On discretization in time in simulations of particulate flows

We propose a time discretization scheme for a class of ordinary differential equations arising in simulations of fluid/particle flows. The scheme is intended to work robustly in the lubrication regime when the distance between two particles immersed in the fluid or between a particle and the wall tends to zero. The idea consists in introducing a small threshold for the particle-wall distance below which the real trajectory of the particle is replaced by an approximated one where the distance is kept equal to the threshold value. The error of this approximation is estimated both theoretically and by numerical experiments. Our time marching scheme can be easily incorporated into a full simulation method where the velocity of the fluid is obtained by a numerical solution to Stokes or Navier-Stokes equations. We also provide a derivation of the asymptotic expansion for the lubrication force (used in our numerical experiments) acting on a disk immersed in a Newtonian fluid and approaching the wall. The method of this derivation is new and can be easily adapted to other cases

Dynamic Nuclear Polarization of Long-Lived Nuclear Spin States in Methyl Groups

We have induced hyperpolarized long-lived states in compounds containing 13C-bearing methyl groups by dynamic nuclear polarization (DNP) at cryogenic temperatures, followed by dissolution with a warm solvent. The hyperpolarized methyl long-lived states give rise to enhanced antiphase 13C NMR signals in solution, which often persist for times much longer than the 13C and 1H spin-lattice relaxation times under the same conditions. The DNP-induced effects are similar to quantum-rotor-induced polarization (QRIP) but are observed in a wider range of compounds because they do not depend critically on the height of the rotational barrier. We interpret our observations with a model in which nuclear Zeeman and methyl tunnelling reservoirs adopt an approximately uniform temperature, under DNP conditions. The generation of hyperpolarized NMR signals that persist for relatively long times in a range of methyl-bearing substances may be important for applications such as investigations of metabolism, enzymatic reactions, protein-ligand binding, drug screening, and molecular imaging

Novel 1,4-dioxane derivatives as NMDA receptor channel blockers

NMDA receptors are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Therefore, NMDA receptors are important therapeutic targets for many CNS disorders [1]. To date, clinically drugs targeting the PCP binding site of NMDA receptors have had only limited success due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits [2]. Recently, it has been demonstrated that the piperidine ring of the potent PCP antagonists dexoxadrol and etoxadrol are not necessary for high NMDA receptor affinity since its replacement with aminomethyl or methylaminomethyl chains led to potent NMDA receptor antagonists [3]. Ring and side chain homologues of aminomethyl analogues of dexoxadrol and etoxadrol resulted in compounds showing high NMDA receptor affinity. The derivative 1 behaved as the most potent NMDA antagonist with an affinity value similar to those of dexoxadrol and etoxadrol, [3]. In the present work a series of regioisomers of 1, bearing the 1,4-dioxane nucleus, were prepared. The biological profiles of the novel compounds were assessed using binding assays at PCP binding site of the NMDA receptor. The functional activity of the most affine compounds 2-4 was investigated on L(tk-)-cells stably expressing the NMDA receptor subunits GluN1a and GluN2A by inhibition of the citotoxicity induced by the activation of NMDA receptors with (S)-glutamate and glycine. Compound 3, showing binding affinity and functional activity not significantly different from those of (S)-(+)-ketamine, displayed a promising therapeutic potential. Moreover, it also showed a cytotoxic activity significantly higher than that of (S)-(+)-ketamine on MCF7 human breast cancer cell lines, expressing NMDA receptors

Sensitivity enhancement for detection of hyperpolarized 13C MRI probes with 1H spin coupling introduced by enzymatic transformation in vivo

PurposeAlthough 1 H spin coupling is generally avoided in probes for hyperpolarized (HP) 13 C MRI, enzymatic transformations of biological interest can introduce large 13 C-1 H couplings in vivo. The purpose of this study was to develop and investigate the application of 1 H decoupling for enhancing the sensitivity for detection of affected HP 13 C metabolic products.MethodsA standalone 1 H decoupler system and custom concentric 13 C/1 H paddle coil setup were integrated with a clinical 3T MRI scanner for in vivo 13 C MR studies using HP [2-13 C]dihydroxyacetone, a novel sensor of hepatic energy status. Major 13 C-1 H coupling JCH  = ∼150 Hz) is introduced after adenosine triphosphate-dependent enzymatic transformation of HP [2-13 C]dihydroxyacetone to [2-13 C]glycerol-3-phosphate in vivo. Application of WALTZ-16 1 H decoupling for elimination of large 13 C-1 H couplings was first tested in thermally polarized glycerol phantoms and then for in vivo HP MR studies in three rats, scanned both with and without decoupling.ResultsAs configured, 1 H-decoupled 13 C MR of thermally polarized glycerol and the HP metabolic product [2-13 C]glycerol-3-phosphate was achieved at forward power of approximately 15 W. High-quality 3-s dynamic in vivo HP 13 C MR scans were acquired with decoupling duty cycle of 5%. Application of 1 H decoupling resulted in sensitivity enhancement of 1.7-fold for detection of metabolic conversion of [2-13 C]dihydroxyacetone to HP [2-13 C]glycerol-3-phosphate in vivo.ConclusionsApplication of 1 H decoupling provides significant sensitivity enhancement for detection of HP 13 C metabolic products with large 1 H spin couplings, and is therefore expected to be useful for preclinical and potentially clinical HP 13 C MR studies. Magn Reson Med 80:36-41, 2018. © 2017 International Society for Magnetic Resonance in Medicine

Kinetic Modeling of Hyperpolarized Carbon-13 Pyruvate Metabolism in the Human Brain.

Kinetic modeling of the in vivo pyruvate-to-lactate conversion is crucial to investigating aberrant cancer metabolism that demonstrates Warburg effect modifications. Non-invasive detection of alterations to metabolic flux might offer prognostic value and improve the monitoring of response to treatment. In this clinical research project, hyperpolarized [1-13C] pyruvate was intravenously injected in a total of 10 brain tumor patients to measure its rate of conversion to lactate ( kPL ) and bicarbonate ( kPB ) via echo-planar imaging. Our aim was to investigate new methods to provide kPL and kPB maps with whole-brain coverage. The approach was data-driven and addressed two main issues: selecting the optimal model for fitting our data and determining an appropriate goodness-of-fit metric. The statistical analysis suggested that an input-less model had the best agreement with the data. It was also found that selecting voxels based on post-fitting error criteria provided improved precision and wider spatial coverage compared to using signal-to-noise cutoffs alone