Reverse-dialysis can be misleading for drug release studies in emulsions as demonstrated by NMR dilution experiments.

Emulsions are an important class of carriers for the delivery of hydrophobic drugs. While knowledge of drug release kinetics is critical to optimizing drug carrying emulsions, there remain many open questions about the validity of standard characterization methods such as the commonly used reverse-dialysis. In this paper, the kinetic parameters of isoflurane release in perfluorotributylamine emulsions determined from both reverse-dialysis and nuclear magnetic resonance (NMR) dilution experiments are compared. The NMR-determined kinetic parameters of isoflurane release were found to be approximately seven orders of magnitude larger than those determined from conventional reverse-dialysis and were also shown to be consistent with prior in vivo observations of the anesthetization of rats.

Determining chemical exchange rate constants in nanoemulsions using nuclear magnetic resonance.

In this work, the second-order kinetics of molecules exchanging between chemically distinct microenvironments, such as those found in nanoemulsions, is studied using nuclear magnetic resonance (NMR). A unique aspect of NMR exchange studies in nanoemulsions is that the difference in molecular resonance frequencies between the two phases, which determines whether the exchange is fast, intermediate, or slow on the NMR timescale, can depend upon the emulsion droplet composition, which is also determined by the kinetic exchange constants themselves. Within the fast-exchange regime, changes in resonance frequencies and line widths with dilution were used to extract the exchange rate constants from the NMR spectra in a manner analogous to determining the kinetic parameters in NMR ligand binding experiments. As a demonstration, the kinetic exchange parameters of isoflurane release from an emulsification of isoflurane and perflurotributylamine (FC43) were determined using NMR dilution and diffusion studies.

In vivo 1 H MR spectroscopy with J-refocusing.

PURPOSE: The goal of this study was to propose a novel localized proton MR spectroscopy (MRS) sequence that reduces signal loss due to J-modulation in the rat brain in vivo. METHODS: Sprague-Dawley rats were studied at 9.4 T. A semi-LASER sequence with evenly distributed echo-time (TE ) was used, and a 90° J-refocusing pulse was inserted at TE /2. Proton spectra were acquired at two TE s (30 and 68 ms), with and without the J-refocused pulse. Data were processed in MATLAB and quantified with LCModel. RESULTS: The J-refocused spectrum acquired at TE = 30 ms did not show any signal losses due to J-modulation and had comparable spectral pattern to the one acquired with semi-LASER using the minimum achievable TE . Higher signal amplitudes for glutamine, γ-aminobutyric acid and glutathione led to more reliable quantification precision for these metabolites. The refocused signal intensities at TE = 68 ms were also unaffected by J-modulation but were smaller than the signals at TE = 30 ms mainly due to transverse T2 relaxation of metabolites. CONCLUSION: The proposed localized MRS sequence will be beneficial in both animal and human MRS studies when using ultra-short TE is not possible while also providing more reliable quantification precision for J-coupled metabolites.

Diffusion Selective Pulses.

The self-diffusion coefficient, D, provides important chemical and physical information about a molecular species and its environment, and D can be routinely measured under equilibrium conditions using nuclear magnetic resonance (NMR). Differences in diffusion coefficients can also be exploited in NMR to suppress signals from fast diffusing species relative to slow diffusing species. To date, no method for selectively suppressing signals only from species with a particular diffusion coefficient has been presented. In this work, diffusion selective pulses are developed that selectively suppress the magnetization only from species for which D = DSel. This is accomplished by interleaving NMR relaxation selective pulses between pulsed field gradients, where the effective transverse relaxation of the magnetization is related to D. Experimental demonstrations of diffusion selective pulses on water and water/acetone/dimethyl sulfoxide samples and on a magnetic resonance imaging phantom are presented.

Breakdown of linear response theory under low-power excitation in NMR. II. The case of "long-lived" signals in homogeneously broadened dipolar spin systems.

