound is proposed as a synthon towards magnetically frustrated systems assembled by linking dicubane transition metal-chalcogenide clusters into polymeric networks.     

The Recognition of and Reactions to Nucleic Acid Nanoparticles by Human Immune Cells

The relatively straightforward methods of designing and assembling various functional nucleic acids into nanoparticles offer advantages for applications in diverse diagnostic and therapeutic approaches. However, due to the novelty of this approach, nucleic acid nanoparticles (NANPs) are not yet used in the clinic. The immune recognition of NANPs is among the areas of preclinical investigation aimed at enabling the translation of these novel materials into clinical settings. NANPs’ interactions with the complement system, coagulation systems, and immune cells are essential components of their preclinical safety portfolio. It has been established that NANPs’ physicochemical properties—composition, shape, and size—determine their interactions with immune cells (primarily blood plasmacytoid dendritic cells and monocytes), enable recognition by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and mediate the subsequent cytokine response. However, unlike traditional therapeutic nucleic acids (e.g., CpG oligonucleotides), NANPs do not trigger a cytokine response unless they are delivered into the cells using a carrier. Recently, it was discovered that the type of carrier provides an additional tool for regulating both the spectrum and the magnitude of the cytokine response to NANPs. Herein, we review the current knowledge of NANPs’ interactions with various components of the immune system to emphasize the unique properties of these nanomaterials and highlight opportunities for their use in vaccines and immunotherapy.     

Synthesis and 15N NMR Signal Amplification by Reversible Exchange of [15N]Dalfampridine at Microtesla Magnetic Fields

Signal Amplification by Reversible Exchange (SABRE) technique enables nuclear spin hyperpolarization of wide range of compounds using parahydrogen. Here we present the synthetic approach to prepare ¹⁵N-labeled [¹⁵N]dalfampridine (4-amino[¹⁵N]pyridine) utilized as a drug to reduce the symptoms of multiple sclerosis. The synthesized compound was hyperpolarized using SABRE at microtesla magnetic fields (SABRE-SHEATH technique) with up to 2.0 % ¹⁵N polarization. The 7-hour-long activation of SABRE pre-catalyst [Ir(IMes)(COD)Cl] in the presence of [¹⁵N]dalfampridine can be remedied by the use of pyridine co-ligand for catalyst activation while retaining the ¹⁵N polarization levels of [¹⁵N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on ¹⁵N polarization levels of free and equatorial catalyst-bound [¹⁵N]dalfampridine were investigated. Moreover, we studied ¹⁵N polarization build-up and decay at magnetic field of less than 0.04 μT as well as ¹⁵N polarization decay at the Earth's magnetic field and at 1.4 T.     

The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry

The reliable determination of stereocenters contained within chemical structures usually requires utilization of NMR data, chemical derivatization, molecular modeling, quantum‐mechanical (QM) calculations and, if available, X‐ray analysis. In this article, we show that the number of stereoisomers which need to be thoroughly verified, can be significantly reduced by the application of NMR chemical shift calculation to the full stereoisomer set of possibilities using a fragmental approach based on HOSE codes. The applicability of this suggested method is illustrated using experimental data published for a series of complex chemical structures. Copyright © 2009 John Wiley & Sons, Ltd.     

A systematic approach for the generation and verification of structural hypotheses

During the process of molecular structure elucidation the selection of the most probable structural hypothesis may be based on chemical shift prediction. The prediction is carried out using either empirical or quantum‐mechanical (QM) methods. When QM methods are used, NMR prediction commonly utilizes the GIAO option of the DFT approximation. In this approach the structural hypotheses are expected to be investigated by scientist. In this article we hope to show that the most rational manner by which to create structural hypotheses is actually by the application of an expert system capable of deducing all potential structures consistent with the experimental spectral data and specifically using 2D NMR data. When an expert system is used the best structure(s) can be distinguished using chemical shift prediction, which is best performed either by an incremental or neural net algorithm. The time‐consuming QM calculations can then be applied, if necessary, to one or more of the ‘best’ structures to confirm the suggested solution. Copyright © 2009 John Wiley & Sons, Ltd.     

Multicriteria estimation of probabilities on basis of expert non-numeric,non-exact and non-complete knowledge

A new method of alternatives’ probabilities estimation under deficiency of expert numeric information (obtained from different sources) is proposed. The method is based on the Bayesian model of uncertainty randomization. Additional non-numeric, non-exact, and non-complete expert knowledge (NNN-knowledge, NNN-information) is used for final estimation of the alternatives’ probabilities. An illustrative example demonstrates the proposed method application to forecasting of oil shares price with the use of NNN-information obtained from different experts (investment firms).     

Univariate splines: Equivalence of moduli of smoothness and applications

Several results on equivalence of moduli of smoothness of univariate splines are obtained. For example, it is shown that, for any , , and , the inequality , , is satisfied, where is a piecewise polynomial of degree on a quasi-uniform (i.e., the ratio of lengths of the largest and the smallest intervals is bounded by a constant) partition of an interval. Similar results for Chebyshev partitions and weighted Ditzian-Totik moduli of smoothness are also obtained. These results yield simple new constructions and allow considerable simplification of various known proofs in the area of constrained approximation by polynomials and splines.