In this work, the previous linear response theory developed to describe low-power, radiofrequency (RF) excitation in inhomogeneously broadened spin systems [Z. Gong and J. D. Walls, J. Chem. Phys. 145, 164201 (2016)] is applied to the problem of low-power excitation in homogeneously broadened dipolar spin systems when the strength of the RF pulse, ν RF , is much less than the homogeneous linewidth, Δ ν 1 2 . Application of a low-power pulse for a time T p with a nominal flip-angle of Θ generates a broad signal with a "dip" at the RF transmitter frequency that deepens with increasing Θ. When a delay is placed before signal acquisition, only a negative, "long-lived" signal from the narrow "dip" remains. If a π X -pulse is applied after low-power excitation, a "long-lived" signal lasting a time t ≈ T p after the π X -pulse is generated where dephasing due to B 0 inhomogeneity, anisotropic bulk magnetic susceptibility, and chemical shift anisotropy is refocused while dephasing due to nonzero chemical shift differences is only partially refocused. Contrary to previous observations, experiments in powdered hexamethylbenzene demonstrate that these "long-lived" signals can exist even in the absence of nonzero chemical shift differences. Additional experimental demonstrations in powdered and single-crystalline adamantane and ferrocene samples are also presented.

Enhancing the detection of edges and non-differentiable points in an NMR spectrum using delayed-acquisition.

Delayed-acquisition, which is a common technique for improving spectral resolution in Fourier transform based spectroscopies, typically relies upon differences in T2 relaxation rates that are often due to underlying differences in dynamics and/or complexities of the spin systems being studied. After an acquisition delay, the broad signals from fast T2-relaxing species are more suppressed relative to the sharp signals from slow T2-relaxing species. In this paper, an alternative source of differential "dephasing" under delayed-acquisition is demonstrated that is based solely upon the mathematical properties of the line shape and is independent of the underlying spin dynamics and/or complexity. Signals associated with frequencies where the line shape either changes sharply and/or is non-differentiable at some finite order dephase at a much slower rate than those signals associated with frequencies where the line shape is smooth. Experiments employing delayed-acquisition to study interfaces in biphasic samples, to measure spatially-dependent longitudinal relaxation, and to highlight sharp features in NMR spectra are presented.

Breakdown of linear response theory under low-power excitation in NMR. I. The case of long-lived signals in inhomogeneously broadened spin systems.

In this work, we examine the application of linear response theory to the problem of low-power excitation in inhomogeneously broadened spin systems when the strength of the radiofrequency (RF) pulse, νRF, is smaller than the inhomogeneous linewidth. Even for small overall excitations [Θ = 2πνRFTp ≪ 1 where Tp is the RF pulse length], linear response theory is shown to break down for spins with resonance frequencies that are on the order of νRF, which is due to the fact that the RF interaction cannot be treated as a small perturbation in this case. This breakdown in linear response theory can be partially corrected for by enforcing unitarity in the linear response. Furthermore, the nature of the spin echo generated by a πX-pulse applied immediately after a low-power pulse is investigated. Numerical calculations and experiments performed in an inhomogeneously broadened H2O/D2O solution confirm the theoretical predictions presented in this work.

(1)H NMR studies distinguish the water soluble metabolomic profiles of untransformed and RAS-transformed cells.

Metabolomic profiling is an increasingly important method for identifying potential biomarkers in cancer cells with a view towards improved diagnosis and treatment. Nuclear magnetic resonance (NMR) provides a potentially noninvasive means to accurately characterize differences in the metabolomic profiles of cells. In this work, we use (1)H NMR to measure the metabolomic profiles of water soluble metabolites extracted from isogenic control and oncogenic HRAS-, KRAS-, and NRAS-transduced BEAS2B lung epithelial cells to determine the robustness of NMR metabolomic profiling in detecting differences between the transformed cells and their untransformed counterparts as well as differences among the RAS-transformed cells. Unique metabolomic signatures between control and RAS-transformed cell lines as well as among the three RAS isoform-transformed lines were found by applying principal component analysis to the NMR data. This study provides a proof of principle demonstration that NMR-based metabolomic profiling can robustly distinguish untransformed and RAS-transformed cells as well as cells transformed with different RAS oncogenic isoforms. Thus, our data may potentially provide new diagnostic signatures for RAS-transformed cells.

The Talbot Effect for two-dimensional massless Dirac fermions.

A monochromatic beam of wavelength λ transmitted through a periodic one-dimensional diffraction grating with lattice constant d will be spatially refocused at distances from the grating that are integer multiples of . This self-refocusing phenomena, commonly referred to as the Talbot effect, has been experimentally demonstrated in a variety of systems ranging from optical to matter waves. Theoretical predictions suggest that the Talbot effect should exist in the case of relativistic Dirac fermions with nonzero mass. However, the Talbot effect for massless Dirac fermions (mDfs), such as those found in monolayer graphene or in topological insulator surfaces, has not been previously investigated. In this work, the theory of the Talbot effect for two-dimensional mDfs is presented. It is shown that the Talbot effect for mDfs exists and that the probability density of the transmitted mDfs waves through a periodic one-dimensional array of localized scatterers is also refocused at integer multiples of zT. However, due to the spinor nature of the mDfs, there are additional phase-shifts and amplitude modulations in the probability density that are most pronounced for waves at non-normal incidence to the scattering array.

Suppressing Klein tunneling in graphene using a one-dimensional array of localized scatterers.

Graphene's unique physical and chemical properties make it an attractive platform for use in micro- and nanoelectronic devices. However, electrostatically controlling the flow of electrons in graphene can be challenging as a result of Klein tunneling, where electrons normally incident to a one-dimensional potential barrier of height V are perfectly transmitted even as V → ∞. In this study, theoretical and numerical calculations predict that the transmission probability for an electron wave normally incident to a one-dimensional array of localized scatterers can be significantly less than unity when the electron wavelength is smaller than the spacing between scatterers. In effect, placing periodic openings throughout a potential barrier can, somewhat counterintuitively, decrease transmission in graphene. Our results suggest that electrostatic potentials with spatial variations on the order of the electron wavelength can suppress Klein tunneling and could find applications in developing graphene electronic devices.

Conditional rotations of heteronuclear coupled spins.

We present a new pulse sequence that conditionally excites I spin magnetization only in the presence of a nonzero heteronuclear coupling to an S spin. The pulse sequence, referred to as the reverse INEPT pathway selective pulse or RIPSP, generates a pure I spin rotation by an angle that depends upon the heteronuclear coupling constant in InS spin systems. Experimental demonstrations are shown in (13)C labeled chloroform, dichloromethane, and toluene samples and in unlabeled 2,3-dibromopropionic acid and brucine samples.

Measuring chirality in NMR in the presence of a time-dependent electric field.

Traditional nuclear magnetic resonance (NMR) experiments are "blind" to chirality since the spectra for left and right handed enantiomers are identical in an achiral medium. However, theoretical arguments have suggested that the effective Hamiltonian for spin-1/2 nuclei in the presence of electric and magnetic fields can be different for left and right handed enantiomers, thereby enabling NMR to be used to spectroscopically detect chirality even in an achiral medium. However, most proposals to detect the chiral NMR signature require measuring signals that are equivalent to picomolar concentrations for (1)H nuclei, which are outside current NMR detection limits. In this work, we propose to use an AC electric field that is resonantly modulated at the Larmor frequency, thereby enhancing the effect of the chiral term by four to six orders of magnitude. We predict that a steady-state transverse magnetization, whose direction will be opposite for different enantiomers, will build up during application of an AC electric field. We also propose an experimental setup that uses a solenoid coil with an AC current to generate the necessary periodic electric fields that can be used to generate chiral signals which are equivalent to the signal from a (1)H submicromolar concentration.

Relaxation selective pulses in fast relaxing systems.

In this work, the selectivity or sharpness of the saturation profiles for relaxation selective pulses (R^rsps) that suppress magnetization possessing relaxation times of T2=T2(rsp) and T1=αT2 for α∈12,∞ was optimized. Along with sharpening the selectivity of the R^rsps, the selective saturation of these pulses was also optimized to be robust to both B0 and B1 inhomogeneities. Frequency-swept hyperbolic secant and adiabatic time-optimal saturation pulse inputs were found to work best in the optimizations, and the pulse lengths required to selectivity saturate the magnetization were always found to be less than the inversion recovery delay, T1ln(2). The selectivity of the optimized relaxation selective pulses was experimentally demonstrated in aqueous solutions with varying concentrations of the paramagnetic species, [Mn(+2)], and for use in solvent suppression. Finally, the "rotational" properties of spin relaxation were explored along with an analytical derivation of adiabatic time-optimal saturation pulses.

Spatially encoded multiple-quantum excitation.

In this work, we present a simple method to spatially encode the transition frequencies of nuclear spin transitions and to read out these frequencies within a single scan. The experiment works by combining pulsed field gradients with an excitation sequence that selectively excites spin transitions within certain sample regions. After the initial excitation, imaging the resulting z-magnetization is used to determine the locations where the excitations occurred, from which the corresponding transition frequencies are determined. Simple experimental demonstrations of this technique on one- and two-spin systems are presented.

Fluorescent stilbazolium dyes as probes of the norepinephrine transporter: structural insights into substrate binding.

We report the synthesis, binding kinetics, optical spectroscopy and predicted binding modes of a series of sterically demanding, fluorescent norepinephrine transporter (NET) ligands. A series of bulky stilbazolium dyes, including six newly synthesized compounds, were evaluated to determine the effect of extending the molecular probes' 'heads' or 'tails'. Taking advantage of the dyes' characteristic 'turn-on' emission, the kinetic binding parameters, k(on) and k(off) were determined revealing that extension of the molecules' tails is well tolerated while expansion of the head is not. Additionally, a 'headfirst' orientation appears to be preferred over a 'tail-first' binding pose. Further details of the possible binding modes were obtained from the emission spectra of the bound probes. A small range of interplanar twist angles, approximately 35° to 60°, is predicted to produce the observed emission. Docking experiments and molecular modelling support the kinetic and spectroscopic data providing structural insights into substrate binding.

Pseudorandom selective excitation in NMR.

In this work, average Hamiltonian theory is used to study selective excitation under a series of small flip-angle θ-pulses [θ≪π/3] applied either periodically [corresponding to the DANTE pulse sequence] or aperiodically to a spin-1/2 system. First, an average Hamiltonian description of the DANTE pulse sequence is developed that is valid for frequencies either at or very far from integer multiples of 1τ, where τ is the interpulse delay. For aperiodic excitation, a single resonance, νsel, can be selectively excited if the θ-pulse phases are modulated in concert with the interpulse delays. The conditions where average Hamiltonian theory can be accurately applied to describe the dynamics under aperiodic selective pulses, which are referred to as pseudorandom-DANTE or p-DANTE sequences, are similar to those found for the DANTE sequence. Signal averaging over different p-DANTE sequences improves the apparent selectivity at νsel by reducing the excitations at other frequencies. Experimental demonstrations of p-DANTE sequences and comparisons with the theory are presented.

Measuring chirality in NMR in the presence of a static electric field.

The scalar Hamiltonian of nuclear spins in the presence of a static electric field supports chirality. However, the eigenvalues of the Hamiltonian are not chiral; hence, chirality is not manifested in the usual NMR experiment. In this work, we show that the magnetization response to certain radio frequency pulse sequences exhibits chirality as well as handedness.

Spin-orbit coupling induced interference in quantum corrals.

Lack of inversion symmetry at a metallic surface can lead to an observable spin-orbit interaction. For certain metal surfaces, such as the Au(111) surface, the experimentally observed spin-orbit coupling results in spin rotation lengths on the order of tens of nanometers, which is the typical length scale associated with quantum corral structures formed on metal surfaces. In this work, multiple scattering theory is used to calculate the local density of states (LDOS) of quantum corral structures composed of nonmagnetic adatoms in the presence of spin-orbit coupling. Contrary to previous theoretical predictions, spin-orbit coupling induced modulations are observed in the theoretical LDOS, which should be observable using scanning tunneling microscopy.

Spin amplification in solution magnetic resonance using radiation damping.

The sensitive detection of dilute solute spins is critical to biomolecular NMR. In this work, a spin amplifier for detecting dilute solute magnetization is developed using the radiation damping interaction in solution magnetic resonance. The evolution of the solvent magnetization, initially placed along the unstable -z direction, is triggered by the radiation damping field generated by the dilute solute magnetization. As long as the radiation damping field generated by the solute is larger than the corresponding thermal noise field generated by the sample coil, the solute magnetization can effectively trigger the evolution of the water magnetization under radiation damping. The coupling between the solute and solvent magnetizations via the radiation damping field can be further improved through a novel bipolar gradient scheme, which allows solute spins with chemical shift differences much greater than the effective radiation damping field strength to affect the solvent magnetizations more efficiently. Experiments performed on an aqueous acetone solution indicate that solute concentrations on the order of 10(-5) that of the solvent concentration can be readily detected using this spin amplifier.

Excitation of magnetization using a modulated radiation damping field.

In this work, pulsed-field gradients are used to modulate the radiation damping field generated by the detection coil in an NMR experiment in order that spins with significantly different chemical shifts can affect one another via the radiation damping field. Experiments performed on solutions of acetone/water and acetone/DMSO/water demonstrate that spins with chemical shift differences much greater than the effective radiation damping field strength can still be coupled by modulating the radiation damping field. Implications for applications in high-field NMR and for developing sensitive magnetization detectors are discussed.